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WO2011076734A1 - Compounds, pharmaceutical composition and methods for use in treating inflammatory diseases - Google Patents

Compounds, pharmaceutical composition and methods for use in treating inflammatory diseases Download PDF

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Publication number
WO2011076734A1
WO2011076734A1 PCT/EP2010/070236 EP2010070236W WO2011076734A1 WO 2011076734 A1 WO2011076734 A1 WO 2011076734A1 EP 2010070236 W EP2010070236 W EP 2010070236W WO 2011076734 A1 WO2011076734 A1 WO 2011076734A1
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Prior art keywords
methyl
amino
thiazol
phenyl
acid
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PCT/EP2010/070236
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French (fr)
Inventor
Hamid Hoveyda
Cyrille Evangelos Brantis
Guillaume Dutheuil
Ludivine Zoute
Didier Schils
Jérôme BERNARD
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Euroscreen S.A.
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Publication of WO2011076734A1 publication Critical patent/WO2011076734A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention concerns methods and compounds useful in treating and/or preventing inflammatory diseases. More specifically, the invention relates to the use of selective GPR43 agonists or partial agonist and their pharmacologically acceptable salts and solvates thereof, previously described in international patent application No. PCT/EP2009/066536 filed on December 2009 in the name of the present Applicant, for the preparation of a medicament for the treatment and/or prevention of inflammatory diseases.
  • the present invention comprises compounds useful in treating and/or preventing diseases, such as Tumor Necrosis Factor a (TNF-a), IL- ⁇ , IL-6 and/or IL-8 mediated diseases and other resulting diseases.
  • diseases such as Tumor Necrosis Factor a (TNF-a), IL- ⁇ , IL-6 and/or IL-8 mediated diseases and other resulting diseases.
  • TNF-a Tumor Necrosis Factor a
  • IL- ⁇ IL-6
  • IL-8 mediated diseases and other resulting diseases.
  • the compounds of the invention are useful for the treatment and/or prevention of diseases or conditions involving inflammation.
  • TNF-a is upstream in the cytokine cascade of inflammation. As a result, elevated levels of TNF-a may lead to elevated levels of other inflammatory and proinflammatory cytokines, such as IL-1, IL-6 and IL-8.
  • TNF-a and Interleukin-1 are pro-inflammatory cytokines secreted by a variety of cells, including monocytes and macrophages, in response to many inflammatory stimuli (e.g. lipopolysaccharide-LPS) or external cellular stress (e.g., osmotic shock and peroxide).
  • inflammatory stimuli e.g. lipopolysaccharide-LPS
  • external cellular stress e.g., osmotic shock and peroxide
  • Elevated levels of TNF-a and/or IL-1 over basal levels have been implicated in mediating or exacerbating a number of disease states including rheumatoid arthritis; inflammatory bowel disease (IBD) including but not limited to Crohn's disease, ulcerative colitis and colitis; Pagets disease; osteoporosis; multiple myeloma; uveitilis; acute and chronic myelogenous leukemia; pancreatic ⁇ cell destruction; rheumatoid spondylitis; osteoarthritis; gouty arthritis and other arthritis conditions; gout; adult respiratory distress syndrome (ARDS); chronic pulmonary inflammation diseases; silicosis; pulmonary sarcoidosis; psoriasis; allergic rhinitis; anaphylaxis; contact dermatitis; pancreatitis; non-alcoholic steato hepatitis (NASH); asthma; muscle degeneration; cachexia such as cachexia secondary to infection or malignancy
  • TNF-a and IL-1 appear to play a role in pancreatic ⁇ cell destruction and diabetes.
  • Pancreatic ⁇ cells produce insulin which helps mediate blood glucose homeostasis. Deterioration of pancreatic ⁇ cell functional abnormalities may occur in patients with type II diabetes.
  • TNF-a TNF-a promotes the release of other cytokines (IL- ⁇ , IL-6) and also chemokines, which promote neutrophil infiltration into the infarct area (Flivtein, Stroke 25, 1481 (1994).
  • IL- ⁇ cytokines
  • chemokines which promote neutrophil infiltration into the infarct area
  • IL-1 is a more potent inducer of stromelysin than TNF-a (Firestein, Am. J. Pathol. 140, 1309 (1992)).
  • neutrophil, lymphocyte, and monocyte emigration has been observed. The emigration is attributed to the induction of chemokines (e.g., IL-8), and the up-regulation of adhesion molecules (Dinarello, Eur. Cytokines Netw. 5, 517-531 (1994)).
  • IL-8 has been implicated in exacerbating and/or causing many disease states in which massive neutrophil infiltration into sites of inflammation or injury (e.g., ischemia) is mediated by the chemotactic nature of IL-8, including, but not limited to, the following: asthma, inflammatory bowel disease (IBD), psoriasis, adult respiratory distress syndrome, cardiac and renal reperfusion injury, thrombosis and glomerulonephritis.
  • IBD inflammatory bowel disease
  • psoriasis psoriasis
  • adult respiratory distress syndrome e.g., pulmonary distress syndrome
  • cardiac and renal reperfusion injury e.g., thrombosis and glomerulonephritis.
  • IL-8 also has the ability to active neutrophils. Thus, reduction in IL-8 levels may lead to diminished neutrophil infiltration.
  • TNF-cc and IL-1 affect a wide variety of cell and tissues and these cytokines as well as other leukocytes derived cytokine, such as IL-6 and IL-8, are important and critical inflammatory mediators of a wide variety of diseases states and conditions.
  • the inhibition of these cytokines is of benefit in controlling, reducing and alleviating many of these disease states mediated by these cytokines.
  • TNF-a Several approaches have been taken to block the effect of TNF-a.
  • TNF-a e.g. TNFR-55 or TNFR-75
  • TNFR-55 or TNFR-75 soluble receptors for TNF-a
  • cA2 a monoclonal antibody specific to TNF-a
  • cA2 has demonstrated improvement in swollen joint count in a Phase II human trial of rheumatoid arthritis (Feldmann et al; Immunological Reviews, pp. 195-223 (1995)).
  • These approaches block the effects of TNF-a and IL-1 by either protein sequestration or receptor antagonism.
  • GPR43 (also named FFA2R) belongs to a subfamily of G-Protein- Coupled Receptors (GPCRs), including GPR40 and GPR41 that have been identified as receptors for free fatty acids (Le Poul et al, J. Biol Chem. 278, 25481-489, 2003; Covington et al., Biochemical Society transaction 34, 770-773, 2006).
  • GPCRs G-Protein- Coupled Receptors
  • the 3 family members share 30 to 40% sequences identity with specificity toward different fatty acids carbon chain length, with short chain fatty acids ((SCFAs): six carbons molecules or shorter) activating GPR41 and GPR43 and medium and long chain fatty acids activating GPR40 (Rayasam et al., Expert Opinion on therapeutic targets, 11 661-671, 2007 ).
  • C2 acetate and C3 propionate are the most potent activators of GPR43.
  • GPR43 is strongly expressed in peripheral blood mononuclear cell (PBMC), bone marrow, and polymorphonuclear cells such as neutrophils.
  • PBMC peripheral blood mononuclear cell
  • the involvement of GPR43 in leukocyte function is supported by the induction of its mRNA during the differentiation and activation of monocytes and neutrophils cells (Le Poul et al, J. Biol. Chem., 2003, 278: 25481-25489; Senga et al, Blood, 2003, 101 : 1185-1187).
  • Recent studies have shown that both acetate and propionate decreased LPS-stimulated TNF-a release from neutrophils.
  • propionate dose-dependently suppressed IL-6 mRNA and protein release from colitis mouse colon organ cultures are examples of colitis mouse colon organ cultures.
  • TNF-a and members of the interleukin family are known to play a key role in the pathogenesis of IBD (Fuss, Curr Drug Targets Inflamm allergy 2003, 2: 101-112; Tedelind et al, World J Gastroenterol 2007, 13(20): 2826-2832). Further, GPR43 has been described to regulate the anti-inflammatory responses by SCFA in various in vivo model such as colitis, rheumatoid arthritis and asthma through a regulation of the neutrophil physio lo logy.
  • GPR43 agonists or partial agonists may be of therapeutic value for the treatment and/or prevention of inflammatory diseases.
  • the invention relates to the use of compounds of general formula
  • Ar 1 is a 5- to 6-membered aryl or heteroaryl group, 3- to 8-membered cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, or a linear or branched C3-C6 alkyl group, each of the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or alkyl groups being optionally substituted by one or more groups selected from halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkoxyalkoxy, alkylamino, amino
  • R 1 is H, halo, allyl, or a C 1 -C 4 alkyl group, which may optionally be substituted by one or more groups selected from halo or C 1 -C 4 alkyl;
  • L 2 is a C 1 -C3 alkylene, C 2 -C 4 alkenylene, C3-C6 cylcloalkylene, each of which being optionally substituted by one or more groups selected from halo, alkyl, alkoxy, or haloalkyl; or L 2 is -0-CH 2 -; or
  • R is H or linear or branched alkyl, aryl, acyloxy alkyl, dioxolene, R 3 is H, methyl or ethyl, and R 4 is hydroxyl -S0 2 CH 3j -S0 2 cyclopropyl or -S0 2 CF 3 ;
  • D is CO or S0 2 ;
  • R 2 is H, linear or branched C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 haloalkyl, C 2 - C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylalkyl, aryl, arylalkyl, heteroarylalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, or aralkyloxyalkyl; each of the alkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroarylalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, and aralkyloxyalkyl groups being optionally substituted by one or more substituents selected from halo, cyano,
  • Ar 2 is a 5- or 6-membered heterocyclic group or a 5- or 6-membered heteroaryl group, optionally substituted by one or more substituents selected from halo, cyano, alkyl, hydroxyalkyl, haloalkyl, alkenyl, alkynyl, heteroalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, alkylcarbonylaminoalkyl, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, halo
  • L 3 is a single bond, C 1 -C 3 alkylene, C 1 -C 3 cycloalkylene C 1 -C 3 alkenylene or carbonylamino;
  • Ar 3 is an aryl, heteroaryl, or C 1 -C4 alkyl group, each of which being optionally substituted by one or more groups selected from halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, ary
  • the invention provides methods for treating and/or preventing in a patient the development of an inflammatory disease, including, but not limited to, rheumatoid arthritis; inflammatory bowel disease (IBD) including but not limited to Crohn's disease, ulcerative colitis and colitis; Pagets disease; osteoporosis; multiple myeloma; uveitilis; acute and chronic myelogenous leukemia; pancreatic ⁇ cell destruction; rheumatoid spondylitis; osteoarthritis; gouty arthritis and other arthritis conditions; gout; adult respiratory distress syndrome (ARDS); chronic pulmonary inflammation diseases; silicosis; pulmonary sarcoidosis; psoriasis; allergic rhinitis; anaphylaxis; contact dermatitis; pancreatitis; asthma; muscle degeneration; cachexia such as cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome; Reiter's syndrome; type I
  • ischemia reperfusion injury comprising the administration of a pharmaceutically effective amount of a compound of formula (I) or pharmaceutically acceptable salt or solvate thereof to a patient in need thereof.
  • the compounds of the invention or pharmaceutically acceptable salts and solvates thereof are those described above in respect to formula (I) with the following provisos:
  • Ar 2 -L 3 -Ar 3 is not 4-(4-butylphenyl)thiazol-2-yl, 4-(4-ethylphenyl)thiazol-2-yl, 4- (para-tolyl)thiazol-2-yl, 4-phenylthiazol-2-yl, 4-(4-propylphenyl)thiazol-2-yl, 4- (4-(sec-butyl)phenyl)thiazol-2-yl, 4-(4-isopropylphenyl)thiazol-2-yl, 4-(4- isobutylphenyl)thiazol-2-yl, 4-(4-(tert-butyl)phenyl)thiazol-2-yl, 4-(4- butylphenyl)-5 -methylthiazo 1-2-yl, 4-(4-ethylphenyl)-5 -methylthiazo 1-2-yl, 5 - methyl-4-(para-tolyl)thiazol-2-y
  • Ar 2 is not 5-cyano-thiazolyl; the compound of formula I is none of.
  • the compound of the invention is not 6-((4-(2- chlorophenyl)thiazol-2-yl)carbamoyl)cyclohex-3-enecarboxylic acid.
  • the invention relates to the use of compounds of formula (I) as well as pharmaceutically acceptable salts and solvates thereof for the preparation of a medicament for the treatment and/or prevention of inflammatory diseases or in other terms to methods for treating and/or preventing in a patient the development of an inflammatory disease, comprising the administration of a pharmaceutically effective amount of a compound of formula (I) or pharmaceutically acceptable salt thereof to a patient in need thereof.
  • Preferred compounds of formula I and pharmaceutically acceptable salts and solvates thereof are those wherein
  • Z is -COOR, wherein R is defined as above in respect to formula I, preferably Z is COOH; and/or
  • R 1 is hydrogen, halogen, or a group selected from C 1-4 alkyl optionally substituted by one or more substituents selected from halogen, allyl or alkyl; preferably R 1 is selected from hydrogen, fluoro, methyl, or ethyl, the methyl or ethyl group being optionally substituted with one or more substituents selected from fluoro or alkyl, more preferably R 1 is hydrogen, fluoro or methyl, and most preferably R 1 is hydrogen, and L 2 is as defined above in respect to formula I, preferably L 2 is cyclopropylene, ethenylene, n-propylene, -CH 2 C(R'R")-, or -C(R'R")-, wherein R' and R" are independently selected from H, halogen, methyl, and ethyl, more preferably L 2 is cyclopropylene, ethenylene, methylene, -CHMe-, -CHF-; even more
  • R 1 and L 2 together are a 5- to 6-membered saturated or unsaturated carbocyclic or heterocyclic group, preferably a non aromatic, saturated or partially unsaturated, 5- to 6-membered carbocyclic group, under the condition that -L 1 -Ar 1 is H, more preferably R 1 and L 2 together are a cyclohexyl or cyclohexenyl group, under the condition that -L 1 -Ar 1 is H, even more preferably R 1 and L 2 together are selected from the group consisting of
  • dotted line is present or absent, preferably present; D is attached at position a and Z is attached at position b under the condition that -L 1 -Ar 1 is H; and/or
  • R 2 is H, linear or branched C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, allyl, propargyl, cyclopropyl, cyclopentyl, cyclopentylmethyl, cyclopropylmethyl, 1 ,1,1- trifluoroethyl, -C 2 H 4 CO 2 CH 3 , -CH 2 C0 2 CH 3 , or -CH 2 CONH 2 , benzyl, benzyloxyethyl, methoxyethyl, preferably R 2 is H, methyl, ethyl, allyl, cyclopropyl, hydroxyethyl, -C 2 H 4 C0 2 CH 3 , -CH 2 C0 2 CH 3, -CH 2 CONH 2 , more preferably R 2 is methyl or cyclopropyl; and/or Ar 1 is a 5- to 6-membered aryl or heteroaryl group, or a 5- to 6-membere
  • Still other preferred compounds of formula I are those wherein D is S0 2 and Ar 1 ,
  • Ar Ar J , R , IT, L , If, I ,and Z are as defined above in respect to formula I.
  • preferred compounds of Formula I are those of formula la:
  • Ar 1 , Ar", Ar J , R , R", L , If and f are as defined above in respect to formula I.
  • Preferred compounds of formula la are those wherein
  • Ar 1 , Ar", Ar J , R", L 1 and f are as defined above in respect to formula I.
  • preferred compounds of Formula I are those of formula lb:
  • X is S or O, preferably X is S;
  • Y is CH or N, preferably Y is CH;
  • L 3 is attached to the heterocyclic group X c 1 either in position 4 or 5, preferably in position 4; and if Y is CH, R 5 is H, halo, hydroxyl, linear or branched C 1 -C3 alkyl, C 1 -C3 hydroxyalkyl, C 1 -C3 haloalkyl, preferably H, methyl, F, CI, or CF 3 , more preferably H or F and R 5 is attached to the heterocyclic group either in position 4, if L 3 is attached in position 5, or in position 5, if L 3 is attached in position 4; preferably R 5 is attached in position 5; if Y is N, R 5 is absent and L 3 is attached in position 5; and
  • Ar 1 and L 1 are as defined above in respect to formula I, preferably Ar 1 is a 5- to 6-membered aryl, preferably phenyl, or heteroaryl group, preferably furanyl, thiophenyl, oxazolyl, isoxazolyl, or thiazolyl optionally substituted by one or more groups selected from halogen, trifluoromethyl, cyano, methoxy trifluoromethoxy, and methoxyethoxy, and L 1 is a single bond, C 1 -C 2 alkylene, or C 2 alkenylene, each optionally being substituted by one or more substituents selected from halo, C 1 -C 2 alkyl, C 1 -C 2 haloalkyl, preferably L 1 is a single bond, or Ci-C 2 alkylene, optionally substituted by C 1 -C 2 alkyl, more preferably L 1 is -CH 2 - ; or Ar 1 is a linear or branched C3-C6
  • Ar 3 is as defined above in respect to formula I, preferably Ar 3 is an aryl or heteroaryl group, optionally substituted by one or more substituents selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, cyano, 5 or 6 membered heteroaryl such as pyridinyl, phenyl, methylcarbonylamino, -NH-SO2CF3, and L 3 is a single bond or C1-C2 alkylene; or Ar 3 is a C1-C4 alkyl group and L 3 is a single bond, more preferably Ar 3 is an aryl, preferably phenyl, or heteroaryl group, preferably thiophenyl, more preferably thiophen-2-yl, furanyl, more preferably furan-2-yl, each of said aryl or heteroaryl being optionally substituted by one or more substituents selected from halo, C1-C4 alkyl
  • R 1 is as defined above in respect to formula I, preferably R 1 is hydrogen, halogen, allyl, or a group selected from C 1 -4 alkyl optionally substituted by one or more substituents selected from halogen or alkyl; more preferably R 1 is selected from hydrogen, fluoro, or methyl or ethyl, the methyl or ethyl group being optionally substituted with one or more substituents selected from fluoro or alkyl, even more preferably R 1 is hydrogen, fluoro or methyl, and most preferably R 1 is hydrogen, and L 2 is as defined above in respect to formula I, preferably L 2 is cyclopropylene, ethenylene, n-propylene, -C(R'R")-, wherein R' and R" are independently selected from H, halogen, methyl, and ethyl, more preferably L 2 is cyclopropylene, ethenylene, methylene, -CHMe-, -CHF-
  • D is attached at position a and Z is attached at position b under the condition that -iZ-Ar 1 is H; and/or R 1 and L 2 together are a non aromatic, saturated or partially unsaturated, carbocyclic group, under the condition that -L 1 -Ar 1 is H, preferably R 1 and L 2 together are a cyclohexyl or cyclohexenyl group, under the condition that -L 1 -Ar 1 is H, more preferably R 1 and L 2 together are selected from the group consisting of
  • dotted line is present or absent, preferably present; D is attached at position a and Z is attached at position b under the condition that -L 1 -Ar 1 is H; and/or
  • Z is as defined above in respect to formula I, preferably Z is -COOR, wherein R is defined as above in respect to formula I, more preferably Z is COOH; and R 2 is as defined above in respect to formula I, preferably R 2 is H, linear or branched C 1 -C 4 alkyl, C 1 -C 2 hydroxyalkyl, allyl, propargyl, cyclopropyl, cyclopentyl, cyclopentylmethyl, cyclopropylmethyl, benzyl, benzyloxyethyl, methoxyethyl, 1 , 1 ,1-trifluoroethyl, -C 2 H 4 CO 2 CH 3 , -CH 2 C0 2 CH 3 , or -CH 2 CONH 2 , more preferably R 2 is H, methyl, ethyl, allyl, cyclopropyl, hydroxyethyl, - C 2 H 4 CO 2 CH 3 , -CH 2 CO 2 CH
  • Preferred compounds of formula lb are those wherein Z is -COOR, preferably COOH, and R, Ar 1 , Ar 2 , Ar 3 , R 1 , R 2 , L 1 , L 2 and L 3 are as defined above in respect to formula I.
  • Particularly preferred compounds of formula lb are those of formula Ib-1
  • L , If, If, Ar", X, Y, Z, R , R", and R" are as defined above in respect to formula lb, preferably L 1 is methylene, optionally substituted by C 1 -C 2 alkyl or halo, preferably by methyl or fluoro, even more preferably L 1 is methylene; and
  • R 6 , R 7 , R' 6 , R' 7 and R 8 are independently selected from H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy, heteroaryloxycarbonyl,
  • Preferred compounds of formula lb- 1 are those of formula lb- la wherein L 2 , L 3 , Ar 3 , X, Y, R 2 , R 5 , R 6 , R 7 , R' 6 , R' 7 and R 8 are as defined above in respect to formula lb- 1.
  • L , L% I , Ar", X, Y, Z, R , R" and R" are as defined above in respect to formula lb, preferably L 1 is methylene;
  • B 1 , B 2 and B 3 are independently CF 2 , O, NR a , CO, or S0 2 , wherein R a is H or alkyl, preferably linear or branched C 1 -C 4 alkyl; C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylaminocarbonyl, C 3 -C 6 cycloalkyl; C 3 -C 6 cycloalkylcarbonyl, C 3 -C 6 cycloalkylsulfonyl, C 3 -C 6 cycloalkylaminocarbonyl, aryl, arylcarbonyl, arylsulfonyl or arylaminocarbonyl, heteroaryl, heteroarylcarbonyl, heteroarylsulfonyl or heteroarylammocarbonyl; preferably B 1 , B 2 and B 3 are O and R 9 , R 10 , R
  • A is -(CH 2 ) compassion-0-, -(CH 2 ) admir-NR a -, -(CH 2 ) n -S0 2 -, or -(CH 2 ) m -, wherein n is equal to 0 or 1 , m is equal to 1 or 2, and R a is as defined above in respect to formula Ib-2b, preferably R a is H or alkyl, preferably linear or branched C1-C4 alkyl; C1-C4 alkylcarbonyl, C1-C4 alkylsulfonyl, more preferably linear or branched C1-C4 alkyl; and
  • A is -(CH 2 ) compassion-0-, -(CH 2 ) admir-NR a -, -(CH 2 ) n -S0 2 -, or -(CH 2 ) m -, wherein n is equal to 0 or 1 , m is equal to 1 or 2, and R a is as defined above in respect to formula Ib-2b, preferably R a is H or alkyl, preferably linear or branched C1-C4 alkyl; C1-C4 alkylcarbonyl, C1-C4 alkylsulfonyl, more preferably linear or branched C1-C4 alkyl; and
  • R 16 , R 17 , R 18 and R 19 are independently selected from H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, alkoxyalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, heteroarylcarbonyloxy, heteroarylcarbonyl,
  • R or R and R or R and R together form an alkylenedioxy group or a
  • R 16 17 17 18 18 19 haloalkylenedioxy group or R and R or R and R or R together form a cycloalkyl, aryl, heterocyclyl or heteroaryl moiety fused to the phenyl group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo, alkoxy, alkyl, alkylamino, alkylcarbonyl, alkylheteroaryl, alkylsulfonyl, aralkyl, aryl, arylamino, aryloxy, cyano, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocyclyl, hydroxyl, oxo, or sulfonyl, preferably R 16 , R 17 , R 18 and R 19 are independently selected from H, halo, cyano, alkyl, hydroxyalkyl, halo
  • Preferred compounds of formula Ib-4 are those of formula Ib-4a
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 , X, Y and Z are as defined above in respect to formula lb- 4,
  • R 20 and R' 20 are independently selected from H, halo (preferably -F and -CI), cyano, C 1 -C 3 alkyl, cyclopropyl, haloalkyl, alkoxy, haloalkoxy, alkoxycarbonylamino, or the two substituents form an alkylenedioxy group or a haloalkylenedioxy group, preferably R 20 and R 20 are H, halo preferably fluoro or chloro, haloalkyl, preferably -CF 3 or -CHF 2 , alkoxy preferably methoxy, haloalkoxy preferably -OCF 3 or -OCHF 2 ;
  • Ar 4 is 5 or 6 membered aryl, preferably phenyl, 5 or 6 membered heteroaryl, preferably furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl, more preferably furan-3-yl, thiophen-3-yl, pyridinyl, still more preferably pyridin- 3-yl, each of said 5 or 6 membered aryl or 5 or 6 membered heteroaryl groups being optionally fused to one or more 5 or 6 membered cycloalkyl, aryl, heterocyclyl or heteroaryl moiety, thus forming a fused ring system, and the latter fused ring system being optionally substituted by one or more further substituents selected from halo, hydroxyl, oxo, alkyl, and/or each of said 5 or 6 membered aryl or 5 or 6 membered heteroaryl groups being optionally substitute
  • Preferred compounds of formula Ib-4a are those of formula Ib-4b
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 , and Z are as defined above in respect to formula lb, and Ar 4 , R 20 and R' 20 , are as defined above in respect to formula Ib-4a.
  • Preferred compounds of formula Ib-4b are those of formula Ib-4c
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 , and Z are as defined above in respect to formula lb;
  • R 20 and R' 20 are as defined above in respect to formula Ib-4a;
  • R and R are independently selected from H, halo, preferably fluoro or chloro, alkoxy, preferably methoxy, preferably R 21 and R 22 are H;
  • R 23 is selected from H, halo, cyano, hydroxyl, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, alkylaminoalkoxy, preferably dimethylaminoethoxy, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, aryloxy, aralkyloxy, alkylamino, alkylaminoalkyl, cycloalkylamino, arylamino, aralkylamino, alkylaminocarbonyl, heteroarylcarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, alkylsulfonyl, preferably C1-C3 alkylsulfonyl, more preferably methylsul
  • Y 1 is C-R 24 and R 24 and R 23 together form a 5 or 6 membered cycloalkyl, aryl, heterocyclyl or heteroaryl moiety, preferably 2-oxopyrrolidinyl, morpholinyl, 2- oxopiperidinyl, furanyl, pyrrolyl, imidazolyl, thus forming a fused ring system, the latter fused ring system being optionally substituted by one or more group selected from oxo, alkyl or halo; and
  • Y 2 is N or C-R 25 where R 25 is H, halo, alkoxy, alkyl, heterocyclyl, preferably pyrrolidinyl, imidazolinyl, piperidinyl or morpholinyl, more preferably 2- oxopyrrolidin-l-yl, 2-oxoimidazolin-l-yl, 2-oxopiperidin-lyl or morpholin-4-yl, each of said substituents being optionally substituted by one or more further substituents selected from halo, preferably chloro or fluoro, oxo, alkyl, preferably methyl, preferably R 25 is H, halo, methoxy, more preferably H, chloro or fluoro, or
  • Y is C-R and R and R together form a 5 or 6 membered cycloalkyl, aryl, heterocyclyl or heteroaryl moiety, preferably 2-oxopyrrolidinyl, morpholinyl, 2- oxopiperidinyl, furanyl, pyrrolyl, imidazolyl, furanyl, thus forming a fused ring system, the latter fused ring system being optionally substituted by one or more group selected from oxo, alkyl or halo, under the condition that R 24 and R 23 together do not form a 5 or 6 membered cycloalkyl, aryl, heterocyclyl or heteroaryl moiety.
  • Preferred compounds of formula Ib-4c are those of formula Ib-4d
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 , and Z are as defined above in respect to formula lb;
  • R 20 and R' 20 are as defined above in respect to formula Ib-4a; and
  • R , R , R" and R" are as defined above in respect to formula Ib-4c.
  • Preferred compounds of formula Ib-4d are those of formula Ib-4e
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 , and Z are as defined above in respect to formula lb;
  • R 20 and R' 20 are as defined above in respect to formula Ib-4a; and
  • R , R , R" and R" are as defined above in respect to formula Ib-4c.
  • Other preferred compounds of formula Ib-4d are those of Ib-4f
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 , and Z are as defined above in respect to formula lb;
  • R 20 and R' 20 are as defined above in respect to formula Ib-4a; and
  • R , R , R" and R" are as defined above in respect to formula Ib-4c. Still other preferred compounds of formula Ib-4d are those of formula Ib-4g
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 , and Z are as defined above in respect to formula lb;
  • R 20 and R' 20 are as defined above in respect to formula Ib-4a; and
  • R , R , R" and R" are as defined above in respect to formula Ib-4c.
  • Other preferred compounds of formula Ib-4c are those of formula Ib-4d'
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 , and Z are as defined above in respect to formula lb;
  • R 20 and R' 20 are as defined above in respect to formula Ib-4a; and
  • R , R , R" and R" are as defined above in respect to formula Ib-4c.
  • Preferred compounds of formula Ib-4d' are those of formula Ib-4e'
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 , and Z are as defined above in respect to formula lb;
  • R 20 and R' 20 are as defined above in respect to formula Ib-4a; and
  • R , R , R" and R" are as defined above in respect to formula Ib-4c.
  • Other preferred compounds of formula Ib-4d' are those of formula Ib-4f
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 , and Z are as defined above in respect to formula lb;
  • R 20 and R' 20 are as defined above in respect to formula Ib-4a; and
  • R , R , R and R are as defined above in respect to formula Ib-4c.
  • Still other preferred compounds of formula Ib-4d' are those of formula Ib-4g'
  • R , R , R" and R" are as defined above in respect to formula Ib-4c.
  • preferred compounds of formula Ib-4a are those of formula Ib-4h,
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 , and Z are as defined above in respect to formula lb; and Ar 4 , R 20 and R' 20 , are as defined above in respect to formula Ib-4a.
  • Preferred compounds of formula Ib-4h are those of formula Ib-4i
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 , and Z are as defined above in respect to formula lb;
  • R 20 and R' 20 are as defined above in respect to formula Ib-4a; and
  • R , R , R , Y and Y are as defined above in respect to formula Ib-4c.
  • Preferred compounds of formula Ib-4i are those of formula Ib-4j
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 , and Z are as defined above in respect to formula lb;
  • R 20 and R' 20 are as defined above in respect to formula Ib-4a;
  • R , R , R" and R" are as defined above in respect to formula Ib-4c.
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 , X, Y, and Z are as defined above in respect to formula lb;
  • R , R , R , R , R are independently selected from H, halo, cyano, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, acylamino, carbamoyl, alkoxycarbamoyl, cycloalkylcarbamoyl, alkylcarbamoylamino, cycloalkylaminocarbamoyl, alkylsulfonyl, haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfony
  • R , R , R i0 are independently selected from H, halo, preferably chloro or fluoro, more preferably chloro, cyano, alkyl, preferably methyl, haloalkyl, preferably - CF 3 or -CHF 2 , cycloalkyl, preferably cyclopropyl, alkoxy, preferably methoxy or isopropyloxy, haloalkoxy, preferably -OCF 3 or -OCHF 2 , alkoxycarbamoyl, or
  • R , R' , R , R' 27 , R 28 are independently selected from H, halo, preferably chloro or fluoro, more preferably chloro, haloalkyl, preferably -CF 3 or -CHF 2 , alkoxy, preferably methoxy.
  • Preferred compounds of formula Ib-4k are those of formula Ib-41
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 and Z are as defined above in respect to formula lb; and R 26 , R' 26 , R 27 , R' 27 and R 28 are as defined above in respect to formula Ib-4k.
  • Preferred compounds of formula Ib-41 are those of formula Ib-4m
  • R' iD and R i are as defined above in respect to formula Ib-4k, preferably R' and are independently selected from H, halo, haloalkyl, haloalkoxy, preferably chloro, fluoro CF 3 , CHF 2 , OCF 3 or OCHF 2 , preferably R' 26 is chloro and R 27 is selected from H, halo, CF 3 , CHF 2 , OCF 3 or OCHF 2 , preferably chloro and fluoro.
  • Other preferred compounds of formula Ib-41 are those of formula Ib-4n,
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 and Z are as defined above in respect to formula lb;
  • R' , 11" and R i0 are as defined above in respect to formula Ib-4k, preferably R' , R 27 and R 28 are independently selected from H, halo, haloalkyl, haloalkoxy, preferably chloro, fluoro, CF 3 , or CHF 2 , preferably OCF 3 or OCHF 2 .
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 and Z are as defined above in respect to formula lb;
  • R and R' are as defined above in respect to formula Ib-4k, preferably R and R' 27 are independently selected from H, halo, haloalkyl, haloalkoxy, preferably chloro, fluoro, CF 3 , CHF 2 OCF 3 or OCHF 2 .
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 and Z are as defined above in respect to formula lb;
  • R" and R i0 are as defined above in respect to formula Ib-4k, preferably R and R 28 are independently selected from H, halo, haloalkyl, alkoxy, haloalkoxy, preferably chloro, fluoro, CF 3 , CHF 2 , methoxy, OCF 3 or OCHF 2 .
  • Still other preferred compounds of formula Ib-41 are those of formula Ib-4q
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 and Z are as defined above in respect to formula lb; and R and R are as defined above in respect to formula Ib-4k, preferably R and are independently selected from H, halo, haloalkyl, alkoxy, haloalkoxy, preferably chloro, fluoro, CF 3 , or CHF 2 , methoxy, OCF 3 or OCHF 2 .
  • preferred compounds of formula I are those of formula Ic
  • Ar , Ar , R , R , L , L , L and Z are as defined above in respect to formula I;
  • R 6 , R 7 , R' 6 , R' 7 and R 8 are independently selected from H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, alkoxyalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy, hetero
  • Preferred compounds of formula Ic are those wherein
  • Z is -COOH; R 1 is H;
  • L 2 is cyclopropylene, ethenylene, methylene, -CHMe-, -CHF-;
  • L 1 is as defined above in respect to formula I, preferably methylene, ethylene, or a single bond; and Ar 2 , Ar 3 , R 2 , R 6 , R 7 , R' 6 , R' 7 R 8 and L 3 are as defined above in respect to formula I.
  • Particularly preferred compounds of formula Ic are those of formula Ic-1
  • Ar 2 , Ar 3 , R 2 , R 6 , R 7 , R' 6 , R' 7 R 8 , L 2 , L 3 , and Z are as defined above in respect to formula Ic.
  • Preferred compounds of formula Ic-1 are those wherein Z is -COOH;
  • L 2 is cyclopropylene, ethenylene, methylene, -CHMe-, -CHF-;
  • Ar 2 , Ar 3 , R 2 , R 6 , R 7 , R' 6 , R' 7 R 8 , and L 3 are as defined above in respect to formula Ic.
  • preferred compounds of formula I are those of formula Id
  • Ar 2 , Ar 3 , R, R 2 and L 3 are as defined above in respect to formula I.
  • Preferred compounds of formula Id are those of formula Id-1
  • dotted line is present or absent, preferably the dotted line is present;
  • X is S or O;
  • Y is CH or N;
  • L 3 is attached to the heterocyclic group either in position 4 or 5, preferably in position 4;
  • R 5 is halo, hydroxyl, linear or branched C 1 -C 3 alkyl, C 1 -C 3 hydroxyalkyl, C 1 -C 3 haloalkyl, preferably F, CI, or CF 3 and R 5 is attached to the heterocyclic group either in position 4, if L 3 is attached in position 5, or in position 5, if L 3 is attached in position 4; preferably R 5 is attached in position 5; If Y is N, R 5 is absent and L 3 is attached in position 5; and
  • Ar 3 is as defined above in respect to formula I, preferably Ar 3 is an aryl or heteroaryl group, optionally substituted by one or more substituents selected from halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, cyano, 5 or 6 membered heteroaryl such as pyridinyl, phenyl, methylcarbonylamino, -NH-SO 2 CF 3 , and L 3 is a single bond or C 1 -C 2 alkylene; or Ar 3 is a C 1 -C 4 alkyl group and L 3 is a single bond, more preferably Ar 3 is an aryl, preferably phenyl, or heteroaryl group, preferably thiophenyl, more preferably thiophen-2-yl, furanyl, more preferably furan-2-yl, each of said aryl or heteroaryl being optionally substituted by one or more substituents selected from halo,
  • R is as defined above in respect to formula I;
  • R 2 is as defined above in respect to formula I, preferably R 2 is H, linear or branched C1-C4 alkyl, C1-C2 hydroxyalkyl, allyl, propargyl, cyclopropyl, cyclopentyl, cyclopentylmethyl, cyclopropylmethyl, benzyl, benzyloxyethyl, methoxyethyl, 1,1,1-trifluoroethyl, -C2H4CO2CH3, -CH 2 C0 2 CH 3 , or -CH 2 CONH 2 , more preferably R 2 is H, methyl, ethyl, allyl, cyclopropyl, hydroxyethyl, - C 2 H 4 C0 2 CH 3 , -CH 2 C0 2 CH 3 , or -CH 2 CONH 2 , more preferably R 2 is methyl or cyclopropyl.
  • preferred compounds of Formula I are those of formula Ie: wherein
  • Y is CH or N
  • R 14 and R 15 are independently H, halo, cyano, hydroxyl, linear or branched C 1 -C3 alkyl, C 1 -C3 hydroxyalkyl, C 1 -C3 haloalkyl, preferably H, F, CI, or CF 3 , more preferably H;
  • Ar 1 and L 1 are as defined above in respect to formula I, preferably as defined in respect to formula lb, more preferably Ar 1 is a 5- to 6-membered aryl or heteroaryl group, optionally substituted by one or more groups selected from halogen, trifluoromethyl, cyano, and methoxy, and L 1 is a methylene group, C 1 -C 2 alkylene, or C 2 alkenylene; or Ar 1 is a linear or branched C 3 -C 6 alkyl group, optionally substituted by one or more groups selected from halogen, trifluoromethyl, cyano, and methoxy, and L 1 is a methylene group;
  • Ar 3 is as defined above in respect to formula I, preferably Ar 3 is an aryl or heteroaryl group, optionally substituted by one or more substituents selected from halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, cyano, 5 or 6 membered heteroaryl such as pyridinyl, phenyl, methylcarbonylamino, -NH-S0 2 CF 3 , and L 3 is a single bond or C 1 -C 2 alkylene; or Ar 3 is a C 1 -C 4 alkyl group and L 3 is a single bond, more preferably Ar 3 is an aryl, preferably phenyl, or heteroaryl group, preferably thiophenyl, more preferably thiophen-2-yl, furanyl, more preferably furan-2-yl, each of said aryl or heteroaryl being optionally substituted by one or more substituents selected from halo
  • R 1 is as defined above in respect to formula I, preferably R 1 is hydrogen, halogen, or a group selected from C 1 -4 alkyl optionally substituted by one or more substituents selected from halogen or alkyl; more preferably R 1 is selected from hydrogen, fluoro, or methyl or ethyl, the methyl or ethyl group being optionally substituted with one or more substituents selected from fluoro or alkyl, even more preferably R 1 is hydrogen, fluoro or methyl, and most preferably R 1 is hydrogen, and L 2 is as defined above in respect to formula I, preferably L 2 is cyclopropylene, ethenylene, n-propylene, or -C(R'R")-, wherein R' and R" are independently selected from H, halogen, methyl, and ethyl, more preferably L 2 is cyclopropylene, ethenylene, methylene, -CHMe-, -CHF-, even more
  • Z is as defined above in respect to formula I, preferably Z is -COOR, wherein R is defined as above in respect to formula I; preferably Z is COOH and
  • R 2 is as defined above in respect to formula I, preferably R 2 is H, linear or branched C 1 -C 4 alkyl, C 1 -C 2 hydroxyalkyl, allyl, propargyl, cyclopropyl, cyclopentyl, cyclopentylmethyl, cyclopropylmethyl, benzyl, benzyloxyethyl, methoxyethyl, 1 , 1 ,1-trifluoroethyl, -C 2 H 4 CO 2 CH 3 , -CH 2 C0 2 CH 3 , or -CH 2 CONH 2 , more preferably R 2 is H, methyl, ethyl, allyl, cyclopropyl, hydroxyethyl, -
  • R 2 is methyl or cyclopropyl.
  • Preferred compounds of formula Ie are those wherein Z is -COOR and R, Ar 1 ,
  • Ar Ar J , R , R", L , If and 1 are as defined above in respect to formula I, preferably L 1 is a methylene group and Ar 1 is phenyl.
  • preferred compounds of Formula I are those of formula If
  • Ar 1 , Ar 3 , L 1 , L 2 , L 3 , R 1 , R 2 , R 14 , R 15 , Y and Z are as defined above in respect to formula Ie.
  • preferred compounds of Formula I are those of formula Ig:
  • B 4 is O or S or N-R b where R b is H or alkyl, preferably linear or branched C 1 -C 4 alkyl; C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkylsulfonyl, C 1 -C4 alkylaminocarbonyl, C3-C6 cycloalkyl; preferably O or S, more preferably O,
  • R 9 , R 9 , and R 11 are independently selected from H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbony
  • Ar Ar J , L , If, If, R , R", and Z are as defined above in respect to formula I.
  • preferred compounds of Formula I are those of formula Ih:
  • B 5 is CH 2 or O preferably O
  • R 9 , R 10 , R' 9 , R' 10 , R 11 , R 12 and R" 13 are independently selected from H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, alkoxyalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclyloxy
  • Ar Ar J , L , If, If, R , R", and Z are as defined above in respect to formula I.
  • preferred compounds of Formula I are those of formula Ii
  • R 9 , R 9 and R 12 are independently selected from H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, alkoxyalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, heteroaryloxycarbonyl, alkylcarbonyloxy, cyclo
  • R 9 , R' 9 , R 10 , R' 10 , R 11 , R 12 and R" 13 are independently selected from H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, alkoxyalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbony
  • Ar Ar J , L , If, If, R , R", and Z are as defined above in respect to formula I.
  • preferred compounds of Formula I are those of formula Ik:
  • R 29 is H, halo, alkyl, haloalkyl preferably -CF 3 or -CF 2 H, alkoxy, haloalkoxy preferably -OCF 3 or -OCF 2 H, cyano, preferably R 29 is H, F, -CF 3 , alkyl preferably methyl, more preferably R 29 is H, F or methyl; and
  • Ar Ar L , If, If, R , R", and Z are as defined above in respect to formula I.
  • preferred compounds of Formula I are those of formula II:
  • R and R are independently selected from H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, alkoxyalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyl
  • Ar Ar J , L , If, If, R , R", and Z are as defined above in respect to formula I.

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Abstract

The present invention relates to compounds of formula (I) (I) useful in treating and/or preventing inflammatory diseases.

Description

COMPOUNDS, PHARMACEUTICAL COMPOSITION AND METHODS FOR USE IN TREATING INFLAMMATORY DISEASES
FIELD OF THE INVENTION
The present invention concerns methods and compounds useful in treating and/or preventing inflammatory diseases. More specifically, the invention relates to the use of selective GPR43 agonists or partial agonist and their pharmacologically acceptable salts and solvates thereof, previously described in international patent application No. PCT/EP2009/066536 filed on December 2009 in the name of the present Applicant, for the preparation of a medicament for the treatment and/or prevention of inflammatory diseases.
BACKGROUND OF THE INVENTION
The present invention comprises compounds useful in treating and/or preventing diseases, such as Tumor Necrosis Factor a (TNF-a), IL-Ιβ, IL-6 and/or IL-8 mediated diseases and other resulting diseases. In particular, the compounds of the invention are useful for the treatment and/or prevention of diseases or conditions involving inflammation.
TNF-a is upstream in the cytokine cascade of inflammation. As a result, elevated levels of TNF-a may lead to elevated levels of other inflammatory and proinflammatory cytokines, such as IL-1, IL-6 and IL-8.
TNF-a and Interleukin-1 (IL-1) are pro-inflammatory cytokines secreted by a variety of cells, including monocytes and macrophages, in response to many inflammatory stimuli (e.g. lipopolysaccharide-LPS) or external cellular stress (e.g., osmotic shock and peroxide). Elevated levels of TNF-a and/or IL-1 over basal levels have been implicated in mediating or exacerbating a number of disease states including rheumatoid arthritis; inflammatory bowel disease (IBD) including but not limited to Crohn's disease, ulcerative colitis and colitis; Pagets disease; osteoporosis; multiple myeloma; uveitilis; acute and chronic myelogenous leukemia; pancreatic β cell destruction; rheumatoid spondylitis; osteoarthritis; gouty arthritis and other arthritis conditions; gout; adult respiratory distress syndrome (ARDS); chronic pulmonary inflammation diseases; silicosis; pulmonary sarcoidosis; psoriasis; allergic rhinitis; anaphylaxis; contact dermatitis; pancreatitis; non-alcoholic steato hepatitis (NASH); asthma; muscle degeneration; cachexia such as cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome; Reiter's syndrome; type I and type II diabetes; bone resorption disease; graft vs. host reaction; ischemia reperfusion injury; atherosclerosis; brain trauma; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; endotoxic shock; gram negative sepsis; fever and myalgias due to infection such as influenza; pyrosis.
TNF-a and IL-1 appear to play a role in pancreatic β cell destruction and diabetes. Pancreatic β cells produce insulin which helps mediate blood glucose homeostasis. Deterioration of pancreatic β cell functional abnormalities may occur in patients with type II diabetes.
Administration of TNF-a into the rat cortex has been reported to result in significant neutrophil accumulation in capillaries and adherence in small blood vessels. TNF-a promotes the release of other cytokines (IL-Ιβ, IL-6) and also chemokines, which promote neutrophil infiltration into the infarct area (Fleurstein, Stroke 25, 1481 (1994).
In rheumatoid arthritis models in animals, multiple intra-articular injections of IL-1 have led to an acute and destructive form of arthritis (Chandrasekhar et al., Clinical Immunol Immunopathol. 55, 382 (1990)). In studies using cultured rheumatoid synovial cells, IL-1 is a more potent inducer of stromelysin than TNF-a (Firestein, Am. J. Pathol. 140, 1309 (1992)). At sites of local injection, neutrophil, lymphocyte, and monocyte emigration has been observed. The emigration is attributed to the induction of chemokines (e.g., IL-8), and the up-regulation of adhesion molecules (Dinarello, Eur. Cytokines Netw. 5, 517-531 (1994)).
IL-8 has been implicated in exacerbating and/or causing many disease states in which massive neutrophil infiltration into sites of inflammation or injury (e.g., ischemia) is mediated by the chemotactic nature of IL-8, including, but not limited to, the following: asthma, inflammatory bowel disease (IBD), psoriasis, adult respiratory distress syndrome, cardiac and renal reperfusion injury, thrombosis and glomerulonephritis. In addition to the chemotaxis effect on neutrophils, IL-8 also has the ability to active neutrophils. Thus, reduction in IL-8 levels may lead to diminished neutrophil infiltration.
TNF-cc and IL-1 affect a wide variety of cell and tissues and these cytokines as well as other leukocytes derived cytokine, such as IL-6 and IL-8, are important and critical inflammatory mediators of a wide variety of diseases states and conditions. The inhibition of these cytokines is of benefit in controlling, reducing and alleviating many of these disease states mediated by these cytokines.
Several approaches have been taken to block the effect of TNF-a. One approach involves using soluble receptors for TNF-a (e.g. TNFR-55 or TNFR-75), which have demonstrated efficacy in animal models of TNF-a- mediated disease states. A second approach to neutralizing TNF-a using a monoclonal antibody specific to TNF-a, cA2, has demonstrated improvement in swollen joint count in a Phase II human trial of rheumatoid arthritis (Feldmann et al; Immunological Reviews, pp. 195-223 (1995)). These approaches block the effects of TNF-a and IL-1 by either protein sequestration or receptor antagonism.
In certain cases, these approaches do not provide effective relief for some sufferers of inflammatory disease and cause adverse effects. Thus, there is currently a need for new anti-inflammatory pharmaceuticals.
GPR43 (also named FFA2R) belongs to a subfamily of G-Protein- Coupled Receptors (GPCRs), including GPR40 and GPR41 that have been identified as receptors for free fatty acids (Le Poul et al, J. Biol Chem. 278, 25481-489, 2003; Covington et al., Biochemical Society transaction 34, 770-773, 2006). The 3 family members share 30 to 40% sequences identity with specificity toward different fatty acids carbon chain length, with short chain fatty acids ((SCFAs): six carbons molecules or shorter) activating GPR41 and GPR43 and medium and long chain fatty acids activating GPR40 (Rayasam et al., Expert Opinion on therapeutic targets, 11 661-671, 2007 ). C2 acetate and C3 propionate are the most potent activators of GPR43.
GPR43 is strongly expressed in peripheral blood mononuclear cell (PBMC), bone marrow, and polymorphonuclear cells such as neutrophils. The involvement of GPR43 in leukocyte function is supported by the induction of its mRNA during the differentiation and activation of monocytes and neutrophils cells (Le Poul et al, J. Biol. Chem., 2003, 278: 25481-25489; Senga et al, Blood, 2003, 101 : 1185-1187). Recent studies have shown that both acetate and propionate decreased LPS-stimulated TNF-a release from neutrophils. In addition propionate dose-dependently suppressed IL-6 mRNA and protein release from colitis mouse colon organ cultures. TNF-a and members of the interleukin family are known to play a key role in the pathogenesis of IBD (Fuss, Curr Drug Targets Inflamm allergy 2003, 2: 101-112; Tedelind et al, World J Gastroenterol 2007, 13(20): 2826-2832). Further, GPR43 has been described to regulate the anti-inflammatory responses by SCFA in various in vivo model such as colitis, rheumatoid arthritis and asthma through a regulation of the neutrophil physio lo logy. SCFA-mediated GPR43 activation decreased TNF-a and ΜΙΡ-Ια levels in mouse DSS colitis model, as well as neutrophil chemotactic responsiveness (Maslowski et al, Nature, 2009, 461(7268): 1282-1286). Taken together these results suggest that therapeutic strategies based on GPR43, the major receptor for acetate and propionate for which anti- inflammatory properties have been clearly demonstrated , could be useful in treatment of inflammatory diseases.
On this basis, GPR43 agonists or partial agonists may be of therapeutic value for the treatment and/or prevention of inflammatory diseases.
SUMMARY OF THE INVENTION
The invention relates to the use of compounds of general formula
(I)
Figure imgf000006_0001
z I,
and pharmacologically acceptable salts and solvates thereof, wherein
Ar1 is a 5- to 6-membered aryl or heteroaryl group, 3- to 8-membered cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, or a linear or branched C3-C6 alkyl group, each of the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or alkyl groups being optionally substituted by one or more groups selected from halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkoxyalkoxy, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, arylalkyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylaminoalkyl, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, haloalkylsulfonylamino, or two substituents form an alkylenedioxy group or a haloalkylenedioxy group, or two substituents form a cycloalkyl or heterocycloalkyl moiety together with the cycloalkyl or heterocycloalkyl group they are attached to, or fused to the aryl, heteroaryl, cycloalkyl or heterocycloalkyl group may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl moiety, each of said substituents being optionally substituted by one or more further substituents selected from halo, alkoxy, alkyl, alkylamino, alkylcarbonyl, alkylheteroaryl, alkylsulfonyl, aralkyl, aryl, arylamino, aryloxy, cyano, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocyclyl, hydroxyl, oxo, or sulfonyl; L1 is a single bond, Ci-C2 alkylene, Ci-C2 alkenylene, each optionally being substituted by one or more substituents selected from halo, Ci-C2 alkyl, Ci-C2 haloalkyl; or L1 is -N(RN)-, wherein RN is H or Ci-C2 alkyl; or L1 and R1 together are =CH-;
R1 is H, halo, allyl, or a C1-C4 alkyl group, which may optionally be substituted by one or more groups selected from halo or C1-C4 alkyl;
L2 is a C1-C3 alkylene, C2-C4 alkenylene, C3-C6 cylcloalkylene, each of which being optionally substituted by one or more groups selected from halo, alkyl, alkoxy, or haloalkyl; or L2 is -0-CH2-; or
R1 and L2 together are =CH-, under the condition that -L1-Ar1 is H; or R1 and L2 together are a 5- to 6-membered saturated or unsaturated carbocyclic or heterocyclic group, preferably a cyclohexenyl group, under the condition that -L1- Ar1 is H; selected from the group consisting of -COOR,
Figure imgf000008_0001
wherein R is H or linear or branched alkyl, aryl, acyloxy alkyl, dioxolene, R3 is H, methyl or ethyl, and R4 is hydroxyl -S02CH3j -S02cyclopropyl or -S02CF3;
D is CO or S02;
R2 is H, linear or branched C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, C2- C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkylalkyl, aryl, arylalkyl, heteroarylalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, or aralkyloxyalkyl; each of the alkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroarylalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, and aralkyloxyalkyl groups being optionally substituted by one or more substituents selected from halo, cyano, alkyl, hydroxyalkyl, haloalkyl, alkenyl, alkynyl, heteroalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, alkylcarbonylaminoalkyl, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, haloalkylsulfonylamino, or two substituents form an alkylenedioxy group or a haloalkylenedioxy group;
Ar2 is a 5- or 6-membered heterocyclic group or a 5- or 6-membered heteroaryl group, optionally substituted by one or more substituents selected from halo, cyano, alkyl, hydroxyalkyl, haloalkyl, alkenyl, alkynyl, heteroalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, alkylcarbonylaminoalkyl, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, haloalkylsulfonylamino, or two substituents form an alkylenedioxy group or a haloalkylenedioxy group;
L3 is a single bond, C1-C3 alkylene, C1-C3 cycloalkylene C1-C3 alkenylene or carbonylamino;
Ar3 is an aryl, heteroaryl, or C1-C4 alkyl group, each of which being optionally substituted by one or more groups selected from halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, arylalkyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylaminoalkyl, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, cycloalkylaminocarbamoyl, alkylsulfonyl, haloalkylsulfbnyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, haloalkylsulfonylamino, or two substituents form an alkylenedioxy group or a haloalkylenedioxy group, or two substituents form a cycloalkyl or heterocycloalkyl moiety together with the cycloalkyl or heterocycloalkyl group they are attached to, or fused to the aryl, heteroaryl, cycloalkyl or heterocycloalkyl group may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl moiety, each of said substituents being optionally substituted by one or more further substituents selected from halo, alkoxy, alkyl, alkoxyalkyl, alkoxyalkoxy, cycloalkylalkyloxy, amino, alkylamino, alky lamino alkoxy, cycloalkylamino, aralkylamino, alkylamino alkyl, alkylamino carbonyl, alkylcarbonyl, cycloalkylcarbonylamino, alkylheterocyclyl, alkylheteroaryl, alkylsulfonyl, alkylsulfonylamino, aralkyl, aralkyloxy, aryl, arylamino, aryloxy, cyano, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocyclyl, heterocyclyloxy, hydroxyl, oxo, or sulfonyl, or L3-Ar3 form an aryl, preferably phenyl, or heteroaryl group fused to Ar2, wherein each of said aryl or heteroaryl groups fused to Ar2 are optionally substituted by one or more halo, preferably chloro and fluoro; for the preparation of a medicament for the treatment and /or prevention of inflammatory diseases, including, but not limited to, rheumatoid arthritis; inflammatory bowel disease (IBD) including but not limited to Crohn's disease, ulcerative colitis and colitis; Pagets disease; osteoporosis; multiple myeloma; uveitilis; acute and chronic myelogenous leukemia; pancreatic β cell destruction; rheumatoid spondylitis; osteoarthritis; gouty arthritis and other arthritis conditions; gout; adult respiratory distress syndrome (ARDS); chronic pulmonary inflammation diseases; silicosis; pulmonary sarcoidosis; psoriasis; allergic rhinitis; anaphylaxis; contact dermatitis; pancreatitis; asthma; muscle degeneration; cachexia such as cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome; Reiter's syndrome; type I diabetes; bone resorption disease; graft vs. host reaction; ischemia reperfusion injury; brain trauma; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; endotoxic shock; gram negative sepsis; fever and myalgias due to infection such as influenza; pyrosis.
In other terms, the invention provides methods for treating and/or preventing in a patient the development of an inflammatory disease, including, but not limited to, rheumatoid arthritis; inflammatory bowel disease (IBD) including but not limited to Crohn's disease, ulcerative colitis and colitis; Pagets disease; osteoporosis; multiple myeloma; uveitilis; acute and chronic myelogenous leukemia; pancreatic β cell destruction; rheumatoid spondylitis; osteoarthritis; gouty arthritis and other arthritis conditions; gout; adult respiratory distress syndrome (ARDS); chronic pulmonary inflammation diseases; silicosis; pulmonary sarcoidosis; psoriasis; allergic rhinitis; anaphylaxis; contact dermatitis; pancreatitis; asthma; muscle degeneration; cachexia such as cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome; Reiter's syndrome; type I diabetes; bone resorption disease; graft vs. host reaction; ischemia reperfusion injury; brain trauma; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; endotoxic shock; gram negative sepsis; fever and myalgias due to infection such as influenza; pyrosis, comprising the administration of a pharmaceutically effective amount of a compound of formula (I) or pharmaceutically acceptable salt or solvate thereof to a patient in need thereof.
Advantageously, the compounds of the invention or pharmaceutically acceptable salts and solvates thereof are those described above in respect to formula (I) with the following provisos:
Ar2-L3-Ar3 is not 4-(4-butylphenyl)thiazol-2-yl, 4-(4-ethylphenyl)thiazol-2-yl, 4- (para-tolyl)thiazol-2-yl, 4-phenylthiazol-2-yl, 4-(4-propylphenyl)thiazol-2-yl, 4- (4-(sec-butyl)phenyl)thiazol-2-yl, 4-(4-isopropylphenyl)thiazol-2-yl, 4-(4- isobutylphenyl)thiazol-2-yl, 4-(4-(tert-butyl)phenyl)thiazol-2-yl, 4-(4- butylphenyl)-5 -methylthiazo 1-2-yl, 4-(4-ethylphenyl)-5 -methylthiazo 1-2-yl, 5 - methyl-4-(para-tolyl)thiazol-2-yl, 5 -methyl-4-phenylthiazo 1-2-yl, 5-methyl-4-(4- propylphenyl)thiazo 1-2-yl, 4-(4-(sec-butyl)phenyl)-5 -methylthiazo 1-2-yl, 4-(4- isopropylphenyl)-5 -methylthiazo 1-2-yl, 4-(4-isobutylphenyl)-5-methylthiazo 1-2-yl,
4-(4-(tert-butyl)phenyl)-5 -methylthiazo 1-2-yl, 4-(4-butyl-3 -methylphenyl)thiazo 1- 2-yl, 4-(4-ethyl-3-methylphenyl)thiazo 1-2-yl, 4-(3 ,4-dimethylphenyl)thiazo 1-2-yl, 4-(meta-tolyl)thiazol-2-yl, 4-(3-methyl-4-propylphenyl)thiazo 1-2-yl, 4-(4-(sec- butyl)-3 -methylphenyl)thiazo 1-2-yl, 4-(4-isopropyl-3 -methylphenyl)thiazo 1-2-yl, 4-(4-isobutyl-3-methylphenyl)thiazol-2-yl, 4-(4-(tert-butyl)-3- methylphenyl)thiazo 1-2-yl, 4-(4-butyl-3 -methylphenyl)-5 -methylthiazo 1-2-yl, 4- (4-ethyl-3-methylphenyl)-5-methylthiazo 1-2-yl, 4-(3,4-dimethylphenyl)-5- methylthiazo 1-2-yl, 5-methyl-4-(meta-tolyl)thiazol-2-yl, 5-methyl-4-(3-methyl-4- propylphenyl)thiazo 1-2-yl, 4-(4-(sec-butyl)-3-methylphenyl)-5 -methylthiazo 1-2-yl, 4-(4-isopropyl-3-methylphenyl)-5 -methylthiazo 1-2-yl, 4-(4-isobutyl-3- methylphenyl)-5 -methylthiazo 1-2-yl, 4-(4-(tert-butyl)-3 -methylphenyl)-5 - methylthiazo 1-2-yl, naphtalen-2-yl; Ar3 is not (7H-pyrrolo[2,3-d]pyrimidin)-4yl;
Ar2 is not 5-cyano-thiazolyl; the compound of formula I is none of.
2- [ [ [4-(4-butylphenyl)-5 -methyl-2-thiazolyl]amino ]carbonyl] -cy clohexane carboxylic acid,
6-[[(4,5-dimethyl-2-thiazolyl) amino] carbonyl]-3-cyclohexene-l -carboxylic acid, 6-[[[5-(cyclopentylmethyl)-l, 3,4-thiadiazol-2-yl]amino]carbonyl]-3-cyclohexene-
1 - carboxylic acid,
3- cyclohexene-l -carboxylic acid, 6-[[(5-acetyl-4-methyl-2- thiazo lyl)amino] carbonyl] -
2- [ [ [4-(4-methoxyphenyl)-5 -methyl-2-thiazo lyl] amino]carbonyl] - cyclohexanecarboxylic acid,
6- [[[4-(3, 4-dimethylphenyl)-5-methyl-2-thiazo lyl] amino] carbonyl] -3 - cyclohexene-1 -carboxylic acid,
6-[[[5-methyl-4-(4-propylphenyl)-2 thiazolyl]amino]carbonyl]-3-cyclohexene- 1 - carboxylic acid,
2-[[[4-(2,4-dichlorophenyl)-5-methyl-2-thiazolyl]amino]carbonyl]- cyclohexanecarboxylic acid,
2-[[[4-(2,5-dimethylphenyl)-5-methyl-2- thiazolyl]amino]carbonyl]- cyclohexanecarboxylic acid, 6-[[[5-(2-chlorophenyl)-l,3,4-thiadiazol-2-yl]amino]carbonyl]-3-cyclohexene-l- carboxylic acid
2-[[[5-[(4-chlorophenoxy)methyl]-l,3,4-thiadiazol-2-yl]amino]carbonyl]- cyclohexanecarboxylic acid,
2- [ [ [5-methyl-4-(4-propylphenyl)-2-thiazo lyl] amino] carbonyl] - cyclohexanecarboxybic acid,
2-[[(5-methyl-l,3,4-thiadiazol-2-yl)amino]carbonyl]-cyclohexanecarboxylic acid, 6- [ [ [4- [4-( 1 , 1 -dimethylethyl)phenyl] -5 -methyl-2-thiazo lyl] amino] carbonyl] -3 - cyclohexene-l-carboxylic acid,
6-[[(5-ethyl-l,3,4-thiadiazol-2-yl)amino]carbonyl]- 3-cyclohexene-l-carboxylic acid-l-methylethyl ester
2-[[(5-methyl-4-phenyl-2-thiazolyl)amino]carbonyl]-cyclohexanecarboxylic acid, 2- [ [ [5-methyl-4- [4-(2-methylpropyl)phenyl] -2-thiazolyl)amino]carbonyl] - cyclohexanecarboxylic acid,
6-[[(5-cyclopropyl-l,3,4-thiadiazol-2-yl)amino]carbonyl]-3-cyclohexene-l- carboxylic acid,
2-[[[5-(cyclopentylmethyl)-l,3,4-thiadiazol-2-yl]amino]carbonyl]- cyclohexanecarboxylic acid,
2- [ [ [4-(4-chlorophenyl)5 -ethyl-2-thiazo lyl)amino]carbonyl] - cyclohexanecarboxylic acid,
2- [ [ [4-(3 -methoxyphenyl)-5 -methyl-2-thiazo lyl] amino]carbonyl] - cyclohexanecarboxylic acid,
6-[[[5-methyl-4-(4-methylphenyl)-2-thiazolyl]amino]carbonyl]-3-cyclohexene-l- carboxylic acid,
2-[[(5-cyclopropyl-l,3,4-thiadiazol-2-yl)amino]carbonyl]-cyclohexanecarboxylic acid,
6-[[[4-(4-chlorophenyl)-5-ethyl-2-thiazolyl]amino]carbonyl]-3-cyclohexene-l- carboxybic acid, 6- [ [ [4-(2,5 -dimethylphenyl)-5 -methyl-2-thiazo lyl] amino] carbonyl] -3 -cyclo hexene-
1- carboxylic acid,
6-[[(5-phenyl-l,3,4-thiadiazol-2-yl)amino]carbonyl]-3-cyclohexene-l-carboxylic acid,
2- [[ [5-(4-methoxyphenyl)- 1 ,3 ,4-thiadiazol-2yl] amino] carbonyl] - cyclohexanecarboxylic acid,
2- [ [(6-carboxy-3 -cyclo hex en- 1 -yl)carbonyl] amino ] -4-phenyl-5 -thiazo lecarboxylic acid-5 -ethyl ester,
2- [ [(4,5 -dimethyl-2-thiazo lyl) amino] carbonyl] -cyclohexanecarboxylic acid, 6-[[(5-cyclopropyl-l,3,4-oxadiazol-2-yl)amino]carbonyl]-3-cyclohexene-l- carboxylic acid,
6-[[[5-methyl-4-[4-(2-methylpropyl)phenyl]-2-thiazolyl)amino]carbonyl]-3- cyclohexene-l-carboxylic acid,
6-[[(5-ethyl-4-phenyl-2-thiazolyl)amino]carbonyl]-3-cyclohexene-l-carboxylic acid,
6- [ [ [4-(2,4-dimethylphenyl)-5 -methyl-2- thiazo lyl)amino]carbonyl] -3 - cyclohexene-l-carboxylic acid,
2-[[[4-(3-chlorophenyl)-5-methyl-2-thiazolyl]amino]carbonyl]- cyclohexanecarboxylic acid,
6-[[[5-(l -ethylphenyl)- 1 ,3,4— thiadiazol-2-yl]amino]carbonyl]-3-cyclohexene- 1 - carboxylic acid,
2- [ [ [4-(3 ,4-dimethylpentyl)-5 -methyl-2-thiazo lyl] amino]carbonyl] - cyclohexanecarboxylic acid,
2-[[[5-(2-thienyl)-l,3,4-thiadiazol-2-yl]amino]carbonyl]-cyclohexanecarboxylic acid,
2- [ [(4,5 -diphenyl-2-thiazo lyl)amino] carbonyl] -cyclo hexanecarboxybic acid, 6- [ [ [4-(4-ethylphenyl)-5 -methyl-2-thiazo lyl] amino ]carbonyl] -3 -cyclo hexene- 1 - carboxylic acid,
2-[[(2-carboxycyclohexyl)carbonyl]amino]-4-methyl-5-thiazo lecarboxylic acid-5- methyl ester, 2-[[(2-carboxycyclohexyl)carbonyl]amino]-4-methyl-5-thiazolecarboxylic acid-5- ethyl ester,
2-[[(5-ethyl-4-phenyl-2- thiazo lyl)amino] carbonyl] -cy clohexanecarboxylic acid,
6-[[(5-methyl-l,3,4-thiadiazol-2-yl)amino]carbonyl]-3-cyclohexene-l-carboxylic acid,
2-[[(5-cyclopropyl-l,3,4-oxadiazol-2-yl)amino]carbonyl]-cyclohexanecarboxybic acid,
2- [ [ [4-(4-fluorophenyl)-5 -methyl-2-thiazo lyl] amino] carbonyl] - cyclohexanecarboxylic acid,
2-[[(2-carboxycyclohexyl)carbonyl]amino]-4-methyl-5-thiazoleacetic acid-5-ethyl ester,
2- [ [ [4-(2,4-dimethylphenyl)-5 -methyl-2-thiazo lyl] amino] carbonyl] - cyclohexanecarboxylic acid,
6-[[[4-(3-chlorophenyl)-5-methyl-2- thiazo lyl]amino]carbonyl]-3-cyclohexene-l- carboxylic acid,
2-((5-cyclohexyl-l,3,4-thiadiazol-2-yl)carbamoyl)cyclohexanecarboxylic acid 2-[[[5-methyl-4-(4-methylphenyl)-2-thiazolyl]amino]carbonyl]- cyclohexanecarboxylic acid,
6-[[[5-(2-thienyl)-l,3,4-thiadiazol-2-yl]amino]carbonyl]-3-cyclohexene-l- carboxylic acid,
6-[[(4,5-diphenyl-2- thiazolyl)amino]carbonyl]-3-cyclohexene- 1 -carboxylic acid,
2- [ [ [4-(4-ethylphenyl)-5 -methyl-2-thiazo lyl] amino ]carbonyl] - cyclohexanecarboxylic acid,
6-[[[5-dimethylamino)carbonyl]-4-methyl-2-thiazolyl]amino] carbonyl]-3- cyclohexene-1 -carboxylic acid,
2-[[(5-ethyl-l,3,4-thiadiazol-2-yl)amino]carbonyl]-cyclohexanecarboxylic acid, 2-[[(2-carboxycyclohexyl)carbonyl]amino]-4-phenyl-5-thiazolecarboxylic acid-5- ethyl ester, 6-[[(5-ethyl-l,3,4-thiadiazol-2-yl)amino]carbonyl]-3-cyclohexene-l-carboxylic acid,
2-[[(4-ethyl-5-methyl-2-thiazolyl]amino] carbonylj-cyclohexanecarboxylic acid, 2- [ [ [5-methyl-4- [4-( 1 -methylethyl)phenyl] -2-thiazolyl] amino] carbonyl] - cyclohexanecarboxylic acid,
2-[[(5-acetyl-4-methyl-2-thiazolyl)amino]carbonyl]-cyclohexanecarboxylic acid, 6-[[[4-(2,4-dichlorophenyl)-5-methyl-2-thiazolyl]amino]carbonyl]-3-cyclohexene-
1- carboxylic acid,
6-[[[4-(4-chlorophenyl)-5-methyl-2-thiazolyl]amino]carbonyl]-3-cyclohexene-l- carboxylic acid,
6-[[(5-cyclohexyl- 1 ,3,4-thiadiazol-2-yl} amino]carbonyl]-3-cyclohexene- 1 - carboxylic acid,
2- [[[4-(4-chlorophenyl)-5-methyl-2-thiazolyl]amino]carbonyl- cyclohexanecarboxylic acid,
6- [[ [4-(4-fluorophenyl)-5 -methyl-2-thiazo lyl] amino] carbonyl] -3 -cyclohexene- 1 - carboxylic acid,
2-[[(6-carboxy-3-cyclohexen- 1 -yl)carbonyl-4-methyl-5-thiazolecarboxylic acid-5- methyl ester,
2- [ [[4 [4-( 1 , 1 -dimethylethyl)phenyl] -5 -methyl-2-thiazo lyl]amino]carbonyl- cyclohexanecarboxylic acid,
2-[[[5[(dimethylethylamino)carbonyl]-4-methyl-2-thiazolyl]amino]carbonyl- cyclohexanecarboxylic acid,
6- [ [(5-methyl-4-phenyl-2-thiazo lyl)amino] carbonyl] -3 -cyclohexene- 1 -carboxylic acid,
2-[[(5-methyl-l,3,4-thiadiazol-2-yl]amino]carbonyl]-cyclohexanecarboxylic acid, and
6-[[(5-(2-thienyl)-l,3,4-thiadiazol-2-yl]amino]carbonyl]-3-cyclohexene-l- carboxylic acid.
According to one embodiment the compound of the invention is not 6-((4-(2- chlorophenyl)thiazol-2-yl)carbamoyl)cyclohex-3-enecarboxylic acid.
DETAILED DESCRIPTION OF THE INVENTION
As noted above, the invention relates to the use of compounds of formula (I) as well as pharmaceutically acceptable salts and solvates thereof for the preparation of a medicament for the treatment and/or prevention of inflammatory diseases or in other terms to methods for treating and/or preventing in a patient the development of an inflammatory disease, comprising the administration of a pharmaceutically effective amount of a compound of formula (I) or pharmaceutically acceptable salt thereof to a patient in need thereof.
Preferred compounds of formula I and pharmaceutically acceptable salts and solvates thereof are those wherein
D is CO; and/or
Z is -COOR, wherein R is defined as above in respect to formula I, preferably Z is COOH; and/or
R1 is hydrogen, halogen, or a group selected from C1-4 alkyl optionally substituted by one or more substituents selected from halogen, allyl or alkyl; preferably R1 is selected from hydrogen, fluoro, methyl, or ethyl, the methyl or ethyl group being optionally substituted with one or more substituents selected from fluoro or alkyl, more preferably R1 is hydrogen, fluoro or methyl, and most preferably R1 is hydrogen, and L2 is as defined above in respect to formula I, preferably L2 is cyclopropylene, ethenylene, n-propylene, -CH2C(R'R")-, or -C(R'R")-, wherein R' and R" are independently selected from H, halogen, methyl, and ethyl, more preferably L2 is cyclopropylene, ethenylene, methylene, -CHMe-, -CHF-; even more preferably L2 is methylene, or
R1 and L2 together are =CH- under the condition that -L1-Ar1 is H, preferably
Figure imgf000018_0001
wherein D is attached at position a and Z is attached at position b under the condition that -L1-Ar1 is H, or
R1 and L2 together are a 5- to 6-membered saturated or unsaturated carbocyclic or heterocyclic group, preferably a non aromatic, saturated or partially unsaturated, 5- to 6-membered carbocyclic group, under the condition that -L1-Ar1 is H, more preferably R1 and L2 together are a cyclohexyl or cyclohexenyl group, under the condition that -L1-Ar1 is H, even more preferably R1 and L2 together are selected from the group consisting of
Figure imgf000018_0002
wherein the dotted line is present or absent, preferably present; D is attached at position a and Z is attached at position b under the condition that -L1-Ar1 is H; and/or
R2 is H, linear or branched C1-C4 alkyl, C1-C4 hydroxyalkyl, allyl, propargyl, cyclopropyl, cyclopentyl, cyclopentylmethyl, cyclopropylmethyl, 1 ,1,1- trifluoroethyl, -C2H4CO2CH3, -CH2C02CH3, or -CH2CONH2, benzyl, benzyloxyethyl, methoxyethyl, preferably R2 is H, methyl, ethyl, allyl, cyclopropyl, hydroxyethyl, -C2H4C02CH3, -CH2C02CH3, -CH2CONH2, more preferably R2 is methyl or cyclopropyl; and/or Ar1 is a 5- to 6-membered aryl or heteroaryl group, or a 5- to 6-membered cycloalkyl or heterocycloalkyl group, each of which may optionally be substituted by one or more groups selected from halogen, trifluoromethyl, cyano, methoxy, trifluoromethoxy, and methoxyethoxy, and L1 is a single bond, Ci-C2 alkylene, or C2 alkenylene, each optionally being substituted by one or more substituents selected from halo, Ci-C2 alkyl, Ci-C2 haloalkyl, preferably L1 is a single bond, Ci-C2 alkylene, optionally substituted by Ci-C2 alkyl, preferably Ar1 is phenyl or cyclohexyl and L1 is methylene, optionally substituted by methyl; or Ar1 is a linear or branched C3-C6 alkyl group, optionally substituted by one or more groups selected from halogen, trifluoromethyl, cyano, and methoxy, and L1 is a single bond, Ci-C2 alkylene, or C2 alkenylene, preferably Ci-C2 alkylene or C2 alkenylene, and even more preferably Ci-C2 alkylene, (Z)-ethenylene, or (E)- ethenylene, each optionally being substituted by one or more substituents selected from halo, Ci-C2 alkyl, Ci-C2 haloalkyl, preferably L1 is a single bond or Ci-C2 alkylene, optionally substituted by Ci-C2 alkyl or one or more fluoro, more preferably L1 is CH2; preferably Ar1 is isopropyl, butyl, isobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, furanyl, thiophenyl, thiazolyl or pyridyl, and L1 is CH2, more preferably Ar1 is cyclopentyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl or furanyl and L1 is CH2; and/or Ar2 is selected from the group consisting of thiazolylene, 1,2,4-thiadiazolylene, pyridinylene, pyrimidinylene, pyrazinylene, pyridazinylene, triazinylene, oxazolylene, 1,2,4-oxadiazolylene, pyrazolylene, each of which being optionally substituted by one or more substituents selected from halo, cyano, hydroxyl, linear or branched C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 haloalkyl, preferably F, CI, CH3, or CF3, preferably Ar2 is thiazolylene, 1,2,4-thiadiazolylene, pyridinylene, more preferably Ar2 is thiazolylene linked to the nitrogen of N-R2 at position 2 and to L3 of L3-Ar3 at position 4, 1,2,4-thiadiazolylene linked to the nitrogen of N-R2 at position 5 and to L3 of L3-Ar3 at position 3, pyridinylene linked to the nitrogen of N-R2 at position 2 and to L3 of L3-Ar3 at position 5; and/or Ar3 is an aryl or heteroaryl group, optionally substituted by one or more substituents selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, cyano, 5 or 6 membered heteroaryl such as pyridinyl, pyrazinyl, and pyridazinyl, phenyl, methylcarbonylamino, -NH-S02CF3, methylenedioxy and L3 is a single bond or Ci-C2 alkylene; Ar3 is a C1-C4 alkyl group and L3 is a single bond; or - L3-Ar3 is a phenyl group fused to Ar2; preferably Ar3 is an aryl, preferably phenyl, or heteroaryl group, preferably thiophenyl, more preferably thiophen-2-yl, furanyl, more preferably furan-2-yl, each of said aryl or heteroaryl being optionally substituted by one or more substituents selected from halo, C1-C4 alkyl, cyclopropyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, ethoxycarbamoyl, methylenedioxy, 5 or 6 membered aryl, preferably phenyl, 5 or 6 membered heteroaryl, preferably furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl, more preferably furan-3-yl, thiophen-3-yl, pyridinyl, still more preferably pyridin-3-yl, each of said 5 or 6 membered aryl or 5 or 6 membered heteroaryl being optionally fused to one or more 5 or 6 membered cycloalkyl, aryl, heterocyclyl or heteroaryl moiety thus forming a fused ring system, and the latter fused ring system being optionally substituted by one or more further substituents selected from halo, hydroxyl, oxo, alkyl, and/or each of said 5 or 6 membered aryl or 5 or 6 membered heteroaryl groups being optionally substituted by one or more substituents selected from cyano, halo, hydroxyl, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, alkylaminoalkoxy, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, aryloxy, aralkyloxy, alkylamino, alkylaminoalkyl, cycloalkylamino, arylamino, aralkylamino, alkylaminocarbonyl, heteroarylcarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, alkylsulfonyl, haloalkylsulfonyl, alkylsulfonylamino, each of said cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, aryloxy, aralkyloxy, heteroarylcarbonyl, cycloalkylamino, arylamino, aralkylamino, cycloalkylcarbonylamino being optionally substituted by one or more further substituents selected from halo, preferably chloro or fluoro, oxo or alkyl, preferably methyl; more preferably Ar3 is phenyl, thiophenyl, preferably thiophen-2-yl, furanyl, preferably furan-2-yl, each of said phenyl, thiophenyl, furanyl, being optionally substituted by one or more substituents selected from halo, C1-C4 alkyl, cyclopropyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, ethoxycarbamoyl, methylenedioxy, phenyl, pyridin-3-yl, each of said phenyl or pyridin-3-yl being optionally fused to one or more 5 or 6 membered heterocyclyl, phenyl, or heteroaryl moiety, preferably oxopyrrolidinyl, imidazolinyl, piperidinyl, morpholinyl, pyrrolyl, imidazolyl, or pyridinyl, more preferably 2-oxopyrrolidinyl 2-oxoimidazolinyl, 2-oxopiperidinyl or pyrrolyl, thus forming a fused ring system, and the latter fused ring system being optionally substituted by one or more further substituents selected from halo, preferably chloro or fluoro, oxo, alkyl, preferably methyl, and/or each of said phenyl or pyridin-3-yl groups being optionally substituted by one or more substituents selected from halo, alkyl, heterocyclyl, heteroaryl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, aralkyloxy, alkylamino, alkylaminoalkyl, cycloalkylamino, aralkylamino, alkylaminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, each of said heterocyclyl, heteroaryl, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, aralkyloxy, cycloalkylamino, aralkylamino, cycloalkylcarbonylamino being optionally substituted by one or more further substituents selected from fluoro, chloro, oxo or methyl.
Still other preferred compounds of formula I are those wherein D is S02 and Ar1,
2 3 1 2 1 2 3
Ar", ArJ, R , IT, L , If, I ,and Z are as defined above in respect to formula I.
In one embodiment, preferred compounds of Formula I are those of formula la:
Figure imgf000021_0001
COOR la and pharmaceutically acceptable salts, and solvates thereof, wherein R is H or linear or branched C1-C4 alkyl; and
1 2 3 1 2 1 2 3
Ar1, Ar", ArJ, R , R", L , If and f are as defined above in respect to formula I.
Preferred compounds of formula la are those wherein
R1 is hydrogen and L2 is ethenylene, ethylene, n-propylene, -CH(Me)-, -CH2-, - CHF-, -CF2-, or cyclopropylene; or R1 and L2 together are =CH-; and
1 2 3 2 1 3
Ar1, Ar", ArJ, R", L1 and f are as defined above in respect to formula I.
In another embodiment, preferred compounds of Formula I are those of formula lb:
Figure imgf000022_0001
lb, and pharmaceutically acceptable salts, and solvates thereof, wherein X is S or O, preferably X is S; Y is CH or N, preferably Y is CH;
L3 is attached to the heterocyclic group X c 1 either in position 4 or 5, preferably in position 4; and if Y is CH, R5 is H, halo, hydroxyl, linear or branched C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 haloalkyl, preferably H, methyl, F, CI, or CF3, more preferably H or F and R5 is attached to the heterocyclic group either in position 4, if L3 is attached in position 5, or in position 5, if L3 is attached in position 4; preferably R5 is attached in position 5; if Y is N, R5 is absent and L3 is attached in position 5; and
Ar1 and L1 are as defined above in respect to formula I, preferably Ar1 is a 5- to 6-membered aryl, preferably phenyl, or heteroaryl group, preferably furanyl, thiophenyl, oxazolyl, isoxazolyl, or thiazolyl optionally substituted by one or more groups selected from halogen, trifluoromethyl, cyano, methoxy trifluoromethoxy, and methoxyethoxy, and L1 is a single bond, C1-C2 alkylene, or C2 alkenylene, each optionally being substituted by one or more substituents selected from halo, C1-C2 alkyl, C1-C2 haloalkyl, preferably L1 is a single bond, or Ci-C2 alkylene, optionally substituted by C1-C2 alkyl, more preferably L1 is -CH2- ; or Ar1 is a linear or branched C3-C6 alkyl group, preferably isopropyl, butyl, isobutyl, optionally substituted by one or more groups selected from halogen, trifluoromethyl, cyano, and methoxy, and L1 is a single bond; or Ar1 is cycloalkyl, preferably cyclopropyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptan-2-yl, more preferably cyclopentyl, or heterocycloalkyl, preferably tetrahydrofuranyl or tetrahydropyranyl and L1 is C1-C2 alkylene or C2 alkenylene, preferably C1-C2 alkylene or C2 alkenylene, and even more preferably -CH2-, (Z)-ethenylene, or (E)-ethenylene, each optionally being substituted by one or more substituents selected from halo, C1-C2 alkyl, C1-C2 haloalkyl, preferably L1 is a single bond or Ci-C2 alkylene, optionally substituted by C1-C2 alkyl, even more preferably L1 is methylene;
Ar3 is as defined above in respect to formula I, preferably Ar3 is an aryl or heteroaryl group, optionally substituted by one or more substituents selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, cyano, 5 or 6 membered heteroaryl such as pyridinyl, phenyl, methylcarbonylamino, -NH-SO2CF3, and L3 is a single bond or C1-C2 alkylene; or Ar3 is a C1-C4 alkyl group and L3 is a single bond, more preferably Ar3 is an aryl, preferably phenyl, or heteroaryl group, preferably thiophenyl, more preferably thiophen-2-yl, furanyl, more preferably furan-2-yl, each of said aryl or heteroaryl being optionally substituted by one or more substituents selected from halo, C1-C4 alkyl, cyclopropyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, ethoxycarbamoyl, methylenedioxy, 5 or 6 membered aryl, preferably phenyl, 5 or 6 membered heteroaryl, preferably furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl, more preferably furan-3-yl, thiophen-3-yl, pyridinyl, still more preferably pyridinyl, each of said 5 or 6 membered aryl or 5 or 6 membered heteroaryl being optionally fused to one or more 5 or 6 membered cycloalkyl, aryl, heterocyclyl or heteroaryl moiety thus forming a fused ring system, and the latter fused ring system being optionally substituted by one or more further substituents selected from halo, hydroxyl, oxo, alkyl, and/or each of said 5 or 6 membered aryl or 5 or 6 membered heteroaryl groups being optionally substituted by one or more substituents selected from cyano, halo, hydroxyl, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, alkylaminoalkoxy, cycloalkyloxy, eye lo alky lalkyloxy, heterocyclyloxy, aryloxy, aralkyloxy, alkylamino, alkylamino alkyl, cycloalkylamino, arylamino, aralkylamino, alkylaminocarbonyl, heteroarylcarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, alkylsulfonyl, haloalkylsulfonyl, alkylsulfonylamino, each of said cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, aryloxy, aralkyloxy, heteroarylcarbonyl, cycloalkylamino, arylamino, aralkylamino, cycloalkylcarbonylamino being optionally substituted by one or more further substituents selected from halo, preferably chloro or fluoro, oxo or alkyl, preferably methyl; still more preferably Ar3 is phenyl, thiophenyl, preferably thiophen-2-yl, furanyl, preferably furan-2-yl, each of said phenyl, thiophenyl, furanyl, being optionally substituted by one or more substituents selected from halo, C1-C4 alkyl, cyclopropyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, ethoxycarbamoyl, methylenedioxy, phenyl, pyridin-3-yl, each of said phenyl or pyridin-3-yl being optionally fused to one or more 5 or 6 membered heterocyclyl, phenyl, or heteroaryl moiety, preferably oxopyrrolidinyl, imidazolinyl, piperidinyl, morpholinyl, pyrrolyl, imidazolyl, or pyridyl, more preferably 2-oxopyrrolidinyl 2-oxoimidazolinyl, 2-oxopiperidinyl or pyrrolyl, thus forming a fused ring system, and the latter fused ring system being optionally substituted by one or more further substituents selected from halo, preferably chloro or fluoro, oxo, alkyl, preferably methyl, and/or each of said phenyl or pyridin-3-yl groups being optionally substituted by one or more substituents selected from halo, alkyl, heterocyclyl, heteroaryl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, aralkyloxy, alkylamino, alkylaminoalkyl, cycloalkylamino, aralkylamino, alkylaminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, each of said heterocyclyl, heteroaryl, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, aralkyloxy, cycloalkylamino, aralkylamino, cycloalkylcarbonylamino being optionally substituted by one or more further substituents selected from fluoro, chloro, oxo or methyl;
R1 is as defined above in respect to formula I, preferably R1 is hydrogen, halogen, allyl, or a group selected from C1 -4 alkyl optionally substituted by one or more substituents selected from halogen or alkyl; more preferably R1 is selected from hydrogen, fluoro, or methyl or ethyl, the methyl or ethyl group being optionally substituted with one or more substituents selected from fluoro or alkyl, even more preferably R1 is hydrogen, fluoro or methyl, and most preferably R1 is hydrogen, and L2 is as defined above in respect to formula I, preferably L2 is cyclopropylene, ethenylene, n-propylene, -C(R'R")-, wherein R' and R" are independently selected from H, halogen, methyl, and ethyl, more preferably L2 is cyclopropylene, ethenylene, methylene, -CHMe-, -CHF-, even more preferably L2 is methylene; or
R1 and L2 together are =CH- under the condition that -L1-Ar1 is H, preferably
Figure imgf000025_0001
wherein D is attached at position a and Z is attached at position b under the condition that -iZ-Ar1 is H; and/or R1 and L2 together are a non aromatic, saturated or partially unsaturated, carbocyclic group, under the condition that -L1-Ar1 is H, preferably R1 and L2 together are a cyclohexyl or cyclohexenyl group, under the condition that -L1-Ar1 is H, more preferably R1 and L2 together are selected from the group consisting of
Figure imgf000025_0002
wherein the dotted line is present or absent, preferably present; D is attached at position a and Z is attached at position b under the condition that -L1-Ar1 is H; and/or
Z is as defined above in respect to formula I, preferably Z is -COOR, wherein R is defined as above in respect to formula I, more preferably Z is COOH; and R2 is as defined above in respect to formula I, preferably R2 is H, linear or branched C1-C4 alkyl, C1-C2 hydroxyalkyl, allyl, propargyl, cyclopropyl, cyclopentyl, cyclopentylmethyl, cyclopropylmethyl, benzyl, benzyloxyethyl, methoxyethyl, 1 , 1 ,1-trifluoroethyl, -C2H4CO2CH3, -CH2C02CH3, or -CH2CONH2, more preferably R2 is H, methyl, ethyl, allyl, cyclopropyl, hydroxyethyl, - C2H4CO2CH3, -CH2CO2CH3, or -CH2CONH2, more preferably R2 is methyl or cyclopropyl.
Preferred compounds of formula lb are those wherein Z is -COOR, preferably COOH, and R, Ar1, Ar2, Ar3, R1, R2, L1, L2 and L3 are as defined above in respect to formula I.
Particularly preferred compounds of formula lb are those of formula Ib-1
Figure imgf000026_0001
1 2 3 3 1 2 5
wherein L , If, If, Ar", X, Y, Z, R , R", and R" are as defined above in respect to formula lb, preferably L1 is methylene, optionally substituted by C1-C2 alkyl or halo, preferably by methyl or fluoro, even more preferably L1 is methylene; and
R6, R7, R'6, R'7 and R8 are independently selected from H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, arylalkyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylaminoalkyl, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfbnyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, haloalkylsulfonylamino, or R6 and R7 or R7 and R8 or R'6 and R'7 or R'7 and R8 together form an alkylenedioxy group or a halo alky lenedioxy group, or R6 and R7 or R 7 and R 8 or R' 6 and R' 7 or R' 7 and R 8 together form a cyclo alkyl, aryl, heterocyclyl or heteroaryl moiety fused to the phenyl group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo, alkoxy, alkyl, alkylamino, alkylcarbonyl, alkylheteroaryl, alkylsulfonyl, aralkyl, aryl, arylamino, aryloxy, cyano, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocyclyl, hydroxyl, oxo, or sulfonyl, preferably R6, R7, R'6, R'7 and R8 are independently selected from H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, alkoxyalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, carboxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfonylamino, cycloalkylsulfonylamino, more preferably R6, R7, R'6, R'7 and R8 are independently selected from H, hydroxyl, halo, alkyl, haloalkyl, alkoxy, alkoxyalkyl preferably methoxyethyl, haloalkoxy preferably - OCF3, alkylsulfonyl, haloalkylsulfonyl and cyano, even more preferably from H, halo, CF3, C1-C2 alkyl, C1-C2 alkoxy, and cyano, still more preferably from H, F, CI, CF3, methyl, methoxy, and cyano, still more preferably R6, R7, R'6, R'7 are H and R8 is selected from H, CI, methyl, hydroxyl and methoxy, and most preferably R6, R7, R'6, R'7 are H and R8 is selected from H, CI, methyl, and methoxy.
Preferred compounds of formula lb- 1 are those of formula lb- la
Figure imgf000028_0001
wherein L2, L3, Ar3, X, Y, R2, R5, R6, R7, R'6, R'7 and R8 are as defined above in respect to formula lb- 1.
Other preferred compounds of formula lb are selected form the group consisting of formulae Ib-2a, Ib-2b, Ib-2c, Ib-2d, Ib-2e and Ib-2f:
Figure imgf000028_0002
Ib-2c,
Figure imgf000029_0001
1 2 3 3 1 2 5
wherein L , L% I , Ar", X, Y, Z, R , R" and R" are as defined above in respect to formula lb, preferably L1 is methylene;
B1, B2 and B3 are independently CF2, O, NRa, CO, or S02, wherein Ra is H or alkyl, preferably linear or branched C1-C4 alkyl; C1-C4 alkylcarbonyl, C1-C4 alkylsulfonyl, C1-C4 alkylaminocarbonyl, C3-C6 cycloalkyl; C3-C6 cycloalkylcarbonyl, C3-C6 cycloalkylsulfonyl, C3-C6 cycloalkylaminocarbonyl, aryl, arylcarbonyl, arylsulfonyl or arylaminocarbonyl, heteroaryl, heteroarylcarbonyl, heteroarylsulfonyl or heteroarylammocarbonyl; preferably B1, B2 and B3 are O and R9, R10, R11, R12, R13, R'9, R'10, R'11, R'12, R'13 and R"13 are independently selected from H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, arylalkyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylaminoalkyl, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, haloalkylsulfonylamino, or one of R9 or R10 and one of R11, R12, R13, R'9, R'10, R'11, R'12, R'13 or R"13, or one of R11 or R12 and one of R9, R10, R13, R'9, R'10, R'11, R'12, R'13 or R"13, or one of R13 or R'13 and one of R9, R10, R11, R12, R'9, R'10, R'11, R'12, or R"13 together form an alkylenedioxy group or a haloalkylenedioxy group, or one of R9 or R10 and one of R11, R12, R13, R'9, R'10, R'11, R'12, R'13 or R"13, or one of R11 or R12 and one of R9, R10, R13, R'9, R'10, R'11, R'12, R'13 or R"13, or one of R13 or R'13 and one of R9, R10, R11, R12, R'9, R'10, R'11, R'12, or R"13 together form a cycloalkyl, aryl, heterocyclyl or heteroaryl moiety together with the cyclic group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo, alkoxy, alkyl, alkylamino, alkylcarbonyl, alkylheteroaryl, alkylsulfonyl, aralkyl, aryl, arylamino, aryloxy, cyano, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocyclyl, hydroxyl, oxo, or sulfonyl, preferably R9, R10, R11, R12, R13, R'9, R'10, R'11, R'12, R'13 and R"13 are independently selected from H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, carboxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfonylamino, cycloalkylsulfonylamino, or one o f R9 or R10 and one of R , R12, R13, R'9, R'10, R'11, R'12, R'13 or R"13, or one of R11 or R12 and one of R9, R10, R13, R'9, R'10, R'11, R'12, R'13 or R"13, or one of R13 or R'13 and one of R9, R10, R11, R12, R'9, R'10, R'11, R'12, or R"13 together form a cycloalkyl, aryl, heterocyclyl or heteroaryl moiety together with the cyclic group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo, alkoxy, alkyl, alkylamino, alkylcarbonyl, alkylheteroaryl, alkylsulfonyl, aralkyl, aryl, arylamino, aryloxy, cyano, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocyclyl, hydroxyl, oxo, or sulfonyl, more preferably R9, R10, R11, R12, R13, R'9, R'10, R'11, R'12, R'13 and R"13 are independently selected from H, hydroxyl, Ci-C3-alkyl, halo, haloalkyl, alkoxy, haloalkoxy, alkylsulfonyl, haloalkylsulfonyl and cyano, even more preferably from H, Ci-C3-alkyl, halo, CF3, C1-C2 alkoxy, and cyano, and still more preferably from H, F, CI, methyl, CF3, methoxy, and cyano, and most preferably H or methyl.
Particularly preferred compounds of formula Ib-2a are
Figure imgf000031_0001
Figure imgf000032_0001
wherein A is -(CH2)„-0-, -(CH2)„-NRa-, -(CH2)n-S02-, or -(CH2)m-, wherein n is equal to 0 or 1 , m is equal to 1 or 2, and Ra is as defined above in respect to formula Ib-2b, preferably Ra is H or alkyl, preferably linear or branched C1-C4 alkyl; C1-C4 alkylcarbonyl, C1-C4 alkylsulfonyl, more preferably linear or branched C1-C4 alkyl; and
1 2 3 3 1 2 5
L , If, If, Ar", X, Y, Z, R , R" and R" are as defined above in respect to formula Ib-2a.
Even more preferred compounds of formula Ib-2a are selected from
Figure imgf000032_0002
Figure imgf000033_0001
wherein A is -(CH2)„-0-, -(CH2)„-NRa-, -(CH2)n-S02-, or -(CH2)m-, wherein n is equal to 0 or 1 , m is equal to 1 or 2, and Ra is as defined above in respect to formula Ib-2b, preferably Ra is H or alkyl, preferably linear or branched C1-C4 alkyl; C1-C4 alkylcarbonyl, C1-C4 alkylsulfonyl, more preferably linear or branched C1-C4 alkyl; and
2 3 3 1 2 5
L% If, Ar", X, Y, R, R , R" and R" are as defined above in respect to formula Ib- 2a.
Further preferred compounds of formula lb are those of formula Ib-
3
Figure imgf000034_0001
COOR Ib-3a,
2 3 3 1 2 5
wherein If, I , Ar", X, Y, R, R , R" and R" are as defined above in respect to formula lb; and
R16, R17, R18 and R19 are independently selected from H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, alkoxyalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, arylalkyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylaminoalkyl, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, haloalkylsulfonylamino, or R16 and
17 17 18 18 19
R or R and R or R and R together form an alkylenedioxy group or a
16 17 17 18 18 19 haloalkylenedioxy group, or R and R or R and R or R and R together form a cycloalkyl, aryl, heterocyclyl or heteroaryl moiety fused to the phenyl group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo, alkoxy, alkyl, alkylamino, alkylcarbonyl, alkylheteroaryl, alkylsulfonyl, aralkyl, aryl, arylamino, aryloxy, cyano, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocyclyl, hydroxyl, oxo, or sulfonyl, preferably R16, R17, R18 and R19 are independently selected from H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, alkoxyalkyl, preferably methoxyethyl, haloalkoxy, preferably trifluoromethoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, carboxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfonylamino, cycloalkylsulfonylamino, more preferably R16, R17, R18 and R19 are independently selected from H, hydroxyl, halo, haloalkyl, alkoxy, haloalkoxy, preferably trifluoromethoxy, alkylsulfonyl, haloalkylsulfonyl and cyano, even more preferably from H, halo, CF3, methyl, C1-C2 alkoxy, and cyano, and most preferably from H, F, CI, CF3, methyl, methoxy, and cyano.
Further preferred compounds of formula lb are those of formula Ib-
4
Figure imgf000035_0001
Ib-4, wherein
1 3 1 2 1 2 5
Ar1, ArJ, L , If, R , R", R", X, Y and Z are as defined above in respect to formula lb.
Preferred compounds of formula Ib-4 are those of formula Ib-4a
Figure imgf000036_0001
Ib-4a, wherein
Ar1, L1, L2, R1, R2, R5, X, Y and Z are as defined above in respect to formula lb- 4,
R20 and R'20 are independently selected from H, halo (preferably -F and -CI), cyano, C1-C3 alkyl, cyclopropyl, haloalkyl, alkoxy, haloalkoxy, alkoxycarbonylamino, or the two substituents form an alkylenedioxy group or a haloalkylenedioxy group, preferably R20 and R 20 are H, halo preferably fluoro or chloro, haloalkyl, preferably -CF3 or -CHF2, alkoxy preferably methoxy, haloalkoxy preferably -OCF3 or -OCHF2;
Ar4 is 5 or 6 membered aryl, preferably phenyl, 5 or 6 membered heteroaryl, preferably furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl, more preferably furan-3-yl, thiophen-3-yl, pyridinyl, still more preferably pyridin- 3-yl, each of said 5 or 6 membered aryl or 5 or 6 membered heteroaryl groups being optionally fused to one or more 5 or 6 membered cycloalkyl, aryl, heterocyclyl or heteroaryl moiety, thus forming a fused ring system, and the latter fused ring system being optionally substituted by one or more further substituents selected from halo, hydroxyl, oxo, alkyl, and/or each of said 5 or 6 membered aryl or 5 or 6 membered heteroaryl groups being optionally substituted by one or more substituents selected from halo, cyano, hydroxyl, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, alkylaminoalkoxy, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, aryloxy, aralkyloxy, alkylamino, alkylaminoalkyl, cycloalkylamino, arylamino, aralkylamino, alkylaminocarbonyl, heteroarylcarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, alkylsulfonyl, haloalkylsulfonyl, alkylsulfonylamino, each of said cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, aryloxy, aralkyloxy, heteroarylcarbonyl, cycloalkylamino, arylamino, aralkylamino, cycloalkylcarbonylamino being optionally substituted by one or more further substituents selected from halo, preferably chloro or fluoro, oxo or alkyl, preferably methyl; preferably Ar4 is phenyl or pyridin-3-yl, each of said phenyl or pyridin-3-yl being optionally fused to one or more 5 or 6 membered heterocyclyl, phenyl, or 5 or 6 membered heteroaryl moiety, preferably oxopyrrolidinyl, imidazolinyl, piperidinyl, morpholinyl, pyrrolyl, imidazolyl, or pyridyl more preferably 2-oxopyrrolidinyl, 2-oxoimidazolinyl, 2-oxopiperidinyl, or pyrrolyl, thus forming a fused ring system, and the latter fused ring system being optionally substituted by one or more further substituents selected from halo, preferably chloro or fluoro, oxo, alkyl, preferably methyl, and/or each of said phenyl or pyridin-3-yl groups being optionally substituted by one or more substituents selected from halo, alkyl, heterocyclyl, heteroaryl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, aralkyloxy, alkylamino, alkylaminoalkyl, cycloalkylamino, aralkylamino, alkylaminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, each of said heterocyclyl, heteroaryl, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, aralkyloxy, cycloalkylamino, aralkylamino, cycloalkylcarbonylamino being optionally substituted by one or more further substituents selected from fluoro, chloro, oxo or methyl.
Preferred compounds of formula Ib-4a are those of formula Ib-4b
Figure imgf000038_0001
wherein
Ar1, L1, L2, R1, R2, R5, and Z are as defined above in respect to formula lb, and Ar4, R20 and R'20, are as defined above in respect to formula Ib-4a.
Preferred compounds of formula Ib-4b are those of formula Ib-4c
Figure imgf000038_0002
Ib-4c,
wherein
Ar1, L1, L2, R1, R2, R5, and Z are as defined above in respect to formula lb; R20 and R'20, are as defined above in respect to formula Ib-4a; R and R are independently selected from H, halo, preferably fluoro or chloro, alkoxy, preferably methoxy, preferably R21 and R22 are H;
R23 is selected from H, halo, cyano, hydroxyl, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, alkylaminoalkoxy, preferably dimethylaminoethoxy, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, aryloxy, aralkyloxy, alkylamino, alkylaminoalkyl, cycloalkylamino, arylamino, aralkylamino, alkylaminocarbonyl, heteroarylcarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, alkylsulfonyl, preferably C1-C3 alkylsulfonyl, more preferably methylsulfonyl, haloalkylsulfonyl, alkylsulfonylamino preferably N- methyl(methylsulfonyl)amino, each of said cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, aryloxy, aralkyloxy, heteroarylcarbonyl, cycloalkylamino, arylamino, aralkylamino, cycloalkylcarbonylamino being optionally substituted by one or more further substituents selected from halo, preferably chloro or fluoro, oxo or alkyl, preferably methyl, preferably R23 is selected from H, halo, preferably chloro or fluoro, alkyl, preferably linear or branched C1-C5 alkyl, more preferably methyl or isopropyl, 5 or 6-membered heterocyclyl, preferably pyrrolidin-l-yl, 2-oxopyrrolidin-l-yl, l-methyl-2-oxoimidazolin-3-yl, 1- methylpiperazin-4-yl, morpholin-4-yl, heteroaryl, preferably 1,3,4-triazol-l-yl, haloalkyl, C1-C3 alkoxy, preferably methoxy, haloalkoxy, alkoxyalkyl, preferably methoxymethyl, alkoxyalkoxy, preferably methoxyethoxy, cycloalkyloxy, cycloalkylalkyloxy, preferably cyclopropylmethyloxy, heterocyclyloxy, preferably (tetrahydropyran-4-yl)oxy, aralkyloxy, preferably benzyloxy, C1-C3 alkylamino, preferably dimethylamino, alkylaminoalkyl, cycloalkylamino, preferably N-methylcyclohexylamino, aralkylamino, preferably N- methylbenzylamino, Ci-C6 alkylaminocarbonyl preferably dimethylaminocarbonyl, Ci-C6 alkylcarbonylamino, preferably methylcarbonylamino, cycloalkylcarbonylamino, each of said 5 or 6-membered heterocyclyl, heteroaryl, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, aralkyloxy, cycloalkylamino, aralkylamino, cycloalkylcarbonylamino being optionally substituted by one or more further substituents selected from fluoro, chloro, oxo or methyl, even more preferably R23 is selected from H, chloro, fluoro, isopropyl, 5 or 6-membered heterocyclyl preferably pyrrolidin-l-yl, 2- oxopyrrolidin-l-yl, morpholin-4-yl, l-methyl-2-oxoimidazolin-3-yl, C1-C3 alkoxy preferably methoxy, alkyloxyalkoxy, preferably methoxyethoxy, aralkyloxy, preferably benzyloxy, C1-C3 alkylamino preferably dimethylamino, each of said 5 or 6-membered heterocyclyl, aralkyloxy being optionally substituted by one or more further substituents selected from fluoro, chloro, oxo, or methyl; Y1 is N or C-R24 where R24 is H, halo, alkoxy, alkyl, heterocyclyl, preferably pyrrolidinyl, imidazolinyl, piperidinyl, morpholinyl, more preferably 2- oxopyrrolidin-l-yl, 2-oxoimidazolin-l-yl, 2-oxopiperidin-l-yl, or morpholin-4-yl, each of said substituents being optionally substituted by one or more further substituents selected from halo, preferably chloro or fluoro, oxo, alkyl, preferably methyl, preferably R24 is H, halo, methoxy, more preferably H, chloro or fluoro, or
Y1 is C-R24 and R24 and R23 together form a 5 or 6 membered cycloalkyl, aryl, heterocyclyl or heteroaryl moiety, preferably 2-oxopyrrolidinyl, morpholinyl, 2- oxopiperidinyl, furanyl, pyrrolyl, imidazolyl, thus forming a fused ring system, the latter fused ring system being optionally substituted by one or more group selected from oxo, alkyl or halo; and
Y2 is N or C-R25 where R25 is H, halo, alkoxy, alkyl, heterocyclyl, preferably pyrrolidinyl, imidazolinyl, piperidinyl or morpholinyl, more preferably 2- oxopyrrolidin-l-yl, 2-oxoimidazolin-l-yl, 2-oxopiperidin-lyl or morpholin-4-yl, each of said substituents being optionally substituted by one or more further substituents selected from halo, preferably chloro or fluoro, oxo, alkyl, preferably methyl, preferably R25 is H, halo, methoxy, more preferably H, chloro or fluoro, or
Y is C-R and R and R together form a 5 or 6 membered cycloalkyl, aryl, heterocyclyl or heteroaryl moiety, preferably 2-oxopyrrolidinyl, morpholinyl, 2- oxopiperidinyl, furanyl, pyrrolyl, imidazolyl, furanyl, thus forming a fused ring system, the latter fused ring system being optionally substituted by one or more group selected from oxo, alkyl or halo, under the condition that R24 and R23 together do not form a 5 or 6 membered cycloalkyl, aryl, heterocyclyl or heteroaryl moiety.
Preferred compounds of formula Ib-4c are those of formula Ib-4d
Figure imgf000041_0001
Ar1, L1, L2, R1, R2, R5, and Z are as defined above in respect to formula lb; R20 and R'20, are as defined above in respect to formula Ib-4a; and
21 22 23 25
R , R , R" and R" are as defined above in respect to formula Ib-4c. Preferred compounds of formula Ib-4d are those of formula Ib-4e
Figure imgf000041_0002
Ib-4e,
wherein,
Ar1, L1, L2, R1, R2, R5, and Z are as defined above in respect to formula lb; R20 and R'20, are as defined above in respect to formula Ib-4a; and
21 22 23 25
R , R , R" and R" are as defined above in respect to formula Ib-4c. Other preferred compounds of formula Ib-4d are those of Ib-4f
Figure imgf000042_0001
Ib-4f,
wherein
Ar1, L1, L2, R1, R2, R5, and Z are as defined above in respect to formula lb; R20 and R'20, are as defined above in respect to formula Ib-4a; and
21 22 23 25
R , R , R" and R" are as defined above in respect to formula Ib-4c. Still other preferred compounds of formula Ib-4d are those of formula Ib-4g
Figure imgf000042_0002
Ib-4g, wherein
Ar1, L1, L2, R1, R2, R5, and Z are as defined above in respect to formula lb; R20 and R'20, are as defined above in respect to formula Ib-4a; and
21 22 23 25
R , R , R" and R" are as defined above in respect to formula Ib-4c. Other preferred compounds of formula Ib-4c are those of formula Ib-4d'
Figure imgf000043_0001
Ib-4d',
wherein
Ar1, L1, L2, R1, R2, R5, and Z are as defined above in respect to formula lb; R20 and R'20, are as defined above in respect to formula Ib-4a; and
21 22 23 25
R , R , R" and R" are as defined above in respect to formula Ib-4c. Preferred compounds of formula Ib-4d' are those of formula Ib-4e'
Figure imgf000044_0001
wherein
Ar1, L1, L2, R1, R2, R5, and Z are as defined above in respect to formula lb; R20 and R'20, are as defined above in respect to formula Ib-4a; and
21 22 23 25
R , R , R" and R" are as defined above in respect to formula Ib-4c. Other preferred compounds of formula Ib-4d' are those of formula Ib-4f
Figure imgf000044_0002
wherein
Ar1, L1, L2, R1, R2, R5, and Z are as defined above in respect to formula lb; R20 and R'20, are as defined above in respect to formula Ib-4a; and R , R , R and R are as defined above in respect to formula Ib-4c.
Still other preferred compounds of formula Ib-4d' are those of formula Ib-4g'
Figure imgf000045_0001
Ib-4g', wherein, Ar1, L1, L2, R1, R2, R5, and Z are as defined above in respect to formula lb; R20 and R'20, are as defined above in respect to formula Ib-4a;
21 22 23 25
R , R , R" and R" are as defined above in respect to formula Ib-4c.
In another embodiment of the invention, preferred compounds of formula Ib-4a are those of formula Ib-4h,
Figure imgf000045_0002
Ib-4h, wherein
Ar1, L1, L2, R1, R2, R5, and Z are as defined above in respect to formula lb; and Ar4, R20 and R'20, are as defined above in respect to formula Ib-4a.
Preferred compounds of formula Ib-4h are those of formula Ib-4i
Figure imgf000046_0001
Ib-4i,
wherein
Ar1, L1, L2, R1, R2, R5, and Z are as defined above in respect to formula lb; R20 and R'20, are as defined above in respect to formula Ib-4a; and
21 22 23 1 2
R , R , R , Y and Y" are as defined above in respect to formula Ib-4c.
Preferred compounds of formula Ib-4i are those of formula Ib-4j
Figure imgf000047_0001
Ib-4j,
wherein
Ar1, L1, L2, R1, R2, R5, and Z are as defined above in respect to formula lb;
R20 and R'20, are as defined above in respect to formula Ib-4a; and
21 22 23 25
R , R , R" and R" are as defined above in respect to formula Ib-4c.
Other preferred compounds of formula Ib-4 are those of formula Ib-4k,
Figure imgf000047_0002
Ib-4k, wherein
Ar1, L1, L2, R1, R2, R5, X, Y, and Z are as defined above in respect to formula lb;
26 26 27 27 28
R , R , R , R , R are independently selected from H, halo, cyano, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, acylamino, carbamoyl, alkoxycarbamoyl, cycloalkylcarbamoyl, alkylcarbamoylamino, cycloalkylaminocarbamoyl, alkylsulfonyl, haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino, or two substituents form an alkylenedioxy group or a haloalkylenedioxy group, preferably R26, R'26,
27 27 28
R , R , Ri0 are independently selected from H, halo, preferably chloro or fluoro, more preferably chloro, cyano, alkyl, preferably methyl, haloalkyl, preferably - CF3 or -CHF2, cycloalkyl, preferably cyclopropyl, alkoxy, preferably methoxy or isopropyloxy, haloalkoxy, preferably -OCF3 or -OCHF2, alkoxycarbamoyl, or
26 26 27 two substituents form an methlenedioxy group, more preferably R , R' , R , R'27, R28 are independently selected from H, halo, preferably chloro or fluoro, more preferably chloro, haloalkyl, preferably -CF3 or -CHF2, alkoxy, preferably methoxy.
Preferred compounds of formula Ib-4k are those of formula Ib-41
Figure imgf000048_0001
Ib-41, wherein
Ar1, L1, L2, R1, R2, R5 and Z are as defined above in respect to formula lb; and R26, R'26, R27, R'27 and R28 are as defined above in respect to formula Ib-4k. Preferred compounds of formula Ib-41 are those of formula Ib-4m
Figure imgf000049_0001
Ib-4m, wherein, Ar1, L1, L2, R1, R2, R5 and Z are as defined above in respect to formula lb; and
26 27 26
R'iD and Ri ; are as defined above in respect to formula Ib-4k, preferably R' and are independently selected from H, halo, haloalkyl, haloalkoxy, preferably chloro, fluoro CF3, CHF2, OCF3 or OCHF2, preferably R'26 is chloro and R27 is selected from H, halo, CF3, CHF2, OCF3 or OCHF2, preferably chloro and fluoro. Other preferred compounds of formula Ib-41 are those of formula Ib-4n,
Figure imgf000049_0002
Ib-4n, wherein,
Ar1, L1, L2, R1, R2, R5 and Z are as defined above in respect to formula lb; and
26 27 28 26
R' , 11" and Ri0 are as defined above in respect to formula Ib-4k, preferably R' , R27 and R28 are independently selected from H, halo, haloalkyl, haloalkoxy, preferably chloro, fluoro, CF3, or CHF2, preferably OCF3 or OCHF2.
Other preferred compounds of formula Ib-41 are those of formula Ib-4o
Figure imgf000050_0001
Ib-4o, wherein
Ar1, L1, L2, R1, R2, R5 and Z are as defined above in respect to formula lb; and
27 27 27 R and R' are as defined above in respect to formula Ib-4k, preferably R and R'27 are independently selected from H, halo, haloalkyl, haloalkoxy, preferably chloro, fluoro, CF3, CHF2OCF3 or OCHF2.
Other preferred compounds of formula Ib-41 are those of formula Ib-4p
Figure imgf000051_0001
wherein,
Ar1, L1, L2, R1, R2, R5 and Z are as defined above in respect to formula lb; and
27 28 27
R" and Ri0 are as defined above in respect to formula Ib-4k, preferably R and R28 are independently selected from H, halo, haloalkyl, alkoxy, haloalkoxy, preferably chloro, fluoro, CF3, CHF2, methoxy, OCF3 or OCHF2.
Still other preferred compounds of formula Ib-41 are those of formula Ib-4q
Figure imgf000051_0002
Ib-4q, wherein, Ar1, L1, L2, R1, R2, R5 and Z are as defined above in respect to formula lb; and R and R are as defined above in respect to formula Ib-4k, preferably R and are independently selected from H, halo, haloalkyl, alkoxy, haloalkoxy, preferably chloro, fluoro, CF3, or CHF2, methoxy, OCF3 or OCHF2.
In yet another embodiment, preferred compounds of formula I are those of formula Ic
Figure imgf000052_0001
and pharmaceutically acceptable salts, and solvates thereof, wherein
2 3 1 2 1 2 3
wherein Ar , Ar , R , R , L , L , L and Z are as defined above in respect to formula I; and
R6, R7, R'6, R'7 and R8 are independently selected from H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, alkoxyalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, arylalkyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylaminoalkyl, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, haloalkylsulfonylamino, or R6 and
7 7 8 6 7 7 8
R or R and R or R' and R' or R' and R together form an alkylenedioxy
6 7 7 8 6 7 group or a haloalkylenedioxy group, or R and R or R and R or R' and R' or R'7 and R8 together form a cycloalkyl, aryl, heterocyclyl or heteroaryl moiety fused to the phenyl group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo, alkoxy, alkyl, alkylamino, alkylcarbonyl, alkylheteroaryl, alkylsulfonyl, aralkyl, aryl, arylamino, aryloxy, cyano, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocyclyl, hydroxyl, oxo, or sulfonyl, preferably R6, R7, R'6, R'7 and R8 are independently selected from H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, alkoxyalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, carboxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfonylamino, cycloalkylsulfonylamino, more preferably R6, R7, R'6, R'7 and R8 are independently selected from H, hydroxyl, halo, alkyl, haloalkyl, alkoxy, alkoxyalkyl preferably methoxyethyl, haloalkoxy, preferably -OCF3, alkylsulfonyl, haloalkylsulfonyl and cyano, even more preferably from H, halo, C1-C2 alkyl, CF3, C1-C2 alkoxy, and cyano, still more preferably from H, F, CI, CF3, methyl, methoxy, and cyano, even more preferably R6, R7, R'6, R'7 are H and R8 is selected from H, CI, methyl, hydroxyl, and methoxy, and most preferably R6, R7, R'6, R'7 are H and R8 is selected from H, CI, methyl, and methoxy.
Preferred compounds of formula Ic are those wherein
Z is -COOH; R1 is H;
L2 is cyclopropylene, ethenylene, methylene, -CHMe-, -CHF-;
L1 is as defined above in respect to formula I, preferably methylene, ethylene, or a single bond; and Ar2, Ar3, R2, R6, R7, R'6, R'7 R8 and L3 are as defined above in respect to formula I.
Particularly preferred compounds of formula Ic are those of formula Ic-1
Figure imgf000054_0001
and pharmaceutically acceptable salts, and solvates thereof, wherein
Ar2, Ar3, R2, R6, R7, R'6, R'7 R8, L2, L3, and Z are as defined above in respect to formula Ic.
Preferred compounds of formula Ic-1 are those wherein Z is -COOH;
L2 is cyclopropylene, ethenylene, methylene, -CHMe-, -CHF-; and
Ar2, Ar3, R2, R6, R7, R'6, R'7 R8, and L3 are as defined above in respect to formula Ic.
In yet another embodiment, preferred compounds of formula I are those of formula Id
Figure imgf000054_0002
Id, and pharmaceutically acceptable salts, esters, esters, amides, phosphates, and solvates thereof, wherein the dotted line is present or absent; and
Ar2, Ar3, R, R2 and L3 are as defined above in respect to formula I.
In one variant of the compounds of formula Id the dotted line is present.
Preferred compounds of formula Id are those of formula Id-1
Figure imgf000055_0001
wherein the dotted line is present or absent, preferably the dotted line is present; X is S or O; Y is CH or N;
L3 is attached to the heterocyclic group either in position 4 or 5, preferably in position 4;
If Y is CH, R5 is halo, hydroxyl, linear or branched C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 haloalkyl, preferably F, CI, or CF3 and R5 is attached to the heterocyclic group either in position 4, if L3 is attached in position 5, or in position 5, if L3 is attached in position 4; preferably R5 is attached in position 5; If Y is N, R5 is absent and L3 is attached in position 5; and
Ar3 is as defined above in respect to formula I, preferably Ar3 is an aryl or heteroaryl group, optionally substituted by one or more substituents selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, cyano, 5 or 6 membered heteroaryl such as pyridinyl, phenyl, methylcarbonylamino, -NH-SO2CF3, and L3 is a single bond or C1-C2 alkylene; or Ar3 is a C1-C4 alkyl group and L3 is a single bond, more preferably Ar3 is an aryl, preferably phenyl, or heteroaryl group, preferably thiophenyl, more preferably thiophen-2-yl, furanyl, more preferably furan-2-yl, each of said aryl or heteroaryl being optionally substituted by one or more substituents selected from halo, C1-C4 alkyl, cyclopropyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, ethoxycarbamoyl, methylenedioxy, 5 or 6 membered aryl, preferably phenyl, 5 or 6 membered heteroaryl, preferably furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl, more preferably furan-3-yl, thiophen-3-yl, pyridinyl, still more preferably pyridin-3-yl each of said 5 or 6 membered aryl or 5 or 6 membered heteroaryl being optionally fused to one or more 5 or 6 membered cycloalkyl, aryl, heterocyclyl or heteroaryl moiety thus forming a fused ring system, and the latter fused ring being optionally substituted by one or more further substituents selected from halo, hydroxyl, oxo, alkyl, and/or each of said 5 or 6 membered aryl or 5 or 6 membered heteroaryl groups being optionally substituted by one or more substituents selected from halo, cyano, hydroxyl, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, alky lamino alkoxy, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, aryloxy, aralkyloxy, alkylamino, alkylaminoalkyl, cyclo alkylamino, arylamino, aralkylamino, alkylaminocarbonyl, heteroarylcarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, alkylsulfonyl, haloalkylsulfonyl, alkylsulfonylamino, each of said cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, aryloxy, aralkyloxy, heteroarylcarbonyl, cycloalkylamino, arylamino, aralkylamino, cycloalkylcarbonylamino being optionally substituted by one or more further substituents selected from halo, preferably chloro or fluoro, oxo or alkyl, preferably methyl; still more preferably Ar3 is phenyl, thiophenyl, furanyl, preferably phenyl, thiophen-2-yl, furan-2-yl, each of said phenyl, thiophenyl, furanyl, being optionally substituted by one or more substituents selected from halo, C1-C4 alkyl, cyclopropyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, ethoxycarbamoyl, methylenedioxy, phenyl, pyridin-3-yl, each of said phenyl or pyridin-3-yl being optionally fused to one or more 5 or 6 membered heterocyclyl, phenyl, or 5 or 6 membered heteroaryl moiety, preferably oxopyrrolidinyl, imidazolinyl, piperidinyl, morpholinyl, pyrrolyl, imidazolyl, or pyridyl, more preferably 2-oxopyrrolidinyl, 2- oxoimidazolinyl, 2-oxopiperidinyl or pyrrolyl, thus forming a fused ring system, and the latter fused ring being optionally substituted by one or more further substituents selected from halo, preferably chloro or fluoro, oxo, alkyl, preferably methyl, and/or each of said phenyl or pyridin-3-yl groups being optionally substituted by one or more substituents selected from halo, alkyl, heterocyclyl, heteroaryl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, aralkyloxy, alkylamino, alkylaminoalkyl, cycloalkylamino, aralkylamino, alkylamino carbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, each of said heterocyclyl, heteroaryl, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, aralkyloxy, cycloalkylamino, aralkylamino, cycloalkylcarbonylamino being optionally substituted by one or more further substituents selected from fluoro, chloro, oxo or methyl;
R is as defined above in respect to formula I; and
R2 is as defined above in respect to formula I, preferably R2 is H, linear or branched C1-C4 alkyl, C1-C2 hydroxyalkyl, allyl, propargyl, cyclopropyl, cyclopentyl, cyclopentylmethyl, cyclopropylmethyl, benzyl, benzyloxyethyl, methoxyethyl, 1,1,1-trifluoroethyl, -C2H4CO2CH3, -CH2C02CH3, or -CH2CONH2, more preferably R2 is H, methyl, ethyl, allyl, cyclopropyl, hydroxyethyl, - C2H4C02CH3, -CH2C02CH3, or -CH2CONH2, more preferably R2 is methyl or cyclopropyl.
In still another embodiment, preferred compounds of Formula I are those of formula Ie:
Figure imgf000058_0001
wherein
Y is CH or N; and
R14 and R15 are independently H, halo, cyano, hydroxyl, linear or branched C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 haloalkyl, preferably H, F, CI, or CF3, more preferably H;
Ar1 and L1 are as defined above in respect to formula I, preferably as defined in respect to formula lb, more preferably Ar1 is a 5- to 6-membered aryl or heteroaryl group, optionally substituted by one or more groups selected from halogen, trifluoromethyl, cyano, and methoxy, and L1 is a methylene group, C1-C2 alkylene, or C2 alkenylene; or Ar1 is a linear or branched C3-C6 alkyl group, optionally substituted by one or more groups selected from halogen, trifluoromethyl, cyano, and methoxy, and L1 is a methylene group;
Ar3 is as defined above in respect to formula I, preferably Ar3 is an aryl or heteroaryl group, optionally substituted by one or more substituents selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, cyano, 5 or 6 membered heteroaryl such as pyridinyl, phenyl, methylcarbonylamino, -NH-S02CF3, and L3 is a single bond or C1-C2 alkylene; or Ar3 is a C1-C4 alkyl group and L3 is a single bond, more preferably Ar3 is an aryl, preferably phenyl, or heteroaryl group, preferably thiophenyl, more preferably thiophen-2-yl, furanyl, more preferably furan-2-yl, each of said aryl or heteroaryl being optionally substituted by one or more substituents selected from halo, C1-C4 alkyl, cyclopropyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, ethoxycarbamoyl, methylenedioxy, 5 or 6 membered aryl, preferably phenyl, 5 or 6 membered heteroaryl, preferably furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl, more preferably furan-3-yl, thiophen-3-yl, pyridinyl, still more preferably pyridin-3-yl each of said 5 or 6 membered aryl or 5 or 6 membered heteroaryl being optionally fused to one or more 5 or 6 membered cycloalkyl, aryl, heterocyclyl or heteroaryl moiety thus forming a fused ring system, and the latter fused ring being optionally substituted by one or more further substituents selected from halo, hydroxyl, oxo, alkyl, and/or each of said 5 or 6 membered aryl or 5 or 6 membered heteroaryl groups being optionally substituted by one or more substituents selected from halo, cyano, hydroxyl, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, alky lamino alkoxy, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, aryloxy, aralkyloxy, alkylamino, alkylaminoalkyl, cyclo alkylamino, arylamino, aralkylamino, alkylaminocarbonyl, heteroarylcarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, alkylsulfonyl, haloalkylsulfonyl, alkylsulfonylamino, each of said cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, aryloxy, aralkyloxy, heteroarylcarbonyl, cyclo alkylamino, arylamino, aralkylamino, cycloalkylcarbonylamino being optionally substituted by one or more further substituents selected from halo, preferably chloro or fluoro, oxo or alkyl, preferably methyl; still more preferably Ar3 is phenyl, thiophenyl, furanyl, preferably phenyl, thiophen-2-yl, furan-2-yl, each of said phenyl, thiophenyl, furanyl, being optionally substituted by one or more substituents selected from halo, C1-C4 alkyl, cyclopropyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, ethoxycarbamoyl, methylenedioxy, phenyl, pyridin-3-yl, each of said phenyl or pyridin-3-yl being optionally fused to one or more 5 or 6 membered heterocyclyl, phenyl, or 5 or 6 membered heteroaryl moiety, preferably oxopyrrolidinyl, imidazolinyl, piperidinyl, morpholinyl, pyrrolyl, imidazolyl, or pyridyl, more preferably 2-oxopyrrolidinyl, 2- oxoimidazolinyl 2-oxopiperidinyl, or pyrrolyl, thus forming a fused ring system, and the latter fused ring being optionally substituted by one or more further substituents selected from halo, preferably chloro or fluoro, oxo, alkyl, preferably methyl, and/or each of said phenyl or pyridin-3-yl groups being optionally substituted by one or more substituents selected from halo, alkyl, heterocyclyl, heteroaryl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, aralkyloxy, alkylamino, alkylaminoalkyl, cycloalkylamino, aralkylamino, alkylaminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, each of said heterocyclyl, heteroaryl, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, aralkyloxy, cycloalkylamino, aralkylamino, cycloalkylcarbonylamino being optionally substituted by one or more further substituents selected from fluoro, chloro, oxo or methyl;
R1 is as defined above in respect to formula I, preferably R1 is hydrogen, halogen, or a group selected from C1 -4 alkyl optionally substituted by one or more substituents selected from halogen or alkyl; more preferably R1 is selected from hydrogen, fluoro, or methyl or ethyl, the methyl or ethyl group being optionally substituted with one or more substituents selected from fluoro or alkyl, even more preferably R1 is hydrogen, fluoro or methyl, and most preferably R1 is hydrogen, and L2 is as defined above in respect to formula I, preferably L2 is cyclopropylene, ethenylene, n-propylene, or -C(R'R")-, wherein R' and R" are independently selected from H, halogen, methyl, and ethyl, more preferably L2 is cyclopropylene, ethenylene, methylene, -CHMe-, -CHF-, even more preferably L2 is methylene; or R1 and L2 together are =CH-under the condition that L1-Ar1 is H.;
Z is as defined above in respect to formula I, preferably Z is -COOR, wherein R is defined as above in respect to formula I; preferably Z is COOH and
R2 is as defined above in respect to formula I, preferably R2 is H, linear or branched C1-C4 alkyl, C1-C2 hydroxyalkyl, allyl, propargyl, cyclopropyl, cyclopentyl, cyclopentylmethyl, cyclopropylmethyl, benzyl, benzyloxyethyl, methoxyethyl, 1 , 1 ,1-trifluoroethyl, -C2H4CO2CH3, -CH2C02CH3, or -CH2CONH2, more preferably R2 is H, methyl, ethyl, allyl, cyclopropyl, hydroxyethyl, -
C2H4C02CH3, -CH2C02CH3, or -CH2CONH2, most preferably R2 is methyl or cyclopropyl.
Preferred compounds of formula Ie are those wherein Z is -COOR and R, Ar1,
2 3 1 2 1 2 3
Ar", ArJ, R , R", L , If and 1 are as defined above in respect to formula I, preferably L1 is a methylene group and Ar1 is phenyl. In still another embodiment, preferred compounds of Formula I are those of formula If
Figure imgf000061_0001
wherein Ar1, Ar3, L1, L2, L3, R1, R2, R14, R15, Y and Z are as defined above in respect to formula Ie.
In still another embodiment, preferred compounds of Formula I are those of formula Ig:
Figure imgf000061_0002
wherein
B4 is O or S or N-Rb where Rb is H or alkyl, preferably linear or branched C1-C4 alkyl; C1-C4 alkylcarbonyl, C1-C4 alkylsulfonyl, C1-C4 alkylaminocarbonyl, C3-C6 cycloalkyl; preferably O or S, more preferably O,
R9, R 9, and R11 are independently selected from H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, arylalkyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylaminoalkyl, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, haloalkylsulfonylamino, or one of R9 or R'9 and R11 together form an alkylenedioxy group or a haloalkylenedioxy group, or one of R9 or R'9 and R11 together form a cycloalkyl, aryl, heterocyclyl or heteroaryl moiety together with the cyclic group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo, alkoxy, alkyl, alkylamino, alkylcarbonyl, alkylheteroaryl, alkylsulfonyl, aralkyl, aryl, arylamino, aryloxy, cyano, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocyclyl, hydroxyl, oxo, or sulfonyl, preferably R9, R 9, and R11 are independently selected from H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, carboxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfonylamino, cycloalkylsulfonylamino, or one of R9 or R' and R together form a cycloalkyl, aryl, heterocyclyl or heteroaryl moiety together with the cyclic group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo, alkoxy, alkyl, alkylamino, alkylcarbonyl, alkylheteroaryl, alkylsulfonyl, aralkyl, aryl, arylamino, aryloxy, cyano, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocyclyl, hydroxyl, oxo, or sulfonyl, more preferably R9, R 9, and R11 are independently selected from H, hydroxyl, Ci-C3-alkyl, halo, preferably chloro or fluoro, haloalkyl, alkoxy, alkoxyalkyl preferably methoxyethyl, haloalkoxy, preferably -OCF3, alkylsulfonyl, haloalkylsulfonyl and cyano, even more preferably from H, Ci-C3-alkyl, halo, CF3, C1-C2 alkoxy, and cyano, and still more preferably from H, F, CI, methyl, CF3, methoxy, and cyano, and most preferably H, F or methyl; and
2 3 1 2 3 1 2
Ar", ArJ, L , If, If, R , R", and Z are as defined above in respect to formula I.
In still another embodiment, preferred compounds of Formula I are those of formula Ih:
Figure imgf000063_0001
wherein
B5 is CH2 or O preferably O;
R9, R10, R'9, R'10, R11, R12 and R"13 are independently selected from H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, alkoxyalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, arylalkyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylaminoalkyl, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, haloalkylsulfonylamino, or one of R11 or R12 and one or R9, R10, R'9 or R'10, or R13 and one of R'9 or R'10 together form an alkylenedioxy group or a haloalkylenedioxy group, or one of R11 or R12 and one of R9, R10, R'9 or R'10, or R13 and one of R'9 or R'10 together form a cycloalkyl, aryl, heterocyclyl or heteroaryl moiety together with the cyclic group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo, alkoxy, alkyl, alkylamino, alkylcarbonyl, alkylheteroaryl, alkylsulfonyl, aralkyl, aryl, arylamino, aryloxy, cyano, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocyclyl, hydroxyl, oxo, or sulfonyl, preferably R9, R10, R11, R12, R'9, R'10, and R"13 are independently selected from H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, carboxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfonylamino, cycloalkylsulfonylamino, or one o f R11 or R12 and one ot R9, R10, R'9 or R'10, or R13 and one of R'9 or R'10 together form an alkylenedioxy group or a haloalkylenedioxy group, or one of R11 or R12 and one of R9, R10, R'9 or R'10, or R13 and one of R'9 or R'10 together form a cycloalkyl, aryl, heterocyclyl or heteroaryl moiety together with the cyclic group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo, alkoxy, alkyl, alkylamino, alkylcarbonyl, alkylheteroaryl, alkylsulfonyl, aralkyl, aryl, arylamino, aryloxy, cyano, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocyclyl, hydroxyl, oxo, or sulfonyl, more preferably R9, R10, R11, R12, R13, R'9, R'10, R'11, R'12, R'13 and R"13 are independently selected from H, hydroxyl, Ci-C3-alkyl, halo, preferably chloro or fluoro, haloalkyl, alkoxy, alkoxyalkyl preferably methoxyethyl, haloalkoxy, preferably -OCF3, alkylsulfonyl, haloalkylsulfonyl and cyano, even more preferably from H, Ci-C3-alkyl, halo, CF3, C1-C2 alkoxy, preferably methoxy, and cyano, and still more preferably from H, F, CI, methyl, CF3, methoxy, and cyano, and most preferably H or methyl; and
2 3 1 2 3 1 2
Ar", ArJ, L , If, If, R , R", and Z are as defined above in respect to formula I.
In still another embodiment, preferred compounds of Formula I are those of formula Ii
Figure imgf000065_0001
wherein
B is as defined above in respect to formula Ig,
R9, R 9 and R12 are independently selected from H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, alkoxyalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, arylalkyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylaminoalkyl, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, halo alkylsulfonylamino, or R9 and R12 together form an alkylenedioxy group or a haloalkylenedioxy group, or R9 and R12 together form a cycloalkyl, aryl, heterocyclyl or heteroaryl moiety together with the cyclic group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo, alkoxy, alkyl, alkylamino, alkylcarbonyl, alkylheteroaryl, alkylsulfonyl, aralkyl, aryl, arylamino, aryloxy, cyano, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocyclyl, hydroxyl, oxo, or sulfonyl, preferably R9, R'9, and R12, are independently selected from H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, carboxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfonylamino, cycloalkylsulfonylamino, or R9 and R12 together form an alkylenedioxy group or a haloalkylenedioxy group, or R9 and R12 together form a cycloalkyl, aryl, heterocyclyl or heteroaryl moiety together with the cyclic group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo, alkoxy, alkyl, alkylamino, alkylcarbonyl, alkylheteroaryl, alkylsulfonyl, aralkyl, aryl, arylamino, aryloxy, cyano, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocyclyl, hydroxyl, oxo, or sulfonyl, more preferably R9, R'9, and R12, are independently selected from H, hydroxyl, Ci-C3-alkyl, halo, preferably chloro or fluoro, haloalkyl, alkoxy, alkoxyalkyl preferably methoxyethyl, haloalkoxy, preferably -OCF3, alkylsulfonyl, haloalkylsulfonyl and cyano, even more preferably from H, Ci-C3-alkyl, halo, CF3, C1-C2 alkoxy, preferably methoxy, and cyano, and still more preferably from H, F, CI, methyl, CF3, methoxy, and cyano, and most preferably H or methyl; and
2 3 1 2 3 1 2
Ar", ArJ, L , If, If, R , R", and Z are as defined above in respect to formula I. In still another embodiment, preferred compounds of Formula I are those of formula Ij:
Figure imgf000067_0001
wherein
B5 is as defined above in respect to formula Ih, R9, R'9, R10, R'10, R11, R12 and R"13 are independently selected from H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, alkoxyalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, arylalkyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylaminoalkyl, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, haloalkylsulfonylamino, or one of R11 or R12 and one or R9, R10, R'9 or R'10, or one of R'9 or R'10 and R"13 together form an alkylenedioxy group or a haloalkylenedioxy group, or one of R11 or R12 and one of R9, R10, R'9 or R'10, or one of R'9 or R'10 and R"13 together form a cycloalkyl, aryl, heterocyclyl or heteroaryl moiety together with the cyclic group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo, alkoxy, alkyl, alkylamino, alkylcarbonyl, alkylheteroaryl, alkylsulfonyl, aralkyl, aryl, arylamino, aryloxy, cyano, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocyclyl, hydroxyl, oxo, or sulfonyl, preferably R9, R 9, R10, R 10, R11, R12 and R"13 are independently selected from H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, carboxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfonylamino, cycloalkylsulfonylamino, or one o f R11 or R12 and one ot R9, R10, R'9 or R'10, or one of R'9 or R'10 and R"13 together form an alkylenedioxy group or a haloalkylenedioxy group, or one of R11 or R12 and one of R9, R10, R'9 or R'10, or one of R'9 or R'10 and R"13 together form a cycloalkyl, aryl, heterocyclyl or heteroaryl moiety together with the cyclic group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo, alkoxy, alkyl, alkylamino, alkylcarbonyl, alkylheteroaryl, alkylsulfonyl, aralkyl, aryl, arylamino, aryloxy, cyano, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocyclyl, hydroxyl, oxo, or sulfonyl, more preferably R9, R 9, R10, R 10, R11, R12 and R"13 are independently selected from H, hydroxyl, Ci-C3-alkyl, halo, preferably chloro or fluoro, haloalkyl, alkoxy, alkoxyalkyl preferably methoxyethyl, haloalkoxy, preferably -OCF3, alkylsulfonyl, haloalkylsulfonyl and cyano, even more preferably from H, Ci-C3-alkyl, halo, CF3, C1-C2 alkoxy, preferably methoxy, and cyano, and still more preferably from H, F, CI, methyl, CF3, methoxy, and cyano, and most preferably H or methyl; and
2 3 1 2 3 1 2
Ar", ArJ, L , If, If, R , R", and Z are as defined above in respect to formula I.
In still another embodiment, preferred compounds of Formula I are those of formula Ik:
Figure imgf000069_0001
wherein
R29 is H, halo, alkyl, haloalkyl preferably -CF3 or -CF2H, alkoxy, haloalkoxy preferably -OCF3 or -OCF2H, cyano, preferably R29 is H, F, -CF3, alkyl preferably methyl, more preferably R29 is H, F or methyl; and
2 3 1 2 3 1 2
Ar", Ar L , If, If, R , R", and Z are as defined above in respect to formula I.
In still another embodiment, preferred compounds of Formula I are those of formula II:
Figure imgf000070_0001
wherein
R and R are independently selected from H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, alkoxyalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, arylalkyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylaminoalkyl, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, haloalkylsulfonylamino, or R9 and R10 together form an alkylenedioxy group or a haloalkylenedioxy group, or R9 and R10 together form a cycloalkyl, aryl, heterocyclyl or heteroaryl moiety together with the cyclic group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo, alkoxy, alkyl, alkylamino, alkylcarbonyl, alkylheteroaryl, alkylsulfonyl, aralkyl, aryl, arylamino, aryloxy, cyano, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocyclyl, hydroxyl, oxo, or sulfonyl, preferably R9 and R10 are independently selected from H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, carboxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfbnyl, alkylsulfonylamino, cycloalkylsulfonylamino, or R9 and R10 together form an alkylenedioxy group or a haloalkylenedioxy group, or one of R9 and R10 together form a cycloalkyl, aryl, heterocyclyl or heteroaryl moiety together with the cyclic group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo, alkoxy, alkyl, alkylamino, alkylcarbonyl, alkylheteroaryl, alkylsulfonyl, aralkyl, aryl, arylamino, aryloxy, cyano, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocyclyl, hydroxyl, oxo, or sulfonyl, more preferably R9 and R10 are independently selected from H, hydroxyl, Ci-C3-alkyl, halo, preferably chloro or fluoro, haloalkyl, alkoxy, alkoxyalkyl preferably methoxyethyl, haloalkoxy, preferably -OCF3, alkylsulfonyl, haloalkylsulfonyl and cyano, even more preferably from H, Ci-C3-alkyl, halo, CF3, C1-C2 alkoxy, preferably methoxy, and cyano, and still more preferably from H, F, CI, methyl, CF3, methoxy, and cyano, and most preferably H or methyl; and
2 3 1 2 3 1 2
Ar", ArJ, L , If, If, R , R", and Z are as defined above in respect to formula I.
Particularly preferred compounds of the invention are those listed in Table 1 hereafter:
Table 1 :
Compoun Compound name (M+H)+ d number
1 6-((4-(2-chlorophenyl)thiazol-2- yl)carbamoyl)cyclohex-3-enecarboxylic acid 363.83
2 (R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2- yl)amino)-4-oxobutanoic acid 401.88
3 (R)-3-benzyl-4-((4-(2,4-dichlorophenyl)thiazol-2- yl)amino)-4-oxobutanoic acid 436.3
4 (R)-3-benzyl-4-((4-(2-fiuorophenyl)thiazol-2- yl)amino)-4-oxobutanoic acid 385.4 (R)-3-benzyl-4-((4-(3,4-dichlorophenyl)thiazol-2- yl)amino)-4-oxobutanoic acid 436.3
(R)-3-benzyl-4-((4-(4-cyanophenyl)thiazol-2- yl)amino)-4-oxobutanoic acid 392.4
(S)-4-((4-(2-chlorophenyl)thiazol-2-yl)amino)-4-oxo- 3-phenylbutanoic acid 387.9
(Z)-4-((4-(2-chlorophenyl)thiazol-2-yl)amino)-4- oxobut-2-enoic acid 309.7
(R)-3-benzyl-4-oxo-4-((3-phenyl-l,2,4-thiadiazol-5- yl)amino)butanoic acid 368.4
(R)-3-benzyl-4-((4-(3-chlorophenyl)thiazol-2- yl)amino)-4-oxobutanoic acid 401.9
(R)-3-benzyl-4-oxo-4-((4-(3-
(trifluoromethyl)phenyl)thiazol-2-yl)amino)butanoic acid 435.4
(R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid 415.9
(R)-3-benzyl-4-((5-(2-chlorophenyl)pyridin-2- yl)amino)-4-oxobutanoic acid 395.9
(R)-3-((4-(2-chlorophenyl)thiazol-2- yl)carbamoyl)heptanoic acid 367.9
(R)-4-((4-(2-chlorophenyl)thiazol-2-yl)amino)-3-(4- fluorobenzyl)-4-oxobutanoic acid 419.9
(R)-4-((4-(2-chlorophenyl)thiazol-2-yl)amino)-3- (cyclohexylmethyl)-4-oxobutanoic acid 407.9
(R)-3-((4-(2-chlorophenyl)thiazol-2-yl)carbamoyl)-5- 367.9 methylhexanoic acid
(R)-3-benzyl-4-((4-(2-chlorophenyl)-5-fluorothiazol- 2-yl)amino)-4-oxobutanoic acid 419.9
(R)-3-benzyl-4-((5-chloro-4-(2-chlorophenyl)thiazol- 2-yl)(methyl)amino)-4-oxobutanoic acid 450.4
(R)-4-(allyl(4-(2-chlorophenyl)thiazol-2-yl)amino)-3- benzyl-4-oxobutanoic acid 441.9 (R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2-yl)(2- methoxy-2-oxoethyl)amino)-4-oxobutanoic acid 473.9
(R)-methyl-3-benzyl-4-((4-(2-chlorophenyl)thiazol- 2-yl)amino)-4-oxobutanoate 415.9
(R)-3-(4-(2-chlorophenyl)thiazol-2-ylcarbamoyl)-5- phenylpentanoic acid 415.9
(S)-3-(4-(2-chlorophenyl)thiazol-2-ylcarbamoyl)-5- phenylpentanoic acid 415.9
(R)-4-(4-(2-chlorophenyl)thiazol-2-ylamino)-4-oxo- 3 -(4-(trifluoromethyl)benzyl)butano ic acid 469.9
(R)-4-((4-(2-chlorophenyl)thiazol-2-yl)amino)-4- oxo-3-(3-(trifluoromethyl)benzyl)butanoic acid 469.9
(R)-4-((4-(2-chlorophenyl)thiazol-2-yl)amino)-3-(2- cyanobenzyl)-4-oxobutanoic acid 426.9
(R)-4-((4-(2-chlorophenyl)thiazol-2-yl)amino)-3-(3- cyanobenzyl)-4-oxobutanoic acid 426.9
(R)-4-((4-(2-chlorophenyl)thiazol-2-yl)amino)-3-(4- cyanobenzyl)-4-oxobutanoic acid 426.9
(R)-4-((4-(2-chlorophenyl)thiazol-2-yl)amino)-3-(4- methoxybenzyl)-4-oxobutanoic acid 431.9
(R)-4-((4-(2-chlorophenyl)thiazol-2-yl)amino)-3-(3- methoxybenzyl)-4-oxobutanoic acid 431.9
(R)-4-((4-(2-chlorophenyl)thiazol-2-yl)amino)-3-(2- methoxybenzyl)-4-oxobutanoic acid 431.9
(R)-3-benzyl-4-((4-(2-methoxyphenyl)thiazol-2- yl)amino)-4-oxobutanoic acid 397.5
(R)-3-benzyl-4-oxo-4-(4-(2,4,6- trichlorophenyl)thiazol-2-ylamino)butano ic acid 470.8
(R)-4-benzyl-5-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-5-oxopentanoic acid 429.9
(S)-4-benzyl-5-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-5-oxopentanoic acid 429.9
(R)-methyl 4-benzyl-5-(4-(2-chlorophenyl)thiazol-2- ylamino)-5-oxopentanoate 429.9 (S)-methyl 4-benzyl-5-(4-(2-chlorophenyl)thiazol-2- ylamino)-5-oxopentanoate
429.9
(R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2- yl)(cyclopropylmethyl)amino)-4-oxobutanoic acid 456.0
(R)-3-benzyl-4-(benzyl(4-(2-chlorophenyl)thiazol-2- yl)amino)-4-oxobutanoic acid 492.0
(R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2- yl)(2,2,2-trifluoroethyl)amino)-4-oxobutanoic acid 483.9
(R)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-3-(4-methoxybenzyl)-4- oxobutanoic acid 445.9
(R)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-3-(3-methoxybenzyl)-4- oxobutanoic acid 445.9
(R)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-3-(2-methoxybenzyl)-4- oxobutanoic acid 445.9
(R)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-3-(4-cyanobenzyl)-4-oxobutanoic acid 440.9
(R)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-3 -(3 -cyanobenzyl)-4-oxobutanoic acid 440.9
(R)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-3-(2-cyanobenzyl)-4-oxobutanoic acid 440.9
(R)-3-(4-chlorobenzyl)-4-((4-(2- chlorophenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid 450.4
(R)-3-(3-chlorobenzyl)-4-((4-(2- chlorophenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid 450.4 (R)-3-(2-chlorobenzyl)-4-((4-(2- chlorophenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid 450.4
(3S)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-3-(2,3-dihydro- 1 H-inden- 1 -yl)-4- oxobutanoic acid 441.9
(S)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-3-(2,3-dihydro-lH-inden-2-yl)-4- oxobutanoic acid 441.9
(R)-4-(benzo [d]thiazo l-2-yl(methyl)amino)-3 -benzyl-
4-oxobutanoic acid 355.4
(R)-4-(benzo[d]oxazol-2-yl(methyl)amino)-3-benzyl-
4-oxobutanoic acid 339.4
(R)-2-((lH-tetrazol-5-yl)methyl)-N-(4-(2- chlorophenyl)thiazol-2-yl)-N-methyl-3- phenylpropanamide 439.9
(R)-2-benzyl-N-(4-(2-chlorophenyl)thiazol-2-yl)-N- methyl-3-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3- yl)propanamide 455.9
(R)-3-benzyl-4-((4-(2-chlorophenyl)-5-fluorothiazol-
2-yl)(methyl)amino)-4-oxobutanoic acid 433.9
(S)-4-(4-(2-chlorophenyl)thiazol-2-ylamino)-3- cyclohexyl-4-oxobutanoic acid 393.9
(S)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-3-cyclohexyl-4-oxobutanoic acid 407.9
(S)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-4-oxo-3-phenylbutanoic acid 401.9
(3R)-3-(4-(2-chlorophenyl)thiazol-2-ylcarbamoyl)-4- phenylpentanoic acid 415.9
(R)-2-((lH-tetrazol-5-yl)methyl)-N-(4-(2- chlorophenyl)thiazol-2-yl)-3-phenylpropanamide 425.9
(R)-2-benzyl-N-(4-(2-chlorophenyl)thiazol-2-yl)-3- (5-oxo-4,5-dihydro-l,2,4-oxadiazol-3- yl)propanamide 441.9 (3R)-3-benzyl-4-(4-(2-chlorophenyl)thiazol-2- ylamino)-2-methyl-4-oxobutanoic acid 415.9
(R)-2-benzyl-N-(4-(2-chlorophenyl)thiazol-2-yl)-3- (3 -hydroxyisoxazo 1-5 -yl)propanamide 440.9
(R)-3-benzyl-4-(4-(2-chlorophenyl)pyrimidin-2- ylamino)-4-oxobutanoic acid 396.8
(R)-3-benzyl-4-(6-(2-chlorophenyl)pyridin-2- ylamino)-4-oxobutanoic acid 395.9
(E)-3-(4-(2-chlorophenyl)thiazol-2-ylcarbamoyl)-4- phenylbut-3-enoic acid 399.9
(Z)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-4-oxo-3-phenylbut-2-enoic acid 399.9
(R)-3-(N-(4-(2-chlorophenyl)thiazol-2-yl)-N- methylsulfamoyl)-4-phenylbutano ic acid 452.0
(S)-3-(N-(4-(2-chlorophenyl)thiazol-2-yl)-N- methylsulfamoyl)-4-phenylbutano ic acid 452.0
(R)-3-benzyl-4-(4-(2-chlorophenyl)thiazol-2- ylamino)-3-fluoro-4-oxobutanoic acid 419.9
(R)-3-benzyl-3-(4-(2-chlorophenyl)thiazol-2- ylcarbamoyl)hex-5-enoic acid 441.9
(E)-3-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)carbamoyl)-4-phenylbut-3 -enoic acid 413.9
(3S)-3-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)carbamoyl)-4-phenylpentano ic acid 429.9
(R)-3-benzyl-4-((3-(2-chlorophenyl)- 1 ,2,4-thiadiazol- 5-yl)(methyl)amino)-4-oxobutanoic acid 416.9
(R)-3-benzyl-4-((3-(2-chlorophenyl)- 1 ,2,4-oxadiazol- 5-yl)(methyl)amino)-4-oxobutanoic acid 400.8
(R)-3 -benzyl-4-(( 1 -(2-chlorophenyl)- 1 H-pyrazol-3 - yl)(methyl)amino)-4-oxobutano ic acid 398.9
(R)-2-benzyl-N-(4-(2-chlorophenyl)thiazol-2-yl)-3- (3 -hydroxyisoxazo 1-5 -yl)-N-methylpropanamide 454.9
(R)-4-((4-(2-chlorophenyl)thiazol-2- 422 yl)(methyl)amino)-3-(cyclohexylmethyl)-4- oxobutanoic acid 90 (R)-3-((4-(2-chlorophenyl)thiazol-2- 381.9 yl)(methyl)carbamoyl)-5 -methylhexano ic acid
91 (R)-3-benzyl-4-((4-(2-cyanophenyl)thiazol-2- 406.5 yl)(methyl)amino)-4-oxobutano ic acid
92 (R)-4-(4-(2-chlorophenyl)thiazol-2-ylamino)-4-oxo- 387.9
3-phenylbutanoic acid
93 (R)-4-(4-(2-chlorophenyl)thiazol-2-ylamino)-3-(3- 419.9 fluorobenzyl)-4-oxobutanoic acid
94 (S)-3-((4-(2-chlorophenyl)thiazol-2- 367.9 yl)(methyl)carbamoyl)-4-methylpentano ic acid
95 4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-4- 423.9 oxo-3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
96 (R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2- 429.9 yl)(ethyl)amino)-4-oxobutanoic acid
97 (R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2- 441.9 yl)(cyclopropyl)amino)-4-oxobutanoic acid
98 cis-6-(4-(2-chlorophenyl)thiazol-2- 363.8 ylcarbamoyl)cyclohex-3-enecarboxylic acid
99 4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-3- 445.9
(4-methoxybenzyl)-4-oxobutanoic acid
100 cis-6-((4-(2-chlorophenyl)thiazol-2- 377.9 yl)(methyl)carbamoyl)cyclohex-3-enecarboxylic acid
101 cis-2-((4-(2-chlorophenyl)thiazol-2- 379.9 yl)(methyl)carbamoyl)cyclohexanecarboxylic acid
102 (R)-3-benzyl-4-(4-(2,5-dimethylthiophen-3- 401.5 yl)thiazol-2-ylamino)-4-oxobutanoic acid
103 4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-3- 422.0
(cyclohexylmethyl)-4-oxobutanoic acid
105 4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-3- 407.9
(cyclopentylmethyl)-4-oxobutano ic acid
106 (3S,4R)-3-((4-(2-chlorophenyl)thiazol-2- 429.9 yl)(methyl)carbamoyl)-4-phenylpentano ic acid
107 (R)-3-benzyl-4-(methyl(4-(2-(thiophen-3- 463.6 yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid 108 (R)-3-benzyl-4-((4-(2-(6-chloropyridin-3- 493.0 yl)phenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
109 (R)-4-((4-(2-chlorophenyl)thiazol-2- 416.9 yl)(methyl)amino)-4-oxo-3 -(phenylamino)butano ic acid
110 4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)- 429.9
3-(4-methylbenzyl)-4-oxobutanoic acid
111 (R)-4-((4-([l,l'-biphenyl]-2-yl)thiazol-2- 457.6 yl)(methyl)amino)-3-benzyl-4-oxobutanoic acid
112 (R)-3-benzyl-4-(4-(2,5-dichlorothiophen-3- 442.4 yl)thiazol-2-ylamino)-4-oxobutanoic acid
113 4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)- 379.9
3-(cyclopropylmethyl)-4-oxobutanoic acid
114 4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)- 422.9
4-0X0-3 -(thiazol-4-ylmethyl)butanoic acid
115 (R)-3-benzyl-4-((4-(2-(6-(dimethylamino)pyridin-3- 501.6 yl)phenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
116 (R)-3-benzyl-4-((4-(2-(6-methoxypyridin-3- 488.6 yl)phenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
117 (R)-3-benzyl-4-((4-(2-(2-methoxypyridin-3- 488.6 yl)phenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
118 (R)-3-benzyl-4-((4-(2- 468.5
((ethoxycarbonyl)amino)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
119 (R)-3-benzyl-4-((4-(2-(6-fluoropyridin-3- 476.5 yl)phenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid 120 (R)-3-benzyl-4-(methyl(4-(2-(6-methylpyridin-3- 472.6 yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
121 (R)-4-((2-amino-2-oxoethyl)(4-(2- 458.9 chlorophenyl)thiazol-2-yl)amino)-3-benzyl-4- oxobutanoic acid
122 (R)-3-benzyl-4-oxo-4-((4-(3- 451.4
(trifluoromethoxy)phenyl)thiazol-2- yl)amino)butanoic acid
123 (R)-3-benzyl-4-((4-(2,5-dichlorophenyl)thiazol-2- 436.3 yl)amino)-4-oxobutanoic acid
124 (R)-3-benzyl-4-((4-(3-chloro-4- 419.9 fluorophenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
125 (R)-3-benzyl-4-((4-(3-chloro-4- 431.9 methoxyphenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
126 (R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2-yl)(3- 488.0 methoxy-3-oxopropyl)amino)-4-oxobutanoic acid
127 3-(bicyclo[2.2.1]heptan-2-ylmethyl)-4-((4-(2- 434.0 chlorophenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
128 (R)-3-benzyl-4-((4-(2-(6-ethoxypyridin-3- 502.6 yl)phenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
129 (R)-3-benzyl-4-((4-(4'-methoxy-[ 1 , 1 '-biphenyl]-2- 487.6 yl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
130 (R)-3-benzyl-4-((4-(2,5-dichlorophenyl)thiazol-2- 450.4 yl)(methyl)amino)-4-oxobutano ic acid 131 (R)- 1 -(5-(2-(2-(2-benzyl-3-carboxy-N- 641.7 methylpropanamido)thiazol-4-yl)phenyl)pyridin-2- yl)pyrrolidin- 1 -ium 2,2,2-trifluoroacetate
132 (R)-4-(2*-(2-(2-benzyl-3-carboxy-N- 656.7 methylpropanamido)thiazol-4-yl)-[ 1 , 1 '-biphenyl]-4- yl)morpholin-4-ium 2,2,2-trifluoroacetate
133 (R)-3-benzyl-4-(methyl(4-(2-(6-morpholinopyridin- 543.6
3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
134 (R)-3-benzyl-4-((4-(3*-chloro-[l,l*-biphenyl]-2- 492.0 yl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
135 (R)-3-benzyl-4-((4-(2-(furan-3-yl)phenyl)thiazol-2- 447.5 yl)(methyl)amino)-4-oxobutano ic acid
136 (R)-3-benzyl-4-((4-(2-(6-(2- 532.6 methoxyethoxy)pyridin-3 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
138 (R)-3-benzyl-4-((4-(4'-isopropyl-[l,r-biphenyl]-2- 499.6 yl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
139 (R)-3-(cyclopentylmethyl)-4-((4-(2-(6- 480.6 methoxypyridin-3 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
140 (R)-3-benzyl-4-((4-(2-(5-fluoro-6-methoxypyridin- 506.6
3 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-4- oxobutanoic acid
141 (R)-3-benzyl-4-(methyl(4-(2-(6-((tetrahydro-2H- 558.7 pyran-4-yl)oxy)pyridin-3 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
142 (R)-3-benzyl-4-(cyclopropyl(4-(2,5- 476.4 dichlorophenyl)thiazol-2-yl)amino)-4-oxobutanoic acid 4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)- 405.9 3 -(furan-2-ylmethyl)-4-oxobutano ic acid
(R)-3-benzyl-4-((4-(2-cyclopropylphenyl)thiazol-2- 421.5 yl)(methyl)amino)-4-oxobutano ic acid
(R)-3-benzyl-4-((4-(4'-(dimethylamino)-[ 1 , 1 '- 500.6 biphenyl]-2-yl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
(R)-3-benzyl-4-((4-(3*-fluoro-[l,r-biphenyl]-2- 475.5 yl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
(R)-3-benzyl-4-((4-(3*,5*-difluoro-[l,r-biphenyl]-2- 493.5 yl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
(R)-3-benzyl-4-((4-(2-chloro-6- 419.9 fluorophenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
(R)-3-benzyl-4-((4-(4'-chloro-[l,r-biphenyl]-2- 492.0 yl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
(R)-3-benzyl-4-(methyl(4-(2-(6-(2-oxopyrrolidin- 1 - 541.6 yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
(R)-3-benzyl-4-((4-(4-chloro-2-(6-methoxypyridin- 523.0 3 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-4- oxobutanoic acid
(R)-3-benzyl-4-((4-(5-chloro-2-(6-methoxypyridin- 523.0 3 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-4- oxobutanoic acid
(R)-3-benzyl-4-((4-(3-fluoro-2-(6-methoxypyridin- 506.6 3 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-4- oxobutanoic acid 154 (3R)-4-((4-(2-chlorophenyl)thiazol-2- 409.9 yl)(methyl)amino)-4-oxo-3-((tetrahydrofuran-2- yl)methyl)butanoic acid
155 (R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2-yl)(2- 445.9 hydroxyethyl)amino)-4-oxobutanoic acid
156 (R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2-yl)(3- 460.0 hydroxypropyl)amino)-4-oxobutanoic acid
157 (R)-3-benzyl-4-((4-(2-(5-chloro-6-methoxypyridin- 523.0
3 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-4- oxobutanoic acid
158 (R)-3-benzyl-4-((4-(2-(6-(benzyloxy)pyridin-3- 564.7 yl)phenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
159 (R)-3-(cyclopentylmethyl)-4-((4-(2,5- 442.4 dichlorophenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
160 (R)-4-((4-(2-(6-methoxypyridin-3- 496.6 yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
161 (R)-3-benzyl-4-((4-(2-chloro-5- 483.9
(trifluoromethyl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
162 (R)-3-benzyl-4-((4-(2-chloro-5- 433.9 fluorophenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
163 (R)-3-benzyl-4-((4-(3,5-dichlorophenyl)thiazol-2- 450.4 yl)(methyl)amino)-4-oxobutano ic acid 164 (R)-3-benzyl-4-((4-(3- 447.5 (difluoromethoxy)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
165 (R)-4-((4-(2-chlorophenyl)thiazol-2- 407.9 yl)(methyl)amino)-3-(cyclopentylmethyl)-4- oxobutanoic acid
166 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2,5- 468.4 dichlorophenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
167 (R)-4-(cyclopropyl(4-(2,5-dichlorophenyl)thiazol-2- 484.4 yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
168 (R)-4-((4-(2,5-dichlorophenyl)thiazol-2- 458.4 yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran- 4-yl)methyl)butanoic acid
169 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 506.6 methoxypyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4- oxobutanoic acid
170 (R)-3-benzyl-4-((2-hydroxyethyl)(4-(2-(6- 518.6 methoxypyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4- oxobutanoic acid
171 (R)-3-(cyclopentylmethyl)-4-(methyl(4-(2-(6- 535.7 morpholinopyridin-3-yl)phenyl)thiazol-2-yl)amino)- 4-oxobutanoic acid
172 (R)-3-(cyclopentylmethyl)-4-((4-(2,5- 472.4 dichlorophenyl)thiazol-2-yl)(2- hydroxyethyl)amino)-4-oxobutanoic acid 173 (R)-4-((4-(2-chlorophenyl)thiazol-2- 423.9 yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran- 4-yl)methyl)butanoic acid
174 (R)-3-benzyl-4-((4-(5-chloro-2- 483.9
(trifluoromethyl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
175 (R)-3-benzyl-4-(methyl(4-(2,3,5- 484.8 trichlorophenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
176 (R)-3-benzyl-4-((4-(4-chloro-[l,r-biphenyl]-3- 492.0 yl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
177 (R)-3-benzyl-4-((4-(2-chloro-5-(6-methoxypyridin- 523.0
3 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-4- oxobutanoic acid
178 (R)-3-benzyl-4-(cyclopropyl(4-(2-(6- 514.6 methoxypyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4- oxobutanoic acid
179 (R)-4-(cyclopropyl(4-(2-(6-methoxypyridin-3- 522.6 yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro- 2H-pyran-4-yl)methyl)butano ic acid
180 (R)-3-benzyl-4-(cyclopropyl(4-(2-(6- 569.7 morpholinopyridin-3-yl)phenyl)thiazol-2-yl)amino)- 4-oxobutanoic acid
181 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 561.7 morpholinopyridin-3-yl)phenyl)thiazol-2-yl)amino)- 4-oxobutanoic acid
182 (R)-3-benzyl-4-(methyl(4-(2-(4-methyl-3,4-dihydro- 529.6
2H-pyrido[3,2-b][l,4]oxazin-7-yl)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid 183 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 559.7 (2-oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid
184 (R)-4-(cyclopropyl(4-(2-(6-morpholinopyridin-3- 577.7 yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro- 2H-pyran-4-yl)methyl)butano ic acid
185 (R)-3-benzyl-4-(methyl(4-(2- 465.5
(trifluoromethoxy)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
186 (R)-4-((4-(2-chloro-5-fluorophenyl)thiazol-2- 452.0 yl)(cyclopropyl)amino)-3-(cyclopentylmethyl)-4- oxobutanoic acid
187 (R)-3-(cyclopentylmethyl)-4-(methyl(4-(2-(6-(2- 533.7 oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid
188 (R)-3 -benzyl-4-(cy clopropyl(4-(3 - 473.5
(difluoromethoxy)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
189 (R)-3-benzyl-4-((4-(2-chloro-5- 459.9 fluorophenyl)thiazol-2-yl)(cyclopropyl)amino)-4- oxobutanoic acid
190 (R)-4-((4-(2-chloro-5-fluorophenyl)thiazol-2- 468.0 yl)(cyclopropyl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
191 (R)-3-benzyl-4-((4-(2-chloro-5- 509.9
(trifluoromethyl)phenyl)thiazol-2- yl)(cyclopropyl)amino)-4-oxobutanoic acid
192 (R)-3-benzyl-4-((4-(2- 447.5
(difluoromethoxy)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid 193 (R)-4-((4-(2-chloro-5- 518.0 (trifluoromethyl)phenyl)thiazol-2- yl)(cyclopropyl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
194 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(4- 547.7 methyl-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-7- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
195 (3R,4S)-3-((4-(2-chlorophenyl)thiazol-2- 429.9 yl)(methyl)carbamoyl)-4-phenylpentano ic acid
196 (R)-2-(2-benzyl-3-carboxypropanamido)-5-(2- 411.9 chlorophenyl)pyridine 1 -oxide
197 (R)-3-benzyl-4-((5-(2-chlorophenyl)pyrazin-2- 396.8 yl)amino)-4-oxobutanoic acid
198 4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)- 424.9
3-(morpholinomethyl)-4-oxobutanoic acid
199 (R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2-yl)(2- 460.0 methoxyethyl)amino)-4-oxobutanoic acid
200 (R)-4-((4-(2-chlorophenyl)thiazol-2- 408.9 yl)(methyl)amino)-3-(cyclopentylamino)-4- oxobutanoic acid
201 (R)-3-benzyl-4-((2-(benzyloxy)ethyl)(4-(2- 536.1 chlorophenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
202 (R)-3-benzyl-4-((4-(5-methylfuran-2-yl)thiazol-2- 371.4 yl)amino)-4-oxobutanoic acid
203 (R)-3-benzyl-4-oxo-4-((3-(3- 418.4
(trifluoromethyl)phenyl)-lH-pyrazol-5- yl)amino)butanoic acid 204 (R)-3-benzyl-4-((4-(5-chloro-2- 431.9 methoxyphenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
205 4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)- 431.9
3-(4-hydroxybenzyl)-4-oxobutanoic acid
206 (R)-3-benzyl-4-((4-(4'-cyano-[ 1 , l'-biphenyl]-2- 482.6 yl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
207 (3R)-3-benzyl-4-((3-carbamoyl-4-(2,4- 492.4 dichlorophenyl)-5-methylthiophen-2-yl)amino)-4- oxobutanoic acid
208 (R)-3-benzyl-4-((4-(3'-methoxy-[ 1 , l'-biphenyl]-2- 487.6 yl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
209 4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)- 436.9
3-((2-methylthiazol-4-yl)methyl)-4-oxobutanoic acid
210 4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)- 420.9
3 -((5 -methylisoxazo 1-3 -yl)methyl)-4-oxobutano ic acid
211 (R)-3-benzyl-4-((4-(2'-chloro-[ 1 , l'-biphenyl]-2- 492.0 yl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
212 (R)-3-benzyl-4-((4-(2-(2-methoxypyrimidin-5- 489.6 yl)phenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
213 (R)-3-benzyl-4-((4-(2,5-difluorophenyl)thiazol-2- 403.4 yl)amino)-4-oxobutanoic acid
214 4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)- 406.9
3-(oxazol-4-ylmethyl)-4-oxobutanoic acid 215 (3R)-4-((4-(2-chlorophenyl)thiazol-2- 409.9 yl)(methyl)amino)-4-oxo-3-((tetrahydrofuran-3- yl)methyl)butanoic acid
216 (R)-3-benzyl-4-(methyl(4-(2-(8-methyl-7-oxo- 541.6
5,6,7,8 -t etr ahydr o -1,8 -naphthyr idin- 3 - yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
217 (R)-3 -benzyl-4-(methyl(4-(2-( 1 -methyl- 1 H- 511.6 pyrrolo [2,3 -b]pyridin-5 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
218 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 519.7
(dimethylamino)pyridin-3 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
219 (R)-4-((4-(2-(5-chloro-6-methoxypyridin-3- 541.1 yl)phenyl)thiazo l-2-yl)(cyclopropyl)amino)-3 - (cyclopentylmethyl)-4-oxobutano ic acid
220 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(5- 524.6 fluoro-6-methoxypyridin-3-yl)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid
221 (R)-3-benzyl-4-((4-(2-chloro-5- 481.9
(difluoromethoxy)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
222 (R)-3-benzyl-4-((4-(5-chloro-2-(5-chloro-6- 557.5 methoxypyridin-3-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
223 (R)-4-((4-(5-chloro-2-(5-chloro-6-methoxypyridin- 575.5
3 -yl)phenyl)thiazo l-2-yl)(cyclopropyl)amino)-3 - (cyclopentylmethyl)-4-oxobutano ic acid (R)-4-((4-(5-chloro-2-(5-fluoro-6-methoxypyridin- 559.1 3 -yl)phenyl)thiazo l-2-yl)(cyclopropyl)amino)-3 - (cyclopentylmethyl)-4-oxobutano ic acid
(S)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2- 401.9 yl)amino)-4-oxobutanoic acid
(R)-3-benzyl-4-((4-benzylthiazol-2-yl)amino)-4- 381.5 oxobutanoic acid
(R)-3-benzyl-4-oxo-4-((5-phenyl-4H- 1 ,2,4-triazol- 351.4 3-yl)amino)butanoic acid
3-([l , 1 '-biphenyl]-4-ylmethyl)-4-((4-(2- 492.0 chlorophenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
(R)-3 -benzyl-4-((4-( 1 -methyl- 1 H-pyrazol-4- 371.4 yl)thiazol-2-yl)amino)-4-oxobutanoic acid
(R)-3-benzyl-4-((4-(4-methyl-l,2,5-oxadiazol-3- 373.4 yl)thiazol-2-yl)amino)-4-oxobutanoic acid
(R)-3 -benzyl-4-(methyl(4-(2-( 1 -methyl- 1 H-pyrazol- 461.5 4-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
(3R)-3-benzyl-4-((4-(2-(3,5-dimethylisoxazol-4- 476.6 yl)phenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
(R)-3-benzyl-4-((4-((2- 444.9 chlorophenyl)carbamoyl)thiazol-2-yl)amino)-4- oxobutanoic acid
(R)-3-benzyl-4-((6-(2-chlorophenyl)pyridazin-3- 396.8 yl)amino)-4-oxobutanoic acid
(R)-3-benzyl-4-(methyl(4-(2-(2-oxopyrrolidin- 1 - 464.5 yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid 238 (S)-2-((l-((4-(2-chlorophenyl)thiazol-2- 431.9 yl)(methyl)amino)- 1 -oxo-3-phenylpropan-2- yl)oxy)acetic acid
239 (R)-3 -benzyl-4-(( 1 -methyl-5 -phenyl- 1 H-imidazo 1-2- 364.4 yl)amino)-4-oxobutanoic acid
240 (R)-3-benzyl-4-((4-(2-(l-(2-methoxyethyl)-6-oxo- 532.6 l,6-dihydropyridin-3-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
241 (R)-3-benzyl-4-(methyl(4-(2-(l-methyl-6-oxo-l,6- 488.6 dihydropyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
242 4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)- 434.9
3 -((2,5 -dimethyloxazo l-4-yl)methyl)-4-oxobutano ic acid
243 4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)- 419.9
3 -(( 1 -methyl- 1 H-pyrazol-5 -yl)methyl)-4- oxobutanoic acid
244 (R)-3-benzyl-4-((4-(2-(6-hydroxypyridin-3- 474.5 yl)phenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
245 (R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2- 460.0 yl)((S)-2-hydroxypropyl)amino)-4-oxobutanoic acid
246 (R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2- 460.0 yl)((R)-2-hydroxypropyl)amino)-4-oxobutanoic acid
247 (R)-3-(cyclohexylmethyl)-4-(cyclopropyl(4-(2-(6- 520.7 methoxypyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4- oxobutanoic acid (R)-3-benzyl-4-((4-(5-fluoro-2-(6-methoxypyridin- 506.6 3 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-4- oxobutanoic acid
(R)-3-benzyl-4-((4-(4,5-difluoro-2-(6- 524.6 methoxypyridin-3 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
(R)-4-((4-(2,5-dichlorophenyl)thiazol-2- 440.3 yl)(methyl)amino)-3-(furan-2-ylmethyl)-4- oxobutanoic acid
(R)-4-((4-(2-chloro-5-fluorophenyl)thiazol-2- 423.9 yl)(methyl)amino)-3-(furan-2-ylmethyl)-4- oxobutanoic acid
(R)-3-(furan-2-ylmethyl)-4-((4-(2-(6- 478.5 methoxypyridin-3 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
(S)-4-((4-(2-chlorophenyl)thiazol-2- 421.9 yl)(methyl)amino)-4-oxo-3-(thiophen-2- ylmethyl)butanoic acid
(R)-4-((4-(5-chloro-2-(6-methoxypyridin-3- 541.1 yl)phenyl)thiazo l-2-yl)(cyclopropyl)amino)-3 - (cyclopentylmethyl)-4-oxobutano ic acid
(R)-3-benzyl-4-(cyclopropyl(4-(2-(6-(2- 567.7 oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid
(R)-3-benzyl-4-((4-(2,3-dichlorophenyl)thiazol-2- 450.4 yl)(methyl)amino)-4-oxobutano ic acid
(R)-3-benzyl-4-(methyl(4-(3- 465.5 (trifluoromethoxy)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid 259 (R)-4-(cyclopropyl(4-(3- 481.5
(difluoromethoxy)phenyl)thiazol-2-yl)amino)-4- oxo-3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
260 (R)-4-((4-(2-chlorophenyl)thiazol-2- 405.9 yl)(methyl)amino)-3-(furan-2-ylmethyl)-4- oxobutanoic acid
261 (R)-4-(methyl(4-(3- 473.5
(trifluoromethoxy)phenyl)thiazol-2-yl)amino)-4- oxo-3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
262 (R)-3 -benzyl-4-(cy clopropyl(4-(3 - 491.5
(trifluoromethoxy)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
263 (R)-4-(cyclopropyl(4-(3- 499.5
(trifluoromethoxy)phenyl)thiazol-2-yl)amino)-4- oxo-3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
264 (R)-3-benzyl-4-((4-(2-(6-isopropoxypyridin-3- 516.6 yl)phenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
265 (R)-3-benzyl-4-((4-(2-(6- 528.6
(cyclopropylmethoxy)pyridin-3 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
266 (R)-3-benzyl-4-((4-(2-(6-(methoxymethyl)pyridin- 502.6
3 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-4- oxobutanoic acid 267 (R)-3-benzyl-4-((4-(2-(6- 515.6 ((dimethylamino)methyl)pyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
268 (R)-3-benzyl-4-(methyl(4-(2-(6-(N- 555.7 methylcyclopropanecarboxamido)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
269 (R)-3-benzyl-4-((4-(2-(6- 529.6
(dimethylcarbamoyl)pyridin-3-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
270 (R)-4-((4-(2-(6-(4H- 1 ,2,4-triazol-4-yl)pyridin-3- 525.6 yl)phenyl)thiazo l-2-yl)(methyl)amino)-3 -benzyl-4- oxobutanoic acid
271 (R)-3-benzyl-4-(methyl(4-(2-(6-(3-methyl-2- 556.6 oxoimidazolidin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid
272 (R)-3-benzyl-4-(methyl(4-(2-(l-methyl-2-oxo-2,3- 527.6 dihydro- 1 H-pyrrolo [2,3 -b]pyridin-5 - yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
273 (R)-3-benzyl-4-(methyl(4-(2-(3-methyl-3H- 512.6 imidazo[4,5-b]pyridin-6-yl)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid
274 (R)-3-benzyl-4-((4-(2-(6- 577.7
(benzyl(methyl)amino)pyridin-3 -yl)phenyl)thiazo 1- 2-yl)(methyl)amino)-4-oxobutanoic acid
275 (R)-3-benzyl-4-((4-(2-(6- 569.7
(cyclohexyl(methyl)amino)pyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid (R)-3-benzyl-4-(methyl(4-(2-(6-(4-methylpiperazin- 556.7 1 -yl)pyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4- oxobutanoic acid
(R)-4-((4-(5-chloro-2-(6-methoxypyridin-3- 541.1 yl)phenyl)thiazo l-2-yl)(cyclopropyl)amino)-3 - (cyclopentylmethyl)-4-oxobutano ic acid
(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(3- 524.6 fluoro-2-(6-methoxypyridin-3-yl)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid
(R)-3-benzyl-4-((4-(2-(5-chloro-6-methoxypyridin- 541.0 3-yl)-3-fluorophenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
(R)-3-benzyl-4-((4-(3-fluoro-2-(5-fluoro-6- 524.6 methoxypyridin-3 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
(R)-3-benzyl-4-((4-(5-chloro-2-(5-fluoro-6- 541.0 methoxypyridin-3 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
(R)-3-benzyl-4-((4-(3,5-difluoro-2-(6- 524.6 methoxypyridin-3 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
(R)-4-((4-(2-chlorophenyl)thiazol-2- 409.9 yl)(methyl)amino)-4-oxo-3-(((S)-tetrahydrofuran-2- yl)methyl)butanoic acid
(R)-4-((4-(2-chlorophenyl)thiazol-2- 409.9 yl)(methyl)amino)-4-oxo-3-(((R)-tetrahydrofuran-2- yl)methyl)butanoic acid 285 (R)-4-((4-(2-chloro-5- 473.9 (trifluoromethyl)phenyl)thiazol-2- yl)(methyl)amino)-3-(furan-2-ylmethyl)-4- oxobutanoic acid
286 (R)-4-((4-(2-chloro-5- 489.9
(trifluoromethoxy)phenyl)thiazol-2- yl)(methyl)amino)-3-(furan-2-ylmethyl)-4- oxobutanoic acid
287 (R)-4-((4-(2-chloro-5- 471.9
(difluoromethoxy)phenyl)thiazol-2- yl)(methyl)amino)-3-(furan-2-ylmethyl)-4- oxobutanoic acid
288 (R)-4-((4-(2-chlorophenyl)thiazol-2- 431.9 yl)(cyclopropyl)amino)-3-(furan-2-ylmethyl)-4- oxobutanoic acid
289 (R)-4-((4-(5-chloro-2-(6-methoxypyridin-3- 513.0 yl)phenyl)thiazo l-2-yl)(methyl)amino)-3 -(furan-2- ylmethyl)-4-oxobutanoic acid
290 (R)-4-((4-(2-chloro-5-(6-methoxypyridin-3- 513.0 yl)phenyl)thiazo l-2-yl)(methyl)amino)-3 -(furan-2- ylmethyl)-4-oxobutanoic acid
291 (R)-3-(furan-2-ylmethyl)-4-((4-(2-(6- 546.5 methoxypyridin-3 -yl)-5 - (trifluoromethyl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
292 (R)-3-(furan-2-ylmethyl)-4-((4-(2-(6- 562.5 methoxypyridin-3 -yl)-5 - (trifluoromethoxy)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid 293 (R)-4-((4-(5-(difluoromethoxy)-2-(6- 544.5 methoxypyridin-3 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-3-(furan-2-ylmethyl)-4- oxobutanoic acid
294 (R)-4-(cyclopropyl(4-(2,5-dichlorophenyl)thiazol-2- 466.4 yl)amino)-3-(furan-2-ylmethyl)-4-oxobutanoic acid
295 (R)-4-((4-(2-chloro-5-fluorophenyl)thiazol-2- 449.9 yl)(cyclopropyl)amino)-3-(furan-2-ylmethyl)-4- oxobutanoic acid
296 (R)-4-((4-(2-chloro-5- 499.9
(trifluoromethyl)phenyl)thiazol-2- yl)(cyclopropyl)amino)-3-(furan-2-ylmethyl)-4- oxobutanoic acid
297 (R)-4-((4-(2-chloro-5- 515.9
(trifluoromethoxy)phenyl)thiazol-2- yl)(cyclopropyl)amino)-3-(furan-2-ylmethyl)-4- oxobutanoic acid
298 (R)-4-((4-(2-chloro-5- 497.9
(difluoromethoxy)phenyl)thiazol-2- yl)(cyclopropyl)amino)-3-(furan-2-ylmethyl)-4- oxobutanoic acid
299 4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)- 419.9
3-((5-methylfuran-2-yl)methyl)-4-oxobutanoic acid
300 4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)- 433.9
3-((4,5-dimethylfuran-2-yl)methyl)-4-oxobutanoic acid
301 3-(benzofuran-2-ylmethyl)-4-((4-(2- 455.9 chlorophenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid 302 (R)-4-((4-(2-chlorophenyl)thiazol-2- 416.9 yl)(methyl)amino)-4-oxo-3-(pyridin-2- ylmethyl)butanoic acid
303 (R)-4-((4-(2-chlorophenyl)thiazol-2- 417.9 yl)(methyl)amino)-4-oxo-3-(pyrimidin-2- ylmethyl)butanoic acid
304 (3R)-4-((4-(2,5-dichlorophenyl)thiazol-2- 458.4 yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran- 2-yl)methyl)butanoic acid
305 (3R)-4-((4-(2,5-dichlorophenyl)thiazol-2- 458.4 yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran- 3-yl)methyl)butanoic acid
306 (R)-4-((4-(2,5-dichlorophenyl)thiazol-2- 472.4 yl)(methyl)amino)-3-(((2R,3R)-2-methyltetrahydro- 2H-pyran-3-yl)methyl)-4-oxobutanoic acid
307 (3R)-4-((4-(2,5-dichlorophenyl)thiazol-2- 472.4 yl)(methyl)amino)-3-(((2R)-2-methyltetrahydro-2H- pyran-4-yl)methyl)-4-oxobutanoic acid
308 (3R)-4-((4-(2,5-dichlorophenyl)thiazol-2- 486.4 yl)(methyl)amino)-3-(((2R,6S)-2,6- dimethyltetrahydro-2H-pyran-4-yl)methyl)-4- oxobutanoic acid
309 (3R)-4-((4-(2,5-dichlorophenyl)thiazol-2- 472.4 yl)(methyl)amino)-3-(((3S)-3-methyltetrahydro-2H- pyran-4-yl)methyl)-4-oxobutanoic acid
310 (3R)-4-((4-(2,5-dichlorophenyl)thiazol-2- 486.4 yl)(methyl)amino)-3-(((3R,5S)-3,5- dimethyltetrahydro-2H-pyran-4-yl)methyl)-4- oxobutanoic acid 311 (R)-2-benzyl-N-(4-(2-chlorophenyl)thiazol-2-yl)-3- 472.0 (4-hydroxy- 1 ,2,5-thiadiazol-3-yl)-N- methylpropanamide
312 (R)-2-benzyl-N-(4-(2-chlorophenyl)thiazol-2-yl)-3- 469.0
(3 -hydro xy-5 -methylisoxazo l-4-yl)-N- methylpropanamide
313 (R)-4-((4-(5-chloro-2-(6-(2-oxopiperidin- 1 - 624.2 yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)(cyclopropyl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
314 (R)-4-((4-(5-chloro-2-(6-(2-oxopiperidin- 1 - 642.2 yl)pyridin-3 -yl)phenyl)-5 -fluorothiazo 1-2- yl)(cyclopropyl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
315 (R)-4-((4-(5-chloro-2-(6-methoxypyridin-3- 557.1 yl)phenyl)thiazol-2-yl)(cyclopropyl)amino)-4-oxo- 3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
316 (R)-4-((4-(5-chloro-2-(6-methoxypyridin-3- 575.1 yl)phenyl)-5 -fluorothiazo 1-2- yl)(cyclopropyl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
317 (R)-4-((4-(5-chloro-2-(6-(2-oxopyrrolidin- 1 - 610.1 yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)(cyclopropyl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
318 (R)-4-((4-(5-chloro-2-(6-(2-oxopyrrolidin- 1 - 628.1 yl)pyridin-3 -yl)phenyl)-5 -fluorothiazo 1-2- yl)(cyclopropyl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid 319 (R)-4-(cyclopropyl(4-(5-(difluoromethoxy)-2-(6-(2- 655.7 oxopiperidin- 1 -yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
320 (R)-4-(cyclopropyl(4-(5-(difluoromethoxy)-2-(6-(2- 673.7 oxopiperidin- 1 -yl)pyridin-3-yl)phenyl)-5- fluorothiazol-2-yl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
321 (R)-4-(cyclopropyl(4-(5-(difluoromethoxy)-2-(6- 588.6 methoxypyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4- oxo-3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
322 (R)-4-(cyclopropyl(4-(5-(difluoromethoxy)-2-(6- 606.6 methoxypyridin-3-yl)phenyl)-5-fluorothiazol-2- yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
323 (R)-4-(cyclopropyl(4-(5-(difluoromethoxy)-2-(6-(2- 641.7 oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2- yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
324 (R)-4-(cyclopropyl(4-(5-(difluoromethoxy)-2-(6-(2- 659.7 oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)-5- fluorothiazol-2-yl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
325 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopiperidin- 1 - 589.7 yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid 326 (R)-4-(cyclopropyl(5-fluoro-4-(2-(6-(2- 607.7 oxopiperidin- 1 -yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
327 (R)-4-(cyclopropyl(5-fluoro-4-(2-(6- 540.6 methoxypyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4- oxo-3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
328 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 - 575.7 yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
329 (R)-4-(cyclopropyl(5-fluoro-4-(2-(6-(2- 593.7 oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2- yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
330 (R)-4-(cyclopropyl(4-(5-fluoro-2-(6-(2- 607.7 oxopiperidin- 1 -yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
331 (R)-4-(cyclopropyl(5-fluoro-4-(5-fluoro-2-(6-(2- 625.7 oxopiperidin- 1 -yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
332 (R)-4-(cyclopropyl(4-(5-fluoro-2-(6- 540.6 methoxypyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4- oxo-3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid 333 (R)-4-(cyclopropyl(5-fluoro-4-(5-fluoro-2-(6- 558.6 methoxypyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4- oxo-3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
334 (R)-4-(cyclopropyl(4-(5-fluoro-2-(6-(2- 593.7 oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2- yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
335 (R)-4-(cyclopropyl(5-fluoro-4-(5-fluoro-2-(6-(2- 611.7 oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2- yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
336 (R)-4-((4-(5-chloro-2-(6-(2-oxopiperidin- 1 - 608.2 yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)(cyclopropyl)amino)-3-(cyclopentylmethyl)-4- oxobutanoic acid
337 (R)-4-((4-(5-chloro-2-(6-(2-oxopiperidin- 1 - 626.2 yl)pyridin-3 -yl)phenyl)-5 -fluorothiazo 1-2- yl)(cyclopropyl)amino)-3-(cyclopentylmethyl)-4- oxobutanoic acid
338 (R)-4-((4-(5-chloro-2-(6-methoxypyridin-3- 559.1 yl)phenyl)-5 -fluorothiazo 1-2- yl)(cyclopropyl)amino)-3-(cyclopentylmethyl)-4- oxobutanoic acid
339 (R)-4-((4-(5-chloro-2-(6-(2-oxopyrrolidin- 1 - 594.1 yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)(cyclopropyl)amino)-3-(cyclopentylmethyl)-4- oxobutanoic acid 340 (R)-4-((4-(5-chloro-2-(6-(2-oxopyrrolidin- 1 - 612.1 yl)pyridin-3 -yl)phenyl)-5 -fluorothiazo 1-2- yl)(cyclopropyl)amino)-3-(cyclopentylmethyl)-4- oxobutanoic acid
341 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5- 639.7
(difluoromethoxy)-2-(6-(2-oxopiperidin- 1 - yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
342 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5- 657.7
(difluoromethoxy)-2-(6-(2-oxopiperidin- 1 - yl)pyridin-3 -yl)phenyl)-5 -fluorothiazo 1-2- yl)amino)-4-oxobutanoic acid
343 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5- 572.6
(difluoromethoxy)-2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
344 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5- 590.6
(difluoromethoxy)-2-(6-methoxypyridin-3- yl)phenyl)-5-fluorothiazol-2-yl)amino)-4- oxobutanoic acid
345 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5- 625.7
(difluoromethoxy)-2-(6-(2-oxopyrrolidin- 1 - yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
346 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5- 643.7
(difluoromethoxy)-2-(6-(2-oxopyrrolidin- 1 - yl)pyridin-3 -yl)phenyl)-5 -fluorothiazo 1-2- yl)amino)-4-oxobutanoic acid
347 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 573.7
(2-oxopiperidin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid 348 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro- 591.7 4-(2-(6-(2-oxopiperidin- 1 -yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
349 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro- 524.6
4-(2-(6-methoxypyridin-3 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
350 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro- 577.7
4-(2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
351 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5- 591.7 fluoro-2-(6-(2-oxopiperidin- 1 -yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
352 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro- 609.7
4-(5-fluoro-2-(6-(2-oxopiperidin- 1 -yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
353 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5- 524.6 fluoro-2-(6-methoxypyridin-3-yl)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid
354 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro- 542.6
4-(5-fluoro-2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
355 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5- 577.7 fluoro-2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
356 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro- 595.7
4-(5 -fluoro-2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3 - yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
357 (R)-3-benzyl-4-((4-(5-chloro-2-(6-(2-oxopiperidin- 616.1
1 -yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)(cyclopropyl)amino)-4-oxobutanoic acid (R)-3-benzyl-4-((4-(5-chloro-2-(6-(2-oxopiperidin- 634.1 1 -yl)pyridin-3 -yl)phenyl)-5 -fluorothiazo 1-2- yl)(cyclopropyl)amino)-4-oxobutanoic acid
(R)-3-benzyl-4-((4-(5-chloro-2-(6-methoxypyridin- 549.1 3-yl)phenyl)thiazol-2-yl)(cyclopropyl)amino)-4- oxobutanoic acid
(R)-3-benzyl-4-((4-(5-chloro-2-(6-methoxypyridin- 567.0 3 -yl)phenyl)-5 -fluorothiazol-2- yl)(cyclopropyl)amino)-4-oxobutanoic acid
(R)-3-benzyl-4-((4-(5-chloro-2-(6-(2-oxopyrrolidin- 602.1 1 -yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)(cyclopropyl)amino)-4-oxobutanoic acid
(R)-3-benzyl-4-((4-(5-chloro-2-(6-(2-oxopyrrolidin- 620.1 1 -yl)pyridin-3 -yl)phenyl)-5 -fluorothiazo 1-2- yl)(cyclopropyl)amino)-4-oxobutanoic acid
(R)-3-benzyl-4-(cyclopropyl(4-(5- 647.7 (difluoromethoxy)-2-(6-(2-oxopiperidin- 1 - yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
(R)-3 -benzyl-4-(cy clopropyl(4-(5 - 665.7 (difluoromethoxy)-2-(6-(2-oxopiperidin- 1 - yl)pyridin-3 -yl)phenyl)-5 -fluorothiazo 1-2- yl)amino)-4-oxobutanoic acid
(R)-3 -benzyl-4-(cy clopropyl(4-(5 - 580.6 (difluoromethoxy)-2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
(R)-3 -benzyl-4-(cy clopropyl(4-(5 - 598.6 (difluoromethoxy)-2-(6-methoxypyridin-3- yl)phenyl)-5-fluorothiazol-2-yl)amino)-4- oxobutanoic acid 367 (R)-3 -benzyl-4-(cy clopropyl(4-(5 - 633.7 (difluoromethoxy)-2-(6-(2-oxopyrrolidin- 1 - yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
368 (R)-3 -benzyl-4-(cy clopropyl(4-(5 - 651.7
(difluoromethoxy)-2-(6-(2-oxopyrrolidin- 1 - yl)pyridin-3 -yl)phenyl)-5 -fluorothiazo 1-2- yl)amino)-4-oxobutanoic acid
369 (R)-3-benzyl-4-(cyclopropyl(4-(2-(6-(2- 581.7 oxopiperidin- 1 -yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
370 (R)-3-benzyl-4-(cyclopropyl(5-fluoro-4-(2-(6-(2- 599.7 oxopiperidin- 1 -yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
371 (R)-3-benzyl-4-(cyclopropyl(5-fluoro-4-(2-(6- 532.6 methoxypyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4- oxobutanoic acid
372 (R)-3-benzyl-4-(cyclopropyl(5-fluoro-4-(2-(6-(2- 585.7 oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid
373 (R)-3-benzyl-4-(cyclopropyl(4-(5-fluoro-2-(6-(2- 599.7 oxopiperidin- 1 -yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
374 (R)-3-benzyl-4-(cyclopropyl(5-fluoro-4-(5-fluoro-2- 617.7
(6-(2-oxopiperidin- 1 -yl)pyridin-3-yl)phenyl)thiazol- 2-yl)amino)-4-oxobutanoic acid
375 (R)-3-benzyl-4-(cyclopropyl(4-(5-fluoro-2-(6- 532.6 methoxypyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4- oxobutanoic acid 376 (R)-3-benzyl-4-(cyclopropyl(5-fluoro-4-(5-fluoro-2- 550.6 (6-methoxypyridin-3-yl)phenyl)thiazol-2-yl)amino)- 4-oxobutanoic acid
377 (R)-3-benzyl-4-(cyclopropyl(4-(5-fluoro-2-(6-(2- 585.7 oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid
378 (R)-3-benzyl-4-(cyclopropyl(5-fluoro-4-(5-fluoro-2- 603.7
(6-(2-oxopyrrolidin- 1 -yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
379 (R)-4-((4-(5-chloro-2-(6-(2-oxopiperidin- 1 - 598.1 yl)pyridin-3-yl)phenyl)thiazol-2-yl)(methyl)amino)- 4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
380 (R)-4-((4-(5-chloro-2-(6-(2-oxopiperidin- 1 - 616.1 yl)pyridin-3 -yl)phenyl)-5 -fluorothiazo 1-2- yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran- 4-yl)methyl)butanoic acid
381 (R)-4-((4-(5-chloro-2-(6-methoxypyridin-3- 531.0 yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
382 (R)-4-((4-(5-chloro-2-(6-methoxypyridin-3- 549.0 yl)phenyl)-5-fluorothiazol-2-yl)(methyl)amino)-4- oxo-3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
383 (R)-4-((4-(5-chloro-2-(6-(2-oxopyrrolidin- 1 - 584.1 yl)pyridin-3-yl)phenyl)thiazol-2-yl)(methyl)amino)- 4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid 384 (R)-4-((4-(5-chloro-2-(6-(2-oxopyrrolidin- 1 - 602.1 yl)pyridin-3 -yl)phenyl)-5 -fluorothiazo 1-2- yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran- 4-yl)methyl)butanoic acid
385 (R)-4-((4-(5-(difluoromethoxy)-2-(6-(2- 629.7 oxopiperidin- 1 -yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran- 4-yl)methyl)butanoic acid
386 (R)-4-((4-(5-(difluoromethoxy)-2-(6-(2- 647.7 oxopiperidin- 1 -yl)pyridin-3-yl)phenyl)-5- fluorothiazol-2-yl)(methyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
387 (R)-4-((4-(5-(difluoromethoxy)-2-(6- 562.6 methoxypyridin-3 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran- 4-yl)methyl)butanoic acid
388 (R)-4-((4-(5-(difluoromethoxy)-2-(6- 580.6 methoxypyridin-3-yl)phenyl)-5-fluorothiazol-2- yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran- 4-yl)methyl)butanoic acid
389 (R)-4-((4-(5-(difluoromethoxy)-2-(6-(2- 615.7 oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran- 4-yl)methyl)butanoic acid
390 (R)-4-((4-(5-(difluoromethoxy)-2-(6-(2- 633.7 oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)-5- fluorothiazol-2-yl)(methyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid 391 (R)-4-(methyl(4-(2-(6-(2-oxopiperidin- 1 -yl)pyridin- 563.7 3-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
392 (R)-4-((5-fluoro-4-(2-(6-(2-oxopiperidin-l- 581.7 yl)pyridin-3-yl)phenyl)thiazol-2-yl)(methyl)amino)- 4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
393 (R)-4-((5-fluoro-4-(2-(6-methoxypyridin-3- 514.6 yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
394 (R)-4-(methyl(4-(2-(6-(2-oxopyrrolidin- 1 - 549.7 yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
395 (R)-4-((5-fluoro-4-(2-(6-(2-oxopyrrolidin-l- 567.6 yl)pyridin-3-yl)phenyl)thiazol-2-yl)(methyl)amino)- 4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
396 (R)-4-((4-(5-fluoro-2-(6-(2-oxopiperidin- 1 - 581.7 yl)pyridin-3-yl)phenyl)thiazol-2-yl)(methyl)amino)- 4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
397 (R)-4-((5-fluoro-4-(5-fluoro-2-(6-(2-oxopiperidin-l- 599.7 yl)pyridin-3-yl)phenyl)thiazol-2-yl)(methyl)amino)- 4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
398 (R)-4-((4-(5-fluoro-2-(6-methoxypyridin-3- 514.6 yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid (R)-4-((5-fluoro-4-(5-fluoro-2-(6-methoxypyridin- 532.6 3 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-4-oxo-3 - ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
(R)-4-((4-(5-fluoro-2-(6-(2-oxopyrrolidin- 1 - 567.6 yl)pyridin-3-yl)phenyl)thiazol-2-yl)(methyl)amino)- 4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
(R)-4-((5-fluoro-4-(5-fluoro-2-(6-(2-oxopyrrolidin- 585.6 1 -yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran- 4-yl)methyl)butanoic acid
(R)-4-((4-(5-chloro-2-(6-(2-oxopiperidin- 1 - 582.1 yl)pyridin-3-yl)phenyl)thiazol-2-yl)(methyl)amino)- 3-(cyclopentylmethyl)-4-oxobutanoic acid
(R)-4-((4-(5-chloro-2-(6-(2-oxopiperidin- 1 - 600.1 yl)pyridin-3 -yl)phenyl)-5 -fluorothiazo 1-2- yl)(methyl)amino)-3-(cyclopentylmethyl)-4- oxobutanoic acid
(R)-4-((4-(5-chloro-2-(6-methoxypyridin-3- 515.0 yl)phenyl)thiazo l-2-yl)(methyl)amino)-3 - (cyclopentylmethyl)-4-oxobutano ic acid
(R)-4-((4-(5-chloro-2-(6-methoxypyridin-3- 533.0 yl)phenyl)-5 -fluorothiazo l-2-yl)(methyl)amino)-3 - (cyclopentylmethyl)-4-oxobutano ic acid
(R)-4-((4-(5-chloro-2-(6-(2-oxopyrrolidin- 1 - 568.1 yl)pyridin-3-yl)phenyl)thiazol-2-yl)(methyl)amino)- 3-(cyclopentylmethyl)-4-oxobutanoic acid 407 (R)-4-((4-(5-chloro-2-(6-(2-oxopyrrolidin- 1 - 586.1 yl)pyridin-3 -yl)phenyl)-5 -fluorothiazo 1-2- yl)(methyl)amino)-3-(cyclopentylmethyl)-4- oxobutanoic acid
408 (R)-3-(cyclopentylmethyl)-4-((4-(5- 613.7
(difluoromethoxy)-2-(6-(2-oxopiperidin- 1 - yl)pyridin-3-yl)phenyl)thiazol-2-yl)(methyl)amino)- 4-oxobutanoic acid
409 (R)-3-(cyclopentylmethyl)-4-((4-(5- 631.7
(difluoromethoxy)-2-(6-(2-oxopiperidin- 1 - yl)pyridin-3 -yl)phenyl)-5 -fluorothiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
410 (R)-3-(cyclopentylmethyl)-4-((4-(5- 546.6
(difluoromethoxy)-2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
411 (R)-3-(cyclopentylmethyl)-4-((4-(5- 564.6
(difluoromethoxy)-2-(6-methoxypyridin-3- yl)phenyl)-5-fluorothiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
412 (R)-3-(cyclopentylmethyl)-4-((4-(5- 599.7
(difluoromethoxy)-2-(6-(2-oxopyrrolidin- 1 - yl)pyridin-3-yl)phenyl)thiazol-2-yl)(methyl)amino)- 4-oxobutanoic acid
413 (R)-3-(cyclopentylmethyl)-4-((4-(5- 617.7
(difluoromethoxy)-2-(6-(2-oxopyrrolidin- 1 - yl)pyridin-3 -yl)phenyl)-5 -fluorothiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid 414 (R)-3-(cyclopentylmethyl)-4-(methyl(4-(2-(6-(2- 547.7 oxopiperidin- 1 -yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
415 (R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(2-(6-(2- 565.7 oxopiperidin- 1 -yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
416 (R)-3-(cyclopentylmethyl)-4-((4-(2-(6- 480.6 methoxypyridin-3 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
417 (R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(2-(6- 498.6 methoxypyridin-3 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
418 (R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(2-(6-(2- 551.6 oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
419 (R)-3-(cyclopentylmethyl)-4-((4-(5-fluoro-2-(6-(2- 565.7 oxopiperidin- 1 -yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
420 (R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(5-fluoro- 583.7
2-(6-(2-oxopiperidin- 1 -yl)pyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
421 (R)-3-(cyclopentylmethyl)-4-((4-(5-fluoro-2-(6- 498.6 methoxypyridin-3 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
422 (R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(5-fluoro- 516.6
2-(6-methoxypyridin-3 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid - I l l -
423 (R)-3-(cyclopentylmethyl)-4-((4-(5-fluoro-2-(6-(2- 551.6 oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
424 (R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(5-fluoro- 569.6
2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
425 (R)-3-benzyl-4-((4-(5-chloro-2-(6-(2-oxopiperidin- 590.1
1 -yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
426 (R)-3-benzyl-4-((4-(5-chloro-2-(6-(2-oxopiperidin- 608.1
1 -yl)pyridin-3 -yl)phenyl)-5 -fluorothiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
427 (R)-3-benzyl-4-((4-(5-chloro-2-(6-methoxypyridin- 541.0
3-yl)phenyl)-5-fluorothiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
428 (R)-3-benzyl-4-((4-(5-chloro-2-(6-(2-oxopyrrolidin- 576.1
1 -yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
429 (R)-3-benzyl-4-((4-(5-chloro-2-(6-(2-oxopyrrolidin- 594.1
1 -yl)pyridin-3 -yl)phenyl)-5 -fluorothiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
430 (R)-3-benzyl-4-((4-(5-(difluoromethoxy)-2-(6-(2- 621.7 oxopiperidin- 1 -yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
431 (R)-3-benzyl-4-((4-(5-(difluoromethoxy)-2-(6-(2- 639.7 oxopiperidin- 1 -yl)pyridin-3-yl)phenyl)-5- fluorothiazol-2-yl)(methyl)amino)-4-oxobutanoic acid 432 (R)-3-benzyl-4-((4-(5-(difluoromethoxy)-2-(6- 554.6 methoxypyridin-3 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
433 (R)-3-benzyl-4-((4-(5-(difluoromethoxy)-2-(6- 572.6 methoxypyridin-3-yl)phenyl)-5-fluorothiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
434 (R)-3-benzyl-4-((4-(5-(difluoromethoxy)-2-(6-(2- 607.6 oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
435 (R)-3-benzyl-4-((4-(5-(difluoromethoxy)-2-(6-(2- 625.6 oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)-5- fluorothiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
436 (R)-3-benzyl-4-(methyl(4-(2-(6-(2-oxopiperidin- 1 - 555.7 yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
437 (R)-3-benzyl-4-((5-fluoro-4-(2-(6-(2-oxopiperidin- 573.7
1 -yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
438 (R)-3-benzyl-4-((5-fluoro-4-(2-(6-methoxypyridin- 506.6
3 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-4- oxobutanoic acid
439 (R)-3-benzyl-4-((5-fluoro-4-(2-(6-(2-oxopyrrolidin- 559.6
1 -yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
440 (R)-3-benzyl-4-((4-(5-fluoro-2-(6-(2-oxopiperidin- 573.7
1 -yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid 441 (R)-3-benzyl-4-((5-fluoro-4-(5-fluoro-2-(6-(2- 591.6 oxopiperidin- 1 -yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
442 (R)-3-benzyl-4-((5-fluoro-4-(5-fluoro-2-(6- 524.6 methoxypyridin-3 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
443 (R)-3-benzyl-4-((4-(5-fluoro-2-(6-(2-oxopyrrolidin- 559.6
1 -yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
444 (R)-3-benzyl-4-((5-fluoro-4-(5-fluoro-2-(6-(2- 577.6 oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
445 (R)-3-(cyclopentylmethyl)-4-((4-(5-fluoro-2-(8- 551.6 methyl-7-oxo-5,6,7,8-tetrahydro-l,8-naphthyridin- 3 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-4- oxobutanoic acid
446 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5- 577.7 fluoro-2-(8-methyl-7-oxo-5,6,7,8-tetrahydro-l,8- naphthyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4- oxobutanoic acid
447 (R)-4-((4-(5-fluoro-2-(8-methyl-7-oxo-5,6,7,8- 567.6 tetrahydro- 1 ,8-naphthyridin-3-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran- 4-yl)methyl)butanoic acid
448 (R)-4-(cyclopropyl(4-(5-fluoro-2-(8-methyl-7-oxo- 593.7
5,6,7,8 -tetrahydro -1,8 -naphthyr idin- 3 - yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro- 2H-pyran-4-yl)methyl)butano ic acid 449 (R)-3-benzyl-4-((4-(5-fluoro-2-(8-methyl-7-oxo- 559.6 5,6,7,8 -t etr ahydr o -1,8 -naphthyr idin- 3 - yl)phenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
450 (R)-3-benzyl-4-(cyclopropyl(4-(5-fluoro-2-(8- 585.7 methyl-7-oxo-5,6,7,8-tetrahydro-l,8-naphthyridin- 3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
451 (R)-3-(cyclopentylmethyl)-4-((4-(5-fluoro-2-(l- 537.6 methy 1-2-oxo -2 , 3 -dihy dro - 1 H-pyrrolo [2,3- b]pyridin-5 -yl)phenyl)thiazo l-2-yl)(methyl)amino)- 4-oxobutanoic acid
452 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5- 563.7 fluoro -2-( 1 -methy 1-2-oxo -2 , 3 -dihy dro - 1 H- pyrrolo [2,3 -b]pyridin-5 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
453 (R)-4-((4-(5-fluoro-2-(l-methyl-2-oxo-2,3-dihydro- 553.6
1 H-pyrro lo [2 , 3 -b]pyr idin-5 -y l)pheny l)thiazo 1-2- yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran- 4-yl)methyl)butanoic acid
454 (R)-4-(cyclopropyl(4-(5-fluoro-2-(l-methyl-2-oxo- 579.7
2,3-dihydro-lH-pyrrolo[2,3-b]pyridin-5- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro- 2H-pyran-4-yl)methyl)butano ic acid
455 (R)-3-benzyl-4-((4-(5-fluoro-2-(l-methyl-2-oxo- 545.6
2,3-dihydro-lH-pyrrolo[2,3-b]pyridin-5- yl)phenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid 456 (R)-3-benzyl-4-(cyclopropyl(4-(5-fluoro-2-(l- 571.6 methy 1-2-oxo -2 , 3 -dihy dro - 1 H-pyrrolo [2,3- b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
457 (R)-3-(cyclopentylmethyl)-4-((4-(5-fluoro-2-(4- 539.6 methyl-3 ,4-dihydro-2H-pyrido[3 ,2-b] [ 1 ,4]oxazin-7- yl)phenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
458 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5- 565.7 fluoro-2-(4-methyl-3 ,4-dihydro-2H-pyrido [3,2- b][l,4]oxazin-7-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
459 (R)-4-((4-(5-fluoro-2-(4-methyl-3,4-dihydro-2H- 555.6 pyrido [3 ,2-b] [ 1 ,4] oxazin-7-yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran- 4-yl)methyl)butanoic acid
460 (R)-4-(cyclopropyl(4-(5-fluoro-2-(4-methyl-3,4- 581.7 dihydro-2H-pyrido[3,2-b][l,4]oxazin-7- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro- 2H-pyran-4-yl)methyl)butano ic acid
461 (R)-3-benzyl-4-((4-(5-fluoro-2-(4-methyl-3,4- 547.6 dihydro-2H-pyrido[3,2-b][l,4]oxazin-7- yl)phenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
462 (R)-3-benzyl-4-(cyclopropyl(4-(5-fluoro-2-(4- 573.7 methyl-3 ,4-dihydro-2H-pyrido[3 ,2-b] [ 1 ,4]oxazin-7- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid 463 (R)-3-(cyclopentylmethyl)-4-((4-(5-fluoro-2-(l- 521.6 methyl- 1 H-pyrrolo[2,3-b]pyridin-5- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
464 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5- 547.7 fluoro-2-( 1 -methyl- 1 H-pyrrolo [2 ,3 -b]pyridin-5 - yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
465 (R)-4-((4-(5-fluoro-2-(l -methyl- 1 H-pyrrolo[2,3- 537.6 b]pyridin-5-yl)phenyl)thiazol-2-yl)(methyl)amino)-4- oxo-3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
466 (R)-4-(cyclopropyl(4-(5-fluoro-2-( 1 -methyl- 1 H- 563.7 pyrrolo [2,3 -b]pyridin-5 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
467 (R)-3 -benzyl-4-((4-(5 -fluoro-2-( 1 -methyl- 1 H- 529.6 pyrrolo [2,3 -b]pyridin-5 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
468 (R)-3-benzyl-4-(cyclopropyl(4-(5-fluoro-2-(l- 555.6 methyl- 1 H-pyrrolo[2,3-b]pyridin-5- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
469 (R)-3-(cyclopentylmethyl)-4-((4-(5-(fluoromethoxy)- 581.7
2-(8-methyl-7-oxo-5,6,7,8-tetrahydro-l,8- naphthyridin-3 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
470 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5- 607.7
(fluoromethoxy)-2-(8-methyl-7-oxo-5, 6,7,8- tetrahydro- 1 ,8-naphthyridin-3-yl)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid 471 (R)-4-((4-(5-(fluoromethoxy)-2-(8-methyl-7-oxo- 597.7 5,6,7,8 -t etr ahydr o -1,8 -naphthyr idin- 3 - yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
472 (R)-4-(cyclopropyl(4-(5-(fluoromethoxy)-2-(8- 623.7 methyl-7-oxo-5,6,7,8-tetrahydro-l,8-naphthyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro- 2H-pyran-4-yl)methyl)butano ic acid
473 (R)-3-benzyl-4-((4-(5-(fluoromethoxy)-2-(8-methyl- 589.6
7-oxo-5, 6,7, 8-tetrahydro-l, 8-naphthyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
474 (R)-3-benzyl-4-(cyclopropyl(4-(5-(fluoromethoxy)-2- 615.7
(8-methyl-7-oxo-5, 6,7, 8-tetrahydro-l, 8-naphthyridin- 3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
475 (R)-3-(cyclopentylmethyl)-4-((4-(5-(fluoromethoxy)- 567.6
2-(l-methyl-2-oxo-2,3-dihydro-lH-pyrrolo[2,3- b]pyridin-5 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-4- oxobutanoic acid
476 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5- 593.7
(fluoromethoxy)-2-(l-methyl-2-oxo-2,3-dihydro-lH- pyrrolo [2,3 -b]pyridin-5 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
477 (R)-4-((4-(5-(fluoromethoxy)-2-(l-methyl-2-oxo-2,3- 583.6 dihydro- 1 H-pyrrolo [2,3 -b]pyridin-5 - yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid 478 (R)-4-(cyclopropyl(4-(5-(fluoromethoxy)-2-(l- 609.7 methy 1-2-oxo -2 , 3 -dihy dro - 1 H-pyrrolo [2 , 3 -b]pyr idin- 5-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
479 (R)-3-benzyl-4-((4-(5-(fluoromethoxy)-2-(l-methyl- 575.6
2-0X0-2, 3-dihydro-lH-pyrro lo[2, 3-b]pyridin-5- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
480 (R)-3-benzyl-4-(cyclopropyl(4-(5-(fluoromethoxy)-2- 601.7
( 1 -methy 1-2-oxo -2 , 3 -dihy dro - 1 H-pyrrolo [2,3- b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
481 (R)-3-(cyclopentylmethyl)-4-((4-(5-(fluoromethoxy)- 569.7
2-(4-methyl-3 ,4-dihydro-2H-pyrido [3 ,2- b][l,4]oxazin-7-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
482 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5- 595.7
(fluoromethoxy)-2-(4-methyl-3,4-dihydro-2H- pyrido [3 ,2-b] [ 1 ,4] oxazin-7-yl)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid
483 (R)-4-((4-(5-(fluoromethoxy)-2-(4-methyl-3,4- 585.7 dihydro-2H-pyrido[3,2-b][l,4]oxazin-7- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
484 (R)-4-(cyclopropyl(4-(5-(fluoromethoxy)-2-(4- 611.7 methyl-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-7- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro- 2H-pyran-4-yl)methyl)butano ic acid 485 (R)-3-benzyl-4-((4-(5-(fluoromethoxy)-2-(4-methyl- 577.6 3 ,4-dihydro-2H-pyrido [3 ,2-b] [ 1 ,4] oxazin-7- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
486 (R)-3-benzyl-4-(cyclopropyl(4-(5-(fluoromethoxy)-2- 603.7
(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin- 7-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
487 (R)-3-(cyclopentylmethyl)-4-((4-(5-(fluoromethoxy)- 551.6
2-(l -methyl- 1 H-pyrrolo[2, 3-b]pyridin-5- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
488 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5- 577.7
(fluoromethoxy)-2-(l -methyl- 1 H-pyrrolo[2,3- b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
489 (R)-4-((4-(5-(fluoromethoxy)-2-( 1 -methyl- 1 H- 567.6 pyrrolo [2,3 -b]pyridin-5 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
490 (R)-4-(cyclopropyl(4-(5-(fluoromethoxy)-2-(l- 593.7 methyl- 1 H-pyrrolo[2,3-b]pyridin-5- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro- 2H-pyran-4-yl)methyl)butano ic acid
491 (R)-3-benzyl-4-((4-(5-(fluoromethoxy)-2-(l-methyl- 559.6
1 H-pyrro lo [2 , 3 -b]pyr idin-5 -y l)pheny l)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
492 (R)-3-benzyl-4-(cyclopropyl(4-(5-(fluoromethoxy)-2- 585.7
(l-methyl-lH-pyrrolo[2,3-b]pyridin-5- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid 493 (R)-4-((4-(5-chloro-2-(8-methyl-7-oxo-5,6,7,8- 568.1 tetrahydro- 1 ,8-naphthyridin-3-yl)phenyl)thiazol-2- yl)(methyl)amino)-3-(cyclopentylmethyl)-4- oxobutanoic acid
494 (R)-4-((4-(5-chloro-2-(8-methyl-7-oxo-5,6,7,8- 594.1 tetrahydro- 1 ,8-naphthyridin-3-yl)phenyl)thiazol-2- yl)(cyclopropyl)amino)-3-(cyclopentylmethyl)-4- oxobutanoic acid
495 (R)-4-((4-(5-chloro-2-(8-methyl-7-oxo-5,6,7,8- 584.1 tetrahydro- 1 ,8-naphthyridin-3-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
496 (R)-4-((4-(5-chloro-2-(8-methyl-7-oxo-5,6,7,8- 610.1 tetrahydro- 1 ,8-naphthyridin-3-yl)phenyl)thiazol-2- yl)(cyclopropyl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
497 (R)-3-benzyl-4-((4-(5-chloro-2-(8-methyl-7-oxo- 576.1
5,6,7,8 -tetrahydro -1,8 -naphthyr idin- 3 - yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
498 (R)-3-benzyl-4-((4-(5-chloro-2-(8-methyl-7-oxo- 602.1
5,6,7,8 -tetrahydro -1,8 -naphthyr idin- 3 - yl)phenyl)thiazol-2-yl)(cyclopropyl)amino)-4- oxobutanoic acid
499 (R)-4-((4-(5-chloro-2-(l-methyl-2-oxo-2,3-dihydro- 554.1
1 H-pyrro lo [2 , 3 -b]pyr idin-5 -y l)pheny l)thiazo 1-2- yl)(methyl)amino)-3-(cyclopentylmethyl)-4- oxobutanoic acid 500 (R)-4-((4-(5-chloro-2-(l-methyl-2-oxo-2,3-dihydro- 580.1 1 H-pyrro lo [2 , 3 -b]pyr idin-5 -y l)pheny l)thiazo 1-2- yl)(cyclopropyl)amino)-3-(cyclopentylmethyl)-4- oxobutanoic acid
501 (R)-4-((4-(5-chloro-2-(l-methyl-2-oxo-2,3-dihydro- 570.1
1 H-pyrro lo [2 , 3 -b]pyr idin-5 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
502 (R)-4-((4-(5-chloro-2-(l-methyl-2-oxo-2,3-dihydro- 596.1 lH-pyrrolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2- yl)(cyclopropyl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
503 (R)-3-benzyl-4-((4-(5-chloro-2-(l-methyl-2-oxo-2,3- 562.1 dihydro- 1 H-pyrrolo [2,3 -b]pyridin-5 - yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
504 (R)-3-benzyl-4-((4-(5-chloro-2-(l-methyl-2-oxo-2,3- 588.1 dihydro- 1 H-pyrrolo [2,3 -b]pyridin-5 - yl)phenyl)thiazol-2-yl)(cyclopropyl)amino)-4- oxobutanoic acid
505 (R)-4-((4-(5-chloro-2-(4-methyl-3,4-dihydro-2H- 556.1 pyrido [3 ,2-b] [ 1 ,4] oxazin-7-yl)phenyl)thiazo 1-2- yl)(methyl)amino)-3-(cyclopentylmethyl)-4- oxobutanoic acid
506 (R)-4-((4-(5-chloro-2-(4-methyl-3,4-dihydro-2H- 582.1 pyrido [3 ,2-b] [ 1 ,4] oxazin-7-yl)phenyl)thiazo 1-2- yl)(cyclopropyl)amino)-3-(cyclopentylmethyl)-4- oxobutanoic acid 507 (R)-4-((4-(5-chloro-2-(4-methyl-3,4-dihydro-2H- 572.1 pyrido [3 ,2-b] [ 1 ,4] oxazin-7-yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
508 (R)-4-((4-(5-chloro-2-(4-methyl-3,4-dihydro-2H- 598.1 pyrido [3 ,2-b] [ 1 ,4] oxazin-7-yl)phenyl)thiazo 1-2- yl)(cyclopropyl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
509 (R)-3-benzyl-4-((4-(5-chloro-2-(4-methyl-3,4- 564.1 dihydro-2H-pyrido[3,2-b][l,4]oxazin-7- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
510 (R)-3-benzyl-4-((4-(5-chloro-2-(4-methyl-3,4- 590.1 dihydro-2H-pyrido[3,2-b][l,4]oxazin-7- yl)phenyl)thiazol-2-yl)(cyclopropyl)amino)-4- oxobutanoic acid
511 (R)-4-((4-(5-chloro-2-(l-methyl-lH-pyrrolo[2,3- 538.1 b]pyridin-5 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-3 - (cyclopentylmethyl)-4-oxobutano ic acid
512 (R)-4-((4-(5-chloro-2-(l-methyl-lH-pyrrolo[2,3- 564.1 b]pyridin-5 -yl)phenyl)thiazo 1-2- yl)(cyclopropyl)amino)-3-(cyclopentylmethyl)-4- oxobutanoic acid
513 (R)-4-((4-(5-chloro-2-(l-methyl-lH-pyrrolo[2,3- 554.1 b]pyridin-5 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-4- oxo-3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid 514 (R)-4-((4-(5-chloro-2-(l-methyl-lH-pyrrolo[2,3- 580.1 b]pyridin-5-yl)phenyl)thiazol-2- yl)(cyclopropyl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
515 (R)-3-benzyl-4-((4-(5-chloro-2-(l-methyl-lH- 546.1 pyrrolo [2,3 -b]pyridin-5 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
516 (R)-3-benzyl-4-((4-(5-chloro-2-(l-methyl-lH- 572.1 pyrrolo [2,3 -b]pyridin-5 -yl)phenyl)thiazo 1-2- yl)(cyclopropyl)amino)-4-oxobutanoic acid
517 (R)-3-(cyclopentylmethyl)-4-(methyl(4-(2-(8-methyl- 533.7
7-0X0-5, 6,7, 8-tetrahydro-l, 8-naphthyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
518 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(8- 559.7 methyl-7-oxo-5,6,7,8-tetrahydro-l,8-naphthyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
519 (R)-4-(methyl(4-(2-(8-methyl-7-oxo-5,6,7,8- 549.7 tetrahydro- 1 ,8-naphthyridin-3-yl)phenyl)thiazol-2- yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
520 (R)-4-(cyclopropyl(4-(2-(8-methyl-7-oxo-5,6,7,8- 575.7 tetrahydro- 1 ,8-naphthyridin-3-yl)phenyl)thiazol-2- yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
521 (R)-3-benzyl-4-(cyclopropyl(4-(2-(8-methyl-7-oxo- 567.7
5,6,7,8 -t etr ahydr o -1,8 -naphthyr idin- 3 - yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid 522 (R)-3 -(cyclopentylmethyl)-4-(methyl(4-(2-( 1 -methyl- 519.6 2-0X0-2, 3-dihydro-lH-pyrro lo[2, 3-b]pyridin-5- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
523 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(l- 545.7 methy 1-2-oxo -2 , 3 -dihy dro - 1 H-pyrrolo [2 , 3 -b]pyr idin- 5-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
524 (R)-4-(methyl(4-(2-(l-methyl-2-oxo-2,3-dihydro-lH- 535.6 pyrrolo [2,3 -b]pyridin-5 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
525 (R)-4-(cyclopropyl(4-(2-(l-methyl-2-oxo-2,3- 561.7 dihy dro- 1 H-pyrrolo [2,3 -b]pyridin-5 - yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro- 2H-pyran-4-yl)methyl)butano ic acid
526 (R)-3-benzyl-4-(cyclopropyl(4-(2-(l-methyl-2-oxo- 553.6
2,3-dihydro-lH-pyrrolo[2,3-b]pyridin-5- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
527 (R)-3-(cyclopentylmethyl)-4-(methyl(4-(2-(4-methyl- 521.6
3 ,4-dihydro-2H-pyrido [3 ,2-b] [ 1 ,4] oxazin-7- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
528 (R)-4-(methyl(4-(2-(4-methyl-3,4-dihydro-2H- 537.6 pyrido [3 ,2-b] [ 1 ,4] oxazin-7-yl)phenyl)thiazo 1-2- yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
529 (R)-4-(cyclopropyl(4-(2-(4-methyl-3,4-dihydro-2H- 563.7 pyrido [3 ,2-b] [ 1 ,4]oxazin-7-yl)phenyl)thiazo 1-2- yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid 530 (R)-3-benzyl-4-(cyclopropyl(4-(2-(4-methyl-3,4- 555.7 dihydro-2H-pyrido[3,2-b][l,4]oxazin-7- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
531 (R)-3 -(cyclopentylmethyl)-4-(methyl(4-(2-( 1 -methyl- 503.6
1 H-pyrro lo [2 , 3 -b]pyr idin-5 -y l)pheny l)thiazo 1-2- yl)amino)-4-oxobutanoic acid
532 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(l- 529.7 methyl-1 H-pyrro lo[2,3-b]pyridin-5- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
533 (R)-4-(methyl(4-(2-(l-methyl-lH-pyrrolo[2,3- 519.6 b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
534 (R)-4-(cyclopropyl(4-(2-(l-methyl-lH-pyrrolo[2,3- 545.7 b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
535 (R)-3 -benzyl-4-(cy clopropyl(4-(2-( 1 -methyl- 1 H- 537.6 pyrrolo [2,3 -b]pyridin-5 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
536 (R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(5-fluoro- 569.6
2-(8-methyl-7-oxo-5,6,7,8-tetrahydro-l,8- naphthyridin-3 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
537 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro- 595.7
4-(5-fluoro-2-(8-methyl-7-oxo-5,6,7,8-tetrahydro- 1 , 8-naphthyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4- oxobutanoic acid
538 (R)-4-((5-fluoro-4-(5-fluoro-2-(8-methyl-7-oxo- 585.6
5,6,7,8 -t etr ahydr o -1,8 -naphthyr idin- 3 - yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid 539 (R)-4-(cyclopropyl(5-fluoro-4-(5-fluoro-2-(8-methyl- 611.7 7-0X0-5, 6,7, 8-tetrahydro-l, 8-naphthyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro- 2H-pyran-4-yl)methyl)butano ic acid
540 (R)-3-benzyl-4-((5-fluoro-4-(5-fluoro-2-(8-methyl-7- 577.6 oxo-5,6,7,8 -tetrahy dro -1,8 -naphthyridin-3 - yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
541 (R)-3-benzyl-4-(cyclopropyl(5-fluoro-4-(5-fluoro-2- 603.7
(8-methyl-7-oxo-5, 6,7, 8-tetrahydro-l, 8-naphthyridin- 3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
542 (R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(5-fluoro- 555.6
2-(l-methyl-2-oxo-2,3-dihydro-lH-pyrrolo[2,3- b]pyridin-5 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-4- oxobutanoic acid
543 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro- 581.6
4-(5-fluoro-2-(l-methyl-2-oxo-2,3-dihydro-lH- pyrrolo [2,3 -b]pyridin-5 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
544 (R)-4-((5-fluoro-4-(5-fluoro-2-(l-methyl-2-oxo-2,3- 571.6 dihydro- 1 H-pyrrolo [2,3 -b]pyridin-5 - yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
545 (R)-4-(cyclopropyl(5-fluoro-4-(5-fluoro-2-(l-methyl- 597.6
2-0X0-2, 3-dihydro-lH-pyrro lo[2, 3-b]pyridin-5- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro- 2H-pyran-4-yl)methyl)butano ic acid 546 (R)-3-benzyl-4-((5-fluoro-4-(5-fluoro-2-(l-methyl-2- 563.6 oxo-2,3-dihydro-lH-pyrrolo[2,3-b]pyridin-5- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
547 (R)-3-benzyl-4-(cyclopropyl(5-fluoro-4-(5-fluoro-2- 589.6
( 1 -methy 1-2-oxo -2 , 3 -dihy dro - 1 H-pyrrolo [2,3- b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
548 (R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(5-fluoro- 557.6
2-(4-methyl-3 ,4-dihydro-2H-pyrido [3 ,2- b][l,4]oxazin-7-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
549 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro- 583.7
4-(5-fluoro-2-(4-methyl-3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazin-7-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
550 (R)-4-((5-fluoro-4-(5-fluoro-2-(4-methyl-3,4- 573.6 dihydro-2H-pyrido[3,2-b][l,4]oxazin-7- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
551 (R)-4-(cyclopropyl(5-fluoro-4-(5-fluoro-2-(4-methyl- 599.7
3 ,4-dihydro-2H-pyrido [3 ,2-b] [ 1 ,4] oxazin-7- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro- 2H-pyran-4-yl)methyl)butano ic acid
552 (R)-3-benzyl-4-((5-fluoro-4-(5-fluoro-2-(4-methyl- 565.6
3 ,4-dihydro-2H-pyrido [3 ,2-b] [ 1 ,4] oxazin-7- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid 553 (R)-3-benzyl-4-(cyclopropyl(5-fluoro-4-(5-fluoro-2- 591.6 (4-methyl-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin- 7-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
554 (R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(5-fluoro- 539.6
2-(l -methyl- 1 H-pyrrolo[2, 3-b]pyridin-5- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
555 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro- 565.6
4-(5 -fluoro-2-( 1 -methyl- 1 H-pyrrolo [2 ,3 -b]pyridin-5 - yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
556 (R)-4-((5 -fluoro-4-(5 - fluoro-2-( 1 -methyl- 1 H- 555.6 pyrrolo [2,3 -b]pyridin-5 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
557 (R)-4-(cyclopropyl(5-fluoro-4-(5-fluoro-2-(l-methyl- 581.6
1 H-pyrro lo [2 , 3 -b]pyr idin-5 -y l)pheny l)thiazo 1-2- yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
558 (R)-3-benzyl-4-((5-fluoro-4-(5-fluoro-2-(l-methyl- 547.6
1 H-pyrro lo [2 , 3 -b]pyr idin-5 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
559 (R)-3-berizyl-4-(cyclopropyl(5-fluoro-4-(5-fluoro-2- 573.6
(l-methyl-lH-pyrrolo[2,3-b]pyridin-5- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
560 (R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(5- 599.7
(fluoromethoxy)-2-(8-methyl-7-oxo-5, 6,7,8- tetrahydro- 1 ,8-naphthyridin-3-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid 561 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro- 625.7 4-(5-(fluoromethoxy)-2-(8-methyl-7-oxo-5, 6,7,8- tetrahydro- 1 ,8-naphthyridin-3-yl)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid
562 (R)-4-((5-fluoro-4-(5-(fluoromethoxy)-2-(8-methyl- 615.7
7-oxo-5, 6,7, 8-tetrahydro-l, 8-naphthyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
563 (R)-4-(cyclopropyl(5-fluoro-4-(5-(fluoromethoxy)-2- 641.7
(8-methyl-7-oxo-5, 6,7, 8-tetrahydro-l, 8-naphthyridin- 3-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
564 (R)-3-benzyl-4-((5-fluoro-4-(5-(fluoromethoxy)-2-(8- 607.6 methyl-7-oxo-5, 6,7, 8-tetrahydro-l, 8-naphthyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
565 (R)-3 -benzyl-4-(cy clopropyl(5 -fluoro-4-(5 - 633.7
(fluoromethoxy)-2-(8-methyl-7-oxo-5, 6,7,8- tetrahydro- 1 ,8-naphthyridin-3-yl)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid
566 (R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(5- 585.6
(fluoromethoxy)-2-(l-methyl-2-oxo-2,3-dihydro-lH- pyrrolo [2,3 -b]pyridin-5 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
567 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro- 611.7
4-(5-(fluoromethoxy)-2-(l-methyl-2-oxo-2,3- dihydro-lH-pyrrolo[2,3-b]pyridin-5- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid 568 (R)-4-((5-fluoro-4-(5-(fluoromethoxy)-2-(l-methyl- 601.6 2-0X0-2, 3-dihydro-lH-pyrro lo[2, 3-b]pyridin-5- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
569 (R)-4-(cyclopropyl(5-fluoro-4-(5-(fluoromethoxy)-2- 627.7
( 1 -methy 1-2-oxo -2 , 3 -dihy dro - 1 H-pyrrolo [2,3- b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
570 (R)-3-benzyl-4-((5-fluoro-4-(5-(fluoromethoxy)-2-(l- 593.6 methy 1-2-oxo -2 , 3 -dihy dro - 1 H-pyrrolo [2 , 3 -b]pyr idin- 5 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-4- oxobutanoic acid
571 (R)-3 -benzyl-4-(cy clopropyl(5 -fluoro-4-(5 - 619.7
(fluoromethoxy)-2-(l-methyl-2-oxo-2,3-dihydro-lH- pyrrolo [2,3 -b]pyridin-5 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
572 (R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(5- 587.7
(fluoromethoxy)-2-(4-methyl-3,4-dihydro-2H- pyrido [3 ,2-b] [ 1 ,4] oxazin-7-yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
573 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro- 613.7
4-(5-(fluoromethoxy)-2-(4-methyl-3,4-dihydro-2H- pyrido [3 ,2-b] [ 1 ,4] oxazin-7-yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
574 (R)-4-((5-fluoro-4-(5-(fluoromethoxy)-2-(4-methyl- 603.6
3 ,4-dihydro-2H-pyrido [3 ,2-b] [ 1 ,4] oxazin-7- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid 575 (R)-4-(cyclopropyl(5-fluoro-4-(5-(fluoromethoxy)-2- 629.7 (4-methyl-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin- 7-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
576 (R)-3-benzyl-4-((5-fluoro-4-(5-(fluoromethoxy)-2-(4- 595.6 methyl-3 ,4-dihydro-2H-pyrido[3 ,2-b] [ 1 ,4]oxazin-7- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
577 (R)-3 -benzyl-4-(cy clopropyl(5 -fluoro-4-(5 - 621.7
(fluoromethoxy)-2-(4-methyl-3,4-dihydro-2H- pyrido [3 ,2-b] [ 1 ,4] oxazin-7-yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
578 (R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(5- 569.6
(fluoromethoxy)-2-(l -methyl- 1 H-pyrrolo[2,3- b]pyridin-5 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-4- oxobutanoic acid
579 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro- 595.7
4-(5-(fluoromethoxy)-2-(l -methyl- 1 H-pyrrolo[2,3- b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
580 (R)-4-((5-fluoro-4-(5-(fluoromethoxy)-2-(l-methyl- 585.6
1 H-pyrro lo [2 , 3 -b]pyr idin-5 -y l)pheny l)thiazo 1-2- yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
581 (R)-4-(cyclopropyl(5-fluoro-4-(5-(fluoromethoxy)-2- 611.7
(l-methyl-lH-pyrrolo[2,3-b]pyridin-5- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro- 2H-pyran-4-yl)methyl)butano ic acid 582 (R)-3-benzyl-4-((5-fluoro-4-(5-(fluoromethoxy)-2-(l- 577.6 methyl- 1 H-pyrrolo[2,3-b]pyridin-5- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
583 (R)-3 -benzyl-4-(cy clopropyl(5 -fluoro-4-(5 - 603.7
(fluoromethoxy)-2-(l -methyl- 1 H-pyrrolo[2,3- b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
584 (R)-4-((4-(5-chloro-2-(8-methyl-7-oxo-5,6,7,8- 586.1 tetrahydro- 1 ,8-naphthyridin-3-yl)phenyl)-5- fluorothiazo l-2-yl)(methyl)amino)-3 - (cyclopentylmethyl)-4-oxobutano ic acid
585 (R)-4-((4-(5-chloro-2-(8-methyl-7-oxo-5,6,7,8- 612.1 tetrahydro- 1 ,8-naphthyridin-3-yl)phenyl)-5- fluorothiazo l-2-yl)(cyclopropyl)amino)-3 - (cyclopentylmethyl)-4-oxobutano ic acid
586 (R)-4-((4-(5-chloro-2-(8-methyl-7-oxo-5,6,7,8- 602.1 tetrahydro- 1 ,8-naphthyridin-3-yl)phenyl)-5- fluorothiazol-2-yl)(methyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
587 (R)-4-((4-(5-chloro-2-(8-methyl-7-oxo-5,6,7,8- 628.1 tetrahydro- 1 ,8-naphthyridin-3-yl)phenyl)-5- fluorothiazol-2-yl)(cyclopropyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
588 (R)-3-benzyl-4-((4-(5-chloro-2-(8-methyl-7-oxo- 594.1
5,6,7,8-tetrahydro-l,8-naphthyridin-3-yl)phenyl)-5- fluorothiazol-2-yl)(methyl)amino)-4-oxobutanoic acid 589 (R)-3-benzyl-4-((4-(5-chloro-2-(8-methyl-7-oxo- 620.1 5,6,7,8-tetrahydro-l,8-naphthyridin-3-yl)phenyl)-5- fluorothiazol-2-yl)(cyclopropyl)amino)-4- oxobutanoic acid
590 (R)-4-((4-(5-chloro-2-(l-methyl-2-oxo-2,3-dihydro- 572.1
1 H-pyrrolo [2,3 -b]pyridin-5 -yl)phenyl)-5 - fluorothiazo l-2-yl)(methyl)amino)-3 - (cyclopentylmethyl)-4-oxobutano ic acid
591 (R)-4-((4-(5-chloro-2-(l-methyl-2-oxo-2,3-dihydro- 598.1
1 H-pyrrolo [2,3 -b]pyridin-5 -yl)phenyl)-5 - fluorothiazo l-2-yl)(cyclopropyl)amino)-3 - (cyclopentylmethyl)-4-oxobutano ic acid
592 (R)-4-((4-(5-chloro-2-(l-methyl-2-oxo-2,3-dihydro- 588.1
1 H-pyrrolo [2,3 -b]pyridin-5 -yl)phenyl)-5 - fluorothiazo l-2-yl)(methyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
593 (R)-4-((4-(5-chloro-2-(l-methyl-2-oxo-2,3-dihydro- 614.1
1 H-pyrrolo [2,3 -b]pyridin-5 -yl)phenyl)-5 - fluorothiazo l-2-yl)(cyclopropyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
594 (R)-3-benzyl-4-((4-(5-chloro-2-(l-methyl-2-oxo-2,3- 580.0 dihydro-lH-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-5- fluorothiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
595 (R)-3-benzyl-4-((4-(5-chloro-2-(l-methyl-2-oxo-2,3- 606.1 dihydro-lH-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-5- fluorothiazol-2-yl)(cyclopropyl)amino)-4- oxobutanoic acid 596 (R)-4-((4-(5-chloro-2-(4-methyl-3,4-dihydro-2H- 574.1 pyrido [3 ,2-b] [ 1 ,4] oxazin-7-yl)phenyl)-5 - fluorothiazo l-2-yl)(methyl)amino)-3 - (cyclopentylmethyl)-4-oxobutano ic acid
597 (R)-4-((4-(5-chloro-2-(4-methyl-3,4-dihydro-2H- 600.1 pyrido [3 ,2-b] [ 1 ,4] oxazin-7-yl)phenyl)-5 - fluorothiazo l-2-yl)(cyclopropyl)amino)-3 - (cyclopentylmethyl)-4-oxobutano ic acid
598 (R)-4-((4-(5-chloro-2-(4-methyl-3,4-dihydro-2H- 590.1 pyrido [3 ,2-b] [ 1 ,4] oxazin-7-yl)phenyl)-5 - fluorothiazo l-2-yl)(methyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
599 (R)-4-((4-(5-chloro-2-(4-methyl-3,4-dihydro-2H- 616.1 pyrido [3 ,2-b] [ 1 ,4] oxazin-7-yl)phenyl)-5 - fluorothiazo l-2-yl)(cyclopropyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
600 (R)-3-benzyl-4-((4-(5-chloro-2-(4-methyl-3,4- 582.1 dihydro-2H-pyrido[3,2-b][l,4]oxazin-7-yl)phenyl)-5- fluorothiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
601 (R)-3-benzyl-4-((4-(5-chloro-2-(4-methyl-3,4- 608.1 dihydro-2H-pyrido[3,2-b][l,4]oxazin-7-yl)phenyl)-5- fluorothiazol-2-yl)(cyclopropyl)amino)-4- oxobutanoic acid
602 (R)-4-((4-(5-chloro-2-(l-methyl-lH-pyrrolo[2,3- 556.1 b]pyridin-5-yl)phenyl)-5-fluorothiazol-2- yl)(methyl)amino)-3-(cyclopentylmethyl)-4- oxobutanoic acid 603 (R)-4-((4-(5-chloro-2-(l-methyl-lH-pyrrolo[2,3- 582.1 b]pyridin-5 -yl)phenyl)-5 -fluorothiazo 1-2- yl)(cyclopropyl)amino)-3-(cyclopentylmethyl)-4- oxobutanoic acid
604 (R)-4-((4-(5-chloro-2-(l-methyl-lH-pyrrolo[2,3- 572.1 b]pyridin-5 -yl)phenyl)-5 -fluorothiazo 1-2- yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
605 (R)-4-((4-(5-chloro-2-(l-methyl-lH-pyrrolo[2,3- 598.1 b]pyridin-5 -yl)phenyl)-5 -fluorothiazo 1-2- yl)(cyclopropyl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
606 (R)-3-benzyl-4-((4-(5-chloro-2-(l-methyl-lH- 564.0 pyrrolo [2,3 -b]pyridin-5 -yl)phenyl)-5 -fluorothiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
607 (R)-3-benzyl-4-((4-(5-chloro-2-(l-methyl-lH- 590.1 pyrrolo [2,3 -b]pyridin-5 -yl)phenyl)-5 -fluorothiazo 1-2- yl)(cyclopropyl)amino)-4-oxobutanoic acid
608 (R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(2-(8- 551.6 methyl-7-oxo-5,6,7,8-tetrahydro-l,8-naphthyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
609 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro- 577.7
4-(2-(8-methyl-7-oxo-5,6,7,8-tetrahydro-l,8- naphthyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4- oxobutanoic acid 610 (R)-4-((5-fluoro-4-(2-(8-methyl-7-oxo-5,6,7,8- 567.6 tetrahydro- 1 ,8-naphthyridin-3-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
611 (R)-4-(cyclopropyl(5-fluoro-4-(2-(8-methyl-7-oxo- 593.7
5,6,7,8 -t etr ahydr o -1,8 -naphthyr idin- 3 - yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro- 2H-pyran-4-yl)methyl)butano ic acid
612 (R)-3-benzyl-4-((5-fluoro-4-(2-(8-methyl-7-oxo- 559.6
5,6,7,8 -t etr ahydr o -1,8 -naphthyr idin- 3 - yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
613 (R)-3-benzyl-4-(cyclopropyl(5-fluoro-4-(2-(8- 585.7 methyl-7-oxo-5,6,7,8-tetrahydro-l,8-naphthyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
614 (R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(2-(l- 537.6 methy 1-2-oxo -2 , 3 -dihy dro - 1 H-pyrrolo [2 , 3 -b]pyr idin- 5 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-4- oxobutanoic acid
615 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro- 563.7
4-(2-(l-methyl-2-oxo-2,3-dihydro-lH-pyrrolo[2,3- b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
616 (R)-4-((5-fluoro-4-(2-(l-methyl-2-oxo-2,3-dihydro- 553.6
1 H-pyrro lo [2 , 3 -b]pyr idin-5 -y l)pheny l)thiazo 1-2- yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid 617 (R)-4-(cyclopropyl(5-fluoro-4-(2-(l-methyl-2-oxo- 579.7 2,3-dihydro-lH-pyrrolo[2,3-b]pyridin-5- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro- 2H-pyran-4-yl)methyl)butano ic acid
618 (R)-3-benzyl-4-((5-fluoro-4-(2-(l-methyl-2-oxo-2,3- 545.6 dihydro- 1 H-pyrrolo [2,3 -b]pyridin-5 - yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
619 (R)-3-benzyl-4-(cyclopropyl(5-fluoro-4-(2-(l- 571.6 methy 1-2-oxo -2 , 3 -dihy dro - 1 H-pyrrolo [2 , 3 -b]pyr idin- 5-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
620 (R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(2-(4- 539.6 methyl-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-7- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
621 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro- 565.7
4-(2-(4-methyl-3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazin-7-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
622 (R)-4-((5-fluoro-4-(2-(4-methyl-3,4-dihydro-2H- 555.6 pyrido [3 ,2-b] [ 1 ,4] oxazin-7-yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
623 (R)-4-(cyclopropyl(5-fluoro-4-(2-(4-methyl-3,4- 581.7 dihydro-2H-pyrido[3,2-b][l,4]oxazin-7- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro- 2H-pyran-4-yl)methyl)butano ic acid 624 (R)-3-benzyl-4-((5-fluoro-4-(2-(4-methyl-3,4- 547.6 dihydro-2H-pyrido[3,2-b][l,4]oxazin-7- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
625 (R)-3-benzyl-4-(cyclopropyl(5-fluoro-4-(2-(4- 573.7 methyl-3 ,4-dihydro-2H-pyrido[3 ,2-b] [ 1 ,4]oxazin-7- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
626 (R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(2-(l- 521.6 methyl- 1 H-pyrrolo[2,3-b]pyridin-5- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
627 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro- 547.7
4-(2-(l-methyl-lH-pyrrolo[2,3-b]pyridin-5- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
628 (R)-4-((5-fluoro-4-(2-(l -methyl- 1 H-pyrrolo[2,3- 537.6 b]pyridin-5 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-4- oxo-3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
629 (R)-4-(cyclopropyl(5 - fluoro-4-(2-( 1 -methyl- 1 H- 563.7 pyrrolo [2,3 -b]pyridin-5 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
630 (R)-3 -benzyl-4-((5 - fluoro-4-(2-( 1 -methyl- 1 H- 529.6 pyrrolo [2,3 -b]pyridin-5 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
631 (R)-3-benzyl-4-(cyclopropyl(5-fluoro-4-(2-(l- 555.6 methyl- 1 H-pyrrolo[2,3-b]pyridin-5- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid 632 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(l- 529.7 methyl- 1 H-pyrrolo[3 ,2-b]pyridin-6- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
633 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(l- 546.7 methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin- 6-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
634 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(l- 560.7 methyl-2-oxo- 1,2,3 ,4-tetrahydropyrido [3,2- d]pyrimidin-7-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
635 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(l- 545.7 methyl-2-oxo-2,3-dihydro-lH-pyrrolo[3,2-b]pyridin- 6-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
636 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 559.7 methyl-5-oxo-5,6,7,8-tetrahydro-l,6-naphthyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
637 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(l,3- 574.7 dimethyl-2-oxo- 1 ,2,3 ,4-tetrahydropyrido [3 ,2- d]pyrimidin-7-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
638 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(7- 559.7 methyl-8-oxo-5,6,7,8-tetrahydro-l,7-naphthyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
639 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 545.7 methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin- 3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
640 (R)-4-((4-(2-(5-chloro-6-(2-oxopyrrolidin- 1 - 594.1 yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)(cyclopropyl)amino)-3-(cyclopentylmethyl)-4- oxobutanoic acid 641 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(3- 530.7 methyl-3 H-imidazo [4,5 -b]pyridin-6- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
642 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(l- 547.7 methy 1-2 , 3 -dihy dro - 1 H-pyr ido [2 , 3 -b] [ 1 ,4] oxazin-7 - yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
643 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(3- 546.7 methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin- 6-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
644 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(7- 559.7 methyl-6-oxo-5,6,7,8-tetrahydro-l,7-naphthyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
645 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 545.7 methyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin- 3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
646 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(l,3- 560.7 dimethyl-2-oxo-2,3-dihydro-lH-imidazo[4,5- b]pyridin-6-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
647 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(l- 530.7 methyl- 1 H-imidazo[4,5-b]pyridin-6- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
648 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(5- 577.7 fluoro-6-(2-oxopyrrolidin- 1 -yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
649 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(l- 559.7 methyl-2-oxo- 1 ,2,3 ,4-tetrahydro- 1 ,5-naphthyridin-7- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid 650 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(3- 560.7 methyl-2-oxo- 1,2,3 ,4-tetrahydropyrido [3,2- d]pyrimidin-7-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
651 (R)-4-(cyclopropyl(5-fluoro-4-(5-methyl-2-(6-(2- 597.7 oxopyrrolidin- 1 -yl)pyridin-3-yl)furan-3-yl)thiazol-2- yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
652 (R)-4-(cyclopropyl(4-(5-methyl-2-(6-(2- 579.7 oxopyrrolidin- 1 -yl)pyridin-3-yl)furan-3-yl)thiazol-2- yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
653 (R)-4-((5-fluoro-4-(5-methyl-2-(6-(2-oxopyrrolidin- 571.6
1 -yl)pyridin-3 -yl)furan-3 -yl)thiazo 1-2- yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
654 (R)-4-(methyl(4-(5-methyl-2-(6-(2-oxopyrrolidin- 1 - 553.6 yl)pyridin-3-yl)furan-3-yl)thiazol-2-yl)amino)-4-oxo- 3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
655 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro- 581.7
4-(5-methyl-2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3- yl)furan-3-yl)thiazol-2-yl)amino)-4-oxobutanoic acid
656 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5- 563.7 methyl-2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3- yl)furan-3-yl)thiazol-2-yl)amino)-4-oxobutanoic acid
657 (R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(5-methyl- 555.6
2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3-yl)furan-3- yl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid 658 (R)-3 -(cyclopentylmethyl)-4-(methyl(4-(5 -methyl-2- 537.6 (6-(2-oxopyrrolidin- 1 -yl)pyridin-3-yl)furan-3- yl)thiazol-2-yl)amino)-4-oxobutanoic acid
659 (R)-3-benzyl-4-(cyclopropyl(5-fluoro-4-(5-methyl-2- 589.6
(6-(2-oxopyrrolidin- 1 -yl)pyridin-3-yl)furan-3- yl)thiazol-2-yl)amino)-4-oxobutanoic acid
660 (R)-3-benzyl-4-(cyclopropyl(4-(5-methyl-2-(6-(2- 571.7 oxopyrrolidin- 1 -yl)pyridin-3-yl)furan-3-yl)thiazol-2- yl)amino)-4-oxobutanoic acid
661 (R)-3-benzyl-4-((5-fluoro-4-(5-methyl-2-(6-(2- 563.6 oxopyrrolidin- 1 -yl)pyridin-3-yl)furan-3-yl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
662 (R)-3-benzyl-4-(methyl(4-(5-methyl-2-(6-(2- 545.6 oxopyrrolidin- 1 -yl)pyridin-3-yl)furan-3-yl)thiazol-2- yl)amino)-4-oxobutanoic acid
663 (R)-3-benzyl-4-(methyl(3-(2-(6-(2-oxopyrrolidin- 1 - 542.6 yl)pyridin-3-yl)phenyl)- 1 ,2,4-thiadiazol-5-yl)amino)- 4-oxobutanoic acid
664 (R)-3-benzyl-4-(cyclopropyl(3-(2-(6-(2- 568.7 oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)- 1 ,2,4- thiadiazol-5-yl)amino)-4-oxobutanoic acid
665 (R)-3-(cyclopentylmethyl)-4-(methyl(3-(2-(6-(2- 534.6 oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)- 1 ,2,4- thiadiazol-5-yl)amino)-4-oxobutanoic acid
666 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(3-(2-(6-(2- 560.7 oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)- 1 ,2,4- thiadiazol-5-yl)amino)-4-oxobutanoic acid
667 (R)-4-(methyl(3-(2-(6-(2-oxopyrrolidin- 1 -yl)pyridin- 550.6
3-yl)phenyl)- 1 ,2,4-thiadiazol-5-yl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid 668 (R)-4-(cyclopropyl(3-(2-(6-(2-oxopyrrolidin- 1 - 576.7 yl)pyridin-3-yl)phenyl)- 1 ,2,4-thiadiazol-5-yl)amino)- 4-oxo-3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
669 (3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2,5- 595.7 dimethyl-4-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3- yl)furan-3 -yl)-5 -fluorothiazo l-2-yl)amino)-4- oxobutanoic acid
670 (3R)-3-(cyclopentylmethyl)-4-((4-(2,5-dimethyl-4-(6- 569.7
(2-oxopyrrolidin- 1 -yl)pyridin-3-yl)furan-3-yl)-5- fluorothiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
671 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2,5- 577.7 dimethyl-4-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3- yl)furan-3-yl)thiazol-2-yl)amino)-4-oxobutanoic acid
672 (R)-3-(cyclopentylmethyl)-4-((4-(2,5-dimethyl-4-(6- 551.7
(2-oxopyrrolidin- 1 -yl)pyridin-3-yl)furan-3-yl)thiazol- 2-yl)(methyl)amino)-4-oxobutanoic acid
673 (3R)-4-(cyclopropyl(4-(2,5-dimethyl-4-(6-(2- 611.7 oxopyrrolidin- 1 -yl)pyridin-3-yl)furan-3-yl)-5- fluorothiazol-2-yl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
674 (3R)-4-((4-(2,5-dimethyl-4-(6-(2-oxopyrrolidin-l- 585.7 yl)pyridin-3 -yl)furan-3 -yl)-5 -fluorothiazo 1-2- yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
675 (R)-4-(cyclopropyl(4-(2,5-dimethyl-4-(6-(2- 593.7 oxopyrrolidin- 1 -yl)pyridin-3-yl)furan-3-yl)thiazol-2- yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid 676 (R)-4-((4-(2,5-dimethyl-4-(6-(2-oxopyrrolidin- 1 - 567.7 yl)pyridin-3 -yl)furan-3 -yl)thiazo 1-2- yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
677 (3R)-3-benzyl-4-(cyclopropyl(4-(2,5-dimethyl-4-(6- 603.7
(2-oxopyrrolidin- 1 -yl)pyridin-3-yl)furan-3-yl)-5- fluorothiazol-2-yl)amino)-4-oxobutanoic acid
678 (3R)-3-benzyl-4-((4-(2,5-dimethyl-4-(6-(2- 577.6 oxopyrrolidin- 1 -yl)pyridin-3-yl)furan-3-yl)-5- fluorothiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
679 (R)-3-benzyl-4-(cyclopropyl(4-(2,5-dimethyl-4-(6-(2- 585.7 oxopyrrolidin- 1 -yl)pyridin-3-yl)furan-3-yl)thiazol-2- yl)amino)-4-oxobutanoic acid
680 (R)-3-benzyl-4-((4-(2,5-dimethyl-4-(6-(2- 559.6 oxopyrrolidin- 1 -yl)pyridin-3-yl)furan-3-yl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
681 (3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 587.7
(l-methyl-6-oxopiperidin-3-yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
682 (3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 587.7
(l-methyl-2-oxopiperidin-4-yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
683 (3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 574.7
(3 -methyl-2-oxoimidazo lidin-4-yl)pyridin-3 - yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
684 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 547.7
(N-methylacetamido)pyridin-3-yl)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid 685 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 602.8 (l,3-dimethyl-2-oxohexahydropyrimidin-5- yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
686 (3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 559.7
(5 -oxopyrrolidin-3 -yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
687 (3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 574.7
(l-methyl-2-oxoimidazolidin-4-yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
688 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 545.7
(pyrrolidin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid
689 (3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 560.7
(2-oxoimidazolidin-4-yl)pyridin-3-yl)phenyl)thiazol- 2-yl)amino)-4-oxobutanoic acid
690 (3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 573.7
(l-methyl-5-oxopyrrolidin-2-yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
691 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(4- 588.7 methyl-3-oxopiperazin- 1 -yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
692 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(4- 602.7 methyl-2,5-dioxopiperazin- 1 -yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
693 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 547.7
(dimethylcarbamoyl)pyridin-3-yl)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid 694 (3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 588.7 (3-methyl-2-oxohexahydropyrimidin-4-yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
695 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 534.7 isopropoxypyridin-3-yl)phenyl)thiazol-2-yl)amino)- 4-oxobutanoic acid
696 (3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 587.7
(l-methyl-6-oxopiperidin-2-yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
697 (3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 573.7
( 1 -methyl-5 -oxopyrrolidin-3 -yl)pyridin-3 - yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
698 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(3- 588.7 methyl-2-oxotetrahydropyrimidin- 1 (2H)-yl)pyridin- 3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
699 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(2- 574.7 oxotetrahydropyrimidin- 1 (2H)-yl)pyridin-3 - yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
700 (3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 588.7
(l,3-dimethyl-2-oxoimidazolidin-4-yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
701 (3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 602.8
(l,3-dimethyl-2-oxohexahydropyrimidin-4- yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
702 (3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 588.7
(l-methyl-2-oxohexahydropyrimidin-4-yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid 703 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 573.7 (N-methylcyclopropanecarboxamido)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
704 (3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 573.7
(l-methyl-2-oxopyrrolidin-3-yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
705 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 546.7
(cyclopropylmethoxy)pyridin-3 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
706 (3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 559.7
(2-oxopyrrolidin-3 -yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
707 (3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 587.7
(l-methyl-2-oxopiperidin-3-yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
708 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 520.7
(methoxymethyl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
709 (3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 588.7
(l-methyl-2-oxohexahydropyrimidin-5-yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
710 (3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 559.7
(5 -oxopyrrolidin-2-yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
711 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(2- 627.7 oxopyrrolidin- 1 -yl)pyridin-3-yl)-5- (trifluoromethyl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid 712 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5- 607.7 (fluoromethoxy)-2-(6-(2-oxopyrrolidin- 1 -yl)pyridin- 3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
713 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(2- 643.7 oxopyrrolidin- 1 -yl)pyridin-3-yl)-5- (trifluoromethoxy)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
714 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 - 568.7 yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3- (pyridin-2-ylmethyl)butanoic acid
715 (R)-2-(2-(carboxymethyl)-3-(cyclopropyl(4-(2-(6-(2- 584.7 oxopyrrolidin- 1 -yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)amino)-3-oxopropyl)pyridine 1 -oxide
716 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 - 575.7 yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3- (((R)-tetrahydro-2H-pyran-2-yl)methyl)butanoic acid
717 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 - 569.6 yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3- (pyrimidin-2-ylmethyl)butanoic acid
718 (S)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 - 573.7 yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3- (thiophen-2-ylmethyl)butano ic acid
719 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 - 561.7 yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3- (((S)-tetrahydrofuran-2-yl)methyl)butano ic acid
720 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 - 575.7 yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3- (((S)-tetrahydro-2H-pyran-3-yl)methyl)butanoic acid 721 (3R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 - 589.7 yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-3-(((2S)- 2-methyltetrahydro-2H-pyran-4-yl)methyl)-4- oxobutanoic acid
722 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 - 575.7 yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3- (((R)-tetrahydro-2H-pyran-3-yl)methyl)butanoic acid
723 (3R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 - 603.7 yl)pyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-3 - (((3R,5S)-3,5-dimethyltetrahydro-2H-pyran-4- yl)methyl)-4-oxobutanoic acid
724 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 - 589.7 yl)pyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-3 - (((2R,3R)-2-methyltetrahydro-2H-pyran-3- yl)methyl)-4-oxobutanoic acid
725 (3R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 - 589.7 yl)pyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-3 -(((3 S)- 3-methyltetrahydro-2H-pyran-4-yl)methyl)-4- oxobutanoic acid
726 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 - 575.7 yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3- (((S)-tetrahydro-2H-pyran-2-yl)methyl)butanoic acid
727 (R)-3-(benzofuran-2-ylmethyl)-4-(cyclopropyl(4-(2- 607.7
(6-(2-oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)thiazol- 2-yl)amino)-4-oxobutanoic acid
728 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 - 561.7 yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3- (((R)-tetrahydrofuran-2-yl)methyl)butanoic acid 729 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 - 571.7 yl)pyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-3 -((5 - methylfuran-2-yl)methyl)-4-oxobutanoic acid
730 (3R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 - 575.7 yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-3-yl)methyl)butanoic acid
731 (3R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 - 603.7 yl)pyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-3 - (((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4- yl)methyl)-4-oxobutanoic acid
732 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 - 557.6 yl)pyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-3 -(furan- 2-ylmethyl)-4-oxobutanoic acid
733 (3R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 - 575.7 yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-2-yl)methyl)butanoic acid
734 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 506.6 methoxypyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4- oxobutanoic acid
735 (R)-4-((4-(5-chloro-2-(6-methoxypyridin-3- 541.1 yl)phenyl)thiazo l-2-yl)(cyclopropyl)amino)-3 - (cyclopentylmethyl)-4-oxobutano ic acid
736 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 - 547.6 yl)pyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-3 - (oxetan-3-ylmethyl)-4-oxobutanoic acid
737 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 532.7
(oxetan-3 -yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid 738 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 - 547.6 yl)pyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-3 - (oxetan-3-ylmethyl)-4-oxobutanoic acid
739 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(3- 546.7 methyloxetan-3 -yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
740 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 - 547.6 yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-3- (oxetan-3-ylmethyl)-4-oxobutanoic acid
741 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(3- 550.7 fluorooxetan-3 -yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
742 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 - 561.7 yl)pyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-3 -((3 - methyloxetan-3-yl)methyl)-4-oxobutanoic acid
743 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 532.7
(oxetan-3 -yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
744 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 - 561.7 yl)pyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-3 -((3 - methyloxetan-3-yl)methyl)-4-oxobutanoic acid
745 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(3- 546.7 methyloxetan-3 -yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
746 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 - 561.7 yl)pyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-3 -((3 - methyloxetan-3-yl)methyl)-4-oxobutanoic acid
747 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(3- 550.7 fluorooxetan-3 -yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid 748 (S)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 - 565.6 yl)pyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-3 -((3 - fluorooxetan-3-yl)methyl)-4-oxobutanoic acid
749 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- 532.7
(oxetan-3 -yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
750 (S)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 - 565.6 yl)pyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-3 -((3 - fluorooxetan-3-yl)methyl)-4-oxobutanoic acid
751 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(3- 546.7 methyloxetan-3 -yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
752 (S)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 - 565.6 yl)pyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-3 -((3 - fluorooxetan-3-yl)methyl)-4-oxobutanoic acid
753 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(3- 550.7 fluorooxetan-3 -yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
The names of the compounds of the invention were generated using
CambridgeSoft's Chemdraw vl2.
The compounds of formula I can be prepared by different ways with reactions known by the person skilled in the art. Reaction schemes as described in the example section illustrate by way of example different possible approaches.
The inflammatory disease may be, without being limited thereto, selected from the group consisting of rheumatoid arthritis; inflammatory bowel disease (IBD) including but not limited to Crohn's disease, ulcerative colitis and colitis; Pagets disease; osteoporosis; multiple myeloma; uveitilis; acute and chronic myelogenous leukemia; pancreatic β cell destruction; rheumatoid spondylitis; osteoarthritis; gouty arthritis and other arthritis conditions; gout; adult respiratory distress syndrome (ARDS); chronic pulmonary inflammation diseases; silicosis; pulmonary sarcoidosis; psoriasis; allergic rhinitis; anaphylaxis; contact dermatitis; pancreatitis; asthma; muscle degeneration; cachexia such as cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome; Reiter's syndrome; type I diabetes; bone resorption disease; graft vs. host reaction; ischemia reperfusion injury; brain trauma; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; endotoxic shock; gram negative sepsis; fever and myalgias due to infection such as influenza; pyrosis. More particularly, the inflammatory disease may be, without being limited thereto, selected from the group consisting of rheumatoid arthritis; inflammatory bowel disease (IBD) including but not limited to Crohn's disease, ulcerative colitis and colitis; Pagets disease; osteoporosis; multiple myeloma; uveitilis; acute and chronic myelogenous leukemia; pancreatic β cell destruction; rheumatoid spondylitis, osteoarthritis; gouty arthritis and other arthritis conditions; gout; adult respiratory distress syndrome (ARDS); chronic pulmonary inflammation diseases; silicosis; pulmonary sarcoidosis; psoriasis; allergic rhinitis; anaphylaxis; contact dermatitis; pancreatitis; asthma; muscle degeneration; cachexia such as cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome; Reiter's syndrome; bone resorption disease; graft vs. host reaction; ischemia reperfusion injury; brain trauma; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; endotoxic shock; gram negative sepsis; fever and myalgias due to infection such as influenza; and pyrosis.
In one embodiment, the inflammatory diseases are TNF, IL-1, IL-6, and/or IL-8 mediated diseases or disease states.
The patient receiving the treatment/medicament according to the invention is preferably a warm-blooded animal, more preferably a human.
The invention also provides a method for delaying in a patient the onset of an inflammatory disease, comprising the administration of a pharmaceutically effective amount of a compound of formula (I) or pharmaceutically acceptable salt or solvate thereof to a patient in need thereof. The inflammatory disease, selected from the group consisting of rheumatoid arthritis; inflammatory bowel disease (IBD) including but not limited to Crohn's disease, ulcerative colitis and colitis; Pagets disease; osteoporosis; multiple myeloma; uveitilis; acute and chronic myelogenous leukemia; pancreatic β cell destruction; rheumatoid spondylitis; osteoarthritis; gouty arthritis and other arthritis conditions; gout; adult respiratory distress syndrome (ARDS); chronic pulmonary inflammation diseases; silicosis; pulmonary sarcoidosis; psoriasis; allergic rhinitis; anaphylaxis; contact dermatitis; pancreatitis; asthma; muscle degeneration; cachexia such as cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome; Reiter's syndrome; type I diabetes; bone resorption disease; graft vs. host reaction; ischemia reperfusion injury; brain trauma; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; endotoxic shock; gram negative sepsis; fever and myalgias due to infection such as influenza; pyrosis, comprising the administration of a pharmaceutically effective amount of a compound of formula (I) or pharmaceutically acceptable salt thereof to a patient in need thereof. More particularly, the inflammatory disease may be, without being limited thereto, selected from the group consisting of rheumatoid arthritis; inflammatory bowel disease (IBD) including but not limited to Crohn's disease, ulcerative colitis and colitis; Pagets disease; osteoporosis; multiple myeloma; uveitilis; acute and chronic myelogenous leukemia; pancreatic β cell destruction; rheumatoid spondylitis, osteoarthritis; gouty arthritis and other arthritis conditions; gout; adult respiratory distress syndrome (ARDS); chronic pulmonary inflammation diseases; silicosis; pulmonary sarcoidosis; psoriasis; allergic rhinitis; anaphylaxis; contact dermatitis; pancreatitis; asthma; muscle degeneration; cachexia such as cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome; Reiter's syndrome; bone resorption disease; graft vs. host reaction; ischemia reperfusion injury; brain trauma; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; endotoxic shock; gram negative sepsis; fever and myalgias due to infection such as influenza; and pyrosis.
In one embodiment, the inflammatory diseases are TNF, IL-1, IL-6, and/or IL-8 mediated diseases or disease states. The patient receiving the treatment for delaying the onset of an inflammatory disease according to the invention is preferably a warm-blooded animal, more preferably a human.
The invention further provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for delaying the onset of an inflammatory disease. The inflammatory disease may be, without being limited thereto, selected from the group consisting of rheumatoid arthritis; inflammatory bowel disease (IBD) including but not limited to Crohn's disease, ulcerative colitis and colitis; Pagets disease; osteoporosis; multiple myeloma; uveitilis; acute and chronic myelogenous leukemia; pancreatic β cell destruction; rheumatoid spondylitis; osteoarthritis; gouty arthritis and other arthritis conditions; gout; adult respiratory distress syndrome (ARDS); chronic pulmonary inflammation diseases; silicosis; pulmonary sarcoidosis; psoriasis; allergic rhinitis; anaphylaxis; contact dermatitis; pancreatitis; asthma; muscle degeneration; cachexia such as cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome; Reiter's syndrome; type I diabetes; bone resorption disease; graft vs. host reaction; ischemia reperfusion injury; brain trauma; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; endotoxic shock; gram negative sepsis; fever and myalgias due to infection such as influenza; pyrosis. More particularly, the inflammatory disease may be, without being limited thereto, selected from the group consisting of rheumatoid arthritis; inflammatory bowel disease (IBD) including but not limited to Crohn's disease, ulcerative colitis and colitis; Pagets disease; osteoporosis; multiple myeloma; uveitilis; acute and chronic myelogenous leukemia; pancreatic β cell destruction; rheumatoid spondylitis, osteoarthritis; gouty arthritis and other arthritis conditions; gout; adult respiratory distress syndrome (ARDS); chronic pulmonary inflammation diseases; silicosis; pulmonary sarcoidosis; psoriasis; allergic rhinitis; anaphylaxis; contact dermatitis; pancreatitis; asthma; muscle degeneration; cachexia such as cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome; Reiter's syndrome; bone resorption disease; graft vs. host reaction; ischemia reperfusion injury; brain trauma; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; endotoxic shock; gram negative sepsis; fever and myalgias due to infection such as influenza; pyrosis.
In one embodiment, the inflammatory diseases are TNF, IL-1, IL-6, and/or IL-8 mediated diseases or disease states.
The patient receiving the medicament for delaying the onset of an inflammatory disease according to the invention is preferably a warm-blooded animal, more preferably a human.
According to a further feature of the present invention there is provided a method for modulating GPR43 receptor activity, in a patient having inflammatory disease(s), preferably a warm blooded animal, and even more preferably a human, in need of such treatment, which comprises administering to said animal an effective amount of compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof.
According to one embodiment, the compounds of the invention, their pharmaceutical acceptable salts or solvates may be administered as part of a combination therapy. Thus, are included within the scope of the present invention embodiments comprising coadministration of, and compositions and medicaments which contain, in addition to a compound of the present invention, a pharmaceutically acceptable salt or solvate thereof as active ingredient, additional therapeutic agents and/or active ingredients. Such multiple drug regimens, often referred to as combination therapy, may be used in the treatment and/or prevention of any of the diseases or conditions mediated by or associated with GPR43 receptor modulation, particularly rheumatoid arthritis; inflammatory bowel disease (IBD) including but not limited to Crohn's disease, ulcerative colitis and colitis; Pagets disease; osteoporosis; multiple myeloma; uveitilis; acute and chronic myelogenous leukemia; pancreatic β cell destruction; rheumatoid spondylitis; osteoarthritis; gouty arthritis and other arthritis conditions; gout; adult respiratory distress syndrome (ARDS); chronic pulmonary inflammation diseases; silicosis; pulmonary sarcoidosis; psoriasis; allergic rhinitis; anaphylaxis; contact dermatitis; pancreatitis; asthma; muscle degeneration; cachexia such as cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome; Reiter's syndrome; type I diabetes; bone resorption disease; graft vs. host reaction; ischemia reperfusion injury; brain trauma; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; endotoxic shock; gram negative sepsis; fever and myalgias due to infection such as influenza; pyrosis.. The use of such combinations of therapeutic agents is especially pertinent with respect to the treatment of the above-mentioned list of diseases within a patient in need of treatment or one at risk of becoming such a patient.
In addition to the requirement of therapeutic efficacy, which may necessitate the use of active agents in addition to the GPR43 agonist or partial agonist compounds of Formula I or their pharmaceutical acceptable salts or solvates thereof, there may be additional rationales which compel or highly recommend the use of combinations of drugs involving active ingredients which represent adjunct therapy, i.e., which complement and supplement the function performed by the GPR43 receptor agonist or partial agonist compounds of the present invention. Suitable supplementary therapeutic agents used for the purpose of auxiliary treatment include drugs which, instead of directly treating or preventing a disease or condition mediated by or associated with GPR43 receptor modulation, treat diseases or conditions which directly result from or indirectly accompany the basic or underlying GPR43 receptor modulated disease or condition.
Thus, the methods of treatment and pharmaceutical compositions of the present invention may employ the compounds of Formula I or their pharmaceutical acceptable salts or solvates thereof in the form of monotherapy, but said methods and compositions may also be used in the form of multiple therapy in which one or more compounds of Formula I or their pharmaceutically acceptable salts or solvates are coadministered in combination with one or more other therapeutic agents such as those described in detail further herein.
Examples of other active ingredients that may be administered in combination with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, and either administered separately or in the same pharmaceutical composition, include but are not limited to:
(i) anti-inflammatory agents including steroids (corticosteroids, such as glucocorticoids),
(ii) non-steroidal anti-inflammatory drugs (NSAIDS) (i.e.
Asacol, Pentasa) and TNFcc inhibitiors such as Remicaide, Enbrel and TNF specific monoclonal antibody such as Humira. Other example of NSAIDS are those mentioned below but no limited to:
(a) salicylates (like aspirin, methyl salicylate, diflunisal, benorylate, faislamine, amoxiprin);
(b) arylalkanoic acids (like diclofenac, indometacin, sulindac, 2-arylpropionic acids);
(c) profens (like carprofen, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, ketorolac, loxoprofen, naproxen, tiaprofenic acid);
(d) N-arylanthranilic acids (like fenamic acids, mefenamic acid, meclofenamic acid);
(e) Pyrazolidine derivatives (like phenylbutazone, oxypheny lbutazone) ;
(f) Oxicams (like piroxicam, meloxicam); (g) Coxibs (like celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib); sulphonanilides (like nimesulide);
(h) Lipoxygenase inhibitors (like baicalein, caffeic acid, esculetin, gossypol, nordihydroguaiaretic acid, flubiprofen, nordihydroguaiaretic acid, eicosatriynoic acid, 5- hydroxyeicosatetraenoic (HETE) lactone, 5(S)-HETE, eicosatetraynoic acid);
(i) Macrolide derivatives (like-9-(S)-dihydroerythromycin derivatives);
(j) Anti-inflammatory peptide (antiflamins) (like peptides derived from seminal vesicle proteins, selectin-binding peptides, cationic peptides based on Bactericidal permeability increasing protein, IL-2 derived peptides);
(k) Anti- inflammatory cytokines (like IL-1 receptor antagonist, IL-4, IL-6, IL-10, IL-11, and IL-13);
(1) Pro-inflammatory cytokines inhibitors (like tumor necrosis factor-alpha, IL-18);
(m) Galectins (like galectin-1)
(n) Antibodies neutralizing pro-inflammatory signaling molecules/cytokines, like antibodies against TNF-alpha, IL- 1 etc; and
(o) Statins.
The above combinations include combinations of a compound of the present invention or a pharmaceutically acceptable salt or solvate not only with one other active compound but also with two or more active compounds.
In the above-described embodiment combinations of the present invention; the compound of Formula I, a pharmaceutically acceptable salt or solvate thereof and other therapeutic active agents may be administered in terms of dosage forms either separately or in conjunction with each other, and in terms of their time of administration, either serially or simultaneously. Thus, the administration of one component agent may be prior to, concurrent with, or subsequent to the administration of the other component agent(s).
The invention also provides pharmaceutical compositions for treating and/or preventing the development or for delaying the onset of an inflammatory disease, comprising a compound of formula I or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant. As indicated above, the invention also covers pharmaceutical compositions which contain, in addition to a compound of the present invention, a pharmaceutically acceptable salt or solvate thereof as active ingredient, additional therapeutic agents and/or active ingredients.
As set forth above, the compounds of the invention, their pharmaceutically acceptable salts or solvates may be used in monotherapy or in combination therapy. Thus, according to one embodiment, the invention provides the use of a compound of the invention for the manufacture of a medicament for at least one of the purposes described above, wherein said medicament is administered to a patient in need thereof, preferably a warm-blooded animal, and even more preferably a human, in combination with at least one additional therapeutic agent and/or active ingredient. The benefits and advantages of such a multiple drug regimen, possible administration regimens as well as suitable additional therapeutic agents and/or active ingredients are those described above.
Generally, the compounds of the invention may be formulated as a pharmaceutical preparation comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant, and optionally one or more further pharmaceutically active compounds.
By means of non-limiting examples, such a formulation may be in a form suitable for oral administration, for parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for topical administration (including ocular), for administration by inhalation, by a skin patch, by an implant, by a suppository, etc. Such suitable administration forms - which may be solid, semi-solid or liquid, depending on the manner of administration - as well as methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the skilled person; reference is made to the latest edition of Remington's Pharmaceutical Sciences.
Some preferred, but non-limiting examples of such preparations include tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, cremes, lotions, soft and hard gelatin capsules, suppositories, drops, sterile injectable solutions and sterile packaged powders (which are usually reconstituted prior to use) for administration as a bolus and/or for continuous administration, which may be formulated with carriers, excipients, and diluents that are suitable per se for such formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate, edible oils, vegetable oils and mineral oils or suitable mixtures thereof. The formulations can optionally contain other substances that are commonly used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, desintegrants, bulking agents, fillers, preserving agents, sweetening agents, flavoring agents, flow regulators, release agents, etc.. The compositions may also be formulated so as to provide rapid, sustained or delayed release of the active compound(s) contained therein.
The pharmaceutical preparations of the invention are preferably in a unit dosage form, and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which may be properly labeled); optionally with one or more leaflets containing product information and/or instructions for use. Generally, such unit dosages will contain between 0,05 and 1000 mg, and usually between 1 and 500 mg, of the at least one compound of the invention, e.g. about 10, 25, 50, 100, 200, 300 or 400 mg per unit dosage.
Usually, depending on the condition to be prevented or treated and the route of administration, the active compound of the invention will usually be administered between 0.01 to 100 mg per kilogram, more often between 0.1 and 50 mg, such as between 1 and 25 mg, for example about 0.5, 1, 5, 10, 15, 20 or 25 mg, per kilogram body weight day of the patient per day, which may be administered as a single daily dose, divided over one or more daily doses, or essentially continuously, e.g. using a drip infusion.
DEFINITIONS
The definitions and explanations below are for the terms as used throughout the entire application, including both the specification and the claims.
When describing the compounds of the invention, the terms used are to be construed in accordance with the following definitions, unless indicated otherwise.
Where groups may be substituted, such groups may be substituted with one or more substituents, and preferably with one, two or three substituents. Substituents may be selected from but not limited to, for example, the group comprising halogen, hydroxyl, oxo, nitro, amido, carboxy, amino, cyano haloalkoxy, and haloalkyl.
As used herein the terms such as "alkyl, aryl, or cycloalkyl, each being optionally substituted with..." or "alkyl, aryl, or cycloalkyl, optionally substituted with..." encompasses "alkyl optionally substituted with...", "aryl optionally substituted with..." and "cycloalkyl optionally substituted with...".
The term "halo" or "halogen" means fluoro, chloro, bromo, or iodo. Preferred halo groups are fluoro and chloro. The term "alkyl" by itself or as part of another substituent refers to a hydrocarbyl radical of Formula CnH2n+i wherein n is a number greater than or equal to 1. Generally, alkyl groups of this invention comprise from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, more preferably from 1 to 3 carbon atoms, still more preferably 1 to 2 carbon atoms. Alkyl groups may be linear or branched and may be substituted as indicated herein.
Suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n- butyl, i-butyl, s-butyl and t-butyl, pentyl and its isomers (e.g. n-pentyl, iso-pentyl), and hexyl and its isomers (e.g. n-hexyl, iso-hexyl). Preferred alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl.
When the suffix "ene" ("alkylene") is used in conjunction with an alkyl group, this is intended to mean the alkyl group as defined herein having two single bonds as points of attachment to other groups. The term "alkylene" includes methylene, ethylene, methylmethylene, propylene, ethylethylene, and 1,2- dimethy lethy lene .
The term "alkenyl" as used herein refers to an unsaturated hydrocarbyl group, which may be linear or branched, comprising one or more carbon-carbon double bonds. Suitable alkenyl groups comprise between 2 and 6 carbon atoms, preferably between 2 and 4 carbon atoms, still more preferably between 2 and 3 carbon atoms. Examples of alkenyl groups are ethenyl, 2- propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2,4-pentadienyl and the like.
The term "alkynyl" as used herein refers to a class of monovalent unsaturated hydrocarbyl groups, wherein the unsaturation arises from the presence of one or more carbon-carbon triple bonds. Alkynyl groups typically, and preferably, have the same number of carbon atoms as described above in relation to alkenyl groups. Non limiting examples of alkynyl groups are ethynyl, 2- propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and its isomers, 2-hexynyl and its isomers-and the like. The terms "alkenylene" and "alkynylene" respectively mean an alkenyl group or an alkinyl group as defined above having two single bonds as points of attachment to other groups. The term "haloalkyl" alone or in combination, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen as defined above. Non-limiting examples of such haloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and the like.
The term "cyclo alkyl" as used herein is a cyclic alkyl group, that is to say, a monovalent, saturated, or unsaturated hydrocarbyl group having 1 or 2 cyclic structures. Cycloalkyl includes monocyclic or bicyclic hydrocarbyl groups. Cycloalkyl groups may comprise 3 or more carbon atoms in the ring and generally, according to this invention comprise from 3 to 10, more preferably from 3 to 8 carbon atoms still more preferably from 3 to 6 carbon atoms. Examples of cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, with cyclopropyl being particularly preferred.
When the suffix "ene" is used in conjunction with a cyclic group, this is intended to mean the cyclic group as defined herein having two single bonds as points of attachment to other groups.
Therefore, "cycloalkylene" herein refers to a saturated homocyclic hydrocarbyl biradical of Formula CnH2n-2. Suitable cycloalkylene groups are C3-6 cycloalkylene group, preferably a C3-5 cycloalkylene (i.e. 1 ,2-cyclopropylene, 1,1- cyclopropylene, 1,1 -cyclo butylene, 1 ,2-cyclobutylene, 1,3-cyclobutylene, 1,3- cyclopentylene, 1 ,2-cyclopentylene or 1,1-cyclopentylene), more preferably a C3-4 cycloalkylene (i.e. 1,3-cyclopropylene, 1,1 -cyclopropylene, 1,1 -cyclo butylene, 1 ,2-cyclobutylene).
Where at least one carbon atom in a cycloalkyl group is replaced with a heteroatom, the resultant ring is referred to herein as "heterocycloalkyl" or "heterocyclyl".
The terms "heterocyclyl", "heterocycloalkyl" or "heterocyclo" as used herein by itself or as part of another group refer to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3 to 7 member monocyclic, 7 to 11 member bicyclic, or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1 , 2, 3 or 4 5 heteroatoms selected from nitrogen, oxygen and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quatemized. Any of the carbon atoms of the heterocyclic group may be substituted by oxo (for example piperidone, pyrrolidinone).The heterocyclic group may be attached at any heteroatom or 10 carbon atom of the ring or ring system, where valence allows. The rings of multi- ring heterocycles may be fused, bridged and/or joined through one or more spiro atoms. Non limiting exemplary heterocyclic groups include oxetanyl, piperidinyl, azetidinyl, 2-imidazolinyl, pyrazolidinyl imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, SHI S indolyl, indolinyl, isoindolinyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, 3-dioxolanyl, 1 ,4-dioxanyl, 2,5-dioximidazolidinyl, 2- oxopiperidinyl, 2-oxopyrrolodinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolin- 1 -yl,
20 tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl, thiomorpholin-4-ylsulfoxide, thiomorpholin-4-ylsulfone, 1,3- dioxolanyl, 1 ,4-oxathianyl, lH-pyrrolizinyl, tetrahydro-l,l-dioxothiophenyl, N- formylpiperazinyl, and morpholin-4-yl.
The ring atoms of heterocyclyl and heterocyclylene moieties are 25 numbered based on scheme below
Figure imgf000167_0001
Figure imgf000167_0002
piperidinyl tetrahydropyranyl piperazinyl morpholinyl
The term "aryl" as used herein refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e. phenyl) or multiple aromatic rings fused together (e.g. naphtyl) or linked covalently, typically containing 5 to 12 atoms; preferably 6 to 10, wherein at least one ring is aromatic. The aromatic ring may optionally include one to two additional rings (either cycloalkyl, heterocyclyl or heteroaryl) fused thereto. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated herein. Non- limiting examples of aryl comprise phenyl, biphenylyl, biphenylenyl, 5- or 6- tetralinyl, naphthalen-1- or -2-yl, 4-, 5-, 6 or 7-indenyl, 1- 2-, 3-, 4- or 5- acenaphtylenyl, 3-, 4- or 5-acenaphtenyl, 1- or 2-pentalenyl, 4- or 5-indanyl, 5-, 6- , 7- or 8-tetrahydronaphthyl, 1 ,2,3,4-tetrahydronaphthyl, 1 ,4-dihydronaphthyl, 1-, 2-, 3-, 4- or 5-pyrenyl.
The term "arylene" as used herein is intended to include divalent carbocyclic aromatic ring systems such as phenylene, biphenylylene, naphthylene, indenylene, pentalenylene, azulenylene and the like. Arylene is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1 ,2,3,4-tetrahydronaphthylene, 1 ,4-dihydronaphthylene and the like.
The term "arylalkyl" or "aralkyl" refers to a linear or branched alkyl group where one carbon is attached to an aryl ring. Non limiting examples of aralkyl comprise benzyl, phenethyl, naphtalen-l-yl or naphtalen-2-yl methyl. When an aralkyl group is substituted, the substituent(s) is/are attached either on the alkyl group or on the aryl ring. A "x-membered aralkyl" refers to a linear or branched alkyl group where one carbon is attached to a x-membered aryl ring.
Where at least one carbon atom in an aryl group is replaced with a heteroatom, the resultant ring is referred to herein as a heteroaryl ring. The term "heteroaryl" as used herein by itself or as part of another group refers but is not limited to 5 to 12 carbon-atom aromatic rings or ring systems containing 1 to 2 rings which are fused together or linked covalently, typically containing 5 to 6 atoms; at least one of which is aromatic, in which one or more carbon atoms in one or more of these rings is replaced by oxygen, nitrogen and/or sulfur atoms where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. Such rings may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring. Non-limiting examples of such heteroaryl, include: furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,l-b][l,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b]thiophenyl, thieno[2,3-d][l,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[l,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzo furanyl, isobenzo furanyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2- benzisoxazolyl, 2,1-benzisoxazolyl, 1,3-benzothiazolyl, 1,2-benzo isothiazolyl, 2,1-benzoisothiazolyl, benzotriazolyl, 1,2,3-benzoxadiazolyl, 2,1,3- benzoxadiazolyl, 1 ,2,3-benzothiadiazolyl, 2, 1 ,3-benzothiadiazolyl, thienopyridinyl, purinyl, imidazo[l,2-a]pyridinyl, 6-oxo-pyridazin-l(6H)-yl, 2- oxopyridin-l(2H)-yl, 6-oxo-pyridazin-l(6H)-yl, 2-oxopyridin-l(2H)-yl, 1,3- benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl.
The term "heteroarylene" as used herein means divalent carbocyclic aromatic ring systems including pyridinylene and the like. The ring atoms of heteroaryl or heteroarylene moieties are numbered on scheme below:
Figure imgf000169_0001
X is selected from: X is selected from: X is selected from: Y is selected from: N, O or S N, O or S N. O or S C, N
Examples: Examples: Examples: Examples:
pyrrolyl imidazolyl pyrazolyl pyridyl
furanyl oxazolyl isooxazolyl pyrimidinyl thiophenyl thiazolyl isothiazolyl
Figure imgf000169_0002
X is selected from: X is selected from:
N, O or S N, O or S
Examples: Examples:
indolyl benzimidazolyl
benzofuranyl benzoxazolyl
benzothiophenyl benzothiazolyl
The term "biaryl" as used herein designates two aryl moieties as defined herein linked via a single bond. Non-limiting examples of such biaryl moieties include biphenyl.
Figure imgf000170_0001
biphenyl
The term "heterobiaryl" as used herein designates two heteroaryl moieties as defined herein or a heteroaryl moiety and an aryl moity as defined herein linked via a single bond. Non-limiting examples of such heterobiaryl moieties include pyridinylphenyl which is meant to include (2-pyridinyl)phenyl, (3-pyridinyl)phenyl and (4-pyridinyl)phenyl, bipyridinyl.
Figure imgf000170_0002
(2-pyridinyl)phenyl (3-pyridinyl)phenyl (4-pyridinyl)phenyl
Figure imgf000170_0003
bipyridinyl
The term "alkylamino" as used herein means an amino group substituted with one or two alkyl groups. This includes monoalkylamino and dialkylamino groups.
The compounds of Formula I and sub formulae thereof contain at least one asymmetric center and thus may exist as different stereoisomeric forms. Accordingly, the present invention includes all possible stereoisomers and includes not only racemic compounds but the individual enantiomers and their non racemic mixtures as well. When a compound is desired as a single enantiomer, such may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as each are known in the art. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley- Interscience, 1994), incorporated by reference with regard to stereochemistry.
The bonds from an asymmetric carbon in compounds of the present invention may be depicted herein using a solid line (— ), a zigzag line ( ■ww ), a solid wedge ( ),a dotted wedge ( ), a solid bar (^^m) or a dotted bar
( ) . The use of a solid line to depict bonds from an asymmetric carbon atom is meant to indicate that all possible stereoisomers are meant to be included, unless it is clear from the context that a specific stereoisomer is intended. The use of either a solid or dotted wedge to depict bonds from an asymmetric carbon atom is meant to indicate that only the stereoisomer shown is meant to be included.
The compounds of the invention may also contain more than one asymmetric carbon atom. In those compounds, the use of a solid line to depict bonds from asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included, unless it is clear from the context that a specific stereoisomer is intended. In those compounds, the use of solid or dotted bars is meant to indicate relative stereochemistry. As an example,
Figure imgf000172_0001
similarly,
Figure imgf000172_0002
The compounds of the invention may be in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the compounds of formula I include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, 2-(diethylamino)ethanol, ethanolamine, morpholine, 4-(2- hydroxyethyl)morpholine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. Preferred, pharmaceutically acceptable salts include hydrochloride/chloride, hydrobromide/bromide, bisulphate/sulphate, nitrate, citrate, and acetate.
When the compounds of the invention contain an acidic group as well as a basic group the compounds of the invention may also form internal salts, and such compounds are within the scope of the invention. When the compounds of the invention contain a hydrogen-donating heteroatom (e.g. NH), the invention also covers salts and/or isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule.
Pharmaceutically acceptable salts of compounds of Formula I may be prepared by one or more of these methods: (i) by reacting the compound of Formula I with the desired acid;
(ii) by reacting the compound of Formula I with the desired base;
(iii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of Formula I or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid; or (iv) by converting one salt of the compound of Formula I to another by reaction with an appropriate acid or by means of a suitable ion exchange column.
All these reactions are typically carried out in solution. The salt, may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized.
The term "solvate" is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water.
All references to compounds of formula I include references to salts, solvates, multi- component complexes and liquid crystals thereof.
The compounds of the invention include compounds of formula I as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) and isotopically- labeled compounds of formula I. In addition, although generally, with respect to the salts of the compounds of the invention, pharmaceutically acceptable salts are preferred, it should be noted that the invention in its broadest sense also included non- pharmaceutically acceptable salts, which may for example be used in the isolation and/or purification of the compounds of the invention. For example, salts formed with optically active acids or bases may be used to form diastereoisomeric salts that can facilitate the separation of optically active isomers of the compounds of Formula I above.
The invention also generally covers all pharmaceutically acceptable predrugs and prodrugs of the compounds of Formula I. The term "prodrug" as used herein means the pharmacologically acceptable derivatives of compounds of formula I such as esters whose in vivo biotransformation product is the active drug. Prodrugs are characterized by increased bio-availability and are readily metabolized into the active compounds in vivo. Suitable prodrugs for the purpose of the invention include carboxylic esters, in particular alkyl esters, aryl esters, acyloxyalkyl esters, and dioxolene carboxylic esters; ascorbic acid esters as well as compounds of formula I in which Z is a substituent selected from the table 2 below. Table 2
Figure imgf000175_0001
The term "predrug", as used herein, means any compound that will be modified to form a drug species, wherein the modification may take place either inside or outside of the body, and either before or after the predrug reaches the area of the body where administration of the drug is indicated.
The term "patient" refers to a warm-blooded animal, more preferably a human, who/which is awaiting or receiving medical care or is or will be the object of a medical procedure.
The term "human" refers to suject of both genders and at any stage of development (i.e. neonate, infant, juvenile, adolescent, adult).
The terms "treat", "treating" and "treatment, as used herein, are meant to include alleviating or abrogating a condition or disease and/or its attendant symptoms.
The terms "prevent", "preventing" and "prevention", as used herein, refer to a method of delaying or precluding the onset of a condition or disease and/or its attendant symptoms, barring a patient from acquiring a condition or disease, or reducing a patient's risk of acquiring a condition or disease.
The term "therapeutically effective amount" (or more simply an "effective amount") as used herein means the amount of active agent or active ingredient (e. g. GPR43 agonist or partial agonist) which is sufficient to achieve the desired therapeutic or prophylactic effect in the individual to which it is administered.
The term "administration", or a variant thereof (e.g. 'administering"), means providing the active agent or active ingredient (e. g. a GPR43 agonist or partial agonist), alone or as part of a pharmaceutically acceptable composition, to the patient in whom/which the condition, symptom, or disease is to be treated or prevented.
By "pharmaceutically acceptable" is meant that the ingredients of a pharmaceutical composition are compatible with each other and not deleterious to the patient thereof.
The term "agonist" as used herein means a ligand that activates an intracellular response when it binds to a receptor. An agonist according to the invention may promote internalization of a cell surface receptor such that the cell surface concentration of a receptor is decreased or remove.
The term "partial agonist" as used herein means an agonist which is unable to induce maximal activation of a receptor, regardless of the amount of compound applied on the receptor.
The term "pharmaceutical vehicle" as used herein means a carrier or inert medium used as solvent or diluent in which the pharmaceutically active agent is formulated and/or administered. Non-limiting examples of pharmaceutical vehicles include creams, gels, lotions, solutions, and liposomes. As used herein the term "inflammatory diseases" are those pertaining to, characterized by, causing, resulting from or becoming affected by inflammation Such inflammatory diseases include but are not limited to rheumatoid arthritis; inflammatory bowel disease (IBD) including but not limited to Crohn's disease, ulcerative colitis and colitis; Pagets disease; osteoporosis; multiple myeloma; uveitilis; acute and chronic myelogenous leukemia; pancreatic β cell destruction; rheumatoid spondylitis; osteoarthritis; gouty arthritis and other arthritis conditions; gout; adult respiratory distress syndrome (ARDS); chronic pulmonary inflammation diseases; silicosis; pulmonary sarcoidosis; psoriasis; allergic rhinitis; anaphylaxis; contact dermatitis; pancreatitis; asthma; muscle degeneration; cachexia such as cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome; Reiter's syndrome; type I diabetes; bone resorption disease; graft vs. host reaction; ischemia reperfusion injury; brain trauma; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; endotoxic shock; gram negative sepsis; fever and myalgias due to infection such as influenza; pyrosis.
As used herein the term "cytokine" refers to any secreted polypeptide that affects the functions of cells and is a molecule which modulates interactions between cells in the immune, inflammatory or hematopoietic response. Examples of cytokine includes, but are not limited to Interleukine 1 (IL-1), preferably IL-Ιβ, Interleukine 6 (IL-6), Interleukine 8 (IL-8) and Tumor Necrosis Factor, preferably TNF-cc.
As used herein the term "TNF, IL-1, IL-6, and/or IL-8 mediated diseases or disease states" means all disease states wherein TNF, IL-1, IL-6, and/or IL-8 plays a role, either directly as TNF, IL-1, IL-6, and/or IL-8 itself, or by TNF, IL-1, IL-6, and/or IL-8 inducing another cytokine to be released. For example, a disease state in which IL-1 plays a major role, but in which the production of or the action of IL-1 is a result of TNF, would be considered mediated by TNF.
The present invention will be better understood with reference to the following examples. These examples intended to representative of specific embodiments of the invention, and are not intended as limiting the scope of the invention.
CHEMISTRY EXAMPLES All temperatures are expressed in °C and all reactions were carried out at room temperature (RT) unless otherwise stated.
Analytical thin layer chromatography (TLC) was used to monitor reactions, establish flash chromatography conditions and verify purity of intermediates or final products. TLC plates used were Merck TLC aluminium sheet silica gel 60 F254 purchased from VWR International. TLC plates were revealed using ultraviolet irradiation (wavelength=254nm) at room temperature or bromocresol green spray reagent at 0.1% in propan-2-ol purchased from VWR International upon heating at 160°C or KMn04 revelator upon heating at 160°C. The KMn04 revelator was prepared by dissolving 3g of potassium permanganate, 20g of sodium carbonate, 0.5g of sodium hydroxide in lOOmL of distilled water.
HPLC-MS spectra were obtained on Agilent LCMS using Electropsray ionization (ESI). The Agilent instrument includes an Autosampler 1200, a binary pump 1100, a 5 wave length detector 1100 and a 6100 Single Quad. The column used was an XBridge CI 8, 4.6 x 50 mm, 3.5 μιη.
Eluent was a mixture of solution A (0.1 % TFA in H20) and solution B (0.1 % TF A in ACN). Gradient was applied at a flow rate of 2 mL min-1 as follows: gradient A: held the initial conditions of 5% solution B for 1 min, increased linearly to 95% solution B in 4 min, held at 95% during 1 min, returned to initial conditions in 0.5 min and maintained for 1 min; gradient B: held the initial conditions of 5% solution B for 1 min, increased linearly to 60% in 10 min, increased linearly to 95% in 0.5 min, held at 95% during 3 min, returned to initial conditions in 0.5 min and maintained for 1 min. Determination of ee was performed on an Agilent 1100 (binary pump and 5 wavelengths detector) with manual or automatic (Autosampler 1100) injection. Columns used were CHIRALPAK IA CHIRALPAK IB or CHIRALPAK IC in isocratic mode. Mixtures of eluents were selected depending on the separation obtained of enantiomers or diastereosiomers. Usual mixtures were:
- Hexane and Ethano 1 (0.1% TFA)
- Hexane and Propanol (0.1% TFA)
- Hexane and Ethyl acetate (0.1% TFA)
- Hexane and Dichloromethane (0.1% TFA)
- Hexane and tert-butyl methyl ether (0.1% TFA)
Selected specific methods A, B and C are reported below. Method A: compound was characterized on a CHIRALPAK I A column (isocratic mode) using a mixture of hexane and dichloromethane (65/35) acidified by 0.4% of TFA at a flow rate of 1.2 mL/min, and confirmed on a CHIRALPAK IC column (isocratic mode) using a mixture of heptane and Ethyl acetate (75/25) acidified by 0.1% of TFA at lml/min. Method B: compound was characterized on a CHIRALPAK IC column (isocratic mode) using a mixture of heptane and ethyl acetate (70/30) acidified by 0.1% of TFA at a flow rate of lml/min. Method C: compound was characterized on a CHIRALPAK IC column (isocratic mode) using a mixture of heptane and ethanol (95/5) acidified by 0.1 % of TFA at a flow rate of 1.5ml/min.
Preparative HPLC purifications were carried out on Fractionlynx instrument, from Waters. This instrument consists of a Fraction Collector, a 2767 Sample Manager, a pump control a module II, a 515 HPLC Pump, a 2525 Binary Gradient Module, a Switching Valve, a 2996 Photodiode Array Detector and a Micromass ZQ. The column used was a Waters Sunfire C18 Eluent was a mixture of solution A (0.1% TFA in H20) and solution B (0.1% TFA in ACN). The gradient was adapted depending on impurities present in samples, to allow sufficient separation between impurities and target compound.
Chiral preparative HPLC purification were performed on an Agilent 1100 instrument (binary pump and 5 wavelengths detector) with manual injection using a CHIRALPAK IA or a CHIRALPAK IB column in isocratic mode. Mixtures of eluents were selected depending on the separation of enantiomers or diastereosiomers obtained with the analytical method. Usual mixtures were the same as those used for the determination of ee.
!H and 13C NMR spectra were recorded on a Bruker ARX 300MHz. Chemical shifts are expressed in parts per million, (ppm, δ units). Coupling constants are expressed in Hertz units (Hz). Splitting patterns describe apparent multiplicities and are described as s (singlet), d (doublet), t (triplet), q (quintet), m (multiplet), or br (broad).
Solvents, reagents and starting materials were purchased from well known chemical suppliers such as for example Sigma Aldrich, Acros Organics, Fluorochem, Eurisotop, VWR International, Sopachem and Polymer labs and the following abbreviations are used:
ACN: Acetonitrile,
DCM: Dichloromethane,
DMF: N,N-dimethylformamide,
EtOAc: Ethyl acetate,
EtOH: Ethanol,
MeOH: Methanol,
RT: Room temperature,
DIEA: N,N-diisopropylethylamine,
HATU: 0-(7-azabenzotriazo 1- 1 -yl)-N,N,N ' ,N ' -tretramethyluronium hexafluorophosphate ,
Y: Yield,
g: Grams,
mg: Milligrams,
L: Liters,
mL: Milliliters,
μί: Microliters, mol: Moles,
mmol: Millimoles,
h: Hours,
min: Minutes,
TLC: Thin layer chromatography,
MW: Molecular weight,
eq: Equivalent,
μ : Microwave,
THF: Tetrahydrofuran,
TFA: Trifluoroacetic acid,
Ac: Acetyl,
NaHMDS: Sodium hexamethyldisilazane,
DCA: Dicyclohexylamine,
TCA: Trichloroacetimidate,
CDI: Carbonyl diimidazole,
ee: Enantiomeric excess,
DPP: Diphenylphosphino,
BINAP: l,l '-Binaphtyl,
tBu: tert-Butyl
P: UV purity at 254nm determined by HPLC-MS,
SPE: Sold phase extraction,
Rt: Retention time,
TMSC1: Chlorotrimethylsilane,
BuLi: Butyllithium,
MCPBA: 3-Chloroperbenzoic acid,
MOM: Methoxymethyl,
NCS: N-chlorosuccinimide,
NBS: N-bromosuccinimide. General synthetic scheme
Most compounds of the invention are synthesized according to Scheme 1.
Figure imgf000182_0001
Figure imgf000182_0002
Scheme 1: General synthetic route for most of the compounds in the present invention
Synthesis of intermediates 1
Chiral syntheses of intermediates 1 were carried out using Evans' chiral auxiliary approach (Evans et al. J. Org. Chem. 1999, 64, 6411-6417; Tararov et al. J. Chem. Soc. Perkin Trans. 1, 1997, 3101-3106) (Scheme 2).
Figure imgf000182_0003
X=halo
Figure imgf000182_0004
Scheme 2: General scheme for the preparation of intermediates 1 using Evans' chiral auxiliary approach
This methodology was also used for the synthesis of (R)- cycloalkylalkylsuccinic acid, (i?)-heterocyclylalkylsuccinic acid, (R)- arylalkylsuccinic acid and (i?)-heteroarylalkylsuccinic acid monoester intermediates 1.
As depicted on Scheme 3, (i?)-benzylsuccinic acid monoester intermediates 1 can also be made starting from maleic anhydride followed by the application of Wittig reaction, asymmetric hydrogenation (Wallace et al. Org. Proc. Res.& Dev. 2004, 8, 738-743), tBu ester protection and selective saponification of the methyl ester (Atkinson et al. J. Org. Chem. 1999, 64, 3467).
Figure imgf000183_0001
TCA-¾u
Figure imgf000183_0002
Figure imgf000183_0003
1b
Scheme 3: Synthesis of (R)-benzyl-succinic acid monoester intermediates 1 using
Wittig approach
This methodology was also used for the synthesis of (R)- cycloalkylalkylsuccinic acid, (i?)-heterocyclylalkylsuccinic acid, (R)- arylalkylsuccinic acid and (i?)-heteroarylalkylsuccinic acid monoester intermediates 1. Synthesis of intermediates 2
4-aryl-2-amino-thiazoles can be made using Hantzsch-type synthetic methodology as shown in Scheme 4. Thus, halogenation of substituted acetophenones (Larock, R. C. Comprehensive Org Transf2nA Ed., Wiley, 1999, pp 709-719; White et al. J Med. Chem. 1996, 39, 4382-95) and subsequent condensation with thiourea (Swain et al. J Med. Chem. 1991, 34, 140-151; Bartoli et al. J Med. Chem. 1998, 41, 1855-68) will furnish 4-aryl-2-amino-thiazoles.
Figure imgf000184_0001
use of μ\Λ = , 3
Scheme 4: General scheme for the preparation of 4-aryl-2-amino-thiazoles using Hantzsch-type synthetic approach
Alternatively, synthesis of N-substituted-4-aryl-2-amino-thiazoles can be achieved through the method described by Rudolph (Rudolph, J. Tetrahedron 2000, 56, 3161)
Figure imgf000184_0002
Scheme 5: General scheme for the preparation of N-substituted-4-aryl-2- amino-thiazoles using Rudolph's synthetic approach
Synthetic Schemes for the Preparation of the Carboxylic Acid Bioisosteres
Synthetic routes for the preparation of selected bioisosteres of the carboxylic acid moiety are given hereunder. Isosterism is a concept defined by I. Langmuir in J Am. Chem. Soc. 1919, 41, 1549 and developed by H.L. Friedman in Symposium on Chemical-Biological correlations, National Council Publication, Washington, DC (1951). As used herein the term "bioisosteres" refers to "groups or molecules which have chemical and physical similarities producing similar biological effects" (as defined in Chem. Soc. Rev. 1979, 8, 563). Suitable well- known bioisosteric replacements of carboxylic acid groups and synthetic routes are reported in The Practice of Medicinal Chemistry, 2nd edition, by C.G. Wermuth. It is obvious to the person skilled in the art to synthesize carboxylic acid isosteres, selected useful references are Drysdale et al. J Med. Chem. 1992, 35, 2573-2581, Liljebris et al. J Med. Chem. 2002, 45, 1785-1798.
Synthesis of tetrazole and hydroxy-oxadiazole isosteres
The tetrazole and hydroxy-oxadiazole isosteres can be synthesized using a common nitrile intermediate (see Scheme below). (Arienti et al. J Med. Chem. 2005, 48, 6, 1882; Rodriguez et al. Tetrahedron 1997, 38, 24, 4221; Claremon et al. Tet. Lett. 1988, 28, 2155).
Figure imgf000185_0001
Treatment of the aforesaid nitrile intermediate with sodium azide can be used to afford the tetrazole isostere (see Scheme below). (Matthews et al. J Comb. Chem. 2000, 2, 19-23)
Figure imgf000185_0002
Treatment of the aforesaid nitrile intermediate with hydroxylamine, followed by dehydrative cyclization can be used to yield the hydroxy-oxadiazole isostere (see Scheme below) (Peretto et al. J Med. Chem. 2005, 48, 5705-5720).
Figure imgf000186_0001
In addition, synthetic approaches to the preparation of other well-recognized carboxylic acid isosteres are outlined below.
A suggested synthetic approach for the preparation of hydroxy-thiadiazole
Figure imgf000186_0002
Synthesis of hydroxy- isoxazole isosteres
Figure imgf000187_0001
Eur. J. Org. Chem.
1998, 473
An alternative suggested synthetic approach for the preparation of hydroxy- isoxazole isosteres
Figure imgf000187_0002
Additional synthetic schemes
An alternative approach towards synthesis of intermediates 1 (see Scheme 2) can be envisioned through Stobbe condensation as depicted in Scheme 6.
Figure imgf000188_0001
Scheme 6: A suggested synthetic approach for the preparation of benzyl
acid monoester intermediates through Stobbe condensation
Synthesis of compound n°68 (Scheme 7):
Figure imgf000188_0002
Scheme 7: Synthesis of compound 68
As shown in Scheme 7, upon treatment of (R)-benzylsuccinic acid t-butyl ester with excess LiHMDS in the presence of Mel, the desired monomethylated intermediate was isolated as an epimeric mixture, which was used in turn to furnish the final target structure (as epimeric mixture), as per the general procedure outlined on Scheme 1. Synthesis of aryl-pyridine and aryl-pyrimidines intermediates 2 (Scheme 8):
Figure imgf000189_0001
R = H
Ref. Suzuki coupling: Reductive amination with
1. Adv. Synth. Catal. 2004, 346, 1859-1867 R = Me formaldehyde or alkylation
2. Tetrahedron Lett. 2005, 46, 3573-3577
Scheme 8: synthesis of aryl-pyridines and pyrimidines
Suzuki coupling between pyridinyl or pyrimidinyl chloride and phenylboronic acid reagents allowed synthesizing the aryl-pyridine and aryl- pyrimidines intermediates 2.
A suggested synthesis of compound n°74 (Scheme 9):
Figure imgf000189_0002
compound 74
Scheme 9: A suggested synthesis of compound n°74 Suggested syntheses of compounds n°75 and n°76 (Scheme 10):
Figure imgf000190_0001
same approach for other enantiomer
Figure imgf000190_0002
+ enantiomer
Scheme 10: Suggested syntheses of compounds n°75 and n°76
Suggested syntheses of compounds n°79 and n°80 (Scheme 11):
Figure imgf000191_0001
LiOH,H202
THF/H20 (4/1), 0°C
FOR OTHER
Figure imgf000191_0002
Scheme 11: Suggested syntheses of compounds n°79 and n°80
uggested syntheses of compounds n°83 to n°85 (Scheme 12):
Figure imgf000192_0001
H2
H
Figure imgf000192_0002
2) H2CO, HC02H compound n°85
■L CN
Scheme 12: Suggested syntheses of compounds n°83 to n°85 Synthesis of intemediates 1 using Horner- Wadsworth Emmons approach (HWE) (Scheme 13):
Figure imgf000193_0001
Org. Proc. Res. Dev. 2004, 8, 738-743
Scheme 13: Synthesis of intemediates 1 using Horner- Wadsworth Emmons approach (HWE)
The HWE methodology as depicted in Scheme 13 is the preferred methodology of the invention for the synthesis of intermediates 1.
Synthesis of compounds 98, 100 and 101 (Scheme 14):
Figure imgf000194_0001
Scheme 14: Synthesis of compounds 98, 100 and 101
General scheme for the preparation of biaryl- or heterobiaryl-thiazole amine intermediates using Suzuki approach (Scheme 15):
Figure imgf000195_0001
reflux
Figure imgf000195_0002
Scheme 15: General scheme for the preparation of biaryl- or heterobiaryl-thiazole amine intermediates using Suzuki approach
Synthesis of intermediates 2n and 2r3 (Scheme 16):
Figure imgf000195_0003
Scheme 16: Synthesis of intermediates 2n and 2r3 Alternative general scheme for the preparation of biaryl- or heterobiaryl-thiazole amine intermediates using Suzuki approach (Scheme 17):
Figure imgf000196_0001
Scheme 17: Alternative general scheme for the preparation of biaryl- or heterobiaryl-thiazole amine intermediates using Suzuki approach
Synthesis of compound n°198 (Scheme 18):
Figure imgf000196_0002
compound n°1 98
Scheme 18: Synthesis of compound n°198 General synthetic scheme for the preparation of substituted acetophenone reagents through Weinreb amide approach (Scheme 20):
Figure imgf000197_0001
DIEA
ACN
Scheme 20: General synthetic scheme for the preparation of substituted acetophenone reagents through Weinreb amide approach
Synthesis of intermediate 2p3 (Scheme 21):
Figure imgf000197_0002
DCM
Figure imgf000197_0003
2p3
Scheme 21: Synthesis of intermediate 2p3 Synthesis of compound n°238(Scheme 22):
Figure imgf000198_0001
Scheme 22: Synthesis of compound
General synthetic scheme for the preparation of substituted thiourea reagents (Scheme 23):
Figure imgf000198_0002
Scheme 23: General synthetic scheme for the preparation of substituted thiourea reagents
General method A: synthesis of intermediate la (S)-4-tert-butoxy-4-oxo-2- phenylbutanoic acid
Step 1 : synthesis of (S)-4-benzyl-3-(2-phenylacetyl)oxazolidin-2-one
(S)-4-benzyloxazolidin-2-one (0.011 mol) was dissolved in THF (50 mL). A 1.6 M solution of n-BuLi (0.0124 mol) was added dropwise at -78 °C. A solution of 2-phenylacetyl chloride (0.011 mol) in THF (20 mL) was added dropwise to the obtained dark solution at the same temperature. The reaction mixture was stirred for 1 h at -78 °C. Then a saturated solution of NH4CI (2 mL) and a solution of NaHC03 (4 mL) were added dropwise, and the reaction mixture was warmed to RT. The organic layer was separated, and the aqueous one was extracted with diethyl ether (3 x 25 mL). The combined extracts were washed with water, brine, dried over Na2S04, and evaporated. The residue was purified by chromatography (silica gel, hexane/ether, 2/1) to yield title compound. Y: 2.1 g (64.7%).
Step 2: synthesis of (S)-tert-butyl 4-((S)-4-benzyl-2-oxooxazolidin-3-yl)- 4-0X0-3 -phenylbutanoate
A IM solution of NaHMDS (7.8 mmol) in THF was added to a solution of (S)-4-benzyl-3-(2-phenylacetyl)oxazolidin-2-one (7.1 mmol) in THF at -78 °C in a flow of argon. After keeping for 1.5 h at the same temperature tert- butyl bromoacetate (21.3 mmol) was added. The reaction mixture was stirred for 2 h at -78 °C and warmed to RT. A saturated solution of NH4C1 (15 mL) and ethyl acetate (12 mL) were added. The organic layer was separated, and the aqueous one was extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with brine, dried over Na2S04, and evaporated to give title compound. Y: 1.64 g (57%).
Step 3: synthesis of intermediate la (S)-4-/er/-butoxy-4-oxo-2- phenylbutanoic acid
(S)-7¾r/-butyl 4-((S)-4-benzyl-2-oxooxazolidin-3-yl)-4-oxo-3- phenylbutanoate (4 mmol) was dissolved in THF, and a 35% solution of H202 in water (16 mmol) was added dropwise at 0 °C. Then a solution of LiOH (8 mmol) in H20 (19 mL) was added. The reaction mixture was stirred for 1.5 h at 0 °C (TLC: CCL/ethyl acetate= 7/3) indicated reaction was complete. A solution of
Na2S03 (15 mL) and NaHC03 (15 mL) were added at 0 °C. The reaction mixture was evaporated in a rotary evaporator by one half. Water (50 mL) was added to the residue, and the mixture was extracted with CH2C12 (3 x 45 mL). The aqueous layer was acidified with 6M HC1 to pH=2 at 0 °C. The product was extracted with ethyl acetate (3 x 50 mL). Combined extracts were washed with brine, dried over
Na2S04, and evaporated. The residue was recrystallized from hexane to give title compound. Y: 0.75 g (75%).
The following intermediates were synthesized or may be synthesized using general method B adapting the oxazolidinone chirality and starting materials to targeted intermediate:
intermediate le: (R)-4-tert-butoxy-4-oxo-2-phenethylbutanoic acid, intermediate If: (S)-4-tert-butoxy-4-oxo-2-phenethylbutanoic acid, intermediate lo: (R)-2-benzyl-5-methoxy-5-oxopentanoic acid; step 2 being replaced by a Michael addition on methyl acrylate using Ti(OiPr)2Cl2 and DIEA in DCM at 0°C as described in W01996/33176, intermediate lp: (S)-2-benzyl-5-methoxy-5-oxopentanoic acid; step 2 being replaced by a Michael addition on methyl acrylate using Ti(OiPr)2Cl2 and DIEA in DCM at 0°C as described in W01996/33176, intermediate It: (2S)-4-tert-butoxy-2-(2,3-dihydro- 1 H-inden- 1 -yl)-4- oxobutanoic acid,
intermediate lu: (S)-4-tert-butoxy-2-(2,3-dihydro-lH-inden-2-yl)-4- oxobutanoic acid,
intermediate lv: (S)-4-tert-butoxy-2-cyclohexyl-4-oxobutanoic acid intermediate lw: (R)-4-tert-butoxy-2-(cyclohexylmethyl)-4-oxobutanoic acid,
intermediate lx: (R)-4-tert-butoxy-4-oxo-2-phenylbutanoic acid, intermediate lz: (S)-4-tert-butoxy-4-oxo-2-((R)- 1 -phenylethyl)butanoic acid,
intermediate lei : (2R)-4-(tert-butoxy)-4-oxo-2-((tetrahydrofuran-2- yl)methyl)butanoic acid,
intermediate lfl: (R)-4-(tert-butoxy)-2-(cyclopentylmethyl)-4- oxobutanoic acid,
intermediate lgl : (R)-4-(tert-butoxy)-4-oxo-2-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid ,
intermediate lhl : (R)-4-(tert-butoxy)-4-oxo-2-((S)- 1 -phenylethyl)butanoic acid
intermediate lol : (2R)-4-(tert-butoxy)-4-oxo-2-((tetrahydrofuran-3- yl)methyl)butanoic acid
intermediate ltl : (R)-4-(tert-butoxy)-2-(furan-2-ylmethyl)-4-oxobutanoic acid
intermediate lul: (S)-4-(tert-butoxy)-4-oxo-2-(thiophen-2- ylmethyl)butanoic acid.
General method B: synthesis of intermediate lb (R)-2-benzyl-4-tert-butoxy-4- oxobutanoic acid Step 1 : synthesis of 3-(triphenylphosphoranylidene)dihydrofuran-2,5- dione
A solution of maleic anhydride (105 g, 1.07 mol) was added dropwise to a solution of triphenylphosphine (270 g, 1.03 mol) in acetone (1.2 L). The reaction mixture was stirred overnight at room temperature, cooled to 5°C, and filtered. The product was washed with acetone (2 x 100 mL), diethyl ether (100 mL), and dried under vacuum to give title compound. Y: 360 g (97%), rt=3.21min (gradient A), (M+H)+ =379.
Step 2: synthesis of 4-methoxy-4-oxo-3- (triphenylphosphoranylidene)butanoic acid
A solution of 3-(triphenylphosphoranylidene)dihydrofuran-2,5-dione (1 10 g, 0.305 mol) in methanol (600 mL) was stirred overnight at room temperature and evaporated. The residue was recrystallized from ethyl acetate (500 mL) to give title compound. Y: 98 g (81%) rt=3.32 min (gradient A), (M+H)+ =393.
Step 3: synthesis of (3E)-3-(methoxycarbonyl)-4-phenylbut-3-enoic acid 4-methoxy-4-oxo-3-(triphenylphosphoranylidene)butanoic acid (50 g, 0.127 mol) was suspended in benzene (100 mL). A solution of benzaldehyde (14.8 g, 0.14 mol) in a mixture of dichloro methane (30 mL) and benzene (7.5 mL) was added dropwise. The reaction mixture was stirred at RT for 20 h, diluted with diethyl ether (200 mL), and extracted with a solution of potassium bicarbonate (0.23 mol) in water (300 mL). The organic layer was discarded and the aqueous one was washed with a mixture of benzene (200 mL) and ether (100 mL). The aqueous solution was acidified with HC1 (30 mL) under cooling and extracted with an ethyl acetate/benzene mixture, 1 :2 (2 x 400 mL). The organic layer was washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, and evaporated. The obtained crude product (28 g) was purified by column chromatography (silica gel, CCL/ethyl acetate, 1 :0→ 9: 1) to give title compound. Y: 18.9 g (67.5%) rt=3.49 min (gradient A), (M+H)+ =221.
Step 4: synthesis of (3i?)-3-benzyl-4-methoxy-4-oxobutanoic acid
A mixture of (3E)-3-(methoxycarbonyl)-4-phenylbut-3-enoic acid (10.75 g, 48.8 mmol), dicyclohexylamine (18.62 g, 102.6 mmol), water (10 mL), and dichloro ((5)-(-)-2,2-bis(diphenylphosphino)-l , l-binaphthyl)ruthenium(I) (40 mg) in methanol (90 mL) was hydrogenated in a Parr apparatus at 60 °C and 60 psi for 30 h. The resulting mixture was evaporated in a rotary evaporator by ½. Acetonitrile (90 mL) was added to the residue, and the mixture was evaporated again by ½. This operation was repeated once more, and the solution was left at RT overnight. The formed precipitate was filtered off and washed with cold acetonitrile. The product (9 g) was dissolved in water (150 mL) and acidified with concentrated HC1 to pH=3 under cooling. The product was extracted with an ethyl acetate/benzene 1 :2 mixture (300 mL). The organic layer was washed with water, brine, dried over Na2S04, and evaporated to give title compound. Y: 6.35 g (58.6%) P>95%, rt= 3.54 min (gradient A), (M+H)+ =222, ee: 96% (method C).
Step 5: synthesis of (R)-4-tert-butyl 1 -methyl 2-benzylsuccinate rert-butyl-2,2,2-trichloroacetimidate (9 mmol, 1.61 mL) and boron trifluoride diethyl etherate (0.675 mmol, 85 μί) was added to a solution of (3R)- 3-Benzyl-4-methoxy-4-oxobutanoic acid (4.5 mmol, 1 g) in anhydrous THF (10 mL) at RT. The mixture stirred at RT under nitrogen for 3h. TLC (cyclohexane/AcOEt=l/l) indicated reaction was complete. Reaction mixture was diluted with sat. aq. NaHC03 (10 mL) and extracted with AcOEt (2x20 mL).
Combined organic layers were washed with brine, dried over MgS04, evaporated. Crude was purified by flash chromatography (cyclohexane/AcOEt=9/l) to give title compound as a very light yellow oil. Y: 1.25 g (62%), P>90% rt=4.65 mn (gradient A), (M+H)+ =222 (-fBu) by 1H NMR.
Step 6: synthesis of intermediate lb (R)-2-benzyl-4-tert-butoxy-4- oxobutanoic acid
To a solution of (R)-4-tert-butyl 1 -methyl 2-benzylsuccinate (308 mg, 1.11 mmol) in THF (3mL) was added a solution of lithium hydroxide (107 mg, 4.44 mmol) in water (3 mL). The mixture was stirred at RT overnight. TLC (cyclohexane/AcOEt=7/3) indicated reaction was complete. Reaction mixture was acidified to pH=l with 2M HC1 and extracted with DCM (2x20 mL). Combined organic layers were passed through a phase separator and evaporated. Crude was purified by flash chromatography (cyclohexane/AcOEt= 9/l->7/3) (loading as solution in starting eluent) to yield title compound as a colorless oil. Y: 274mg (94%), P>95%, rt=4.17 mn (gradient A), (M+H)+ =209 (-tBu).
The following intermediates were or may be synthesized using general method B:
intermediate lc: (R)-4-tert-butoxy-2-(4-fluorobenzyl)-4-oxobutanoic acid, intermediate Id: (R)-4-tert-butoxy-2-(cyclohexylmethyl)-4-oxobutanoic acid,
intermediate lg: (R)-4-tert-butoxy-4-oxo-2-(4-
(trifluoromethyl)benzyl)butano ic acid,
intermediate lh: (R)-4-tert-butoxy-4-oxo-2-(3- (trifluoromethyl)benzyl)butanoic acid,
intermediate li: (R)-4-tert-butoxy-2-(2-cyanobenzyl)-4-oxobutanoic acid intermediate lj: (R)-4-tert-butoxy-2-(3-cyanobenzyl)-4-oxobutanoic acid, intermediate lk: (R)-4-tert-butoxy-2-(4-cyanobenzyl)-4-oxobutanoic acid, intermediate 11: (R)-4-tert-butoxy-2-(4-methoxybenzyl)-4-oxobutanoic acid,
intermediate lm: (R)-4-tert-butoxy-2-(3-methoxybenzyl)-4-oxobutanoic acid,
intermediate In: (R)-4-tert-butoxy-2-(2-methoxybenzyl)-4-oxobutanoic acid,
intermediate lq: (R)-4-tert-butoxy-2-(4-chlorobenzyl)-4-oxobutanoic acid, intermediate lr: (R)-4-tert-butoxy-2-(3-chlorobenzyl)-4-oxobutanoic acid, intermediate Is: (R)-4-tert-butoxy-2-(2-chlorobenzyl)-4-oxobutanoic acid, intermediate ly: (R)-4-tert-butoxy-2-(3-fiuorobenzyl)-4-oxobutanoic acid.
General method C: synthesis of intermediate 2a 4-(2-chlorophenyl)thiazol-2- amine
Thiourea (2.1 g, 27.45 mmol) was added to a solution 2-bromo-l-(2- chlorophenyl)ethanone (7 g, 27.45 mmol) in ethanol (10 mL) and reaction mixture was stirred at RT for 18h. The solvent was evaporated and refluxed for 5 minutes in DCM. Suspension was filtered to yield 7.84 g of 4-(2-chlorophenyl)thiazol-2- amine hydrobromide as a white powder. This powder was stirred in a mixture of aq. sat. Na2C03 and AcOEt. Phases are separated and organic layer dried over MgS04, concentrated in vacuo to yield title compound as a yellow oil which solidifies spontaneously. Y: 5.37 g (93%), P=100%, rt=2.84 mn (gradient A), (M+H)+ = 211.
The following intermediates were or may be synthesized from the appropriate bromoketone (for which synthesis is described in Scheme 20) and thiourea (for which synthesis is described in Scheme 23) using general method C: intermediate 2c: 4-(2-chlorophenyl)-N-methylthiazol-2-amine, using N- methylthiourea instead of thiourea,
intermediate 2f: 4-(2,4,6-trichlorophenyl)thiazol-2-amine,
intermediate 2g: N-benzyl-4-(2-chlorophenyl)thiazol-2-amine,
intermediate 2i: 2-(2-(methylamino)thiazol-4-yl)benzonitrile
intermediate 2j: 4-(2-chlorophenyl)-N-ethylthiazol-2-amine,
intermediate 21: 4-(2-bromophenyl)-N-methylthiazol-2-amine,
intermediate 2o: N-methyl-4-(2-nitrophenyl)thiazol-2-amine, intermediate 2s: 4-(3-(trifluoromethoxy)phenyl)thiazol-2-amine
intermediate 2w: N-cyclopropyl-4-(2,5-dichlorophenyl)thiazol-2-amine, intermediate 2al : 4-(2,5-dichlorophenyl)-N-methylthiazol-2-amine, intermediate 2yl : 4-(2-chloro-5-(trifluoromethyl)phenyl)-N-methylthiazol- 2-amine,
intermediate 2zl : 4-(2-chloro-5-fluorophenyl)-N-methylthiazol-2-amine intermediate 2a2: 4-(3,5-dichlorophenyl)-N-methylthiazol-2-amine, intermediate 2b2 : 4-(3 -(difluoromethoxy)phenyl)-N-methylthiazo 1-2- amine,
intermediate 2e2: 4-(5-chloro-2-(trifluoromethyl)phenyl)-N-methylthiazol-
2-amine,
intermediate 2f2: N-methyl-4-(2,3,5-trichlorophenyl)thiazol-2-amine, intermediate 212 : N-methyl-4-(2-(trifluoromethoxy)phenyl)thiazol-2-amine, intermediate 2m2: 4-(2-chloro-5-fluorophenyl)-N-cyclopropylthiazol-2- amine,
intermediate 2n2: N-cyclopropyl-4-(3-(difluoromethoxy)phenyl)thiazol-2- amine,
intermediate 2o2: 4-(2-chloro-5-(trifluoromethyl)phenyl)-N- cyclopropylthiazo 1-2-amine,
intermediate 2d3: N-(2-(benzyloxy)ethyl)-4-(2,5-dichlorophenyl)thiazol-2- amine,
intermediate 2e3 : 4-(2-chloro-5 -(difluoromethyl)phenyl)-N-methylthiazo 1- 2-amine,
intermediate 2j3: (4-(2-chloro-5-(difluoromethoxy)phenyl)-N- methylthiazo 1-2-amine),
intermediate 2v3 : (S)- 1 -((4-(2-chlorophenyl)thiazol-2-yl)amino)propan-2- ol,
intermediate 2w3 : (R)- 1 -((4-(2-chlorophenyl)thiazol-2-yl)amino)propan-2- ol,
intermediate 2z3: 4-(2,3-dichlorophenyl)-N-methylthiazol-2-amine, intermediate 2a4 : N-methyl-4-(3 -(trifluoromethoxy)phenyl)thiazol-2- amine,
intermediate 2b4: N-cyclopropyl-4-(3-(trifluoromethoxy)phenyl)thiazol-2- amine
intermediate 2c4 : (4-(2-(difluoromethoxy)phenyl)-N-methylthiazo 1-2- amine).
General method D: synthesis of intermediate 2b 4-(2-chlorophenyl)-N- (cyclopropylmethyl)thiazol-2-amine
2-bromo-l-(2-chlorophenyl)ethanone (0.5 mmol, 116 mg) and dry sodium thiocyanate (0.55 mmol, 45 mg) were stirred in 1 mL ethanol for 3 h at 50°C. A solution of cyclopropane methyl amine (0.55 mmol, 39 mg) in 0.5 mL of ethanol was added at once and the reaction mixture was stirred for 12 h. The ethanol was distilled off, and ethyl acetate and water were added. The aqueous phase was extracted twice with ethyl acetate, the combined organic phases were dried over Na2S04, and the solvent was removed in vacuo. Crude was purified by flash chromatography (cyclohexane/DCM=6/4) to give title compound as a dark yellow oil. Y: 40 mg (30%), P=100%, rt=3.5 mn (gradient A), (M+H)+=264.8.
The following intermediates were or may be synthesized from the appropriate bromoketone (for which synthesis is described in Scheme 20) and amine reagents using general method D:
intermediate 2d: N-allyl-4-(2-chlorophenyl)thiazol-2-amine,
intermediate 2e: methyl 2-(4-(2-chlorophenyl)thiazol-2-ylamino)acetate, intermediate 2h: 4-(2-chlorophenyl)-N-(2,2,2-trifluoroethyl)thiazol-2- amine,
intermediate 2k: 4-(2-chlorophenyl)-N-cyclopropylthiazol-2-amine, intermediate 2r: 2-((4-(2-chlorophenyl)thiazol-2-yl)amino)acetamide, intermediate 2x: methyl 3-((4-(2-chlorophenyl)thiazol-2- yl)amino)propanoate,
intermediate 2ul : N-(2-(benzyloxy)ethyl)-4-(2-chlorophenyl)thiazol-2- amine,
intermediate 2vl : N-(3-(benzyloxy)propyl)-4-(2-chlorophenyl)thiazol-2- amine,
intermediate 2s2: 4-(2-chlorophenyl)-N-(2-methoxyethyl)thiazol-2-amine, intermediate 2t2: N-(2-(benzyloxy)ethyl)-4-(2-chlorophenyl)thiazol-2- amine.
General method E: synthesis of Example 1: compound n°2: (R)-3-benzyl-4-(4- (2-chlorophenyl)thiazol-2-ylamino)-4-oxobutanoic acid Step 1 : synthesis of (R)-tert-butyl 3-benzyl-4-(4-(2-chlorophenyl)thiazol-2- ylamino)-4-oxobutanoate
To a solution of (R)-2-benzyl-4-tert-butoxy-4-oxobutanoic acid lb (1.21 mmol, 320 mg) in anhydrous DMF (5mL) was added HATU (1.33mmol, 505mg). After 5 min was added 4-(2-chlorophenyl)thiazol-2-amine 2a (1.33 mmol, 279 mg) and DIEA (1.815 mmol, 300 μί). Reaction mixture was stirred at RT for 4 days. TLC (cyclohexane/AcOEt=8/2) indicated reaction was complete. Reaction mixture (rm) was diluted with AcOEt (20mL) and washed with sat. aq. NaHC03 (lOmL) and water (3x10 mL). The organic phase was dried over MgSC^ and evaporated. Crude was purified by flash chromatography (cyclohexane/AcOEt= 9/1) (loading onto silica) to yield title compound as a yellow gum. Y: 370 mg (67%), P>95%, rt=5.24 mn (gradient A), (M+H)+ =457.1.
ACN was also used instead of DMF.
Step 2: synthesis of Example 1: compound n°2: (R)-3-benzyl-4-(4-(2- chlorophenyl)thiazol-2-ylamino)-4-oxobutanoic acid To a solution of (R)-tert-butyl 3-benzyl-4-(4-(2-chlorophenyl)thiazol-2- ylamino)-4-oxobutanoate (0.7 mmol, 320 mg) in DCM (8 mL) was added TFA (2 mL). Rm was stirred at RT overnight. TLC (cyclohexane/AcOEt=7/3) indicated reaction was complete. Reaction mixture was evaporated and residue purified using a Biotage PEAX SPE cartridge. The oil obtained was triturated in diethyl ether/pentane=2/8 to yield title compound as a colorless solid. Y: 280 mg (99%), P>99% rt=9.32 mn (gradient B), (M+H)+ =401.1, ee=96% (method B), !HNMR (CDC13): δ=12.2 (br s, 1H), 7.39-7.33 (m, 9H), 7.14 (s, 1H), 3.36 (q, 1H), 3.14 (m, 1H), 2.89-2.77 (m, 2H), 2.57 (dd, 1H).
Examples 2 to 18 were synthesized using general method E and intermediates described above or commercially available.
Example 2: compound n°9: (S)-4-(4-(2-chlorophenyl)thiazol-2-ylamino)-4-oxo-3- phenylbutanoic acid was synthesized using intermediates la and 2a. P=99%, (M+H)+ =387, ee=98% (method A), !HNMR (DMSO-d6): δ=7.78 (d, J=2.8Hz, 1H), 7.5 (m, 2H), 7.4-7.1 (m, 9H), 4.3 (q, 1H), 3.18 (dd, J=17Hz, J=27Hz, 1H), 2.66 (dd, J=4.8Hz, J=22Hz, 1H).
Example 3: compound n°3: (R)-3-benzyl-4-(4-(2,4-dichlorophenyl)thiazol-2- ylamino)-4-oxobutanoic acid was synthesized using intermediate lb and 4-(2,4- dichlorophenyl)thiazol-2-amine.
Example 4: compound n°4: (R)-3-benzyl-4-(4-(2-fluorophenyl)thiazol-2- ylamino)-4-oxobutanoic acid was synthesized using intermediate lb and 4-(2- fluorophenyl)thiazol-2-amine.
Example 5: compound n°5: (R)-3-benzyl-4-(4-(3,4-dichlorophenyl)thiazol-2- ylamino)-4-oxobutanoic acid was synthesized using intermediate lb and 4-(3,4- dichlorophenyl)thiazol-2-amine.
Example 8: compound n°8: (R)-3-benzyl-4-(4-(4-cyanophenyl)thiazol-2- ylamino)-4-oxobutanoic acid was synthesized using intermediate lb and 4-(2- aminothiazol-4-yl)benzonitrile. Example 9: compound n°12: (R)-3-benzyl-4-(4-(3-chlorophenyl)thiazol-2- ylamino)-4-oxobutanoic acid was synthesized using intermediate lb and 4-(3- chlorophenyl)thiazol-2-amine. Example 10: compound n°13: (R)-3-benzyl-4-oxo-4-(4-(3-
(trifluoromethyl)phenyl)thiazol-2-ylamino)butanoic acid was synthesized using intermediate lb and 4-(3-(trifluoromethyl)phenyl)thiazol-2-amine.
Example 11: compound n°14: (R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-4-oxobutanoic acid was synthesized using intermediates lb and 2c. Y: 142 mg (80%), P>99% rt=10.5 mn (gradient B), (M+H)+ =414.8, ee=96% (method B), !HNMR (CDC13): δ= 7.92 (d, 1H), 7.54 (s, 1H), 7.45 (d, 1H), 7.34-7.13 (m, 7H), 3.62 (s, 3H), 3.47 (m, 1H), 3.15-3.01 (m, 2H), 2.61-2.54 (m, 1H), 2.53-2.51 (dd, 1H). Example 12: compound n°17: (R)-4-(4-(2-chlorophenyl)thiazol-2-ylamino)-3-(4- fluorobenzyl)-4-oxobutanoic acid was synthesized using intermediates lc and 2a.
Example 13: compound n°18: (R)-4-(4-(2-chlorophenyl)thiazol-2-ylamino)-3- (cyclohexylmethyl)-4-oxobutanoic acid was synthesized using intermediates Id and 2a. Y: 15 mg (30%), P>90% rt=10.76 mn (gradient B), (M+H)+=401.1, ee=96% (method B), !HNMR (CDC13): δ= 12.26 (br s, 1H), 7.35-7.45 (m, 2H), 7.15-7.30 (m, 4H), 3.15-3.25 (m, 1H), 2.7 (dd, 1H), 2.5 (dd, 1H), 1.45-1.8 (m, 6H), 1.1-1.4 (m, 5H), 0.8-1.0 (m, 2H).
Example 14: compound n°22: (R)-4-(allyl(4-(2-chlorophenyl)thiazol-2-yl)amino)- 3-benzyl-4-oxobutanoic acid was synthesized using intermediates lb and 2d. Example 15: compound n°23: (R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2-yl)(2- methoxy-2-oxoethyl)amino)-4-oxobutanoic acid was synthesized using intermediate lb and 2e.
Example 16: compound n°l l : (R)-3-benzyl-4-oxo-4-(3-phenyl-l,2,4-thiadiazol-5- ylamino)butanoic acid was synthesized using intermediate lb and 3-phenyl- 1,2,4- thiadiazol-5-amine.
Example 17: compound n°20: (R)-3-benzyl-4-(4-(2-chlorophenyl)-5- fluorothiazol-2-ylamino)-4-oxobutanoic acid was synthesized using intermediate lb and 4-(2-chlorophenyl)-5-fluorothiazol-2-amine which was prepared in one step from intermediate 2a as described in Chem. Res. Toxicol. 2007, 1954-1965.
Example 18: compound n°21 : (R)-3-benzyl-4-((5-chloro-4-(2- chlorophenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized using intermediate lb and 5-chloro-4-(2-chlorophenyl)-N-methylthiazol-2-amine which was prepared by reacting intermediate 2c with N-chlorosuccinimide and triethylamine in chloroform.
Example 19: compound n°15: (R)-3-benzyl-4-(5-(2-chlorophenyl)pyridin-2- ylamino)-4-oxobutanoic acid was synthesized using intermediate lb and 5- iodopyridin-2-amine. Amide coupling such as in general method E, subsequent Suzuki coupling with 2-chlorophenylboronic acid using PdCl2(PPh3)4 catalyst and K2C03 in dioxane/H20 followed by tBu deprotection as described in general method E provided title compound.
Example 20: compound n°10: (Z)-4-(4-(2-chlorophenyl)thiazol-2-ylamino)-4- oxobut-2-enoic acid was synthesized using intermediate 2a and (Z)-4-methoxy-4- oxobut-2-enoic acid. Amide coupling such as in general method E followed by saponification such as in step 6 of general method B provided title compound.
Example 21: compound n°16: (R)-3-(4-(2-chlorophenyl)thiazol-2- ylcarbamoyl)heptanoic acid was synthesized using intermediate 2a and (R)-2-(2- tert-butoxy-2-oxoethyl)hexanoic acid. (R)-2-(2-tert-butoxy-2-oxoethyl)hexanoic acid was prepared from (R)-3-(methoxycarbonyl)heptanoic acid as done in steps 5 and 6 of general method B.
Example 22: compound n°19: (R)-3-(4-(2-chlorophenyl)thiazol-2-ylcarbamoyl)-5- methylhexanoic acid was synthesized using intermediate 2a and (R)-2-(2-tert- butoxy-2-oxoethyl)-4-methylpentanoic acid. (R)-2-(2-tert-butoxy-2-oxoethyl)-4- methylpentanoic acid was prepared from (R)-3-(methoxycarbonyl)-5- methylhexanoic acid as done in steps 5 and 6 of general method B.
Example 23: compound n°l : 6-((4-(2-chlorophenyl)thiazol-2- yl)carbamoyl)cyclohex-3-enecarboxylic acid was synthesized using intermediate 2a and 6-(methoxycarbonyl)cyclohex-3-enecarboxylic acid. Amide coupling such as in general method E followed by saponification such as in step 6 of general method B provided title compound.
Example 24: compound n°24: (R)-methyl 3-benzyl-4-(4-(2-chlorophenyl)thiazol- 2-ylamino)-4-oxobutanoate may be synthesized by treating compound n°2 with TMSC1 in MeOH.
Example 26: compound n°26: (R)-3-(4-(2-chlorophenyl)thiazol-2-ylcarbamoyl)-5- phenylpentanoic acid may be synthesized from intermediates le and 2a using general method E. Example 27: compound n°27: (S)-3-(4-(2-chlorophenyl)thiazol-2-ylcarbamoyl)-5- phenylpentanoic acid may be synthesized from intermediates If and 2a using general method E.
Example 28: compound n°28: (R)-4-(4-(2-chlorophenyl)thiazol-2-ylamino)-4- oxo-3-(4-(trifluoromethyl)benzyl)butanoic acid was synthesized from intermediates lg and 2a using general method E.
Example 29: compound n°29: (R)-4-(4-(2-chlorophenyl)thiazol-2-ylamino)-4- oxo-3-(3-(trifluoromethyl)benzyl)butanoic acid was synthesized from intermediates lh and 2a using general method E.
Example 30: compound n°30: (R)-4-(4-(2-chlorophenyl)thiazol-2-ylamino)-3-(2- cyanobenzyl)-4-oxobutanoic acid may be synthesized from intermediates li and 2a using general method E.
Example 31: compound n°31 : (R)-4-(4-(2-chlorophenyl)thiazol-2-ylamino)-3-(3- cyanobenzyl)-4-oxobutanoic acid may be synthesized from intermediates lj and 2a using general method E. Example 32: compound n°32: (R)-4-(4-(2-chlorophenyl)thiazol-2-ylamino)-3-(4- cyanobenzyl)-4-oxobutanoic acid may be synthesized from intermediates lk and 2a using general method E.
Example 33: compound n°33: (R)-4-(4-(2-chlorophenyl)thiazol-2-ylamino)-3-(4- methoxybenzyl)-4-oxobutanoic acid may be synthesized from intermediates 11 and 2a using general method E. Example 34: compound n°34: (R)-4-(4-(2-chlorophenyl)thiazol-2-ylamino)-3-(3- methoxybenzyl)-4-oxobutanoic acid may be synthesized from intermediates lm and 2a using general method E.
Example 35: compound n°35: (R)-4-(4-(2-chlorophenyl)thiazol-2-ylamino)-3-(2- methoxybenzyl)-4-oxobutanoic acid may be synthesized from intermediates In and 2a using general method E.
Example 36: compound n°36: (R)-3-benzyl-4-(4-(2-methoxyphenyl)thiazol-2- ylamino)-4-oxobutanoic acid was synthesized from intermediate lb and 4-(2- methoxyphenyl)thiazol-2-amine using general method E. Example 37: compound n°37: ((R)-3-benzyl-4-oxo-4-(4-(2,4,6- trichlorophenyl)thiazol-2-ylamino)butanoic acid may be synthesized from intermediates lb and 2f using general method E.
Example 38: compound n°38: (R)-4-benzyl-5-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-5-oxopentanoic acid may be synthesized from intermediates lo and 2c using general method E, replacing the TFA tBu ester deprotection by a methyl ester saponification using LiOH in THF/H20.
Example 39: compound n°39: (S)-4-benzyl-5-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-5-oxopentanoic acid was synthesized from intermediates lp and 2c using general method E, replacing the TFA tBu ester deprotection by a methyl ester saponification using LiOH in THF/H20.
Example 40: compound n°40: (R)-methyl 4-benzyl-5-(4-(2-chlorophenyl)thiazol- 2-ylamino)-5-oxopentanoate may be synthesized from intermediates lo and 2a using general method E.
Example 41: compound n°41 : (S)-methyl 4-benzyl-5-(4-(2-chlorophenyl)thiazol- 2-ylamino)-5-oxopentanoate may be synthesized from intermediates lp and 2a using general method E.
Example 42: compound n°42: (R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2- yl)(cyclopropylmethyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2b using general method E. Example 43: compound n°43:(R)-3-benzyl-4-(benzyl(4-(2-chlorophenyl)thiazol- 2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2g using general method E.
Example 44: compound n°44: (R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2- yl)(2,2,2-trifluoroethyl)amino)-4-oxobutanoic acid may be synthesized from intermediates lb and 2h using general method E.
Example 45: compound n°45: (R)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-3-(4-methoxybenzyl)-4-oxobutanoic acid was synthesized from 4-(tert-butoxy)-2-(4-methoxybenzyl)-4-oxobutanoic acid and intermediate 2c using general method E and chiral preparative HPLC purification. 4-(tert- butoxy)-2-(4-methoxybenzyl)-4-oxobutanoic acid was synthesized from commercially available 4-methoxybenzaldehyde using the HWE methodology (Scheme 13).
Example 46: compound n°46: (R)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-3-(3-methoxybenzyl)-4-oxobutanoic acid may be synthesized from intermediates lm and 2c using general method E.
Example 47: compound n°47: (R)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-3-(2-methoxybenzyl)-4-oxobutanoic acid may be synthesized from intermediates In and 2c using general method E.
Example 48: compound n°48: (R)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-3-(4-cyanobenzyl)-4-oxobutanoic acid was synthesized from 4-(tert-butoxy)-2-(4-cyanobenzyl)-4-oxobutanoic acid and intermediate 2c using general method E and chiral preparative HPLC purification. 4-(tert-butoxy)-2-(4- cyanobenzyl)-4-oxobutanoic acid was synthesized from commercially available 4- cyanobenzaldehyde using the HWE methodology (Scheme 13). Example 49: compound n°49: (R)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-3-(3-cyanobenzyl)-4-oxobutanoic acid may be synthesized from intermediates lj and 2c using general method E.
Example 50: compound n°50: (R)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-3-(2-cyanobenzyl)-4-oxobutanoic acid may be synthesized from intermediates li and 2c using general method E.
Example 51: compound n°51 : (R)-3-(4-Chlorobenzyl)-4-((4-(2- chlorophenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from 4-(tert-butoxy)-2-(4-chlorobenzyl)-4-oxobutanoic acid and intermediate 2c using general method E and chiral preparative HPLC purification. 4-(tert-butoxy)- 2-(4-chlorobenzyl)-4-oxobutanoic acid was synthesized from commercially available 4-chlorobenzaldehyde using the HWE methodology (Scheme 13).
Example 52: compound n°52: (R)-3-(3-chlorobenzyl)-4-((4-(2- chlorophenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid may be synthesized from intermediates lr and 2c using general method E.
Example 53: compound n°53: (R)-3-(2-chlorobenzyl)-4-((4-(2- chlorophenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid may be synthesized from intermediates Is and 2c using general method E.
Example 54: compound n°54: (3S)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-3-(2,3-dihydro-lH-inden-l-yl)-4-oxobutanoic acid may be synthesized from intermediates It and 2c using general method E. It may be synthesized using Stobbe's condensation (Scheme 6).
Example 55: compound n°55: (S)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-3-(2,3-dihydro-lH-inden-2-yl)-4-oxobutanoic acid may be synthesized from intermediates lu and 2c using general method E. lu may be synthesized using Stobbe's condensation (Scheme 6). Example 56: compound n°56: (R)-4-(benzo[d]thiazol-2-yl(methyl)amino)-3- benzyl-4-oxobutanoic acid may be synthesized from intermediate lb and N- methylbenzo[d]thiazol-2-amine using general method E. N- methylbenzo[d]thiazol-2-amine may be prepared by Eischweiler-Clarke methylation of benzo[d]thiazol-2-amine. Example 57: compound n°57: (R)-4-(benzo[d]oxazol-2-yl(methyl)amino)-3- benzyl-4-oxobutanoic acid may be synthesized from intermediate lb and N- methylbenzo[d]oxazol-2-amine using general method E. N- methylbenzo[d]oxazol-2-amine may be prepared by Eischweiler-Clarke methylation of benzo[d]oxazol-2-amine. Example 58: compound n°58: (R)-2-((lH-tetrazol-5-yl)methyl)-N-(4-(2- chlorophenyl)thiazol-2-yl)-N-methyl-3-phenylpropanamide may be synthesized from compound n°14 using methodologies described in the isosteres synthetic schemes section.
Example 59: compound n°59: (R)-2-benzyl-N-(4-(2-chlorophenyl)thiazol-2-yl)- N-methyl-3-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)propanamide may be synthesized from compound n°14 using methodologies described in the isosteres synthetic schemes section.
Example 60: compound n°60: (R)-3-benzyl-4-((4-(2-chlorophenyl)-5- fluorothiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized using intermediate lb and 4-(2-chlorophenyl)-5-fluoro-N-methylthiazol-2-amine which was prepared in one step from intermediate 2c as described in Chem. Res. Toxicol. 2007, 1954-1965.
Example 61: compound n°61 : (S)-4-(4-(2-chlorophenyl)thiazol-2-ylamino)-3- cyclohexyl-4-oxobutanoic acid may be synthesized from intermediates lv and 2a using general method E. Example 62: compound n°62: (S)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-3-cyclohexyl-4-oxobutanoic acid was synthesized from (S)-4- (tert-butoxy)-2-cyclohexyl-4-oxobutanoic acid and intermediate 2c using general method E. (S)-4-(tert-butoxy)-2-cyclohexyl-4-oxobutanoic acid was synthesized from commercially available (S)-3-cyclohexyl-4-methoxy-4-oxobutanoic acid as described in steps 5 and 6 of general method B.
Example 63: compound n°63: (S)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-4-oxo-3-phenylbutanoic acid may be synthesized from intermediates la and 2c using general method E.
Example 64: compound n°64: (3R)-3-(4-(2-chlorophenyl)thiazol-2-ylcarbamoyl)- 4-phenylpentanoic acid may be synthesized from intermediate 2a and (2R)-4-tert- butoxy-4-oxo-2-(l-phenylethyl)butanoic acid using general method E. (2R)-4- tert-butoxy-4-oxo-2-(l-phenylethyl)butanoic acid may be obtained by Stobbe condensation (Scheme 6).
Example 65: compound n°65: (R)-2-((lH-tetrazol-5-yl)methyl)-N-(4-(2- chlorophenyl)thiazol-2-yl)-3-phenylpropanamide was synthesized from compound n°2 using methodologies described in the isosteres synthetic schemes section.
Example 66: compound n°66: (R)-2-benzyl-N-(4-(2-chlorophenyl)thiazol-2-yl)-3- (5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)propanamide was synthesized from compound n°2 using methodologies described in the isosteres synthetic schemes section.
Example 68: compound n°68: (3R)-3-benzyl-4-(4-(2-chlorophenyl)thiazol-2- ylamino)-2-methyl-4-oxobutanoic acid was synthesized as described in Scheme 7.
Example 69: compound n°69: (R)-2-benzyl-N-(4-(2-chlorophenyl)thiazol-2-yl)-3- (3-hydroxyisoxazol-5-yl)propanamide may be synthesized using methodologies described in the isosteres synthetic schemes section.
Example 70: compound n°70: (R)-3-benzyl-4-(4-(2-chlorophenyl)pyrimidin-2- ylamino)-4-oxobutanoic acid was synthesized from intermediate lb and 4-(2- chlorophenyl)pyrimidin-2-amine using general method E. 4-(2- chlorophenyl)pyrimidin-2-amine was synthesized as described in Scheme 8. Example 71: compound n°71 : (R)-3-benzyl-4-(6-(2-chlorophenyl)pyridin-2- ylamino)-4-oxobutanoic acid was synthesized from intermediate lb and 6-(2- chlorophenyl)pyridin-2-amine using general method E. 6-(2- chlorophenyl)pyridin-2-amine was synthesized as described in Scheme 8.
Example 72: compound n°72: (E)-3-(4-(2-chlorophenyl)thiazol-2-ylcarbamoyl)-4- phenylbut-3-enoic acid may be synthesized from (E)-2-benzylidene-4-tert-butoxy- 4-oxobutanoic acid and intermediate 2a using general method E. (E)-2- benzylidene-4-tert-butoxy-4-oxobutanoic acid was synthesized from maleic anhydride following steps 1, 2, 3, 5 and 6 of general method B.
Example 74: compound n°74: (Z)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-4-oxo-3-phenylbut-2-enoic acid may be synthesized as described in Scheme 9.
Example 75: compound n°75: (R)-3-(N-(4-(2-chlorophenyl)thiazol-2-yl)-N- methylsulfamoyl)-4-phenylbutanoic acid may be synthesized as described in Scheme 10. Example 76: compound n°76: (S)-3-(N-(4-(2-chlorophenyl)thiazol-2-yl)-N- methylsulfamoyl)-4-phenylbutanoic acid may be synthesized as described in Scheme 10.
Example 79: compound n°79: (R)-3-benzyl-4-(4-(2-chlorophenyl)thiazol-2- ylamino)-3-fluoro-4-oxobutanoic acid may be synthesized as described in Scheme 11.
Example 80: compound n°80: (R)-3-benzyl-3-(4-(2-chlorophenyl)thiazol-2- ylcarbamoyl)hex-5-enoic acid may be synthesized as described in Scheme 11.
Example 81: compound n°81 : (E)-3-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)carbamoyl)-4-phenylbut-3-enoic acid was synthesized from (E)-2- benzylidene-4-tert-butoxy-4-oxobutanoic acid and intermediate 2c using general method E. (E)-2-benzylidene-4-tert-butoxy-4-oxobutanoic acid was synthesized from maleic anhydride following steps 1, 2, 3, 5 and 6 of general method B.
Example 82: compound n°82: (3S)-3-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)carbamoyl)-4-phenylpentanoic acid may be synthesized from intermediate 2c and (2R)-4-tert-butoxy-4-oxo-2-(l-phenylethyl)butanoic acid using general method E. (2R)-4-tert-butoxy-4-oxo-2-(l-phenylethyl)butanoic acid may be obtained by Stobbe condensation (Scheme 6).
Example 83: compound n°83: (R)-3-benzyl-4-((3-(2-chlorophenyl)- 1,2,4- thiadiazol-5-yl)(methyl)amino)-4-oxobutanoic acid was synthesized as described in Scheme 12.
Example 84: compound n°84: (R)-3-benzyl-4-((3-(2-chlorophenyl)- 1,2,4- oxadiazol-5-yl)(methyl)amino)-4-oxobutanoic acid may be synthesized as described in Scheme 12.
Example 85: compound n°85: (R)-3-benzyl-4-((l-(2-chlorophenyl)-lH-pyrazol-3- yl(methyl)amino)-4-oxobutanoic acid may be synthesized as described in Scheme
12.
Example 86: compound n°86: (R)-2-benzyl-N-(4-(2-chlorophenyl)thiazol-2-yl)-3- (3-hydroxyisoxazol-5-yl)-N-methylpropanamide was synthesized using methodologies described in the isosteres synthetic schemes section.
Example 89: compound n°89: (R)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-3-(cyclohexylmethyl)-4-oxobutanoic acid was synthesized from intermediates lw and 2c using general method E. Intermediate lw was synthesized by hydrogenation of intermediate lb using Pt02 in MeOH.
Example 90: compound n°90: (R)-3-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)carbamoyl)-5-methylhexanoic acid was synthesized from intermediate 2c and (R)-2-(2-tert-butoxy-2-oxoethyl)-4-methylpentanoic acid using general method E. (R)-2-(2-tert-butoxy-2-oxoethyl)-4-methylpentanoic acid was synthesized from (R)-3-(methoxycarbonyl)-5-methylhexanoic acid using methodology described in steps 5 and 6 of general method B. Example 91: compound n°91 : (R)-3-benzyl-4-((4-(2-cyanophenyl)thiazol-2- yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2i using general method E.
Example 92: compound n°92: (R)-4-(4-(2-chlorophenyl)thiazol-2-ylamino)-4- oxo-3-phenylbutanoic. Phenylacetic acid was converted to its tBu ester using tBu- TCA. Treatment of this tBu ester with LiHMDS followed by the addition of t- butyl bromoacetate provided 1-tert-butyl 4-methyl 2-phenylsuccinate. tBu deprotection with TFA yielded 4-methoxy-4-oxo-2-phenylbutanoic acid. HATU coupling of this acid with intermediate 2a and subsequent methyl ester saponification using LiOH yielded 4-(4-(2-chlorophenyl)thiazol-2-ylamino)-4- oxo-3-phenylbutanoic. Chiral preparative HPLC purification of this racemic mixture allowed isolating compound n°92.
Example 93: compound n°93: (R)-4-(4-(2-chlorophenyl)thiazol-2-ylamino)-3-(3- fluorobenzyl)-4-oxobutanoic acid was synthesized from intermediates ly and 2a using general method E and preparative HPLC purification. Example 94: compound n°94: (S)-3-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)carbamoyl)-4-methylpentanoic acid was synthesized from (S)-4-tert- butoxy-2-isopropyl-4-oxobutanoic acid and intermediate 2c using general method E. (S)-4-tert-butoxy-2-isopropyl-4-oxobutanoic acid was synthesized from commercially available (S)-3-(methoxycarbonyl)-4-methylpentanoic acid using reactions described in steps 5 and 6 of general method B.
Example 95: compound n°95: 4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)- 4-oxo-3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid was synthesized from (R)-4-tert-butoxy-4-oxo-2-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid and intermediate 2c using general method E. (R)-4-tert-butoxy-4-oxo-2-((tetrahydro- 2H-pyran-4-yl)methyl)butanoic acid was synthesized from commercially available tetrahydro-2H-pyran-4-carbaldehyde using the HWE methodology (Scheme 13).
Example 96: compound n°96: (R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2- yl)(ethyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2j using general method E. Example 97: compound n°97: (R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2- yl)(cyclopropyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2k using general method E.
Example 98: compound n°98: cis-6-(4-(2-chlorophenyl)thiazol-2- ylcarbamoyl)cyclohex-3-enecarboxylic acid was synthesized from cis-3a,4,7,7a- tetrahydroisobenzofuran-l,3-dione and intermediate 2a as described in Scheme 14.
Example 99: compound n°99: 4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-
3- (4-methoxybenzyl)-4-oxobutanoic acid was synthesized from 4-tert-butoxy-2- (4-methoxybenzyl)-4-oxobutanoic acid and intermediate 2c using general method E. 4-tert-butoxy-2-(4-methoxybenzyl)-4-oxobutanoic acid was synthesized from
4- methoxybenzaldehyde using the HWE methodology (Scheme 13).
Example 100: compound n°100: cis-6-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)carbamoyl)cyclohex-3-enecarboxylic acid was synthesized from cis- 3a,4,7,7a-tetrahydroisobenzofuran-l,3-dione and intermediate 2c as described in Scheme 14.
Example 101: compound n°101 : cis-2-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)carbamoyl)cyclohexanecarboxylic acid was synthesized from cis- hexahydroisobenzofuran-l,3-dione and intermediate 2c as described in Scheme 14. Example 102: compound n°102: (R)-3-benzyl-4-(4-(2,5-dimethylthiophen-3- yl)thiazol-2-ylamino)-4-oxobutanoic acid was synthesized from intermediate lb and commercially available 4-(2,5-dimethylthiophen-3-yl)thiazol-2-amine using general method E.
Example 103: compound n°103: 4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-3-(cyclohexylmethyl)-4-oxobutanoic acid was synthesized from 4-tert-butoxy-2-(cyclohexylmethyl)-4-oxobutanoic acid and intermediate 2c using general method E. 4-tert-butoxy-2-(cyclohexylmethyl)-4-oxobutanoic acid was synthesized by hydrogenation of (E)-4-tert-butyl 1 -methyl 2- benzylidenesuccinate using Pt02 in MeOH.
Example 105: compound n°105: 4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-3-(cyclopentylmethyl)-4-oxobutanoic acid was synthesized from 4-tert-butoxy-2-(cyclopentylmethyl)-4-oxobutanoic acid and intermediate 2c using general method E. 4-tert-butoxy-2-(cyclopentylmethyl)-4-oxobutanoic acid was synthesized from commercially available cyclopentanecarbaldehyde using the HWE methodology (Scheme 13). Example 106: compound n°106: (3S,4R)-3-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)carbamoyl)-4-phenylpentanoic acid from intermediates lz and 2c using general method E.
Example 107: compound n°107: (R)-3-benzyl-4-(methyl(4-(2-(thiophen-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediate lb and N-methyl-4-(2-(thiophen-3-yl)phenyl)thiazol-2-amine using general method E. N-methyl-4-(2-(thiophen-3-yl)phenyl)thiazol-2-amine was synthesized from commercially available thiophen-3-ylboronic acid using the methodology shown in Scheme 15.
Example 108: compound n°108: (R)-3-benzyl-4-((4-(2-(6-chloropyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediate lb and 4-(2-(6-chloropyridin-3-yl)phenyl)-N-methylthiazol-2-amine using general method E. 4-(2-(6-chloropyridin-3-yl)phenyl)-N-methylthiazol-2- amine was synthesized from commercially available 6-chloropyridin-3-ylboronic acid using the methodology shown in Scheme 15. Example 109: compound n°109: (R)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-4-oxo-3-(phenylamino)butanoic acid was synthesized from (R)-4-tert-butoxy-4-oxo-2-(phenylamino)butanoic acid and intermediate 2c using general method E. (R)-4-tert-butoxy-4-oxo-2-(phenylamino)butanoic acid was synthesized from commercially available (R)-2-amino-4-tert-butoxy-4- oxobutanoic acid and iodobenzene using Cul catalyzed coupling as described in J Am. Chem. Soc. 1998, 120, 12459. Example 110: compound n°110: 4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-3-(4-methylbenzyl)-4-oxobutanoic acid was synthesized from 4-tert-butoxy-2-(4-methylbenzyl)-4-oxobutanoic acid and intermediate 2c using general method E. 4-tert-butoxy-2-(4-methylbenzyl)-4-oxobutanoic acid was synthesized from 4-methylbenzaldehyde using the HWE methodology (Scheme 13).
Example 111: compound n°l l l : (R)-4-((4-([l,l'-biphenyl]-2-yl)thiazol-2- yl)(methyl)amino)-3-benzyl-4-oxobutanoic acid was synthesized from intermediate lb and 4-([l, -biphenyl]-2-yl)-N-methylthiazol-2-amine using general method E. 4-([l,l'-biphenyl]-2-yl)-N-methylthiazol-2-amine was synthesized from commercially available phenylboronic acid using the methodology shown in Scheme 15.
Example 112: compound n°112: (R)-3-benzyl-4-(4-(2,5-dichlorothiophen-3- yl)thiazol-2-ylamino)-4-oxobutanoic acid was synthesized from intermediate lb and commercially available 4-(2,5-dichlorothiophen-3-yl)thiazol-2-amine using general method E.
Example 113: compound n°113: 4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-3-(cyclopropylmethyl)-4-oxobutanoic acid was synthesized from intermediates lal (4-(tert-butoxy)-2-(cyclopropylmethyl)-4-oxobutanoic acid) and 2c using general method E. lal was synthesized from cyclopropanecarbaldehyde using the HWE methodology (Scheme 13).
Example 114: compound n°114: 4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-4-oxo-3-(thiazol-4-ylmethyl)butanoic acid was synthesized from intermediates lbl (4-(tert-butoxy)-4-oxo-2-(thiazol-4-ylmethyl)butanoic acid) and 2c using general method E. lbl was synthesized from thiazole-4- carbaldehyde using the HWE methodology (Scheme 13).
Example 115: compound n°115: (R)-3-benzyl-4-((4-(2-(6- (dimethylamino)pyridin-3-yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediate lb and 4-(2-(6-(dimethylamino)pyridin-3- yl)phenyl)-N-methylthiazol-2-amine using general method E. 4-(2-(6- (dimethylamino)pyridin-3 -yl)phenyl)-N-methylthiazol-2-amine was synthesized from (6-(dimethylamino)pyridin-3-yl)boronic acid and 21 using the methodology shown in Scheme 15.
Example 116: compound n°116: (R)-3-benzyl-4-((4-(2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediate lb and intermediate 2m (4-(2-(6-methoxypyridin-3-yl)phenyl)-N- methylthiazol-2-amine) using general method E. Intermediate 2m was synthesized from (6-methoxypyridin-3-yl)boronic acid and 21 using the methodology shown in Scheme 15.
Example 117: compound n°117: (R)-3-benzyl-4-((4-(2-(2-methoxypyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediate lb and (4-(2-(2-methoxypyridin-3-yl)phenyl)-N-methylthiazol-2- amine) using general method E. (4-(2-(2-methoxypyridin-3-yl)phenyl)-N- methylthiazol-2-amine) was synthesized from (2-methoxypyridin-3-yl)boronic acid and 21 using the methodology shown in Scheme 15.
Example 118: compound n°118: (R)-3-benzyl-4-((4-(2-
((ethoxycarbonyl)amino)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2n (ethyl (2-(2-(methylamino)thiazol- 4-yl)phenyl)carbamate) using general method E. Intermediate 2n was synthesized using the methodology described in Scheme 16.
Example 119: compound n°119: (R)-3-benzyl-4-((4-(2-(6-fluoropyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2p (4-(2-(6-fluoropyridin-3-yl)phenyl)-N-methylthiazol-2- amine) using general method E and preparative HPLC purification. Intermediate 2p was synthesized from (6-fluoropyridin-3-yl)boronic acid and 21 using the methodology described in Scheme 15.
Example 120: compound n°120: (R)-3-benzyl-4-(methyl(4-(2-(6-methylpyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2q (N-methyl-4-(2-(6-methylpyridin-3-yl)phenyl)thiazol-2- amine) using general method E and preparative HPLC purification. Intermediate 2q was synthesized from (6-methylpyridin-3-yl)boronic acid and 21 using the methodology described in Scheme 15.
Example 121: compound n°121 : (R)-4-((2-amino-2-oxoethyl)(4-(2- chlorophenyl)thiazol-2-yl)amino)-3-benzyl-4-oxobutanoic acid was synthesized from intermediates lb and 2r using general method E.
Example 122: compound n°122: (R)-3-benzyl-4-oxo-4-((4-(3-
(trifluoromethoxy)phenyl)thiazol-2-yl)amino)butanoic acid was synthesized from intermediates lb and commercially available 2s (4-(3- (trifluoromethoxy)phenyl)thiazol-2-amine) using general method E. Example 123: compound n°123: (R)-3-benzyl-4-((4-(2,5-dichlorophenyl)thiazol- 2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and commercially available 2t (4-(2,5-dichlorophenyl)thiazol-2-amine) using general method E.
Example 124: compound n°124: (R)-3-benzyl-4-((4-(3-chloro-4- fluorophenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and commercially available 2u (4-(3-chloro-4- fluorophenyl)thiazol-2-amine) using general method E^
Example 125: compound n°125: (R)-3-benzyl-4-((4-(3-chloro-4- methoxyphenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and commercially available 2v (4-(3-chloro-4- methoxyphenyl)thiazol-2-amine) using general method E.
Example 126: compound n°126: (R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2- yl)(3-methoxy-3-oxopropyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2x using general method E. Example 127: compound n°127: 3-(bicyclo[2.2.1]heptan-2-ylmethyl)-4-((4-(2- chlorophenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lcl (2-(bicyclo[2.2.1]heptan-2-ylmethyl)-4-(tert-butoxy)-4- oxobutanoic acid) and 2c using general method E. lcl was synthesized from bicyclo[2.2.1]heptane-2-carbaldehyde using the HWE methodology (Scheme 13). Example 128: compound n°128: (R)-3-benzyl-4-((4-(2-(6-ethoxypyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2y (4-(2-(6-ethoxypyridin-3-yl)phenyl)-N-methylthiazol-2- amine) using general method E. Intermediate 2y was synthesized from (6- ethoxypyridin-3-yl)boronic acid and 21 using the methodology described in Scheme 15. Example 129: compound n°129: (R)-3-benzyl-4-((4-(4'-methoxy-[l,l'-biphenyl]- 2-yl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2z (4-(4'-methoxy-[l, -biphenyl]-2-yl)-N-methylthiazol-2- amine) using general method E and preparative HPLC purification. Intermediate 2z was synthesized from (4-methoxyphenyl)boronic acid and 21 using the methodology described in Scheme 15.
Example 130: compound n°130: (R)-3-benzyl-4-((4-(2,5-dichlorophenyl)thiazol- 2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2al using general method E.
Example 131: compound n°131 : (R)-l-(5-(2-(2-(2-benzyl-3-carboxy-N- methylpropanamido)thiazol-4-yl)phenyl)pyridin-2-yl)pyrrolidin-l-ium 2,2,2- trifluoroacetate was synthesized from intermediates lb and 2bl (N-methyl-4-(2- (6-(pyrrolidin-l-yl)pyridin-3-yl)phenyl)thiazol-2-amine) using general method E. Intermediate 2bl was synthesized from 2-(pyrrolidin-l-yl)-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyridine and 21 by Suzuki coupling with the conditions described in Scheme 15
Example 132: compound n°132: (R)-4-(2'-(2-(2-benzyl-3-carboxy-N- methylpropanamido)thiazol-4-yl)-[ 1 , 1 '-biphenyl]-4-yl)morpholin-4-ium 2,2,2- trifluoroacetate was synthesized from intermediates lb and 2cl (N-methyl-4-(4'- morpholino-[l, -biphenyl]-2-yl)thiazol-2-amine) using general method E. Intermediate 2cl was synthesized from 4-(4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)morpholine and 21 by Suzuki coupling with the conditions described in Scheme 15
Example 133: compound n°133: (R)-3-benzyl-4-(methyl(4-(2-(6- morpholinopyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2dl (N-methyl-4-(2-(6- morpholinopyridin-3-yl)phenyl)thiazol-2-amine) using general method E. Intermediate 2dl was synthesized from 4-(5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2-yl)morpholine and 21 using the methodology described in Scheme 15
Example 134: compound n°134: (R)-3-benzyl-4-((4 3'-chloro-[l,l'-biphenyl]-2- yl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2el (4-(3'-chloro-[l,l'-biphenyl]-2-yl)-N-methylthiazol-2- amine) using general method E and preparative HPLC purification. Intermediate 2el was synthesized from (3-chlorophenyl)boronic acid and 21 using the methodology described in Scheme 15.
Example 135: compound n°135: (R)-3-benzyl-4-((4-(2-(furan-3-yl)phenyl)thiazol- 2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2fl (4-(2-(furan-3-yl)phenyl)-N-methylthiazol-2-amine) using general method E. Intermediate 2fl was synthesized from furan-3-ylboronic acid and 21 by Suzuki coupling with the conditions described in Scheme 15.
Example 136: compound n°136: (R)-3-benzyl-4-((4-(2-(6-(2- methoxyethoxy)pyridin-3 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2gl (4-(2-(6-(2- methoxyethoxy)pyridin-3 -yl)phenyl)-N-methylthiazol-2-amine) using general method E. Intermediate 2gl was synthesized from 5-bromo-2-(2- methoxyethoxy)pyridine and 21 using the methodology described in Scheme 17. Example 138: compound n°138: (R)-3-benzyl-4-((4-(4'-isopropyl-[l,r-biphenyl]- 2-yl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2hl (4-(4'-isopropyl-[l,l'-biphenyl]-2-yl)-N-methylthiazol- 2-amine) using general method E and preparative HPLC purification. Intermediate 2hl was synthesized from (4-isopropylphenyl)boronic acid and 21 by Suzuki coupling with the conditions described in Scheme 15.
Example 139: compound n°139: (R)-3-(cyclopentylmethyl)-4-((4-(2-(6- methoxypyridin-3 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from (R)-4-tert-butoxy-2-(cyclopentylmethyl)-4-oxobutanoic acid (ee=50%) and intermediate 2m using general method E and chiral preparative HPLC purification. (R)-4-tert-butoxy-2-(cyclopentylmethyl)-4-oxobutanoic acid
(ee=50%) was synthesized from commercially available cyclopentanecarbaldehyde using the HWE methodology as described in Scheme 13.
Example 140: compound n°140: (R)-3-benzyl-4-((4-(2-(5-fluoro-6- methoxypyridin-3 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2il (4-(2-(5-fluoro-6-methoxypyridin-3- yl)phenyl)-N-methylthiazol-2-amine) using general method E. Intermediate 2il was synthesized from 5-bromo-3-fluoro-2-methoxypyridine using the methodology described in Scheme 17.
Example 141: compound n°141 : (R)-3-benzyl-4-(methyl(4-(2-(6-((tetrahydro-2H- pyran-4-yl)oxy)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2jl (N-methyl-4-(2-(6-((tetrahydro-2H- pyran-4-yl)oxy)pyridin-3-yl)phenyl)thiazol-2-amine) using general method E. Intermediate 2jl was synthesized from 5-bromo-2-((tetrahydro-2H-pyran-4- yl)oxy)pyridine and 21 using the methodology described in Scheme 17.
Example 142: compound n°142: (R)-3-benzyl-4-(cyclopropyl(4-(2,5- dichlorophenyl)thiazol-2-yl)amino)-4-oxobutanoic acid from intermediates lb and 2w using general method E.
Example 143: compound n°143: 4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-3-(furan-2-ylmethyl)-4-oxobutanoic acid was synthesized from intermediates ldl (4-(tert-butoxy)-2-(furan-2-ylmethyl)-4-oxobutanoic acid) and 2c using general method E. ldl was synthesized from furan-2-carbaldehyde using the HWE methodology described Scheme 13.
Example 144: compound n°144: (R)-3-benzyl-4-((4-(2- cyclopropylphenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2kl (4-(2-cyclopropylphenyl)-N- methylthiazol-2-amine) using general method E and preparative HPLC purification. Intermediate 2kl was synthesized from cyclopropylboronic acid and 21 using the methodology described in Scheme 15.
Example 145: compound n°145: (R)-3-benzyl-4-((4-(4'-(dimethylamino)-[l, - biphenyl]-2-yl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 211 (4-(4'-(dimethylamino)-[l, -biphenyl]-2-yl)-N- methylthiazol-2-amine) using general method E. Intermediate 211 was synthesized from N,N-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline using the methodology described in Scheme 15.
Example 146: compound n°146: (R)-3-benzyl-4-((4-(3'-fluoro-[l,r-biphenyl]-2- yl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2ml (4-(3'-fluoro-[l, -biphenyl]-2-yl)-N-methylthiazol-2- amine) using general method E and preparative HPLC purification. Intermediate 2ml was synthesized from (3-fluorophenyl)boronic acid and 4-(2-bromophenyl)- N-methylthiazol-2-amine by Suzuki coupling with the conditions described in Scheme 15.
Example 147: compound n°147: (R)-3-benzyl-4-((4-(3',5'-difiuoro-[l,r- biphenyl]-2-yl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2nl (4-(3',5'-difluoro-[l, -biphenyl]-2-yl)-N- methylthiazol-2-amine) using general method E. Intermediate 2nl was synthesized from (3,5-difluorophenyl)boronic acid and 21 by Suzuki coupling with the conditions described in Scheme 15. Example 148: compound n°148: (R)-3-benzyl-4-((4-(2-chloro-6- fluorophenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and commercially available 2ol (4-(2-chloro-6- fluorophenyl)thiazol-2-amine) using general method E.
Example 149: compound n°149: (R)-3-benzyl-4-((4 4'-chloro-[l,l'-biphenyl]-2- yl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2pl (4-(4'-chloro-[l,l'-biphenyl]-2-yl)-N-methylthiazol-2- amine) using general method E and preparative HPLC purification. Intermediate 2pl was synthesized from (4-chlorophenyl)boronic acid and 21 by Suzuki coupling with the conditions described in Scheme 15. Example 150: compound n° 150: (R)-3-benzyl-4-(methyl(4-(2-(6-(2- oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2ql (l-(5-(2-(2-(methylamino)thiazol- 4-yl)phenyl)pyridin-2-yl)pyrrolidin-2-one) using general method E. Intermediate 2ql was synthesized from l-(5-bromopyridin-2-yl)pyrrolidin-2-one and 21 using the methodology described in Scheme 17.
Example 151: compound n°151 : (R)-3-benzyl-4-((4-(4-chloro-2-(6- methoxypyridin-3 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2rl (4-(4-chloro-2-(6-methoxypyridin-3- yl)phenyl)-N-methylthiazol-2-amine) using general method E. Intermediate 2rl was synthesized from (6-methoxypyridin-3-yl)boronic acid and 4-(2-bromo-4- chlorophenyl)-N-methylthiazol-2-amine by Suzuki coupling with the conditions described in Scheme 15. 4-(2-bromo-4-chlorophenyl)-N-methylthiazol-2-amine was synthesized using general method C.
Example 152: compound n°152: (R)-3-benzyl-4-((4-(5-chloro-2-(6- methoxypyridin-3 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2sl (4-(5-chloro-2-(6-methoxypyridin-3- yl)phenyl)-N-methylthiazol-2-amine) using general method E. Intermediate 2sl was synthesized from (6-methoxypyridin-3-yl)boronic acid and 4-(2-bromo-5- chlorophenyl)-N-methylthiazol-2-amine by Suzuki coupling with the conditions described in Scheme 15. 4-(2-bromo-5-chlorophenyl)-N-methylthiazol-2-amine was synthesized using general method C. Example 153: compound n°153: (R)-3-benzyl-4-((4-(3-fluoro-2-(6- methoxypyridin-3 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2tl (4-(3-fluoro-2-(6-methoxypyridin-3- yl)phenyl)-N-methylthiazol-2-amine) using general method E and preparative HPLC purification. Intermediate 2tl was synthesized from (6-methoxypyridin-3- yl)boronic acid and 4-(2-bromo-3-fluorophenyl)-N-methylthiazol-2-amine by Suzuki coupling with the conditions described in Scheme 15. 4-(2-bromo-3- fluorophenyl)-N-methylthiazol-2-amine was synthesized using general method C.
Example 154: compound n°154: (3R)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-4-oxo-3-((tetrahydrofuran-2-yl)methyl)butanoic acid was synthesized from intermediates lei and 2c using general method E.
Example 155: compound n°155: (3R)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-4-oxo-3-((tetrahydrofuran-2-yl)methyl)butanoic acid was synthesized from intermediates lb and 2ul using general method E followed by debenzylation with FeCl3 in DCM. Example 156: compound n°156: (R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2- yl)(3-hydroxypropyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2vl using general method E followed by debenzylation with FeCl3 in DCM.
Example 157: compound n°157: (R)-3-benzyl-4-((4-(2-(5-chloro-6- methoxypyridin-3 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2wl (4-(2-(5-chloro-6-methoxypyridin-3- yl)phenyl)-N-methylthiazol-2-amine) using general method E. Intermediate 2wl was synthesized from 5-bromo-3-chloro-2-methoxypyridine and 21 using the methodology described in Scheme 17.
Example 158: compound n°158: (R)-3-benzyl-4-((4-(2-(6-(benzyloxy)pyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2x1 (4-(2-(6-(benzyloxy)pyridin-3-yl)phenyl)-N- methylthiazol-2-amine) using general method E and preparative HPLC purification. Intermediate 2x1 was synthesized from (6-benzyloxypyridin-3- yl)boronic acid and 21 by Suzuki coupling with the conditions described in Scheme 15. Example 159: compound n°159: (R)-3-(cyclopentylmethyl)-4-((4-(2,5- dichlorophenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lfl and 2al using general method E.
Example 160: compound n°160: (R)-4-((4-(2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid was synthesized from intermediates lgl and 2c using general method E.
Example 161: compound n°161 : (R)-3-benzyl-4-((4-(2-chloro-5- (trifluoromethyl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2yl using general method E. Example 162: compound n°162: (R)-3-benzyl-4-((4-(2-chloro-5- fluorophenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2zl using general method E.
Example 163: compound n°163: (R)-3-benzyl-4-((4-(3,5-dichlorophenyl)thiazol- 2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2a2 using general method E.
Example 164: compound n°164: (R)-3-benzyl-4-((4-(3- (difluoromethoxy)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2b2 using general method E.
Example 165: compound n°165: (R)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-3-(cyclopentylmethyl)-4-oxobutanoic acid was synthesized from intermediates lfl and 2c using general method E.
Example 166: compound n°166: (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4- (2,5-dichlorophenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lfl and 2w using general method E.
Example 167: compound n°167: (R)-4-(cyclopropyl(4-(2,5- dichlorophenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid was synthesized from intermediates lgl and 2w using general method E.
Example 168: compound n°168: (R)-4-((4-(2,5-dichlorophenyl)thiazol-2- yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid was synthesized from intermediates lgl and 2al using general method E.
Example 169: compound n°169: (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2- (6-methoxypyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lfl and 2c2 (N-cyclopropyl-4-(2-(6- methoxypyridin-3-yl)phenyl)thiazol-2-amine) using general method E. Intermediate 2c2 was synthesized from (6-methoxypyridin-3-yl)boronic acid and 4-(2-bromo-4-chlorophenyl)-N-cyclopropylthiazol-2-amine by Suzuki coupling with the conditions described_in Scheme 15. 4-(2-bromo-4-chlorophenyl)-N- cyclopropylthiazol-2-amine was synthesized using general method C.
Example 170: compound n°170: (R)-3-benzyl-4-((2-hydroxyethyl)(4-(2-(6- methoxypyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2d2 (N-(2-(benzyloxy)ethyl)-4-(2-(6- methoxypyridin-3-yl)phenyl)thiazol-2-amine) using general method E followed by debenzylation with FeCl3 in DCM. Intermediate 2d2 was synthesized from (6- methoxypyridin-3-yl)boronic acid and N-(2-(benzyloxy)ethyl)-4-(2- bromophenyl)thiazol-2-amine by Suzuki coupling with the conditions described in Scheme 15. N-(2-(benzyloxy)ethyl)-4-(2-bromophenyl)thiazol-2-amine was synthesized using general method C. Example 171: compound n°171: (R)-3-(cyclopentylmethyl)-4-(methyl(4-(2-(6- morpholinopyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lfl and 2dl using general method E.
Example 172: compound n°172: (R)-3-(cyclopentylmethyl)-4-((4-(2,5- dichlorophenyl)thiazol-2-yl)(2-hydroxyethyl)amino)-4-oxobutanoic acid was synthesized from intermediates lfl and 2d3 using general method E followed by debenzylation with FeCl3 in DCM.
Example 173: compound n°173: (R)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid was synthesized from intermediates lgl and 2c using general method E.
Example 174: compound n°174: (R)-3-benzyl-4-((4-(2-chloro-5- (trifluoromethyl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2e2 using general method E.
Example 175: compound n°175: (R)-3-benzyl-4-(methyl(4-(2,3,5- trichlorophenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2f2 using general method E.
Example 176: compound n°176: (R)-3-benzyl-4-((4-(4-chloro-[l,l'-biphenyl]-3- yl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2g2 (4-(4-chloro-[l,l'-biphenyl]-3-yl)-N-methylthiazol-2- amine) using general method E. Intermediate 2g2 was synthesized from phenylboronic acid and 4-(5-bromo-2-chlorophenyl)-N-methylthiazol-2-amine by Suzuki coupling with the conditions described in Scheme 15. 4-(5-bromo-2- chlorophenyl)-N-methylthiazol-2-amine was synthesized using general method C.
Example 177: compound n°177: (R)-3-benzyl-4-((4-(2-chloro-5-(6- methoxypyridin-3-yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2h2 (4-(2-chloro-5-(6-methoxypyridin-3- yl)phenyl)-N-methylthiazol-2-amine) using general method E. Intermediate 2h2 was synthesized from (6-methoxypyridin-3-yl)boronic acid and 4-(5-bromo-2- chlorophenyl)-N-methylthiazol-2-amine by Suzuki coupling with the conditions described in Scheme 15. 4-(5-bromo-2-chlorophenyl)-N-methylthiazol-2-amine was synthesized using general method C. Example 178: compound n°178: (R)-3-benzyl-4-(cyclopropyl(4-(2-(6- methoxypyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2c2 using general method E.
Example 179: compound n°179: (R)-4-(cyclopropyl(4-(2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid was synthesized from intermediates lgl and 2c2 using general method E.
Example 180: compound n°180: (R)-3-benzyl-4-(cyclopropyl(4-(2-(6- morpholinopyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2i2 (N-cyclopropyl-4-(2-(6- morpholinopyridin-3-yl)phenyl)thiazol-2-amine) using general method E. Intermediate 2i2 was synthesized from 4-(4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)morpholine and 4-(2-bromophenyl)-N- cyclopropylthiazol-2-amine by Suzuki coupling with the conditions described in Scheme 15. 4-(2-bromophenyl)-N-cyclopropylthiazol-2-amine was synthesized using general method C.
Example 181: compound n°181 : (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2- (6-morpholinopyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lfl and 2i2 using general method E.
Example 182: compound n°182: (R)-3-benzyl-4-(methyl(4-(2-(4-methyl-3,4- dihydro-2H-pyrido[3,2-b][l,4]oxazin-7-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid was synthesized from intermediates lb and 2j2 (N-methyl-4-(2- (4-methyl-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-7-yl)phenyl)thiazol-2-amine) using general method E and preparative HPLC purification. Intermediate 2j2 was synthesized from commercially available 7-bromo-4-methyl-3,4-dihydro-2H- pyrido[3,2-b][l,4]oxazine and 21 using the methodology described in Scheme 17.
Example 183: compound n°183: (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2- (6-(2-oxopyrrolidin-l-yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2k2 (l-(5-(2-(2- (cyclopropylamino)thiazol-4-yl)phenyl)pyridin-2-yl)pyrrolidin-2-one) using general method E. Intermediate 2k2 was synthesized from l-(5-bromopyridin-2- yl)pyrrolidin-2-one and 4-(2-bromo-4-chlorophenyl)-N-cyclopropylthiazol-2- amine using the methodology described in Scheme 17. l-(5-bromopyridin-2- yl)pyrrolidin-2-one was synthesized by reacting 5-bromopyridin-2-amine with Na2HP04 in CHC13, 4-bromobutyryl chloride and NaOMe in MeOH as described in Tetrahedron 1957, 1, 9635. 4-(2-bromo-4-chlorophenyl)-N- cyclopropylthiazol-2-amine was synthesized using general method C.
Example 184: compound n°184: (R)-4-(cyclopropyl(4-(2-(6-morpholinopyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid was synthesized from intermediates lgl and 2i2 using general method E.
Example 185: compound n°185: (R)-3-benzyl-4-(methyl(4-(2- (trifluoromethoxy)phenyl)thiazo l-2-yl)amino)-4-oxobutano ic acid was synthesized from intermediates lb and 212 using general method E.
Example 186: compound n°186: (R)-4-((4-(2-chloro-5-fluorophenyl)thiazol-2- yl)(cyclopropyl)amino)-3-(cyclopentylmethyl)-4-oxobutanoic acid was synthesized from intermediates lb and 2m2 using general method E and preparative HPLC purification.
Example 187: compound n°187: (R)-3-(cyclopentylmethyl)-4-(methyl(4-(2-(6-(2- oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lfl and 2ql using general method E.
Example 188: compound n°188: (R)-3-benzyl-4-(cyclopropyl(4-(3- (difluoromethoxy)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2n2 using general method E and preparative HPLC purification. Example 189: compound n°189: (R)-3-benzyl-4-((4-(2-chloro-5- fluorophenyl)thiazol-2-yl)(cyclopropyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2m2 using general method E and preparative HPLC purification.
Example 190: compound n°190: (R)-4-((4-(2-chloro-5-fluorophenyl)thiazol-2- yl)(cyclopropyl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid was synthesized from intermediates lgl and 2m2 using general method E and preparative HPLC purification.
Example 191: compound n°191 : (R)-3-benzyl-4-((4-(2-chloro-5- (trifluoromethyl)phenyl)thiazol-2-yl)(cyclopropyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2o2 using general method E and preparative HPLC purification.
Example 192: compound n°192: (R)-3-benzyl-4-((4-(2-
(difluoromethoxy)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2c4 using general method E
Example 193: compound n°193: (R)-4-((4-(2-chloro-5- (trifluoromethyl)phenyl)thiazol-2-yl)(cyclopropyl)amino)-4-oxo-3-((tetrahydro- 2H-pyran-4-yl)methyl)butanoic acid was synthesized from intermediates lgl and 2o2 using general method E.
Example 194: compound n°194: (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2- (4-methyl-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-7-yl)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid was synthesized from intermediates lfl and 2p2 (N-cyclopropyl-4-(2-(4-methyl-3 ,4-dihydro-2H-pyrido [3 ,2-b] [ 1 ,4] oxazin-7- yl)phenyl)thiazol-2-amine) using general method E. Intermediate 2p2 was synthesized from commercially available 7-bromo-4-methyl-3,4-dihydro-2H- pyrido[3,2-b][l,4]oxazine and 21 using the methodology described in Scheme 17. 4-(2-bromo-4-chlorophenyl)-N-cyclopropylthiazol-2-amine was synthesized using general method C.
Example 195: compound n°195: (3R,4S)-3-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)carbamoyl)-4-phenylpentanoic acid was synthesized from intermediates lhl and 2c using general method E. Example 196: compound n°196: (R)-2-(2-benzyl-3-carboxypropanamido)-5-(2- chlorophenyl)pyridine 1 -oxide was synthesized from intermediates lb and 2q2 (2- amino-5-(2-chlorophenyl)pyridine) using general method E followed by oxidation with MCPBA. 2q2 was made from commercially available 5-bromopyridin-2- amine and (2-chlorophenyl)boronic acid using Suzuki coupling. Example 197: compound n°197: (R)-3-benzyl-4-((5-(2-chlorophenyl)pyrazin-2- yl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2r2 (5- (2-chlorophenyl)pyrazin-2-amine) using general method E. 2r2 was made from commercially available 5-bromopyrazin-2-amine and (2-chlorophenyl)boronic acid using Suzuki coupling.
Example 198: compound n°198: 4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-3-(morpholinomethyl)-4-oxobutanoic acid was synthesized as described in Scheme 18.
Example 199: compound n°199: (R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2- yl)(2-methoxyethyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2s2 using general method E. Example 200: compound n°200: (R)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-3-(cyclopentylamino)-4-oxobutanoic acid was synthesized from intermediates Ijl ((R)-4-(tert-butoxy)-2-(cyclopentylamino)-4-oxobutanoic acid) and 2c using general method E. Ijl was made from (R)-2-amino-4-(tert- butoxy)-4-oxobutanoic acid and cyclopentanone by reductive amination using sodium cyanoborohydride in methanol.
Example 201: compound n°201 : (R)-3-benzyl-4-((2-(benzyloxy)ethyl)(4-(2- chlorophenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2ul using general method E.
Example 202: compound n°202: (R)-3-benzyl-4-((4-(5-methylfuran-2-yl)thiazol- 2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and commercially available 2u2 (4-(5-methylfuran-2-yl)thiazol-2-amine) using general method E.
Example 203: compound n°203: (R)-3-benzyl-4-oxo-4-((3-(3- (trifluoromethyl)phenyl)-lH-pyrazol-5-yl)amino)butanoic acid was synthesized from intermediates lb and commercially available 2v2 (3-(3-
(trifluoromethyl)phenyl)-lH-pyrazol-5-amine) using general method E.
Example 204: compound n°204: (R)-3-benzyl-4-((4-(5-chloro-2- methoxyphenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and commercially available 2w2 (4-(5-chloro-2- methoxyphenyl)thiazol-2-amine) using general method E.
Example 205: compound n°205: 4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-3-(4-hydroxybenzyl)-4-oxobutanoic acid was synthesized from from intermediates lkl (4-(tert-butoxy)-2-(4-(methoxymethoxy)benzyl)-4- oxobutanoic acid) and 2c using general method E, the MOM group was deprotected with TFA in DCM. lkl was synthesized from 4- (methoxymethoxy)benzaldehyde using the HWE methodology (Scheme 13).
Example 206: compound n°206: (R)-3-benzyl-4-((4-(4'-cyano-[l,l'-biphenyl]-2- yl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2x2 (2'-(2-(methylamino)thiazol-4-yl)-[l, -biphenyl]-4- carbonitrile) using general method E. Intermediate 2x2 was synthesized from (4- cyanophenyl)boronic acid and 21 by Suzuki coupling with the conditions described in Scheme 15.
Example 207: compound n°207: (3R)-3-benzyl-4-((3-carbamoyl-4-(2,4- dichlorophenyl)-5-methylthiophen-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and commercially available 2y2 (2-amino-4- (2,4-dichlorophenyl)-5-methylthiophene-3-carbonitrile) using general method E.
Example 208: compound n°208: (R)-3-benzyl-4-((4-(3'-methoxy-[l,r-biphenyl]- 2-yl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2z2 (4-(3'-methoxy-[l, -biphenyl]-2-yl)-N-methylthiazol-2- amine) using general method E. Intermediate 2z2 was synthesized from (3- methoxyphenyl)boronic acid and 21 by Suzuki coupling with the conditions described in Scheme 15.
Example 209: compound n°209: 4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-3-((2-methylthiazol-4-yl)methyl)-4-oxobutanoic acid was synthesized from intermediates 111 (4-(tert-butoxy)-2-((2-methylthiazol-4- yl)methyl)-4-oxobutanoic acid) and 2c using general method E. Ill was synthesized from 2-methylthiazole-5-carbaldehyde using the HWE methodology (Scheme 13).
Example 210: compound n°210: 4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-3-((5-methylisoxazol-3-yl)methyl)-4-oxobutanoic acid was synthesized from intermediates 1ml (4-(tert-butoxy)-2-((5-methylisoxazol-3- yl)methyl)-4-oxobutanoic acid) and 2c using general method E. 1ml was synthesized from 5-methylisoxazole-3-carbaldehyde using the HWE methodology (Scheme 13).
Example 211: compound n°211 : (R)-3-benzyl-4-((4-(2'-chloro-[l, -biphenyl]-2- yl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2a3 (4-(2'-chloro-[l,l'-biphenyl]-2-yl)-N-methylthiazol-2- amine) using general method E and preparative HPLC purification. Intermediate 2a3 was synthesized from (2-chlorophenyl)boronic acid and 21 by Suzuki coupling with the conditions described in Scheme 15.
Example 212: compound n°212: (R)-3-benzyl-4-((4-(2-(2-methoxypyrimidin-5- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2b3 (4-(2-(2-methoxypyrimidin-5-yl)phenyl)-N- methylthiazol-2-amine) using general method E. Intermediate 2b3 was synthesized from 5-bromo-2-methoxypyrimidine and 21 using the methodology described in Scheme 17.
Example 213: compound n°213: (R)-3-benzyl-4-((4-(2,5-difluorophenyl)thiazol- 2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and commercially available 2c3 (4-(2,5-difluorophenyl)thiazol-2-amine) using general method E.
Example 214: compound n°214: 4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-3-(oxazol-4-ylmethyl)-4-oxobutanoic acid was synthesized from intermediates lnl (4-(tert-butoxy)-2-(oxazol-4-ylmethyl)-4-oxobutanoic acid) and 2c using general method E. lnl was synthesized from oxazole-4- carbaldehyde using the HWE methodology (Scheme 13).
Example 215: compound n°215: (3R)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-4-oxo-3-((tetrahydrofuran-3-yl)methyl)butanoic acid was synthesized from intermediates lol and 2c using general method E.
Example 216: compound n°216: (R)-3-benzyl-4-(methyl(4-(2-(8-methyl-7-oxo- 5,6,7,8-tetrahydro-l,8-naphthyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid was synthesized from intermediates lb and 2e3 (l-methyl-6-(2- (2-(methylamino)thiazol-4-yl)phenyl)-3,4-dihydro-l,8-naphthyridin-2(lH)-one) using general method E.
Intermediate 2e3 was synthesized from 6-bromo-l-methyl-3,4-dihydro-l,8- naphthyridin-2(lH)-one (which was obtained by treatment of 6-bromo-3,4- dihydro-l,8-naphthyridin-2(lH)-one with NaH in DMF and Mel) and 21 using the methodology described in Scheme 17. Intermediate lb was synthesized using the HWE methodology (Scheme 13): 38.125 mmol of (E)-2-benzylidene-4-(tert-butoxy)-4-oxobutanoic acid, 75 mL of methanol and 38.125 mmol of DCA were successively introduced into a Schlenck tube under Ar. The solution was degassed using three argon/vacuum cycles, and subsequently transferred into the reaction vessel under inert atmosphere. To this degassed solution was added, under argon flow, 0.121 mmol of the RuCl2-[(S)- BINAP] catalyst. The reaction vessel was then transferred into a Parr autoclave, under Ar flow. The Parr vessel was purged 3 times with H2 with a pressure up to 20 sbars; the pressure was then adjusted to 10 bars. The Parr autoclave was put into an oil bath at 55°C. The reaction mixture was stirred at this temperature for 3 days. The reaction mixture was allowed to cool to RT and the hydrogen pressure was released carefully and the Parr vessel opened. The crude reaction mixture was concentrated to dryness using rotary evaporator to afford 16.74 g of a colored solid. An aliquot of the solid was diluted with water and acidified with HC1 6N to pH 1; then, the solution was extracted with EtOAc. The organic layer was dried over magnesium sulfate, concentrated using rotary evaporator to yield the desired intermediate (ee= 82.6%, determined by chiral HPLC).
Solid (16.74 g) was recrystallized from an ACN/water mixture. Recrystallized product was diluted with water and acidified with 6N HC1 to pH 1 , the solution was extracted with EtOAc. The organic layer was dried over magnesium sulfate, concentrated at rotavap to yield the desired intermediate lb (ee= 96.6%, determined by chiral HPLC)
Example 217: compound n°217: (R)-3 -benzyl-4-(methyl(4-(2-( 1 -methyl- 1 H- pyrrolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2f3 (N-methyl-4-(2-(l -methyl- 1H- pyrrolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2-amine) using general method E. Intermediate 2f3 was synthesized from 5-bromo-l-methyl-lH-pyrrolo[2,3- b]pyridine (which was obtained by treatment of 5-bromo-lH-pyrrolo[2,3- b]pyridine with NaH in DMF and Mel) and 21 using the methodology described in Scheme 17. Example 218: compound n°218: (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2- (6-(dimethylamino)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lfl and 2g3 (N-cyclopropyl-4-(2-(6- (dimethylamino)pyridin-3-yl)phenyl)thiazol-2-amine) using general method E and preparative HPLC purification. 2g3 was synthesized from 4-(2-bromophenyl)-N- cyclopropylthiazol-2-amine and 6-(dimethylamino)pyridin-3-ylboronic acid by Suzuki coupling with the conditions described in Scheme 15. 4-(2-bromophenyl)- N-cyclopropylthiazol-2-amine was synthesized using general method C.
Example 219: compound n°219: (R)-4-((4-(2-(5-chloro-6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)(cyclopropyl)amino)-3-(cyclopentylmethyl)-4-oxobutanoic acid was synthesized from intermediates lfl and 2h3 (4-(2-(5-chloro-6- methoxypyridin-3 -yl)phenyl)-N-cy clopropylthiazol-2-amine) using general method E. 2g3 was synthesized from 5-bromo-3-chloro-2-methoxypyridine and 4- (2-bromophenyl)-N-cyclopropylthiazol-2-amine using the methodology described in Scheme 17. 4-(2-bromophenyl)-N-cyclopropylthiazol-2-amine was synthesized using general method C.
Example 220: compound n°220: (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2- (5-fluoro-6-methoxypyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lfl and 2i3 (N-cyclopropyl-4-(2-(5-fluoro-6- methoxypyridin-3-yl)phenyl)thiazol-2-amine) using general method E. 2i3 was synthesized from 5-bromo-3-fluoro-2-methoxypyridine and 4-(2-bromophenyl)- N-cyclopropylthiazol-2-amine using the methodology described in Scheme 17. 4- (2-bromophenyl)-N-cyclopropylthiazol-2-amine was synthesized using general method C.
Example 221: compound n°221 : (R)-3-benzyl-4-((4-(2-chloro-5- (difluoromethoxy)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2j3 using general method E.
Example 222: compound n°222: (R)-3-benzyl-4-((4-(5-chloro-2-(5-chloro-6- methoxypyridin-3 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2k3 (4-(5-chloro-2-(5-chloro-6- methoxypyridin-3-yl)phenyl)-N-methylthiazol-2-amine) using general method E. 2k3 was synthesized from 5-bromo-3-chloro-2-methoxypyridine and 4-(2-bromo- 5-chlorophenyl)-N-methylthiazol-2-amine using the methodology described in Scheme 17. 4-(2-bromo-5-chlorophenyl)-N-methylthiazol-2-amine was synthesized using general method C.
Example 223: compound n°223: (R)-4-((4-(5-chloro-2-(5-chloro-6- methoxypyridin-3 -yl)phenyl)thiazo l-2-yl)(cyclopropyl)amino)-3 - (cyclopentylmethyl)-4-oxobutanoic acid was synthesized from intermediates lfl and 213 (4-(5-chloro-2-(5-chloro-6-methoxypyridin-3-yl)phenyl)-N- cyclopropylthiazol-2-amine) using general method E. 213 was synthesized from 5- bromo-3-chloro-2-methoxypyridine and 4-(2-bromo-5-chlorophenyl)-N- cyclopropylthiazol-2-amine using the methodology described in Scheme 17. 4-(2- bromo-5-chlorophenyl)-N-cyclopropylthiazol-2-amine was synthesized using general method C. Example 224: compound n°224: (R)-4-((4-(5-chloro-2-(5-fiuoro-6- methoxypyridin-3 -yl)phenyl)thiazo l-2-yl)(cyclopropyl)amino)-3 - (cyclopentylmethyl)-4-oxobutanoic acid was synthesized from intermediates lfl and 2m3 (4-(5-chloro-2-(5-fluoro-6-methoxypyridin-3-yl)phenyl)-N- cyclopropylthiazol-2-amine) using general method E. 2m3 was synthesized from 5-bromo-3-fluoro-2-methoxypyridine and 4-(2-bromo-5-chlorophenyl)-N- cyclopropylthiazol-2-amine using the methodology described in Scheme 17. 4-(2- bromo-5-chlorophenyl)-N-cyclopropylthiazol-2-amine was synthesized using general method C.
Example 225: compound n°225: (S)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2- yl)amino)-4-oxobutanoic acid was synthesized from intermediates lpl ((S)-2- benzyl-4-(tert-butoxy)-4-oxobutanoic acid) and 2a using general method E. lpl was synthesized from (S)-3-benzyl-4-methoxy-4-oxobutanoic acid using the chemistry described in steps 5 and 6 of general method B. Example 227: compound n°227: (R)-3-benzyl-4-((4-benzylthiazol-2-yl)amino)-4- oxobutanoic acid was synthesized from intermediates lb and commercially available 4-benzylthiazol-2-amine using general method E.
Example 229: compound n°229: (R)-3-benzyl-4-oxo-4-((5-phenyl-4H- 1,2,4- triazol-3-yl)amino)butanoic acid was synthesized from intermediates lb and commercially available 5-phenyl-4H-l,2,4-triazol-3-amine using general method E.
Example 230: compound n°230: 3-([l,l'-biphenyl]-4-ylmethyl)-4-((4-(2- chlorophenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lql (2-([l,l'-biphenyl]-4-ylmethyl)-4-(tert-butoxy)-4- oxobutanoic acid) and 2c using general method E. lql was synthesized from [l,l'-biphenyl]-4-carbaldehyde using the HWE methodology described in Scheme 13.
Example 231: compound n°231 : (R)-3-benzyl-4-((4-(l-methyl-lH-pyrazol-4- yl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and commercially available 4-(l-methyl-lH-pyrazol-4-yl)thiazol-2-amine using general method E.
Example 232: compound n°232: ((R)-3-benzyl-4-((4-(4-methyl-l,2,5-oxadiazol-3- yl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and commercially available 4-(4-methyl-l,2,5-oxadiazol-3-yl)thiazol-2-amine using general method E.
Example 233: compound n°233: (R)-3-benzyl-4-(methyl(4-(2-(l -methyl- 1H- pyrazol-4-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2n3 (N-methyl-4-(2-(l -methyl- lH-pyrazol-4- yl)phenyl)thiazol-2-amine) using general method E. 2n3 was synthesized from commercially available l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-pyrazole and 21 using the methodology described in Scheme 15.
Example 234: compound n°234: (3R)-3-benzyl-4-((4-(2-(3,5-dimethylisoxazol-4- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2o3 (4-(2-(3,5-dimethylisoxazol-4-yl)phenyl)-N- methylthiazol-2-amine) using general method E. 2o3 was synthesized from commercially available 3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)isoxazole and 21 using the methodology described in Scheme 15. Example 235: compound n°235: (R)-3-benzyl-4-((4-((2- chlorophenyl)carbamoyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2p3 using general method E and preparative HPLC purification. 2p3 was synthesized as described in Scheme 21.
Example 236: compound n°236: (R)-3-benzyl-4-((6-(2-chlorophenyl)pyridazin-3- yl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2q3 (6- (2-chlorophenyl)pyridazin-3-amine) using general method E. 2q3 was synthesized from 6-bromopyridazin-3-amine and 2-chlorophenylboronic acid by Suzuki coupling with the conditions described in Scheme 8.
Example 237: compound n°237: (R)-3-benzyl-4-(methyl(4-(2-(2-oxopyrrolidin-l- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2r3 (l-(2-(2-(methylamino)thiazol-4-yl)phenyl)pyrrolidin-2- one) using general method E. 2r3 was synthesized as described in Scheme 16.
Example 238: compound n°238: (S)-2-((l-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-l-oxo-3-phenylpropan-2-yl)oxy)acetic acid was synthesized as described in Scheme 22.
Example 239: compound n°239: (R)-3-benzyl-4-((l-methyl-5 -phenyl- 1H- imidazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and commercially available l-methyl-5-phenyl-lH-imidazol-2-amine using general method E.
Example 240: compound n°240: (R)-3-benzyl-4-((4-(2-(l-(2-methoxyethyl)-6- oxo- l,6-dihydropyridin-3-yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2s3 (l-(2-methoxyethyl)-5-(2-(2- (methylamino)thiazol-4-yl)phenyl)pyridin-2(lH)-one) using general method E. 2s3 was synthesized from 5-bromo-l-(2-methoxyethyl)pyridin-2(lH)-one and 21 using the methodology described in Scheme 17.
Example 241: compound n°241 : (R)-3-benzyl-4-(methyl(4-(2-(l-methyl-6-oxo- 1 ,6-dihydropyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2t3 (l-methyl-5-(2-(2- (methylamino)thiazol-4-yl)phenyl)pyridin-2(lH)-one) using general method E. 2t3 was synthesized from 5-bromo-l-methylpyridin-2(lH)-one and 21 using the methodology described in Scheme 17.
Example 242: compound n°242: 4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-3-((2,5-dimethyloxazol-4-yl)methyl)-4-oxobutanoic acid was synthesized from intermediates lrl (tert-butyl 4-amino-3-((2,5-dimethyloxazol-4- yl)methyl)-4-oxobutanoate) and 2c using general method E. lrl was synthesized from 2,5-dimethyloxazole-4-carbaldehyde using the HWE methodology described in Scheme 13. Example 243: compound n°243: 4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-3-((l -methyl- lH-pyrazol-5-yl)methyl)-4-oxobutanoic acid was synthesized from intermediates lsl (4-(tert-butoxy)-2-((l -methyl- lH-pyrazol-5- yl)methyl)-4-oxobutanoic acid) and 2c using general method E. lsl was synthesized from l-methyl-lH-pyrazole-5-carbaldehyde using the HWE methodology described in Scheme 13.
Example 244: compound n°244: (R)-3-benzyl-4-((4-(2-(6-hydroxypyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized by debenzylation of compound n°158 with FeCl3 in DCM and preparative HPLC purification.
Example 245: compound n°245: (R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2- yl)((S)-2-hydroxypropyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2v3 using general method E and preparative HPLC purification.
Example 246: compound n°246: (R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2- yl)((R)-2-hydroxypropyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2w3 using general method E and preparative HPLC purification. Example 247: compound n°247: (R)-3-(cyclohexylmethyl)-4-(cyclopropyl(4-(2- (6-methoxypyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lw and 2c2 using general method E and preparative HPLC purification.
Example 248: compound n°248: (R)-3-benzyl-4-((4-(5-fluoro-2-(6- methoxypyridin-3-yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2u3 (4-(5-fluoro-2-(6-methoxypyridin-3- yl)phenyl)-N-methylthiazol-2-amine) using general method E. Intermediate 2u3 was synthesized from (6-methoxypyridin-3-yl)boronic acid and 4-(2-bromo-5- fluorophenyl)-N-methylthiazol-2-amine by Suzuki coupling with the conditions described in Scheme 15. 4-(2-bromo-5-fluorophenyl)-N-methylthiazol-2-amine was synthesized using general method C.
Example 250: compound n°250: (R)-3-benzyl-4-((4-(4,5-difluoro-2-(6- methoxypyridin-3 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2x3 (4-(4,5-difluoro-2-(6-methoxypyridin- 3-yl)phenyl)-N-methylthiazol-2-amine) using general method E. Intermediate 2x3 was synthesized from (6-methoxypyridin-3-yl)boronic acid and 4-(2-bromo-4,5- difluorophenyl)-N-methylthiazol-2-amine by Suzuki coupling with the conditions described in Scheme 15. 4-(2-bromo-4,5-difluorophenyl)-N-methylthiazol-2- amine was synthesized using general method C.
Example 251: compound n°251 : (R)-4-((4-(2,5-dichlorophenyl)thiazol-2- yl)(methyl)amino)-3-(furan-2-ylmethyl)-4-oxobutanoic acid was synthesized from intermediates ltl and 2al using general method E. Example 252: compound n°252: (R)-4-((4-(2-chloro-5-fluorophenyl)thiazol-2- yl)(methyl)amino)-3-(furan-2-ylmethyl)-4-oxobutanoic acid was synthesized from intermediates ltl and 2zl using general method E.
Example 253: compound n°253: (R)-3-(furan-2-ylmethyl)-4-((4-(2-(6- methoxypyridin-3 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates ltl and 2m using general method E.
Example 254: compound n°254: (S)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-4-oxo-3-(thiophen-2-ylmethyl)butanoic acid was synthesized from intermediates lul and 2c using general method E.
Example 255: compound n°255: (R)-4-((4-(5-chloro-2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)(cyclopropyl)amino)-3-(cyclopentylmethyl)-4-oxobutanoic acid was synthesized from intermediates lb and 2y3 (4-(5-chloro-2-(6- methoxypyridin-3 -yl)phenyl)-N-cy clopropylthiazol-2-amine) using general method E. Intermediate 2y3 was synthesized from (6-methoxypyridin-3- yl)boronic acid and 4-(2-bromo-5-chlorophenyl)-N-cyclopropylthiazol-2-amine by Suzuki coupling with the conditions described in Scheme 15. 4-(2-bromo-5- chlorophenyl)-N-cyclopropylthiazol-2-amine was synthesized using general method C.
Example 256: compound n°256: (R)-3-benzyl-4-(cyclopropyl(4-(2-(6-(2- oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2k2 using general method E.
Example 257: compound n°257: (R)-3-benzyl-4-((4-(2,3-dichlorophenyl)thiazol- 2-yl)(methyl)amino)-4-oxobutanoic acid was synthesized from intermediates lb and 2z3 using general method E. Example 258: compound n°258: (R)-3-benzyl-4-(methyl(4-(3- (trifluoromethoxy)phenyl)thiazo l-2-yl)amino)-4-oxobutano ic acid was synthesized from intermediates lb and 2a4 using general method E.
Example 259: compound n°259: (R)-4-(cyclopropyl(4-(3- (difluoromethoxy)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid was synthesized from intermediates Igl and 2n2 using general method E.
Example 260: compound n°260: (R)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-3-(furan-2-ylmethyl)-4-oxobutanoic acid was synthesized from intermediates ltl and 2c using general method E.
Example 261: compound n°261 : (R)-4-(methyl(4-(3-
(trifluoromethoxy)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid was synthesized from intermediates Igl and 2a4 using general method E. Example 262: compound n°262: (R)-3-benzyl-4-(cyclopropyl(4-(3- (trifluoromethoxy)phenyl)thiazo l-2-yl)amino)-4-oxobutano ic acid was synthesized from intermediates lb and 2b4 using general method E.
Example 263: compound n°263: (R)-4-(cyclopropyl(4-(3-
(trifluoromethoxy)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid was synthesized from intermediates Igl and 2b4 using general method E.
BIOLOGY EXAMPLES
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 represents the inhibition of in-vitro TNFa release from LPS-stimulated PBMC following the activation by the compounds 2; 14; 97; 126; 169; 170; 183 and 216. Figure 2 represents the inhibition of in-vitro IL-6 release from LPS-stimulated PBMC following the activation by the compounds 2; 14; 89; 116 and 126.
Figure 3 represents the effect of compounds 14; 89; 116; 126; 142 and 155 on TNFcc-induced IL-8 release from HT-29 cell line. Figure 4 represents the decrease of blood circulating TNFcc level after compounds 157 and 169 injection in LPS challenged mice.
Membrane binding assay: GTPyS binding assay.
The following assay can be used for determination of GPR43 activation. When a GPCPv is in its active state, either as a result of ligand binding or constitutive activation, the receptor couples to a G protein and stimulates the release of GDP and subsequent binding of GTP to the G protein. The alpha subunit of the G protein-receptor complex acts as a GTPase and slowly hydro lyses the GTP to GDP, at which point the receptor normally is deactivated. Activated receptors continue to exchange GDP for GTP. The non-hydro lysable GTP analog, [35S]GTPyS, was used to demonstrate enhance binding of [35S]GTPyS to membranes expressing receptors. The assay uses the ability of GPCR to stimulate [35S]GTPyS binding to membranes expressing the relevant receptors. The assay can, therefore, be used in the direct identification method to screen candidate compounds to endogenous or not endogenous GPCR.
Preparation of membrane extracts:
Membrane extracts were prepared from cells expressing the human GPR43 receptor (hGPR43) as follows: the medium was aspirated and the cells were scraped from the plates in Ca++ and Mg++-free Phosphate-buffered saline (PBS).
The cells were then centrifuged for 3 min at 1500 g and the pellets were resuspended in buffer A (15 mM Tris-HCl pH 7.5, 2 mM MgCl2, 0.3 mM EDTA, 1 mM EGTA) and homogenized in a glass homogenizer. The crude membrane fraction was collected by two consecutive centrifugation steps at 40.000 x g for 25 min separated by a washing step in buffer A. The final pellet was resuspended in 500 μΐ of buffer B (75 mM Tris-HCl pH 7.5, 12.5 mM MgCl2, 0.3 mM EDTA, ImM EGTA, 250 mM sucrose) and flash frozen in liquid nitrogen. Protein content was assayed by the Folin method.
GTPYS assay (SPA method): The assay was performed in the presence of SCFA, and was used to determine the activity of the compounds of the invention.
The [35S]GTPyS assay was incubated in 20 mM HEPES pH7.4, 100 mM NaCl, 10 μg/ml saponin, 30 mM of MgCl2, 10 μΜ of GDP, 5 μg membrane-expressing hGPR43, 250μg of wheatgerm agglutinin beads (Amersham, ref: RPNQ001), a range concentration of compounds (from 30 μΜ to 1 nM) in a final volume of 100 μΐ for 30 min at room temperature. The SCFA propionate was used at 1 mM final concentration as positive control. The plates were then centrifuged for 10 minutes at 2000 rpm, incubated for 2 hours at room temperature and counted for 1 min in a scintillation counter (TopCount, PerkinElmer). The results of the tested compounds are reported as the concentration of the compound required to reach 50% (EC50) of the maximum level of the activation induced by these compounds.
When tested in the assay described above and by way of illustration the compounds in Table 3 activate GPR43 receptor. The EC50 value obtained is represented as follows: "++" means EC50 < 100 nM; "+"means EC50 >100 nM .
Table 3: Compounds EC50 values in GTPy35S assay.
Compound n° EC50 (nM)
1 +
2 +
3 +
4 +
5 +
8 +
9 ++
10 + 11 +
12 +
13 +
14 +
16 +
17 +
18 +
19 +
20 ++
21 +
22 +
23 +
83 ++
89 ++
90 ++
91 +
92 +
93 +
60 ++
94 +
95 +
96 +
97 ++
98 +
99 +
100 +
101 ++
103 +
105 ++
106 +
107 +
108 +
109 +
110 + 111 +
112 +
113 +
114 +
115 ++
116 +
119 +
121 +
123 +
126 +
129 +
131 ++
132 +
133 +
135 +
139 ++
141 +
142 ++
143 ++
144 +
149 +
150 +
154 +
155 ++
156 +
157 ++
158 ++
160 +
164 +
165 ++ 166 ++
168 ++
169 ++
170 ++
171 ++
172 +
175 ++
177 +
178 ++
182 ++
183 ++
191 ++
194 ++
195 +
199 +
201 +
202 +
206 +
209 +
210 +
216 +
217 +
218 ++
220 ++
222 +
223 ++
224 ++
246 + In Vitro Assays
Cytokines release from whole blood
Fresh blood samples drawn from informed volunteer donors are stimulated with or without LPS (100 ng/ml) and compounds of the invention for 3 hours at 37°C. Plasma are recovered after centrifugation and human soluble TNFcc¾.IL-6, IL-Ιβ, or other cytokines, are quantified using ELISA assay (R&D system) according manufacturer's recommendation.
MMP-9 release from whole blood
Fresh blood samples drawn from informed volunteer donors are pre-incubated for 1 hour with the compounds of the invention and then stimulated with or without FMLP or IL-8 (10 nM) for 30 minutes at 37°C. Plasma are recovered after centrifugation and human soluble MMP-9 is quantified using ELISA assay (R&D system) according manufacturer's recommendation.
Cytokines release from Peripheral Blood Mononuclear Cell assay Peripheral blood mononuclear cell (PBMC) are purified from heparinised fresh blood sample on a Lymphoprep gradient. PBMC are plated in 96-well assay plate (2xl06 cells/well) and stimulated with or without LPS (100 ng/ml) and increasing concentration of compounds of the invention for 3 hours at 37°C. Cell supernatants are recovered after centrifugation and human soluble TNFcc,..IL-6, IL-Ιβ, or other cytokines, are quantified using ELISA assay (R&D system) according manufacturer's recommendation.
When tested in the cytokines release from PBMC assay described above and by way of illustration the compounds n° 2; 14; 97; 126; 169; 170; 183 and 216 significantly inhibit the TNFcc secretion from PBMC (Figure 1). When tested in the cytokines release from PBMC assay described above and by way of illustration the compounds n° 2; 14; 89; 116 and 126 significantly inhibit the IL-6 secretion from PBMC (Figure 2). IL-8 release from epithelial colon cells
HT-29 epithelial colon cell line (ATCC, Manassas) are plated in -well assay plate (2xl05 cells/well) and stimulated with or without TNFcc (100 ng/ml) and increasing concentration of compounds of the invention for 3 hours at 37°C. Cell supematants are recovered after centrifugation and human soluble IL-8, or other cytokines, are quantified using ELISA assay (R&D system) according manufacturer's recommendation.
When tested in the IL-8 release from epithelial colon cells assay described above and by way of illustration the compounds n° 14; 89; 116; 126; 142 and 155 significantly inhibit the IL-8 secretion from HT-29 cell line (Figure 3).
Chemotactic assay
Blood is diluted 1/2 with PBS supplemented with 2.6 mM EDTA (PBS-EDTA) and placed v/v onto a Ficoll solution. Blood cells are separated by centrifugation at 500g at room temperature for 30 min. After centrifugation, cells at the interface (mainly lymphocytes + monocytes) and cells in the pellet (mainly neutrophils + erythrocytes) are collected separately. Neutrophils are washed in 8 ml HBSS and erythrocytes are lysed by hypotonic shock. Then neutrophils are resuspended in HBSS supplemented with 0.1% of Foetal Bovine Serum (FBS). For chemotactic assay, cells (1x105) are plated in the upper part of a 96-well multiscreen assay plate (Millipore). The tested compounds, in combination with or without IL-8 or FMLP, are dispensed in the bottom part of the assay plate. Then, the plate is incubated at 37 °C in cell incubator for at least 2 hours. Then, the cells are recovered from the bottom part of the assay plate by centrifugation at 250g for 5 minutes. The chemotactic response is assessed using ATP light assay. Phagocytosis assay
Neutrophils (2xl05 cells/ weel) are seeded in 96-well assay plate and pre- incubated with or without the tested compounds for 1 hour at 37°C in cell incubator. Then, zymosan is added in each well, and the plate is incubated for 2 hours at 37°C in cell incubator. The phagocytosis is measured using the cytoselect 96-well phagocytosis assay, following manufacturer's recommendations.
Septic Shock mouse model
Mouse male BALB/c, 8 weeks of age, are acclimatized for 7 days. During acclimation and following dosing, animals are housed within a limited access rodent facility and kept in groups of maximum 10 mice, in polypropylene cages, fitted with solid bottoms and filled with wood shavings as bedding material. Animals are provided ad libitum a commercial rodent diet and free access to drinking water, supplied to each cage via polyethylene bottles with stainless steel sipper tubes. The day of the experiments, animals are randomized and experimental groups (n=10) are distributed across cages. A tO on day 0, the compounds of the invention or controls are administered via oral gavage. At time t 0.5h on day 0, mice are subjected to an intra-peritoneal injection of 100 μg of lipopolysachharide (LPS). On day 0 at time t 2h, all mice are tailed bled and serum prepared. On day 0 at time t 6h, all mice are culled, terminal bleeds taken and serum prepared.
TNFa, IL-Ιβ and IL-6 levels, or other markers, are measured in each serum using ELISA assay, according to manufacturer's recommendations.
When tested in the septic shock mouse model described above and by way of illustration the compounds n° 157; and 169 significantly inhibit the TNFa plasmatic level (Figure 4).
Colitis mouse model
Dextran Sodium Sulfate (DSS) induces a robust colitis used as well-known model of inflammatory bowel diseases including ulcerative colitis and Crohn's. Male C57BL6 mice, 25-30 g, receive DSS in drinking water at the concentration of 5 % for 7 days. The tested compound or vehicle control are pre-dosed, via oral or intra-rectal routes, beginning two days prior to DSS treatment and continuing throughout the 7-day exposure to DSS. The disease activity index (DAI) is measured daily as well as water consumption. At the end of the 7 days of treatment, mice are euthanized and tissues are collected for colonic length, histology, Myeloperoxydase (MPO) and permeability studies.
Disease Activity Index (DAI): Each parameter is on a 0-4 scale, and the daily DAI score is the average of the scores for each parameter. Weight loss: 0-4; Stool consistency: 0, 2, 4. Rectal Bleeding: 0, 2, 4. Colonic Length: Colonic length will be recorded ex-vivo in all mice. Histology: Colonic tissue from the proximal, medial and distal colon will be processed with H & E staining and serial sections will be mounted and scored by a blinded, qualified observer. The sum of each parameter is the total histological score. Grade of damage: 0-4; Extent of damage: 0-4; Severity of inflammation: 0-3. Myeloperoxidase (MPO) activity: MPO activity will be measured as an additional biochemical marker of inflammation using a spectrophotometric assay. Colonic Permeability: To assess the tissue integrity, colonic permeability will be measured in vitro. Specifically, colonic tissues will be mounted in modified Ussing chambers and maintained at 37 °C in oxygenated Krebs buffer. Basal potential difference ("PD") and flux of horseradish peroxidase will be monitored over 90 min.
Murine model of asthma
Nine week-old male BALB/c mice are sensitised on days 1 and 7 by intraperitoneal (i.p.) injection of 50μg ovalbumin (OVA) adsorbed with 2 mg aluminium hydroxide in saline (NaCl 0,9 %). Unsensitised animals received i.p. injections of aluminium hydroxide only. Mice are challenged on days 12 to 15 by intranasal (i.n.) instillations (12.5 μΐ per nostril) of 10 μg OA in saline or of saline alone for unsensitised animals under anaesthesia (50 mg/kg ketamine and 3.33 mg/kg xylazine i.p.). The tested compounds are given by oral gavage (o.g.) 1 h before each OVA challenge on these days. Control mice received NaCl 0.9% alone. Bronchoalveolar lavage (BAL) is performed 18-24 hours after the last allergen challenge. Mice are anaesthetised by i.p. injection of ketamine (150 mg/kg) and xylazine (10 mg/kg). The trachea is canulated and lungs lavaged by 10 instillations of 0.5 ml ice-cold saline supplemented with 2.6 mM ethylenediamine tetraacetic acid (saline-EDTA). BAL fluid (BALF) is centrifuged (400 g for 5 min at 4°C) to pellet cells. Erythrocytes are lysed by hypotonic choc. Total cell counts are determined using a hemocytometer. Differential cell counts are assessed on one cytologic preparation obtained by cytocentrifugation (Cytospin 3, Shandon Ltd, Runcorn, Chershire, UK) of 200 μΐ of diluted BALF (250,000 cells/ml in ice-cold saline-EDTA), stained with Diff-Quik (Dade Behring AG). Murine cytokines and chemokines in BAL fluid are assayed by ELISA using paired Abs, according to the manufacturers' recommendations. Blood is collected by cardiac puncture immediately after the thoracic cavity is opened and before BAL is performed. Blood is allowed to clot, then iss centrifuged, and aliquots of serum are stored at -70°C before analysis by ELISA for serum immunoglobulins Igs.
After BAL sampling is completed, the lungs are removed from the thoracic cavity by careful dissection. The lungs are inflated with 1 ml of 10% neutral-buffered Formalin and then fixed in 10% neutral-buffered Formalin for 72 h. After fixation, the left lung is dissected free and embedded in paraffin, and 6-μιη sections are cut. Sections are then stained with H&E. Total lung inflammation is defined as the sum of the peribronchial and perivascular scores. Peribronchial and perivascular inflammation is quantified by a treatment-blind observer and graded on the following scale: 0, none; 1, mild; 2, moderate; 3, marked; and 4, severe. An increment of 0.5 is used when the inflammation fell between two levels. Arthritis mouse models
K/BxN model
To induce K/BxN arthritis, sera are pooled from arthritic adult K/BxN mice. Recipient C/57black 6 mice are injected intraperitoneally with 150 μΐ on days 0 and 2 and disease progression is monitored as described. Development of arthritis is assessed in a blinded manner using a semiquantitative clinical scoring system for each paw: 0 = normal, 1 = mild to moderate swelling of the ankle/wrist joint or erythema and swelling limited to individual digits, 2 = swollen ankle or swelling in two or more digits, and 3 = severe swelling along all aspects of paw or all five digits swollen. Compounds of the invention are given by oral gavage (o.g.) 2 days before arthritis induction, as well as during disease monitoring. Control mice received NaCl 0.9% alone. Sera are analyzed for IL-6, TNFcc by ELISA (R&D Systems) according manufacturer's recommendations.
Collagen-induced arthritis DBA-1 male mice of 10-12 weeks of age are immunized with 0.1 ml of collagen II emulsified in complete Freund's adjuvant, injected at the base of the tail (collagen concentration, 2 mg ml~1). After 21 days, mice received an i.p. injection of 0.1 mg of collagen II in saline. The arthritis is monitored by scoring inflamed joints in each paw as described: 0 = no inflammation; 1 = mild erythema and swelling of individual digits; 2 = moderate erythema and swelling of the joint; 3 = severe erythema and swelling of the entire paw; 4 = severe erythema and ankylosis of the paw. The arthritic index is the sum of the scores of the four mouse paws; the maximum possible score being 16. Animals are observed every day and, when the first symptom of arthritis is evident, each mouse received an oral gavage of vehicle or the tested compound, once daily for 11 days. Mice are monitored daily during the period of treatment by an observer unaware of the treatment. At 1 day after the last administration of the compound (day 12), blood from the retro-orbital plexus is collected in heparinized tubes and animals killed. Plasma samples are frozen and levels of cytokines and chemokines determined by ELISA (R&D Systems), according to the manufacturer's instructions. Plasma levels of anti-collagen IgGi and IgG2A antibodies are determined by direct ELISA.
The effect of treatments on joint inflammation and cartilage and bone damage are evaluated histologically. From each mouse, both hindpaws are removed, fomalin- fixed, decalcified and wax-embedded before sectioning and staining with hematoxilin-eosin. The joint damage score is recorded by assessing the degree of pannus formation, cartilage erosion, and bone destruction. For each parameter a scale ranging from 0 (normal) to 4 (severe) is used. While embodiments of the invention have been illustrated and described, it is not intended that these embodiments illustrate and describe all possible forms of the invention. Rather, the words used in the specification are words of description rather than limitation ant it is understood that various changes may be made without departing from the spirit and scope of the invention.

Claims

1. A compound of general formula Ib-4
Figure imgf000259_0001
Ib-4,
harmaceutically acceptable salts, and solvates thereof, wherein
Ar1 is a 5- to 6-membered aryl or heteroaryl group, 3- to 8-membered cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, or a linear or branched C3-C6 alkyl group, each of the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or alkyl groups being optionally substituted by one or more groups selected from halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkoxyalkoxy, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, arylalkyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylaminoalkyl, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, haloalkylsulfonylamino, or two substituents form an alkylenedioxy group or a haloalkylenedioxy group, or two substituents form a cycloalkyl or heterocycloalkyl moiety together with the cycloalkyl or heterocycloalkyl group they are attached to, or fused to the aryl, heteroaryl, cycloalkyl or heterocycloalkyl group may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl moiety, each of said substituents being optionally substituted by one or more further substituents selected from halo, alkoxy, alkyl, alkylamino, alkylcarbonyl, alkylheteroaryl, alkylsulfonyl, aralkyl, aryl, arylamino, aryloxy, cyano, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocyclyl, hydroxyl, oxo, or sulfonyl;
L1 is a single bond, Ci-C2 alkylene, Ci-C2 alkenylene, each optionally being substituted by one or more substituents selected from halo, Ci-C2 alkyl, Ci-C2 haloalkyl; or L1 is -N(RN)-, wherein RN is H or Ci-C2 alkyl; or L1 and R1 together are =CH-;
R1 is H, halo, allyl, or a C1-C4 alkyl group, which may optionally be substituted by one or more groups selected from halo or C1-C4 alkyl;
L2 is a C1-C3 alkylene, C2-C4 alkenylene, C3-C6 cylcloalkylene, each of which being optionally substituted by one or more groups selected from halo, alkyl, alkoxy, or haloalkyl; or L2 is -0-CH2-; or
R1 and L2 together are =CH-, under the condition that -L1-Ar1 is H; or
R1 and L2 together are a cyclohexyl or cyclohexenyl group, under the condition that -ΐ Αι·1 is H;
Z is selected from the group consisting of -COOR,
Figure imgf000261_0001
wherein R is H or linear or branched alkyl, aryl, acyloxyalkyl, dioxolene, R3 is H, methyl or ethyl, and R4 is hydroxyl -S02CH3j -S02cyclopropyl or -S02CF3;
R2 is H, linear or branched C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, C2- C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkylalkyl, aryl, arylalkyl, heteroarylalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, or aralkyloxyalkyl; each of the alkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroarylalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, and aralkyloxyalkyl groups being optionally substituted by one or more substituents selected from halo, cyano, alkyl, hydroxyalkyl, haloalkyl, alkenyl, alkynyl, heteroalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, alkylcarbonylaminoalkyl, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, haloalkylsulfonylamino, or two substituents form an alkylenedioxy group or a haloalkylenedioxy group,
Ar3 is an aryl or heteroaryl group, each of which being optionally substituted by one or more groups selected from halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, arylalkyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylaminoalkyl, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, cycloalkylaminocarbamoyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, haloalkylsulfonylamino, or two substituents form an alkylenedioxy group or a haloalkylenedioxy group, or two substituents form a cycloalkyl or heterocycloalkyl moiety together with the cycloalkyl or heterocycloalkyl group they are attached to, or fused to the aryl, heteroaryl, cycloalkyl or heterocycloalkyl group may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl moiety, each of said substituents being optionally substituted by one or more further substituents selected from halo, alkoxy, alkyl, alkoxyalkyl, alkoxyalkoxy, cycloalkylalkyloxy, amino, alkylamino, alkylamino alkoxy, cycloalkylamino, aralkylamino, alkylamino alkyl, alkylamino carbonyl, alkylcarbonyl, cycloalkylcarbonylamino, alkylheterocyclyl, alkylheteroaryl, alkylsulfonyl, alkylsulfonylamino, aralkyl, aralkyloxy, aryl, arylamino, aryloxy, cyano, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocyclyl, heterocyclyloxy, hydroxyl, oxo, or sulfonyl, or Ar3 form an aryl, or heteroaryl group fused to Ar2, wherein each of said aryl or heteroaryl groups fused to Ar2 are optionally substituted by one or more halo;
X is S or O; Y is CH or N;
Figure imgf000263_0001
Ar s attac e to t e eterocyc c group either in position 4 or
5; and if Y is CH, R5 is H, halo, hydroxyl, linear or branched C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 haloalkyl, and R5 is attached to the heterocyclic group either in position 4, if Ar3 is attached in position 5, or in position 5, if Ar3 is attached in position 4; if Y is N, R5 is absent and Ar3 is attached in position 5; with the following provisos:
Figure imgf000263_0002
is not 4-(4-butylphenyl)thiazol-2-yl, 4-(4-ethylphenyl)thiazol- 2-yl, 4-(para-tolyl)thiazol-2-yl, 4-phenylthiazol-2-yl, 4-(4-propylphenyl)thiazol-2- yl, 4-(4-(sec-butyl)phenyl)thiazol-2-yl, 4-(4-isopropylphenyl)thiazol-2-yl, 4-(4- isobutylphenyl)thiazol-2-yl, 4-(4-(tert-butyl)phenyl)thiazol-2-yl, 4-(4- butylphenyl)-5 -methylthiazo 1-2-yl, 4-(4-ethylphenyl)-5 -methylthiazo 1-2-yl, 5 - methyl-4-(para-tolyl)thiazol-2-yl, 5 -methyl-4-phenylthiazo 1-2-yl, 5-methyl-4-(4- propylphenyl)thiazo 1-2-yl, 4-(4-(sec-butyl)phenyl)-5 -methylthiazo 1-2-yl, 4-(4- isopropylphenyl)-5 -methylthiazo 1-2-yl, 4-(4-isobutylphenyl)-5-methylthiazo 1-2-yl, 4-(4-(tert-butyl)phenyl)-5 -methylthiazo 1-2-yl, 4-(4-butyl-3 -methylphenyl)thiazo 1- 2-yl, 4-(4-ethyl-3-methylphenyl)thiazo 1-2-yl, 4-(3 ,4-dimethylphenyl)thiazo 1-2-yl, 4-(meta-tolyl)thiazol-2-yl, 4-(3-methyl-4-propylphenyl)thiazo 1-2-yl, 4-(4-(sec- butyl)-3-methylphenyl)thiazo 1-2-yl, 4-(4-isopropyl-3-methylphenyl)thiazo 1-2-yl, 4-(4-isobutyl-3-methylphenyl)thiazo 1-2-yl, 4-(4-(tert-butyl)-3- methylphenyl)thiazo 1-2-yl, 4-(4-butyl-3 -methylphenyl)-5 -methylthiazo 1-2-yl, 4- (4-ethyl-3-methylphenyl)-5 -methylthiazo 1-2-yl, 4-(3,4-dimethylphenyl)-5- methylthiazo 1-2-yl, 5-methyl-4-(meta-tolyl)thiazol-2-yl, 5-methyl-4-(3-methyl-4- propylphenyl)thiazo 1-2-yl, 4-(4-(sec-butyl)-3-methylphenyl)-5 -methylthiazo 1-2-yl, 4-(4-isopropyl-3-methylphenyl)-5 -methylthiazo 1-2-yl, 4-(4-isobutyl-3- methylphenyl)-5 -methylthiazo 1-2-yl, 4-(4-(tert-butyl)-3 -methylphenyl)-5 - methylthiazo 1-2-yl, naphtalen-2-yl;
Ar3 is not (7H-pyrrolo[2,3-d]pyrimidin)-4yl;
Figure imgf000264_0001
is not 5-cyano-thiazolyl; the compound of formula I is none of.
2- [ [ [4-(4-butylphenyl)-5 -methyl-2-thiazolyl]amino ]carbonyl] -cy clohexane carboxylic acid,
2- [ [ [4-(4-methoxyphenyl)-5 -methyl-2-thiazo lyl] amino]carbonyl] - cyclohexanecarboxylic acid,
6-[[[4-(3,4-dimethylphenyl)-5-methyl-2-thiazolyl]amino]carbonyl]-3- cyclohexene-1 -carboxylic acid,
6-[[[5-methyl-4-(4-propylphenyl)-2 thiazolyl]amino]carbonyl]-3-cyclohexene- 1 - carboxylic acid,
2-[[[4-(2,4-dichlorophenyl)-5-methyl-2-thiazolyl]amino]carbonyl]- cyclohexanecarboxylic acid,
2- [ [ [4-(2,5 -dimethylphenyl)-5 -methyl-2- thiazolyl] amino] carbonyl] - cyclohexanecarboxylic acid, 6-[[[5-(2-chlorophenyl)-l,3,4-thiadiazol-2-yl]amino]carbonyl]-3-cyclohexene-l- carboxylic acid,
2- [ [ [5-methyl-4-(4-propylphenyl)-2-thiazo lyl] amino] carbonyl] - cyclohexanecarboxybic acid,
6- [ [ [4- [4-( 1 , 1 -dimethylethyl)phenyl] -5 -methyl-2-thiazo lyl] amino] carbonyl] -3 - cyclohexene-l-carboxylic acid,
2-[[(5-methyl-4-phenyl-2-thiazolyl)amino]carbonyl]-cyclohexanecarboxylic acid, 2- [ [ [5-methyl-4- [4-(2-methylpropyl)phenyl] -2-thiazolyl)amino]carbonyl] - cyclohexanecarboxylic acid,
2- [ [ [4-(4-chlorophenyl)5 -ethyl-2-thiazo lyl)amino]carbonyl] - cyclohexanecarboxylic acid,
2- [ [ [4-(3 -methoxyphenyl)-5 -methyl-2-thiazo lyl] amino]carbonyl] - cyclohexanecarboxylic acid,
6-[[[5-methyl-4-(4-methylphenyl)-2-thiazolyl]amino]carbonyl]-3-cyclohexene-l- carboxylic acid,
6-[[[4-(4-chlorophenyl)-5-ethyl-2-thiazolyl]amino]carbonyl]-3-cyclohexene-l- carboxybic acid,
6- [ [ [4-(2,5 -dimethylphenyl)-5 -methyl-2-thiazo lyl] amino] carbonyl] -3 -cyclohexene- l-carboxylic acid,
6-[[(5-phenyl-l,3,4-thiadiazol-2-yl)amino]carbonyl]-3-cyclohexene-l-carboxylic acid,
2-[[[5-(4-methoxyphenyl)-l,3,4-thiadiazol-2yl]amino]carbonyl]- cyclohexanecarboxylic acid,
2-[[(6-carboxy-3-cyclohexen-l-yl)carbonyl]amino]-4-phenyl-5-thiazolecarboxylic acid-5 -ethyl ester,
6-[[[5-methyl-4-[4-(2-methylpropyl)phenyl]-2-thiazolyl)amino]carbonyl]-3- cyclohexene-l-carboxylic acid,
6-[[(5-ethyl-4-phenyl-2-thiazolyl)amino]carbonyl]-3-cyclohexene-l-carboxylic acid,
6-[[[4-(2,4-dimethylphenyl)-5-methyl-2- thiazolyl)amino]carbonyl]-3- cyclohexene-l-carboxylic acid, 2- [ [ [4-(3 -chlorophenyl)-5 -methyl-2-thiazolyl] amino]carbonyl] - cyclohexanecarboxylic acid,
6- [ [ [5-( 1 -ethylphenyl)- 1 ,3 ,4-thiadiazol-2-yl] amino ]carbonyl] -3 -cy clohexene- 1 - carboxylic acid,
2-[[[5-(2-thienyl)-l,3,4-thiadiazol-2-yl]amino]carbonyl]-cyclohexanecarboxylic acid,
2- [ [(4,5 -diphenyl-2-thiazo lyl)amino] carbonyl] -cyclohexanecarboxybic acid, 6- [ [ [4-(4-ethylphenyl)-5 -methyl-2-thiazo lyl] amino ]carbonyl] -3 -cy clohexene- 1 - carboxylic acid,
2-[[(5-ethyl-4-phenyl-2-thiazolyl)amino]carbonyl]-cyclohexanecarboxylic acid, 2- [ [ [4-(4-fluorophenyl)-5 -methyl-2-thiazo lyl] amino] carbonyl] - cyclohexanecarboxylic acid,
2- [ [ [4-(2,4-dimethylphenyl)-5 -methyl-2-thiazo lyl] amino] carbonyl] - cyclohexanecarboxylic acid,
6-[[[4-(3-chlorophenyl)-5-methyl-2- thiazolyl]amino]carbonyl]-3-cyclohexene-l- carboxylic acid,
2-[[[5-methyl-4-(4-methylphenyl)-2-thiazolyl]amino]carbonyl]- cyclohexanecarboxylic acid,
6-[[[5-(2-thienyl)-l,3,4-thiadiazol-2-yl]amino]carbonyl]-3-cyclohexene-l- carboxylic acid,
2- [ [ [4-(4-ethylphenyl)-5 -methyl-2-thiazo lyl] amino ]carbonyl] - cyclohexanecarboxylic acid,
2-[[(2-carboxycyclohexyl)carbonyl]amino]-4-phenyl-5-thiazolecarboxylic acid-5- ethyl ester,
2- [ [ [5-methyl-4- [4-( 1 -methylethyl)phenyl] -2-thiazolyl] amino] carbonyl] - cyclohexanecarboxylic acid,
6-[[[4-(2,4-dichlorophenyl)-5-methyl-2-thiazolyl]amino]carbonyl]-3-cyclohexene- 1 -carboxylic acid,
6-[[[4-(4-chlorophenyl)-5-methyl-2-thiazolyl]amino]carbonyl]-3-cyclohexene-l- carboxylic acid, 2-[[[4-(4-chlorophenyl)-5-methyl-2-thiazolyl]amino]carbonyl- cyclohexanecarboxylic acid,
6- [ [ [4-(4-fluorophenyl)-5 -methyl-2-thiazo lyl] amino] carbonyl] -3 -cy clohexene- 1 - carboxylic acid,
2- [ [[4 [4-( 1 , 1 -dimethylethyl)phenyl] -5 -methyl-2-thiazo lyl]amino]carbonyl- cyclohexanecarboxylic acid,
6- [ [(5-methyl-4-phenyl-2-thiazo lyl)amino] carbonyl] -3 -eye lohexene- 1 -carboxylic acid,
6-[[(5-(2-thienyl)-l,3,4-thiadiazol-2-yl]amino]carbonyl]-3-cyclohexene-l- carboxylic acid for use in the treatment and /or prevention of inflammatory diseases.
2. The compound according to claim 1 having the formula Ib-4a:
Figure imgf000267_0001
Ib-4a,
and pharmaceutically acceptable salts, and solvates thereof, wherein
Ar1, L1, L2, R1, R2, R5, X, Y and Z are as defined in claim 1 ;
R20 and R'20 are independently selected from H, halo, cyano, C1-C3 alkyl, cyclopropyl, haloalkyl, alkoxy, haloalkoxy, alkoxycarbonylamino, or the two substituents form an alkylenedioxy group or a haloalkylenedioxy group;
Ar4 is 5 or 6 membered aryl, 5 or 6 membered heteroaryl, each of said 5 or 6 membered aryl or 5 or 6 membered heteroaryl groups being optionally fused to one or more 5 or 6 membered cycloalkyl, aryl, heterocyclyl or heteroaryl moiety, thus forming a fused ring system, and the latter fused ring system being optionally substituted by one or more further substituents selected from halo, hydroxyl, oxo, alkyl, and/or each of said 5 or 6 membered aryl or 5 or 6 membered heteroaryl groups being optionally substituted by one or more substituents selected from halo, cyano, hydroxyl, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, alkylaminoalkoxy, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, aryloxy, aralkyloxy, alkylamino, alkylaminoalkyl, cycloalkylamino, arylamino, aralkylamino, alkylaminocarbonyl, heteroarylcarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, alkylsulfonyl, haloalkylsulfonyl, alkylsulfonylamino, each of said cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, aryloxy, aralkyloxy, heteroarylcarbonyl, cycloalkylamino, arylamino, aralkylamino, cycloalkylcarbonylamino being optionally substituted by one or more further substituents selected from halo, oxo or alkyl; for use in the treatment and /or prevention of inflammatory diseases.
3. The compound according to claim 2 having the formula Ib-4b:
Figure imgf000268_0001
Ib-4b,
harmaceutically acceptable salts, and solvates thereof, wherein Ar1, Ar4, L1, L2, R1, R2, R5, R20, R'20 and Z are as defined in claim 2; for use in the treatment and /or prevention of inflammatory diseases.
4. The of a compound according to claim 3 having the formula Ib-4c:
Figure imgf000269_0001
Ib-4c,
and pharmaceutically acceptable salts, and solvates thereof, wherein
Ar1, L1, L2, R1, R2, R5, and Z are as defined in claim 1 ,
R20 and R'20, are as defined in claim 2,
R21 and R22 are independently selected from H, halo, alkoxy;
R23 is selected from H, halo, cyano, hydroxyl, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, alkylaminoalkoxy, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, aryloxy, aralkyloxy, alkylamino, alkylaminoalkyl, cycloalkylamino, arylamino, aralkylamino, alkylaminocarbonyl, heteroarylcarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, alkylsulfonyl, each of said cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, aryloxy, aralkyloxy, heteroarylcarbonyl, cycloalkylamino, arylamino, aralkylamino, cycloalkylcarbonylamino being optionally substituted by one or more further substituents selected from halo, oxo or alkyl;
Y1 is N or C-R24 where R24 is H, halo, alkoxy, alkyl, heterocyclyl, or Y1 is C-R24 and R24 and R23 together form a 5 or 6 membered cycloalkyl, aryl, heterocyclyl or heteroaryl moiety, thus forming a fused ring system, the latter fused ring system being optionally substituted by one or more group selected from oxo, alkyl or halo; and Y2 is N or C-R25 where R25 is H, halo, alkoxy, alkyl, heterocyclyl, or
2 25 25 23
Y is C-R and R and R together form a 5 or 6 membered cycloalkyl, aryl, heterocyclyl or heteroaryl moiety, thus forming a fused ring system, the latter fused ring system being optionally substituted by one or more group selected from oxo, alkyl or halo, under the condition that R24 and R23 together do not form a 5 or 6 membered cycloalkyl, aryl, heterocyclyl or heteroaryl moiety; for use in the treatment and /or prevention of inflammatory diseases.
5. The compound according to claim 4 having the formula Ib-4d:
Figure imgf000270_0001
Ib-4d,
harmaceutically acceptable salts, and solvates thereof, wherein Ar1, L1, L2, R1, R2, R5, and Z are as defined in claim 1 ;
R and R' , are as defined above in claim 2; and
21 22 23 25
R , R , R" and R" are as defined above in claim 4; for use in the treatment and /or prevention of inflammatory diseases.
6. The compound according to claim 5 having the formula Ib-4e:
Figure imgf000271_0001
Ib-4e, and pharmaceutically acceptable salts, and solvates thereof, wherein
Ar1, L1, L2, R1, R2, R5, R20, R'20, R21, R22, R23, R25 and Z are as defined 5;
for use in the treatment and /or prevention of inflammatory diseases. 7. The compound according to claim 1 having the formula Ib-4k:
Figure imgf000272_0001
Ib-4k, and pharmaceutically acceptable salts, and solvates thereof, wherein Ar1, L1, L2, R1, R2, R5, X, Y, and Z are defined as in claim 1 ;
26 26 27 27 28
R , R' , R , R' , R are independently selected from H, halo, cyano, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, acylamino, carbamoyl, alkoxycarbamoyl, cycloalkylcarbamoyl, alkylcarbamoylamino, cycloalkylaminocarbamoyl, alkylsulfonyl, haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino, or two substituents form an alkylenedioxy group or a halo alky lenedioxy group; for use in the treatment and /or prevention of inflammatory diseases.
8. The compound according to claim 7 having the formula Ib-41:
Figure imgf000273_0001
and pharmaceutically acceptable salts, and solvates thereof, wherein
Ar1, L1, L2, R1, R2, R5 R26, R'26, R27, R'27, R28and Z are as defined in claim 7; for use in the treatment and /or prevention of inflammatory diseases.
9. The compound according to claim 1 having the formula Ib-4m:
Figure imgf000273_0002
Ib-4m,
harmaceutically acceptable salts, and solvates thereof, wherein Ar1, L1, L2, R1, R2, R5, and Z are as defined in claim 1 ; and
R'26 and R27 are independently selected from H, halo, cyano, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, acylamino, carbamoyl, alkoxycarbamoyl, cycloalkylcarbamoyl, alkylcarbamoylamino, cycloalkylaminocarbamoyl, alkylsulfonyl, haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino, or the two substituents form an alkylenedioxy group or a haloalkylenedioxy group; for use in the treatment and /or prevention of inflammatory diseases.
10. The compound according to any one of the preceeding claims, wherein the compound is selected from the group consisting of:
1 6-((4-(2-chlorophenyl)thiazol-2-yl)carbamoyl)cyclohex-3- enecarboxylic acid
2 (R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
3 (R)-3-benzyl-4-((4-(2,4-dichlorophenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
4 (R)-3-benzyl-4-((4-(2-fluorophenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
5 (R)-3-benzyl-4-((4-(3,4-dichlorophenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
8 (R)-3-benzyl-4-((4-(4-cyanophenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
9 (S)-4-((4-(2-chlorophenyl)thiazol-2-yl)amino)-4-oxo-3- phenylbutanoic acid
10 (Z)-4-((4-(2-chlorophenyl)thiazol-2-yl)amino)-4-oxobut-2-enoic acid
11 (R)-3-benzyl-4-oxo-4-((3-phenyl-l,2,4-thiadiazol-5- yl)amino)butanoic acid (R)-3-benzyl-4-((4-(3-chlorophenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
(R)-3 -benzyl-4-oxo-4-((4-(3 -(trifluoromethyl)phenyl)thiazo 1-2- yl)amino)butanoic acid
(R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
(R)-3-((4-(2-chlorophenyl)thiazol-2-yl)carbamoyl)heptanoic acid (R)-4-((4-(2-chlorophenyl)thiazol-2-yl)amino)-3-(4-fluorobenzyl)-4- oxobutanoic acid
(R)-4-((4-(2-chlorophenyl)thiazol-2-yl)amino)-3-(cyclohexylmethyl)- 4-oxobutanoic acid
(R)-3-((4-(2-chlorophenyl)thiazol-2-yl)carbamoyl)-5-methylhexanoic acid
(R)-3-benzyl-4-((4-(2-chlorophenyl)-5-fluorothiazol-2-yl)amino)-4- oxobutanoic acid
(R)-3-benzyl-4-((5-chloro-4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
(R)-4-(allyl(4-(2-chlorophenyl)thiazol-2-yl)amino)-3-benzyl-4- oxobutanoic acid
(R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2-yl)(2-methoxy-2- oxoethyl)amino)-4-oxobutanoic acid
(R)-methyl-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2-yl)amino)-4- oxobutanoate
(R)-3 -(4-(2-chlorophenyl)thiazo l-2-ylcarbamoyl)-5 -phenylpentano ic acid
(S)-3-(4-(2-chlorophenyl)thiazol-2-ylcarbamoyl)-5-phenylpentanoic acid
(R)-4-(4-(2-chlorophenyl)thiazol-2-ylamino)-4-oxo-3-(4- (trifluoromethyl)benzyl)butano ic acid
(R)-4-((4-(2-chlorophenyl)thiazol-2-yl)amino)-4-oxo-3-(3- (trifluoromethyl)benzyl)butano ic acid
(R)-4-((4-(2-chlorophenyl)thiazol-2-yl)amino)-3-(2-cyanobenzyl)-4- oxobutanoic acid (R)-4-((4-(2-chlorophenyl)thiazol-2-yl)amino)-3-(3-cyanobenzyl)-4- oxobutanoic acid
(R)-4-((4-(2-chlorophenyl)thiazol-2-yl)amino)-3-(4-cyanobenzyl)-4- oxobutanoic acid
(R)-4-((4-(2-chlorophenyl)thiazol-2-yl)amino)-3-(4-methoxybenzyl)- 4-oxobutanoic acid
(R)-4-((4-(2-chlorophenyl)thiazol-2-yl)amino)-3-(3-methoxybenzyl)- 4-oxobutanoic acid
(R)-4-((4-(2-chlorophenyl)thiazol-2-yl)amino)-3-(2-methoxybenzyl)- 4-oxobutanoic acid
(R)-3-benzyl-4-((4-(2-methoxyphenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
(R)-3-benzyl-4-oxo-4-(4-(2,4,6-trichlorophenyl)thiazol-2- ylamino)butanoic acid
(R)-4-benzyl-5 -((4-(2-chlorophenyl)thiazo l-2-yl)(methyl)amino)-5 - oxopentanoic acid
(S)-4-benzyl-5-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-5- oxopentanoic acid
(R)-methyl 4-benzyl-5-(4-(2-chlorophenyl)thiazol-2-ylamino)-5- oxopentanoate
(S)-methyl 4-benzyl-5-(4-(2-chlorophenyl)thiazol-2-ylamino)-5- oxopentanoate
(R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2- yl)(cyclopropylmethyl)amino)-4-oxobutanoic acid
(R)-3-benzyl-4-(benzyl(4-(2-chlorophenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
(R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2-yl)(2,2,2- trifluoroethyl)amino)-4-oxobutanoic acid
(R)-4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-3-(4- methoxybenzyl)-4-oxobutanoic acid
(R)-4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-3-(3- methoxybenzyl)-4-oxobutanoic acid
(R)-4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-3-(2- methoxybenzyl)-4-oxobutanoic acid (R)-4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-3-(4- cyanobenzyl)-4-oxobutanoic acid
(R)-4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-3-(3- cyanobenzyl)-4-oxobutanoic acid
(R)-4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-3-(2- cyanobenzyl)-4-oxobutanoic acid
(R)-3-(4-chlorobenzyl)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
(R)-3-(3-chlorobenzyl)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
(R)-3-(2-chlorobenzyl)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
(3S)-4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-3-(2,3- dihydro- 1 H-inden- 1 -yl)-4-oxobutanoic acid
(S)-4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-3-(2,3- dihydro- 1 H-inden-2-yl)-4-oxobutanoic acid
(R)-4-(benzo[d]thiazol-2-yl(methyl)amino)-3-benzyl-4-oxobutanoic acid
(R)-4-(benzo[d]oxazol-2-yl(methyl)amino)-3-benzyl-4-oxobutanoic acid
(R)-2-((lH-tetrazol-5-yl)methyl)-N-(4-(2-chlorophenyl)thiazol-2-yl)- N-methyl-3 -phenylpropanamide
(R)-2-benzyl-N-(4-(2-chlorophenyl)thiazol-2-yl)-N-methyl-3-(5-oxo- 4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)propanamide
(R)-3-benzyl-4-((4-(2-chlorophenyl)-5-fluorothiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
(S)-4-(4-(2-chlorophenyl)thiazol-2-ylamino)-3-cyclohexyl-4- oxobutanoic acid
(S)-4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-3-cyclohexyl- 4-oxobutanoic acid
(S)-4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3- phenylbutanoic acid
(3R)-3-(4-(2-chlorophenyl)thiazol-2-ylcarbamoyl)-4-phenylpentanoic acid (R)-2-((lH-tetrazol-5-yl)methyl)-N-(4-(2-chlorophenyl)thiazol-2-yl)- 3 -phenylpropanamide
(R)-2-benzyl-N-(4-(2-chlorophenyl)thiazol-2-yl)-3-(5-oxo-4,5- dihydro- 1 ,2,4-oxadiazol-3-yl)propanamide
(3R)-3-benzyl-4-(4-(2-chlorophenyl)thiazol-2-ylamino)-2-methyl-4- oxobutanoic acid
(R)-2-benzyl-N-(4-(2-chlorophenyl)thiazol-2-yl)-3-(3- hydroxyisoxazo 1-5 -yl)propanamide
(E)-3 -(4-(2-chlorophenyl)thiazo l-2-ylcarbamoyl)-4-phenylbut-3 - enoic acid
(Z)-4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3- phenylbut-2-enoic acid
(R)-3-benzyl-4-(4-(2-chlorophenyl)thiazol-2-ylamino)-3-fluoro-4- oxobutanoic acid
(R)-3-benzyl-3-(4-(2-chlorophenyl)thiazol-2-ylcarbamoyl)hex-5 -enoic acid
(E)-3-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)carbamoyl)-4- phenylbut-3 -enoic acid
(3S)-3-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)carbamoyl)-4- phenylpentanoic acid
(R)-3-benzyl-4-((3-(2-chlorophenyl)- 1 ,2,4-thiadiazol-5- yl)(methyl)amino)-4-oxobutano ic acid
(R)-3-benzyl-4-((3-(2-chlorophenyl)-l,2,4-oxadiazol-5- yl)(methyl)amino)-4-oxobutano ic acid
(R)-2-benzyl-N-(4-(2-chlorophenyl)thiazol-2-yl)-3-(3- hydroxyisoxazo 1-5 -yl)-N-methylpropanamide
(R)-4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-3-
(cyclohexylmethyl)-4-oxobutanoic acid
(R)-3 -((4-(2-chlorophenyl)thiazo l-2-yl)(methyl)carbamoyl)-5 - methylhexanoic acid
(R)-3-benzyl-4-((4-(2-cyanophenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
(R)-4-(4-(2-chlorophenyl)thiazol-2-ylamino)-4-oxo-3-phenylbutanoic acid 93 (R)-4-(4-(2-chlorophenyl)thiazol-2-ylamino)-3-(3-fluorobenzyl)-4- oxobutanoic acid
94 (S)-3-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)carbamoyl)-4- methylpentanoic acid
95 4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
96 (R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2-yl)(ethyl)amino)-4- oxobutanoic acid
97 (R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2-yl)(cyclopropyl)amino)- 4-oxobutanoic acid
98 cis-6-(4-(2-chlorophenyl)thiazol-2-ylcarbamoyl)cyclohex-3- enecarboxylic acid
99 4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-3-(4- methoxybenzyl)-4-oxobutanoic acid
100 cis-6-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)carbamoyl)cyclohex-3- enecarboxylic acid
101 cis-2-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)carbamoyl)cyclohexanecarboxylic acid
102 (R)-3-benzyl-4-(4-(2,5-dimethylthiophen-3-yl)thiazol-2-ylamino)-4- oxobutanoic acid
103 4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-3- (cyclohexylmethyl)-4-oxobutanoic acid
105 4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-3- (cyclopentylmethyl)-4-oxobutano ic acid
106 (3S,4R)-3-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)carbamoyl)-4- phenylpentanoic acid
107 (R)-3-benzyl-4-(methyl(4-(2-(thiophen-3-yl)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid
108 (R)-3-benzyl-4-((4-(2-(6-chloropyridin-3-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
109 (R)-4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3- (phenylamino)butanoic acid
110 4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-3-(4- methylbenzyl)-4-oxobutanoic acid (R)-4-((4-([l,r-biphenyl]-2-yl)thiazol-2-yl)(methyl)amino)-3-benzyl- 4-oxobutanoic acid
(R)-3-benzyl-4-(4-(2,5-dichlorothiophen-3-yl)thiazol-2-ylamino)-4- oxobutanoic acid
4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-3- (cyclopropylmethyl)-4-oxobutanoic acid
4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3-(thiazol- 4-ylmethyl)butanoic acid
(R)-3-benzyl-4-((4-(2-(6-(dimethylamino)pyridin-3-yl)phenyl)thiazol-
2- yl)(methyl)amino)-4-oxobutanoic acid
(R)-3 -benzyl-4-((4-(2-(6-methoxypyridin-3 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
(R)-3 -benzyl-4-((4-(2-(2-methoxypyridin-3 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
(R)-3-benzyl-4-((4-(2-((ethoxycarbonyl)amino)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
(R)-3-benzyl-4-((4-(2-(6-fluoropyridin-3-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
(R)-3 -benzyl-4-(methyl(4-(2-(6-methylpyridin-3 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
(R)-4-((2-amino-2-oxoethyl)(4-(2-chlorophenyl)thiazol-2-yl)amino)-
3- benzyl-4-oxobutanoic acid
(R)-3 -benzyl-4-oxo-4-((4-(3 -(trifluoromethoxy)phenyl)thiazo 1-2- yl)amino)butanoic acid
(R)-3-benzyl-4-((4-(2,5-dichlorophenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
(R)-3-benzyl-4-((4-(3-chloro-4-fluorophenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
(R)-3-benzyl-4-((4-(3-chloro-4-methoxyphenyl)thiazol-2-yl)amino)-4- oxobutanoic acid 126 (R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2-yl)(3-methoxy-3- oxopropyl)amino)-4-oxobutanoic acid
127 3-(bicyclo[2.2.1]heptan-2-ylmethyl)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
128 (R)-3-benzyl-4-((4-(2-(6-ethoxypyridin-3-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
129 (R)-3-benzyl-4-((4-(4'-methoxy-[ 1 , 1 '-biphenyl]-2-yl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
130 (R)-3-benzyl-4-((4-(2,5-dichlorophenyl)thiazol-2-yl)(methyl)amino)- 4-oxobutanoic acid
131 (R)- 1 -(5-(2-(2-(2-benzyl-3-carboxy-N-methylpropanamido)thiazol-4- yl)phenyl)pyridin-2-yl)pyrrolidin- 1 -ium 2,2,2-trifluoroacetate
132 (R)-4-(2'-(2-(2-benzyl-3-carboxy-N-methylpropanamido)thiazol-4-yl)- [1,1 '-biphenyl]-4-yl)morpholin-4-ium 2,2,2-trifluoroacetate
133 (R)-3-benzyl-4-(methyl(4-(2-(6-morpholinopyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
134 (R)-3-benzyl-4-((4-(3*-chloro-[l,r-biphenyl]-2-yl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
135 (R)-3-benzyl-4-((4-(2-(furan-3-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
136 (R)-3-benzyl-4-((4-(2-(6-(2-methoxyethoxy)pyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
138 (R)-3-benzyl-4-((4-(4'-isopropyl-[ 1 , 1 '-biphenyl]-2-yl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
139 (R)-3-(cyclopentylmethyl)-4-((4-(2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
140 (R)-3-benzyl-4-((4-(2-(5-fiuoro-6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
141 (R)-3-benzyl-4-(methyl(4-(2-(6-((tetrahydro-2H-pyran-4- yl)oxy)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid (R)-3-benzyl-4-(cyclopropyl(4-(2,5-dichlorophenyl)thiazol-2- yl)amino)-4-oxobutanoic acid
4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-3-(furan-2- ylmethyl)-4-oxobutanoic acid
(R)-3-benzyl-4-((4-(2-cyclopropylphenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
(R)-3-benzyl-4-((4-(4'-(dimethylamino)-[ 1 , 1 '-biphenyl]-2-yl)thiazol- yl)(methyl)amino)-4-oxobutano ic acid
(R)-3-benzyl-4-((4-(3*-fluoro-[ 1 , 1 *-biphenyl]-2-yl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
(R)-3-benzyl-4-((4-(3*,5*-difluoro-[l,r-biplienyl]-2-yl)tliiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
(R)-3-benzyl-4-((4-(2-chloro-6-fluorophenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
(R)-3-benzyl-4-((4-(4'-chloro-[ 1 , 1 '-biphenyl]-2-yl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
(R)-3-benzyl-4-(methyl(4-(2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
(R)-3-benzyl-4-((4-(4-chloro-2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
(R)-3-benzyl-4-((4-(5-chloro-2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
(R)-3-benzyl-4-((4-(3-fluoro-2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
(3R)-4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3- ((tetrahydrofuran-2-yl)methyl)butanoic acid
(R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2-yl)(2- hydroxyethyl)amino)-4-oxobutanoic acid
(R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2-yl)(3- hydroxypropyl)amino)-4-oxobutanoic acid 157 (R)-3-benzyl-4-((4-(2-(5-chloro-6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
158 (R)-3-benzyl-4-((4-(2-(6-(benzyloxy)pyridin-3-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
159 (R)-3-(cyclopentylmethyl)-4-((4-(2,5-dichlorophenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
160 (R)-4-((4-(2-(6-methoxypyridin-3-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
161 (R)-3-benzyl-4-((4-(2-chloro-5-(trifluoromethyl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
162 (R)-3-benzyl-4-((4-(2-chloro-5-fluorophenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
163 (R)-3-benzyl-4-((4-(3,5-dichlorophenyl)thiazol-2-yl)(methyl)amino)- 4-oxobutanoic acid
164 (R)-3-benzyl-4-((4-(3-(difluoromethoxy)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
165 (R)-4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-3- (cyclopentylmethyl)-4-oxobutano ic acid
166 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2,5- dichlorophenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
167 (R)-4-(cyclopropyl(4-(2,5-dichlorophenyl)thiazol-2-yl)amino)-4-oxo- 3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
168 (R)-4-((4-(2,5-dichlorophenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
169 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
170 (R)-3-benzyl-4-((2-hydroxyethyl)(4-(2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
171 (R)-3-(cyclopentylmethyl)-4-(methyl(4-(2-(6-morpholinopyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid 172 (R)-3-(cyclopentylmethyl)-4-((4-(2,5-dichlorophenyl)thiazol-2-yl)(2- hydroxyethyl)amino)-4-oxobutanoic acid
173 (R)-4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
174 (R)-3-benzyl-4-((4-(5-chloro-2-(trifluoromethyl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
175 (R)-3-benzyl-4-(methyl(4-(2,3,5-trichlorophenyl)thiazol-2-yl)amino)- 4-oxobutanoic acid
176 (R)-3-benzyl-4-((4-(4-chloro-[l,r-biphenyl]-3-yl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
177 (R)-3-benzyl-4-((4-(2-chloro-5-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
178 (R)-3-benzyl-4-(cyclopropyl(4-(2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
179 (R)-4-(cyclopropyl(4-(2-(6-methoxypyridin-3-yl)phenyl)thiazol-2- yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
180 (R)-3-benzyl-4-(cyclopropyl(4-(2-(6-morpholinopyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
181 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-morpholinopyridin- 3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
182 (R)-3-benzyl-4-(methyl(4-(2-(4-methyl-3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazin-7-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
183 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 - yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
184 (R)-4-(cyclopropyl(4-(2-(6-morpholinopyridin-3-yl)phenyl)thiazol-2- yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
185 (R)-3-benzyl-4-(methyl(4-(2-(trifluoromethoxy)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid
186 (R)-4-((4-(2-chloro-5-fluorophenyl)thiazol-2-yl)(cyclopropyl)amino)- 3-(cyclopentylmethyl)-4-oxobutanoic acid 187 (R)-3-(cyclopentylmethyl)-4-(methyl(4-(2-(6-(2-oxopyrrolidin- 1 - yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
188 (R)-3-benzyl-4-(cyclopropyl(4-(3-(difluoromethoxy)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid
189 (R)-3-benzyl-4-((4-(2-chloro-5-fluorophenyl)thiazol-2- yl)(cyclopropyl)amino)-4-oxobutanoic acid
190 (R)-4-((4-(2-chloro-5-fluorophenyl)thiazol-2-yl)(cyclopropyl)amino)- 4-oxo-3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
191 (R)-3-benzyl-4-((4-(2-chloro-5-(trifluoromethyl)phenyl)thiazol-2- yl)(cyclopropyl)amino)-4-oxobutanoic acid
192 (R)-3-benzyl-4-((4-(2-(difluoromethoxy)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
193 (R)-4-((4-(2-chloro-5-(trifluoromethyl)phenyl)thiazol-2- yl)(cyclopropyl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
194 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(4-methyl-3,4- dihydro-2H-pyrido[3,2-b][l,4]oxazin-7-yl)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid
195 (3R,4S)-3-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)carbamoyl)-4- phenylpentanoic acid
198 4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-3- (morpholinomethyl)-4-oxobutanoic acid
199 (R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2-yl)(2- methoxyethyl)amino)-4-oxobutanoic acid
200 (R)-4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-3- (cyclopentylamino)-4-oxobutanoic acid
201 (R)-3-benzyl-4-((2-(benzyloxy)ethyl)(4-(2-chlorophenyl)thiazol-2- yl)amino)-4-oxobutanoic acid
202 (R)-3-benzyl-4-((4-(5-methylfuran-2-yl)thiazol-2-yl)amino)-4- oxobutanoic acid 204 (R)-3-benzyl-4-((4-(5-chloro-2-methoxyphenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
205 4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-3-(4- hydroxybenzyl)-4-oxobutanoic acid
206 (R)-3-benzyl-4-((4-(4*-cyano-[ 1 , 1 *-biphenyl]-2-yl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
208 (R)-3-benzyl-4-((4-(3'-methoxy-[ 1 , 1 *-biphenyl]-2-yl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
209 4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-3-((2- methylthiazo l-4-yl)methyl)-4-oxobutanoic acid
210 4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-3-((5- methylisoxazol-3-yl)methyl)-4-oxobutanoic acid
211 (R)-3-benzyl-4-((4-(2'-chloro-[ 1 , 1 '-biphenyl]-2-yl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
212 (R)-3-benzyl-4-((4-(2-(2-methoxypyrimidin-5-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
213 (R)-3-benzyl-4-((4-(2,5-difluorophenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
214 4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-3-(oxazol-4- ylmethyl)-4-oxobutanoic acid
215 (3R)-4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3- ((tetrahydrofuran-3 -yl)methyl)butanoic acid
216 (R)-3-benzyl-4-(methyl(4-(2-(8-methyl-7-oxo-5,6,7,8-tetrahydro-l,8- naphthyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4-oxobutanoic acid
217 (R)-3-benzyl-4-(methyl(4-(2-(l -methyl- lH-pyrrolo [2,3 -b]pyridin-5- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
218 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- (dimethylamino)pyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4- oxobutanoic acid
219 (R)-4-((4-(2-(5-chloro-6-methoxypyridin-3-yl)phenyl)thiazol-2- yl)(cyclopropyl)amino)-3-(cyclopentylmethyl)-4-oxobutanoic acid 220 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(5-fluoro-6- methoxypyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4-oxobutanoic acid
221 (R)-3-benzyl-4-((4-(2-chloro-5-(difluoromethoxy)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
222 (R)-3-benzyl-4-((4-(5-chloro-2-(5-chloro-6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
223 (R)-4-((4-(5-chloro-2-(5-chloro-6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)(cyclopropyl)amino)-3-(cyclopentylmethyl)-4- oxobutanoic acid
224 (R)-4-((4-(5-chloro-2-(5-fluoro-6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)(cyclopropyl)amino)-3-(cyclopentylmethyl)-4- oxobutanoic acid
225 (S)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
230 3-([l,r-biphenyl]-4-ylmethyl)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
231 (R)-3 -benzyl-4-((4-( 1 -methyl- 1 H-pyrazol-4-yl)thiazol-2-yl)amino)-4- oxobutanoic acid
232 (R)-3-benzyl-4-((4-(4-methyl-l,2,5-oxadiazol-3-yl)thiazol-2- yl)amino)-4-oxobutanoic acid
233 (R)-3-benzyl-4-(methyl(4-(2-(l -methyl- lH-pyrazol-4- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
234 (3R)-3-benzyl-4-((4-(2-(3,5-dimethylisoxazol-4-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
235 (R)-3-benzyl-4-((4-((2-chlorophenyl)carbamoyl)thiazol-2-yl)amino)- 4-oxobutanoic acid
237 (R)-3-benzyl-4-(methyl(4-(2-(2-oxopyrrolidin- 1 -yl)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid
238 (S)-2-((l-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-l-oxo-3- phenylpropan-2-yl)oxy)acetic acid 240 (R)-3-benzyl-4-((4-(2-(l-(2-methoxyethyl)-6-oxo-l,6-dihydropyridin- 3-yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
241 (R)-3-benzyl-4-(methyl(4-(2-(l -methyl-6-oxo- 1 ,6-dihydropyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
242 4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-3-((2,5- dimethyloxazol-4-yl)methyl)-4-oxobutanoic acid
243 4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-3-((l-methyl-lH- pyrazol-5-yl)methyl)-4-oxobutanoic acid
244 (R)-3-benzyl-4-((4-(2-(6-hydroxypyridin-3-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
245 (R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2-yl)((S)-2- hydroxypropyl)amino)-4-oxobutanoic acid
246 (R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2-yl)((R)-2- hydroxypropyl)amino)-4-oxobutanoic acid
247 (R)-3-(cyclohexylmethyl)-4-(cyclopropyl(4-(2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
248 (R)-3-benzyl-4-((4-(5-fluoro-2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
250 (R)-3-benzyl-4-((4-(4,5-difluoro-2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
251 (R)-4-((4-(2,5-dichlorophenyl)thiazol-2-yl)(methyl)amino)-3-(furan- 2-ylmethyl)-4-oxobutanoic acid
252 (R)-4-((4-(2-chloro-5-fluorophenyl)thiazol-2-yl)(methyl)amino)-3- (furan-2-ylmethyl)-4-oxobutanoic acid
253 (R)-3-(furan-2-ylmethyl)-4-((4-(2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
254 (S)-4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3- (thiophen-2-ylmethyl)butano ic acid
255 (R)-4-((4-(5-chloro-2-(6-methoxypyridin-3-yl)phenyl)thiazol-2- yl)(cyclopropyl)amino)-3-(cyclopentylmethyl)-4-oxobutanoic acid 256 (R)-3-benzyl-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin-l-yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
257 (R)-3-benzyl-4-((4-(2,3-dichlorophenyl)thiazol-2-yl)(methyl)amino)- 4-oxobutanoic acid
258 (R)-3-benzyl-4-(methyl(4-(3-(trifluoromethoxy)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid
259 (R)-4-(cyclopropyl(4-(3-(difluoromethoxy)phenyl)thiazol-2- yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
260 (R)-4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-3-(furan-2- ylmethyl)-4-oxobutanoic acid
261 (R)-4-(methyl(4-(3-(trifluoromethoxy)phenyl)thiazol-2-yl)amino)-4- oxo-3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
262 (R)-3-benzyl-4-(cyclopropyl(4-(3-(trifluoromethoxy)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid
263 (R)-4-(cyclopropyl(4-(3-(trifluoromethoxy)phenyl)thiazol-2- yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
264 (R)-3-benzyl-4-((4-(2-(6-isopropoxypyridin-3-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
265 (R)-3-benzyl-4-((4-(2-(6-(cyclopropylmethoxy)pyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
266 (R)-3-benzyl-4-((4-(2-(6-(methoxymethyl)pyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
267 (R)-3-benzyl-4-((4-(2-(6-((dimethylamino)methyl)pyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
268 (R)-3-benzyl-4-(methyl(4-(2-(6-(N- methylcyclopropanecarboxamido)pyridin-3 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
269 (R)-3-benzyl-4-((4-(2-(6-(dimethylcarbamoyl)pyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
270 (R)-4-((4-(2-(6-(4H- 1 ,2,4-triazol-4-yl)pyridin-3-yl)phenyl)thiazol-2- yl)(methyl)amino)-3-benzyl-4-oxobutanoic acid 271 (R)-3-benzyl-4-(methyl(4-(2-(6-(3-methyl-2-oxoimidazolidin- 1 - yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
272 (R)-3-benzyl-4-(methyl(4-(2-(l-methyl-2-oxo-2,3-dihydro-lH- pyrrolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
273 (R)-3-benzyl-4-(methyl(4-(2-(3-methyl-3H-imidazo[4,5-b]pyridin-6- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
274 (R)-3-benzyl-4-((4-(2-(6-(benzyl(methyl)amino)pyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
275 (R)-3-benzyl-4-((4-(2-(6-(cyclohexyl(methyl)amino)pyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
276 (R)-3-benzyl-4-(methyl(4-(2-(6-(4-methylpiperazin- 1 -yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
277 (R)-4-((4-(5-chloro-2-(6-methoxypyridin-3-yl)phenyl)thiazol-2- yl)(cyclopropyl)amino)-3-(cyclopentylmethyl)-4-oxobutanoic acid
278 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(3-fluoro-2-(6- methoxypyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4-oxobutanoic acid
279 (R)-3-benzyl-4-((4-(2-(5-chloro-6-methoxypyridin-3-yl)-3- fluorophenyl)thiazo l-2-yl)(methyl)amino)-4-oxobutanoic acid
280 (R)-3-benzyl-4-((4-(3-fluoro-2-(5-fluoro-6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
281 (R)-3-benzyl-4-((4-(5-chloro-2-(5-fluoro-6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
282 (R)-3-benzyl-4-((4-(3,5-difluoro-2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
283 (R)-4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3-(((S)- tetrahydrofuran-2-yl)methyl)butano ic acid
284 (R)-4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3-(((R)- tetrahydrofuran-2-yl)methyl)butano ic acid
285 (R)-4-((4-(2-chloro-5-(trifluoromethyl)phenyl)thiazol-2- yl)(methyl)amino)-3 -(furan-2-ylmethyl)-4-oxobutano ic acid 286 (R)-4-((4-(2-chloro-5-(trifluoromethoxy)phenyl)thiazol-2- yl)(methyl)amino)-3 -(furan-2-ylmethyl)-4-oxobutano ic acid
287 (R)-4-((4-(2-chloro-5-(difluoromethoxy)phenyl)thiazol-2- yl)(methyl)amino)-3 -(furan-2-ylmethyl)-4-oxobutano ic acid
288 (R)-4-((4-(2-chlorophenyl)thiazol-2-yl)(cyclopropyl)amino)-3-(furan- 2-ylmethyl)-4-oxobutanoic acid
289 (R)-4-((4-(5-chloro-2-(6-methoxypyridin-3-yl)phenyl)thiazol-2- yl)(methyl)amino)-3 -(furan-2-ylmethyl)-4-oxobutano ic acid
290 (R)-4-((4-(2-chloro-5-(6-methoxypyridin-3-yl)phenyl)thiazol-2- yl)(methyl)amino)-3 -(furan-2-ylmethyl)-4-oxobutano ic acid
291 (R)-3-(furan-2-ylmethyl)-4-((4-(2-(6-methoxypyridin-3-yl)-5- (trifluoromethyl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
292 (R)-3-(furan-2-ylmethyl)-4-((4-(2-(6-methoxypyridin-3-yl)-5- (trifluoromethoxy)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
293 (R)-4-((4-(5-(difluoromethoxy)-2-(6-methoxypyridin-3- yl)phenyl)thiazo l-2-yl)(methyl)amino)-3 -(furan-2-ylmethyl)-4- oxobutanoic acid
294 (R)-4-(cyclopropyl(4-(2,5-dichlorophenyl)thiazol-2-yl)amino)-3- (furan-2-ylmethyl)-4-oxobutanoic acid
295 (R)-4-((4-(2-chloro-5-fluorophenyl)thiazol-2-yl)(cyclopropyl)amino)- 3 -(furan-2-ylmethyl)-4-oxobutano ic acid
296 (R)-4-((4-(2-chloro-5-(trifluoromethyl)phenyl)thiazol-2- yl)(cyclopropyl)amino)-3-(furan-2-ylmethyl)-4-oxobutanoic acid
297 (R)-4-((4-(2-chloro-5-(trifluoromethoxy)phenyl)thiazol-2- yl)(cyclopropyl)amino)-3-(furan-2-ylmethyl)-4-oxobutanoic acid
298 (R)-4-((4-(2-chloro-5-(difluoromethoxy)phenyl)thiazol-2- yl)(cyclopropyl)amino)-3-(furan-2-ylmethyl)-4-oxobutanoic acid
299 4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-3-((5-methylfuran- 2-yl)methyl)-4-oxobutanoic acid 4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-3-((4,5- dimethylfuran-2-yl)methyl)-4-oxobutanoic acid
3-(benzofuran-2-ylmethyl)-4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
(R)-4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3- (pyridin-2-ylmethyl)butanoic acid
(R)-4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3- (pyrimidin-2-ylmethyl)butanoic acid
(3R)-4-((4-(2,5-dichlorophenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3-
((tetrahydro-2H-pyran-2-yl)methyl)butanoic acid
(3R)-4-((4-(2,5-dichlorophenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3-
((tetrahydro-2H-pyran-3-yl)methyl)butanoic acid
(R)-4-((4-(2,5 -dichlorophenyl)thiazo l-2-yl)(methyl)amino)-3 -
(((2R,3R)-2-methyltetrahydro-2H-pyran-3-yl)methyl)-4-oxobutanoic acid
(3R)-4-((4-(2,5-dichlorophenyl)thiazol-2-yl)(methyl)amino)-3-(((2R)
2- methyltetrahydro-2H-pyran-4-yl)methyl)-4-oxobutanoic acid (3R)-4-((4-(2,5-dichlorophenyl)thiazol-2-yl)(methyl)amino)-3- (((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)methyl)-4- oxobutanoic acid
(3R)-4-((4-(2,5-dichlorophenyl)thiazol-2-yl)(methyl)amino)-3-(((3S)-
3- methyltetrahydro-2H-pyran-4-yl)methyl)-4-oxobutanoic acid (3R)-4-((4-(2,5-dichlorophenyl)thiazol-2-yl)(methyl)amino)-3- (((3R,5S)-3,5-dimethyltetrahydro-2H-pyran-4-yl)methyl)-4- oxobutanoic acid
(R)-2-benzyl-N-(4-(2-chlorophenyl)thiazol-2-yl)-3-(4-hydroxy-l,2,5- thiadiazo 1-3 -yl)-N-methylpropanamide
(R)-2-benzyl-N-(4-(2-chlorophenyl)thiazol-2-yl)-3-(3-hydroxy-5- methylisoxazol-4-yl)-N-methylpropanamide 313 (R)-4-((4-(5-chloro-2-(6-(2-oxopiperidin- 1 -yl)pyridin-3- yl)phenyl)thiazol-2-yl)(cyclopropyl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
314 (R)-4-((4-(5-chloro-2-(6-(2-oxopiperidin-l-yl)pyridin-3-yl)phenyl)-5- fluorothiazol-2-yl)(cyclopropyl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
315 (R)-4-((4-(5-chloro-2-(6-methoxypyridin-3-yl)phenyl)thiazol-2- yl)(cyclopropyl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
316 (R)-4-((4-(5-chloro-2-(6-methoxypyridin-3-yl)phenyl)-5- fluorothiazol-2-yl)(cyclopropyl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
317 (R)-4-((4-(5-chloro-2-(6-(2-oxopyrrolidin-l-yl)pyridin-3- yl)phenyl)thiazol-2-yl)(cyclopropyl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
318 (R)-4-((4-(5-chloro-2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)- 5-fluorothiazol-2-yl)(cyclopropyl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
319 (R)-4-(cyclopropyl(4-(5-(difluoromethoxy)-2-(6-(2-oxopiperidin- 1 - yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
320 (R)-4-(cyclopropyl(4-(5-(difluoromethoxy)-2-(6-(2-oxopiperidin- 1 - yl)pyridin-3-yl)phenyl)-5-fluorothiazol-2-yl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
321 (R)-4-(cyclopropyl(4-(5-(difluoromethoxy)-2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
322 (R)-4-(cyclopropyl(4-(5-(difluoromethoxy)-2-(6-methoxypyridin-3- yl)phenyl)-5-fluorothiazol-2-yl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid 323 (R)-4-(cyclopropyl(4-(5-(difluoromethoxy)-2-(6-(2-oxopyrrolidin- 1 - yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
324 (R)-4-(cyclopropyl(4-(5-(difluoromethoxy)-2-(6-(2-oxopyrrolidin- 1 - yl)pyridin-3-yl)phenyl)-5-fluorothiazol-2-yl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
325 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopiperidin- 1 -yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
326 (R)-4-(cyclopropyl(5-fluoro-4-(2-(6-(2-oxopiperidin- 1 -yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
327 (R)-4-(cyclopropyl(5-fluoro-4-(2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
328 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin-l-yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
329 (R)-4-(cyclopropyl(5-fluoro-4-(2-(6-(2-oxopyrrolidin-l-yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
330 (R)-4-(cyclopropyl(4-(5-fluoro-2-(6-(2-oxopiperidin-l-yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
331 (R)-4-(cyclopropyl(5-fluoro-4-(5-fluoro-2-(6-(2-oxopiperidin-l- yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
332 (R)-4-(cyclopropyl(4-(5-fluoro-2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid (R)-4-(cyclopropyl(5-fluoro-4-(5-fluoro-2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
(R)-4-(cyclopropyl(4-(5-fluoro-2-(6-(2-oxopyrrolidin-l-yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
(R)-4-(cyclopropyl(5-fluoro-4-(5-fluoro-2-(6-(2-oxopyrrolidin-l- yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
(R)-4-((4-(5-chloro-2-(6-(2-oxopiperidin- 1 -yl)pyridin-3- yl)phenyl)thiazol-2-yl)(cyclopropyl)amino)-3-(cyclopentylmethyl)-4- oxobutanoic acid
(R)-4-((4-(5-chloro-2-(6-(2-oxopiperidin-l-yl)pyridin-3-yl)phenyl)-5- fluorothiazol-2-yl)(cyclopropyl)amino)-3-(cyclopentylmethyl)-4- oxobutanoic acid
(R)-4-((4-(5-chloro-2-(6-methoxypyridin-3-yl)phenyl)-5- fluorothiazol-2-yl)(cyclopropyl)amino)-3-(cyclopentylmethyl)-4- oxobutanoic acid
(R)-4-((4-(5-chloro-2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3- yl)phenyl)thiazol-2-yl)(cyclopropyl)amino)-3-(cyclopentylmethyl)-4- oxobutanoic acid
(R)-4-((4-(5-chloro-2-(6-(2-oxopyrrolidin-l-yl)pyridin-3-yl)phenyl)- 5 -fluorothiazo l-2-yl)(cyclopropyl)amino)-3 -(cyclopentylmethyl)-4- oxobutanoic acid
(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5-(difluoromethoxy)-2- (6-(2-oxopiperidin-l-yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5-(difluoromethoxy)-2- (6-(2-oxopiperidin- 1 -yl)pyridin-3-yl)phenyl)-5-fluorothiazol-2- yl)amino)-4-oxobutanoic acid 343 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5-(difluoromethoxy)-2- (6-methoxypyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
344 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5-(difluoromethoxy)-2- (6-methoxypyridin-3 -yl)phenyl)-5 -fluorothiazo l-2-yl)amino)-4- oxobutanoic acid
345 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5-(difluoromethoxy)-2- (6-(2-oxopyrrolidin-l-yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
346 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5-(difluoromethoxy)-2- (6-(2-oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)-5-fluorothiazol-2- yl)amino)-4-oxobutanoic acid
347 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(2-oxopiperidin- 1 - yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
348 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro-4-(2-(6-(2- oxopiperidin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
349 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro-4-(2-(6- methoxypyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4-oxobutanoic acid
350 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro-4-(2-(6-(2- oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
351 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5-fluoro-2-(6-(2- oxopiperidin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
352 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro-4-(5-fluoro-2-(6- (2-oxopiperidin-l-yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
353 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5-fluoro-2-(6- methoxypyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4-oxobutanoic acid 354 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro-4-(5-fluoro-2-(6- methoxypyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4-oxobutanoic acid
355 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5-fluoro-2-(6-(2- oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
356 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro-4-(5-fluoro-2-(6- (2-oxopyrrolidin- 1 -yl)pyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4- oxobutanoic acid
357 (R)-3-benzyl-4-((4-(5-chloro-2-(6-(2-oxopiperidin-l-yl)pyridin-3- yl)phenyl)thiazol-2-yl)(cyclopropyl)amino)-4-oxobutanoic acid
358 (R)-3-benzyl-4-((4-(5-chloro-2-(6-(2-oxopiperidin-l-yl)pyridin-3- yl)phenyl)-5-fluorothiazol-2-yl)(cyclopropyl)amino)-4-oxobutanoic acid
359 (R)-3-benzyl-4-((4-(5-chloro-2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)(cyclopropyl)amino)-4-oxobutanoic acid
360 (R)-3-benzyl-4-((4-(5-chloro-2-(6-methoxypyridin-3-yl)phenyl)-5- fluorothiazol-2-yl)(cyclopropyl)amino)-4-oxobutanoic acid
361 (R)-3-benzyl-4-((4-(5-chloro-2-(6-(2-oxopyrrolidin-l-yl)pyridin-3- yl)phenyl)thiazol-2-yl)(cyclopropyl)amino)-4-oxobutanoic acid
362 (R)-3-benzyl-4-((4-(5-chloro-2-(6-(2-oxopyrrolidin-l-yl)pyridin-3- yl)phenyl)-5-fluorothiazol-2-yl)(cyclopropyl)amino)-4-oxobutanoic acid
363 (R)-3-benzyl-4-(cyclopropyl(4-(5-(difluoromethoxy)-2-(6-(2- oxopiperidin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
364 (R)-3-benzyl-4-(cyclopropyl(4-(5-(difluoromethoxy)-2-(6-(2- oxopiperidin-l-yl)pyridin-3-yl)phenyl)-5-fluorothiazol-2-yl)amino)-4- oxobutanoic acid
365 (R)-3-benzyl-4-(cyclopropyl(4-(5-(difluoromethoxy)-2-(6- methoxypyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4-oxobutanoic acid (R)-3-benzyl-4-(cyclopropyl(4-(5-(difluoromethoxy)-2-(6- methoxypyridin-3-yl)phenyl)-5-fluorothiazol-2-yl)amino)-4- oxobutanoic acid
(R)-3-benzyl-4-(cyclopropyl(4-(5-(difluoromethoxy)-2-(6-(2- oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
(R)-3-benzyl-4-(cyclopropyl(4-(5-(difluoromethoxy)-2-(6-(2- oxopyrrolidin- 1 -yl)pyridin-3 -yl)phenyl)-5 -fluorothiazo l-2-yl)amino)- 4-oxobutanoic acid
(R)-3-benzyl-4-(cyclopropyl(4-(2-(6-(2-oxopiperidin-l-yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
(R)-3-benzyl-4-(cyclopropyl(5-fluoro-4-(2-(6-(2-oxopiperidin-l- yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid (R)-3-benzyl-4-(cyclopropyl(5-fluoro-4-(2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
(R)-3-benzyl-4-(cyclopropyl(5-fluoro-4-(2-(6-(2-oxopyrrolidin-l- yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid (R)-3-benzyl-4-(cyclopropyl(4-(5-fluoro-2-(6-(2-oxopiperidin-l- yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid (R)-3-benzyl-4-(cyclopropyl(5-fluoro-4-(5-fluoro-2-(6-(2- oxopiperidin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
(R)-3-benzyl-4-(cyclopropyl(4-(5-fluoro-2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
(R)-3-benzyl-4-(cyclopropyl(5-fluoro-4-(5-fluoro-2-(6- methoxypyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4-oxobutanoic acid (R)-3-benzyl-4-(cyclopropyl(4-(5-fluoro-2-(6-(2-oxopyrrolidin-l- yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid (R)-3-benzyl-4-(cyclopropyl(5-fluoro-4-(5-fluoro-2-(6-(2- oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid 379 (R)-4-((4-(5-chloro-2-(6-(2-oxopiperidin-l-yl)pyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
380 (R)-4-((4-(5-chloro-2-(6-(2-oxopiperidin-l-yl)pyridin-3-yl)phenyl)-5- fluorothiazol-2-yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
381 (R)-4-((4-(5-chloro-2-(6-methoxypyridin-3-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
382 (R)-4-((4-(5-chloro-2-(6-methoxypyridin-3-yl)phenyl)-5- fluorothiazol-2-yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
383 (R)-4-((4-(5-chloro-2-(6-(2-oxopyrrolidin-l-yl)pyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
384 (R)-4-((4-(5-chloro-2-(6-(2-oxopyrrolidin-l-yl)pyridin-3-yl)phenyl)- 5 -nuorothiazo l-2-yl)(methyl)amino)-4-oxo-3 -((tetrahydro-2H-pyran- 4-yl)methyl)butanoic acid
385 (R)-4-((4-(5-(difluoromethoxy)-2-(6-(2-oxopiperidin-l-yl)pyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
386 (R)-4-((4-(5-(difluoromethoxy)-2-(6-(2-oxopiperidin-l-yl)pyridin-3- yl)phenyl)-5-fluorothiazol-2-yl)(methyl)amino)-4-oxo-3-((tetrahydro- 2H-pyran-4-yl)methyl)butano ic acid
387 (R)-4-((4-(5-(difluoromethoxy)-2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
388 (R)-4-((4-(5-(difluoromethoxy)-2-(6-methoxypyridin-3-yl)phenyl)-5- fluorothiazol-2-yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid 389 (R)-4-((4-(5-(difluoromethoxy)-2-(6-(2-oxopyrrolidin-l-yl)pyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
390 (R)-4-((4-(5-(difluoromethoxy)-2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3- yl)phenyl)-5-fluorothiazol-2-yl)(methyl)amino)-4-oxo-3-((tetrahydro- 2H-pyran-4-yl)methyl)butano ic acid
391 (R)-4-(methyl(4-(2-(6-(2-oxopiperidin- 1 -yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
392 (R)-4-((5-fluoro-4-(2-(6-(2-oxopiperidin-l-yl)pyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
393 (R)-4-((5-fluoro-4-(2-(6-methoxypyridin-3-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
394 (R)-4-(methyl(4-(2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
395 (R)-4-((5-fluoro-4-(2-(6-(2-oxopyrrolidin-l-yl)pyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
396 (R)-4-((4-(5-fluoro-2-(6-(2-oxopiperidin-l-yl)pyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
397 (R)-4-((5-fluoro-4-(5-fluoro-2-(6-(2-oxopiperidin-l-yl)pyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
398 (R)-4-((4-(5-fluoro-2-(6-methoxypyridin-3-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid (R)-4-((5 -fluoro-4-(5 -fluoro-2-(6-methoxypyridin-3 -yl)phenyl)thiazo 1- 2-yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
(R)-4-((4-(5-fluoro-2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
(R)-4-((5-fluoro-4-(5-fluoro-2-(6-(2-oxopyrrolidin-l-yl)pyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
(R)-4-((4-(5-chloro-2-(6-(2-oxopiperidin- 1 -yl)pyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-3-(cyclopentylmethyl)-4- oxobutanoic acid
(R)-4-((4-(5-chloro-2-(6-(2-oxopiperidin-l-yl)pyridin-3-yl)phenyl)-5- fluorothiazo l-2-yl)(methyl)amino)-3 -(cyclopentylmethyl)-4- oxobutanoic acid
(R)-4-((4-(5-chloro-2-(6-methoxypyridin-3-yl)phenyl)thiazol-2- yl)(methyl)amino)-3-(cyclopentylmethyl)-4-oxobutanoic acid
(R)-4-((4-(5-chloro-2-(6-methoxypyridin-3-yl)phenyl)-5- fluorothiazo l-2-yl)(methyl)amino)-3 -(cyclopentylmethyl)-4- oxobutanoic acid
(R)-4-((4-(5-chloro-2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-3-(cyclopentylmethyl)-4- oxobutanoic acid
(R)-4-((4-(5-chloro-2-(6-(2-oxopyrrolidin-l-yl)pyridin-3-yl)phenyl)- 5 -fluorothiazo l-2-yl)(methyl)amino)-3 -(cyclopentylmethyl)-4- oxobutanoic acid
(R)-3-(cyclopentylmethyl)-4-((4-(5-(difluoromethoxy)-2-(6-(2- oxopiperidin- 1 -yl)pyridin-3 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-4- oxobutanoic acid (R)-3-(cyclopentylmethyl)-4-((4-(5-(difluoromethoxy)-2-(6-(2- oxopiperidin- 1 -yl)pyridin-3-yl)phenyl)-5-fluorothiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
(R)-3-(cyclopentylmethyl)-4-((4-(5-(difluoromethoxy)-2-(6- methoxypyridin-3 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-4- oxobutanoic acid
(R)-3-(cyclopentylmethyl)-4-((4-(5-(difluoromethoxy)-2-(6- methoxypyridin-3-yl)phenyl)-5-fluorothiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
(R)-3-(cyclopentylmethyl)-4-((4-(5-(difluoromethoxy)-2-(6-(2- oxopyrrolidin- 1 -yl)pyridin-3 -yl)phenyl)thiazo l-2-yl)(methyl)amino)- 4-oxobutanoic acid
(R)-3-(cyclopentylmethyl)-4-((4-(5-(difluoromethoxy)-2-(6-(2- oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)-5-fluorothiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
(R)-3-(cyclopentylmethyl)-4-(methyl(4-(2-(6-(2-oxopiperidin-l- yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid (R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(2-(6-(2-oxopiperidin-l- yl)pyridin-3-yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
(R)-3 -(cyclopentylmethyl)-4-((4-(2-(6-methoxypyridin-3 - yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
(R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
(R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(2-(6-(2-oxopyrrolidin-l- yl)pyridin-3-yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
(R)-3-(cyclopentylmethyl)-4-((4-(5-fluoro-2-(6-(2-oxopiperidin-l- yl)pyridin-3-yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid 420 (R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(5-fluoro-2-(6-(2- oxopiperidin- 1 -yl)pyridin-3 -yl)phenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
421 (R)-3-(cyclopentylmethyl)-4-((4-(5-fluoro-2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
422 (R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(5-fluoro-2-(6- methoxypyridin-3 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-4- oxobutanoic acid
423 (R)-3-(cyclopentylmethyl)-4-((4-(5-fluoro-2-(6-(2-oxopyrrolidin- 1 - yl)pyridin-3-yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
424 (R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(5-flucMO-2-(6-(2- oxopyrrolidin- 1 -yl)pyridin-3 -yl)phenyl)thiazo l-2-yl)(methyl)amino)- 4-oxobutanoic acid
425 (R)-3-benzyl-4-((4-(5-chloro-2-(6-(2-oxopiperidin-l-yl)pyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
426 (R)-3-benzyl-4-((4-(5-chloro-2-(6-(2-oxopiperidin-l-yl)pyridin-3- yl)phenyl)-5-fluorothiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
427 (R)-3-benzyl-4-((4-(5-chloro-2-(6-methoxypyridin-3-yl)phenyl)-5- fluorothiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
428 (R)-3-benzyl-4-((4-(5-chloro-2-(6-(2-oxopyrrolidin-l-yl)pyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
429 (R)-3-benzyl-4-((4-(5-chloro-2-(6-(2-oxopyrrolidin-l-yl)pyridin-3- yl)phenyl)-5-fluorothiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
430 (R)-3-benzyl-4-((4-(5-(difluoromethoxy)-2-(6-(2-oxopiperidin-l- yl)pyridin-3-yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
431 (R)-3-benzyl-4-((4-(5-(difluoromethoxy)-2-(6-(2-oxopiperidin- 1 - yl)pyridin-3 -yl)phenyl)-5 -fluorothiazo l-2-yl)(methyl)amino)-4- oxobutanoic acid 432 (R)-3-benzyl-4-((4-(5-(difluoromethoxy)-2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
433 (R)-3-benzyl-4-((4-(5-(difluoromethoxy)-2-(6-methoxypyridin-3- yl)phenyl)-5-fluorothiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
434 (R)-3-benzyl-4-((4-(5-(difluoromethoxy)-2-(6-(2-oxopyrrolidin-l- yl)pyridin-3-yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
435 (R)-3-benzyl-4-((4-(5-(difluoromethoxy)-2-(6-(2-oxopyrrolidin-l- yl)pyridin-3 -yl)phenyl)-5 -fluorothiazo l-2-yl)(methyl)amino)-4- oxobutanoic acid
436 (R)-3-benzyl-4-(methyl(4-(2-(6-(2-oxopiperidin- 1 -yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
437 (R)-3-benzyl-4-((5-fluoro-4-(2-(6-(2-oxopiperidin-l-yl)pyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
438 (R)-3-benzyl-4-((5-fluoro-4-(2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
439 (R)-3 -benzyl-4-((5 -fluoro-4-(2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3 - yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
440 (R)-3-benzyl-4-((4-(5-fluoro-2-(6-(2-oxopiperidin-l-yl)pyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
441 (R)-3-benzyl-4-((5-fluoro-4-(5-fluoro-2-(6-(2-oxopiperidin-l- yl)pyridin-3-yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
442 (R)-3-benzyl-4-((5-fluoro-4-(5-fluoro-2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
443 (R)-3-benzyl-4-((4-(5-fluoro-2-(6-(2-oxopyrrolidin-l-yl)pyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
444 (R)-3-benzyl-4-((5-fluoro-4-(5-fluoro-2-(6-(2-oxopyrrolidin-l- yl)pyridin-3-yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid (R)-3-(cyclopentylmethyl)-4-((4-(5-fluoro-2-(8-methyl-7-oxo-5,6,7,8- tetrahydro- 1 , 8-naphthyridin-3 -yl)phenyl)thiazo l-2-yl)(methyl)amino)- 4-oxobutanoic acid
(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5-fluoro-2-(8-methyl-7- oxo-5,6,7,8 -tetrahydro -1,8 -naphthyridin-3 -y l)pheny l)thiazo 1-2- yl)amino)-4-oxobutanoic acid
(R)-4-((4-(5-fluoro-2-(8-methyl-7-oxo-5,6,7,8-tetrahydro-l,8- naphthyridin-3-yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
(R)-4-(cyclopropyl(4-(5-fluoro-2-(8-methyl-7-oxo-5,6,7,8-tetrahydro- 1 , 8-naphthyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4-oxo-3 - ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
(R)-3-benzyl-4-((4-(5-fluoro-2-(8-methyl-7-oxo-5,6,7,8-tetrahydro- 1 , 8-naphthyridin-3 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-4- oxobutanoic acid
(R)-3-benzyl-4-(cyclopropyl(4-(5-fluoro-2-(8-methyl-7-oxo-5,6,7,8- tetrahydro- 1 , 8-naphthyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4- oxobutanoic acid
(R)-3-(cyclopentylmethyl)-4-((4-(5-fluoro-2-(l-methyl-2-oxo-2,3- dihydro-lH-pyrrolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5-fluoro-2-(l-methyl-2- oxo-2,3 -dihydro- 1 H-pyrrolo [2,3 -b]pyridin-5 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
(R)-4-((4-(5-fluoro-2-(l-methyl-2-oxo-2,3-dihydro-lH-pyrrolo[2,3- b]pyridin-5-yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
(R)-4-(cyclopropyl(4-(5-fluoro-2-(l-methyl-2-oxo-2,3-dihydro-lH- pyrrolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid (R)-3-benzyl-4-((4-(5-fluoro-2-(l-methyl-2-oxo-2,3-dihydro-lH- pyrTolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
(R)-3-benzyl-4-(cyclopropyl(4-(5-fluoro-2-(l-methyl-2-oxo-2,3- dihydro-lH-pyrrolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
(R)-3-(cyclopentylmethyl)-4-((4-(5-fluoro-2-(4-methyl-3,4-dihydro- 2H-pyrido [3 ,2-b] [ 1 ,4]oxazin-7-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5-fluoro-2-(4-methyl- 3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-7-yl)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid
(R)-4-((4-(5-fluoro-2-(4-methyl-3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazin-7-yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
(R)-4-(cyclopropyl(4-(5-fluoro-2-(4-methyl-3,4-dihydro-2H- pyrido[3,2-b][l,4]oxazin-7-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
(R)-3-benzyl-4-((4-(5-fluoro-2-(4-methyl-3,4-dihydro-2H-pyrido[3,2- b] [ 1 ,4] oxazin-7-yl)phenyl)thiazo l-2-yl)(methyl)amino)-4-oxobutanoic acid
(R)-3-benzyl-4-(cyclopropyl(4-(5-fluoro-2-(4-methyl-3,4-dihydro-2H- pyrido[3,2-b][l,4]oxazin-7-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
(R)-3-(cyclopentylmethyl)-4-((4-(5-fluoro-2-(l -methyl- 1 H- pyrTolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5-fluoro-2-(l-methyl- lH-pyrrolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid 465 (R)-4-((4-(5-fluoro-2-(l-methyl-lH-pyrrolo[2,3-b]pyridin-5- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
466 (R)-4-(cyclopropyl(4-(5-fluoro-2-(l-methyl-lH-pyrrolo[2,3-b]pyridin- 5-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
467 (R)-3-benzyl-4-((4-(5-fluoro-2-(l-methyl-lH-pyrrolo[2,3-b]pyridin-5- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
468 (R)-3-benzyl-4-(cyclopropyl(4-(5-fluoro-2-(l-methyl-lH-pyrrolo[2,3- b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
469 (R)-3-(cyclopentylmethyl)-4-((4-(5-(fluoromethoxy)-2-(8-methyl-7- oxo-5,6,7,8 -tetrahydro -1,8 -naphthyridin-3 -y l)pheny l)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
470 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5-(fluoromethoxy)-2-(8- methyl-7-oxo-5,6,7,8-tetrahydro-l,8-naphthyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
471 (R)-4-((4-(5-(fluoromethoxy)-2-(8-methyl-7-oxo-5,6,7,8-tetrahydro- l,8-naphthyridin-3-yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
472 (R)-4-(cyclopropyl(4-(5-(fluoromethoxy)-2-(8-methyl-7-oxo-5,6,7,8- tetrahydro- 1 , 8-naphthyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4-oxo-3 - ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
473 (R)-3-benzyl-4-((4-(5-(fluoromethoxy)-2-(8-methyl-7-oxo-5,6,7,8- tetrahydro- 1 , 8-naphthyridin-3 -yl)phenyl)thiazo l-2-yl)(methyl)amino)- 4-oxobutanoic acid
474 (R)-3-benzyl-4-(cyclopropyl(4-(5-(fluoromethoxy)-2-(8-methyl-7- oxo-5,6,7,8 -tetrahydro -1,8 -naphthyridin-3 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
475 (R)-3-(cyclopentylmethyl)-4-((4-(5-(fluoromethoxy)-2-(l-methyl-2- oxo-2,3 -dihydro- 1 H-pyrrolo [2,3 -b]pyridin-5 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid 476 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5-(fluoromethoxy)-2-(l- methyl-2-oxo-2,3-dihydro-lH-pyrrolo[2,3-b]pyridin-5- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
477 (R)-4-((4-(5-(fluoromethoxy)-2-(l-methyl-2-oxo-2,3-dihydro-lH- pyrTolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo- 3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
478 (R)-4-(cyclopropyl(4-(5-(fluoromethoxy)-2-(l-methyl-2-oxo-2,3- dihydro-lH-pyrrolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4- oxo-3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
479 (R)-3-benzyl-4-((4-(5-(fluoromethoxy)-2-(l-methyl-2-oxo-2,3- dihydro-lH-pyrrolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
480 (R)-3-benzyl-4-(cyclopropyl(4-(5-(fluoromethoxy)-2-(l-methyl-2- oxo-2,3 -dihydro- 1 H-pyrrolo [2,3 -b]pyridin-5 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
481 (R)-3-(cyclopentylmethyl)-4-((4-(5-(fluoromethoxy)-2-(4-methyl-3,4- dihydro-2H-pyrido[3,2-b][l,4]oxazin-7-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
482 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5-(fluoromethoxy)-2-(4- methyl-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-7-yl)phenyl)thiazol-
2- yl)amino)-4-oxobutanoic acid
483 (R)-4-((4-(5-(fluoromethoxy)-2-(4-methyl-3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazin-7-yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
484 (R)-4-(cyclopropyl(4-(5-(fluoromethoxy)-2-(4-methyl-3,4-dihydro- 2H-pyrido [3 ,2-b] [ 1 ,4]oxazin-7-yl)phenyl)thiazol-2-yl)amino)-4-oxo-
3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
485 (R)-3-benzyl-4-((4-(5-(fluoromethoxy)-2-(4-methyl-3,4-dihydro-2H- pyrido [3 ,2-b] [ 1 ,4] oxazin-7-yl)phenyl)thiazo l-2-yl)(methyl)amino)-4- oxobutanoic acid 486 (R)-3-benzyl-4-(cyclopropyl(4-(5-(fluoromethoxy)-2-(4-methyl-3,4- dihydro-2H-pyrido[3,2-b][l,4]oxazin-7-yl)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid
487 (R)-3-(cyclopentylmethyl)-4-((4-(5-(fluoromethoxy)-2-(l -methyl- 1 H- pyrrolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
488 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5-(fluoromethoxy)-2-(l- methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
489 (R)-4-((4-(5-(fluoromethoxy)-2-(l-methyl-lH-pyrrolo[2,3-b]pyridin- 5 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-4-oxo-3 -((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
490 (R)-4-(cyclopropyl(4-(5 -(fluoromethoxy)-2-( 1 -methyl- 1 H- pyrrolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
491 (R)-3-benzyl-4-((4-(5-(fluoromethoxy)-2-(l-methyl-lH-pyrrolo[2,3- b]pyridin-5-yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
492 (R)-3-benzyl-4-(cyclopropyl(4-(5-(fluoromethoxy)-2-(l-methyl-lH- pyrrolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
493 (R)-4-((4-(5-chloro-2-(8-methyl-7-oxo-5,6,7,8-tetrahydro-l,8- naphthyridin-3 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-3 - (cyclopentylmethyl)-4-oxobutano ic acid
494 (R)-4-((4-(5-chloro-2-(8-methyl-7-oxo-5,6,7,8-tetrahydro-l,8- naphthyridin-3 -yl)phenyl)thiazo l-2-yl)(cyclopropyl)amino)-3 - (cyclopentylmethyl)-4-oxobutano ic acid
495 (R)-4-((4-(5-chloro-2-(8-methyl-7-oxo-5,6,7,8-tetrahydro-l,8- naphthyridin-3-yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid (R)-4-((4-(5-chloro-2-(8-methyl-7-oxo-5,6,7,8-tetrahydro-l,8- naphthyridin-3-yl)phenyl)thiazol-2-yl)(cyclopropyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
(R)-3-benzyl-4-((4-(5-chloro-2-(8-methyl-7-oxo-5,6,7,8-tetrahydro- l,8-naphthyridin-3-yl)phenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
(R)-3-benzyl-4-((4-(5-chloro-2-(8-methyl-7-oxo-5,6,7,8-tetrahydro- 1 , 8-naphthyridin-3 -yl)phenyl)thiazo l-2-yl)(cyclopropyl)amino)-4- oxobutanoic acid
(R)-4-((4-(5-chloro-2-(l-methyl-2-oxo-2,3-dihydro-lH-pyrrolo[2,3- b]pyridin-5 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-3 - (cyclopentylmethyl)-4-oxobutano ic acid
(R)-4-((4-(5-chloro-2-(l-methyl-2-oxo-2,3-dihydro-lH-pyrrolo[2,3- b]pyridin-5 -yl)phenyl)thiazo l-2-yl)(cyclopropyl)amino)-3 - (cyclopentylmethyl)-4-oxobutano ic acid
(R)-4-((4-(5-chloro-2-(l-methyl-2-oxo-2,3-dihydro-lH-pyrrolo[2,3- b]pyridin-5 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-4-oxo-3 - ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
(R)-4-((4-(5-chloro-2-(l-methyl-2-oxo-2,3-dihydro-lH-pyrrolo[2,3- b]pyridin-5-yl)phenyl)thiazol-2-yl)(cyclopropyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
(R)-3-benzyl-4-((4-(5-chloro-2-(l-methyl-2-oxo-2,3-dihydro-lH- pyrTolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
(R)-3-benzyl-4-((4-(5-chloro-2-(l-methyl-2-oxo-2,3-dihydro-lH- pyrrolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2-yl)(cyclopropyl)amino)- 4-oxobutanoic acid
(R)-4-((4-(5-chloro-2-(4-methyl-3,4-dihydro-2H-pyrido[3,2- b] [ 1 ,4] oxazin-7-yl)phenyl)thiazo l-2-yl)(methyl)amino)-3 - (cyclopentylmethyl)-4-oxobutano ic acid (R)-4-((4-(5-chloro-2-(4-methyl-3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazin-7-yl)phenyl)thiazol-2-yl)(cyclopropyl)amino)-3-
(cyclopentylmethyl)-4-oxobutano ic acid
(R)-4-((4-(5-chloro-2-(4-methyl-3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazin-7-yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3-
((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
(R)-4-((4-(5-chloro-2-(4-methyl-3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazin-7-yl)phenyl)thiazol-2-yl)(cyclopropyl)amino)-4-oxo-3-
((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
(R)-3-benzyl-4-((4-(5-chloro-2-(4-methyl-3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazin-7-yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
(R)-3-benzyl-4-((4-(5-chloro-2-(4-methyl-3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazin-7-yl)phenyl)thiazol-2-yl)(cyclopropyl)amino)-4- oxobutanoic acid
(R)-4-((4-(5-chloro-2-(l-methyl-lH-pyrrolo[2,3-b]pyridin-5- yl)phenyl)thiazol-2-yl)(methyl)amino)-3-(cyclopentylmethyl)-4- oxobutanoic acid
(R)-4-((4-(5-chloro-2-(l-methyl-lH-pyrrolo[2,3-b]pyridin-5- yl)phenyl)thiazol-2-yl)(cyclopropyl)amino)-3-(cyclopentylmethyl)-4- oxobutanoic acid
(R)-4-((4-(5-chloro-2-(l-methyl-lH-pyrrolo[2,3-b]pyridin-5- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
(R)-4-((4-(5-chloro-2-(l-methyl-lH-pyrrolo[2,3-b]pyridin-5- yl)phenyl)thiazol-2-yl)(cyclopropyl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
(R)-3 -benzyl-4-((4-(5 -chloro-2-( 1 -methyl- 1 H-pyrrolo [2 ,3 -b]pyridin-5 - yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
(R)-3 -benzyl-4-((4-(5 -chloro-2-( 1 -methyl- 1 H-pyrrolo [2 ,3 -b]pyridin-5 - yl)phenyl)thiazol-2-yl)(cyclopropyl)amino)-4-oxobutanoic acid (R)-3-(cyclopentylmethyl)-4-(methyl(4-(2-(8-methyl-7-oxo-5,6,7,8- tetrahydro- 1 , 8-naphthyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4- oxobutanoic acid
(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(8-methyl-7-oxo- 5,6,7,8-tetrahydro-l,8-naphthyridin-3-yl)phenyl)thiazol-2-yl)amino)- 4-oxobutanoic acid
(R)-4-(methyl(4-(2-(8-methyl-7-oxo-5,6,7,8-tetrahydro-l,8- naphthyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro- 2H-pyran-4-yl)methyl)butano ic acid
(R)-4-(cyclopropyl(4-(2-(8-methyl-7-oxo-5,6,7,8-tetrahydro-l,8- naphthyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro- 2H-pyran-4-yl)methyl)butano ic acid
(R)-3-benzyl-4-(cyclopropyl(4-(2-(8-methyl-7-oxo-5,6,7,8-tetrahydro 1 , 8-naphthyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4-oxobutanoic acid (R)-3-(cyclopentylmethyl)-4-(methyl(4-(2-(l-methyl-2-oxo-2,3- dihydro-lH-pyrrolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(l-methyl-2-oxo-2,3- dihydro-lH-pyrrolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
(R)-4-(methyl(4-(2-(l-methyl-2-oxo-2,3-dihydro-lH-pyrrolo[2,3- b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
(R)-4-(cyclopropyl(4-(2-(l-methyl-2-oxo-2,3-dihydro-lH-pyrrolo[2,3 b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
(R)-3-benzyl-4-(cyclopropyl(4-(2-(l-methyl-2-oxo-2,3-dihydro-lH- pyrrolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid (R)-3-(cyclopentylmethyl)-4-(methyl(4-(2-(4-methyl-3,4-dihydro-2H- pyrido[3,2-b][l,4]oxazin-7-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
(R)-4-(methyl(4-(2-(4-methyl-3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazin-7-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro- 2H-pyran-4-yl)methyl)butano ic acid
(R)-4-(cyclopropyl(4-(2-(4-methyl-3 ,4-dihydro-2H-pyrido [3,2- b][l,4]oxazin-7-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro- 2H-pyran-4-yl)methyl)butano ic acid
(R)-3-benzyl-4-(cyclopropyl(4-(2-(4-methyl-3,4-dihydro-2H- pyrido[3,2-b][l,4]oxazin-7-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
(R)-3-(cyclopentylmethyl)-4-(methyl(4-(2-(l-methyl-lH-pyrrolo[2,3- b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-( 1 -methyl- 1 H- pyrrolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
(R)-4-(methyl(4-(2-(l-methyl-lH-pyrrolo[2,3-b]pyridin-5- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
(R)-4-(cyclopropyl(4-(2-(l-methyl-lH-pyrrolo[2,3-b]pyridin-5- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
(R)-3-benzyl-4-(cyclopropyl(4-(2-(l-methyl-lH-pyrrolo[2,3- b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid (R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(5-fluoro-2-(8-methyl-7- oxo-5,6,7,8 -tetrahy dro -1,8 -naphthyridin-3 -y l)pheny l)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro-4-(5-fluoro-2-(8- methyl-7-oxo-5,6,7,8-tetrahydro-l,8-naphthyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid 538 (R)-4-((5-fluoro-4-(5-fluoro-2-(8-methyl-7-oxo-5,6,7,8-tetrahydro- l,8-naphthyridin-3-yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
539 (R)-4-(cyclopropyl(5-fluoro-4-(5-fluoro-2-(8-methyl-7-oxo-5,6,7,8- tetrahydro- 1 , 8-naphthyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4-oxo-3 - ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
540 (R)-3-benzyl-4-((5-fluoro-4-(5-fluoro-2-(8-methyl-7-oxo-5,6,7,8- tetrahydro- 1 , 8-naphthyridin-3 -yl)phenyl)thiazo l-2-yl)(methyl)amino)- 4-oxobutanoic acid
541 (R)-3-benzyl-4-(cyclopropyl(5-fluoro-4-(5-fluoro-2-(8-methyl-7-oxo- 5,6,7,8-tetrahydro-l,8-naphthyridin-3-yl)phenyl)thiazol-2-yl)amino)- 4-oxobutanoic acid
542 (R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(5-fluoro-2-(l-methyl-2- oxo-2,3 -dihydro- 1 H-pyrrolo [2,3 -b]pyridin-5 -yl)phenyl)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
543 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro-4-(5-fluoro-2-(l- methyl-2-oxo-2,3-dihydro-lH-pyrrolo[2,3-b]pyridin-5- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
544 (R)-4-((5-fluoro-4-(5-fluoro-2-(l-methyl-2-oxo-2,3-dihydro-lH- pyrTolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo- 3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
545 (R)-4-(cyclopropyl(5-fluoro-4-(5-fluoro-2-(l-methyl-2-oxo-2,3- dihydro-lH-pyrrolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4- oxo-3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
546 (R)-3-benzyl-4-((5-fluoro-4-(5-fluoro-2-(l-methyl-2-oxo-2,3-dihydro- lH-pyrTolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
547 (R)-3-benzyl-4-(cyclopropyl(5-fluoro-4-(5-fluoro-2-(l-methyl-2-oxo- 2,3-dihydro-lH-pyrrolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid (R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(5-fluoro-2-(4-methyl-3,4- dihydro-2H-pyrido[3,2-b][l,4]oxazin-7-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro-4-(5-fluoro-2-(4- methyl-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-7-yl)phenyl)thiazol 2-yl)amino)-4-oxobutanoic acid
(R)-4-((5-fluoro-4-(5-fluoro-2-(4-methyl-3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazin-7-yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
(R)-4-(cyclopropyl(5-fluoro-4-(5-fluoro-2-(4-methyl-3,4-dihydro-2H pyrido[3,2-b][l,4]oxazin-7-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
(R)-3-benzyl-4-((5-fluoro-4-(5-fluoro-2-(4-methyl-3,4-dihydro-2H- pyrido [3 ,2-b] [ 1 ,4] oxazin-7-yl)phenyl)thiazo l-2-yl)(methyl)amino)-4- oxobutanoic acid
(R)-3-benzyl-4-(cyclopropyl(5-fluoro-4-(5-fluoro-2-(4-methyl-3,4- dihydro-2H-pyrido[3,2-b][l,4]oxazin-7-yl)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid
(R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(5-fluoro-2-(l-methyl-lH- pyrTolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro-4-(5-fluoro-2-(l- methyl-lH-pyrTolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
(R)-4-((5-fluoro-4-(5-fluoro-2-(l-methyl-lH-pyrrolo[2,3-b]pyridin-5- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
(R)-4-(cyclopropyl(5-fluoro-4-(5-fluoro-2-(l-methyl-lH-pyrrolo[2,3- b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid 558 (R)-3-benzyl-4-((5-fluoro-4-(5-fluoro-2-(l-methyl-lH-pyrrolo[2,3- b]pyridin-5-yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
559 (R)-3 -benzyl-4-(cy clopropyl(5 - fluoro-4-(5 - fluoro-2-( 1 -methyl- 1 H- pyrrolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
560 (R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(5-(fluoromethoxy)-2-(8- methyl-7-oxo-5,6,7,8-tetrahydro-l,8-naphthyridin-3- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
561 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro-4-(5- (fluoromethoxy)-2-(8-methyl-7-oxo-5,6,7,8-tetrahydro-l,8- naphthyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4-oxobutanoic acid
562 (R)-4-((5-fluoro-4-(5-(fluoromethoxy)-2-(8-methyl-7-oxo-5,6,7,8- tetrahydro- 1 , 8-naphthyridin-3 -yl)phenyl)thiazo l-2-yl)(methyl)amino)- 4-oxo-3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
563 (R)-4-(cyclopropyl(5-fluoro-4-(5-(fluoromethoxy)-2-(8-methyl-7-oxo- 5,6,7,8-tetrahydro-l,8-naphthyridin-3-yl)phenyl)thiazol-2-yl)amino)- 4-oxo-3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
564 (R)-3-benzyl-4-((5-fluoro-4-(5-(fluoromethoxy)-2-(8-methyl-7-oxo- 5,6,7,8 -tetrahydro - 1 , 8-naphthyridin-3 -y l)pheny l)thiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
565 (R)-3-benzyl-4-(cyclopropyl(5-fluoro-4-(5-(fluoromethoxy)-2-(8- methyl-7-oxo-5,6,7,8-tetrahydro-l,8-naphthyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
566 (R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(5-(fluoromethoxy)-2-(l- methyl-2-oxo-2,3-dihydro-lH-pyrrolo[2,3-b]pyridin-5- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
567 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro-4-(5- (fluoromethoxy)-2-(l-methyl-2-oxo-2,3-dihydro-lH-pyrrolo[2,3- b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid (R)-4-((5-fluoro-4-(5-(fluoromethoxy)-2-(l-methyl-2-oxo-2,3- dihydro-lH-pyrrolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
(R)-4-(cyclopropyl(5-fluoro-4-(5-(fluoromethoxy)-2-(l-methyl-2-oxo- 2,3-dihydro-lH-pyrrolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2- yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid (R)-3-benzyl-4-((5-fluoro-4-(5-(fluoromethoxy)-2-(l-methyl-2-oxo- 2,3-dihydro-lH-pyrrolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
(R)-3-benzyl-4-(cyclopropyl(5-fluoro-4-(5-(fluoromethoxy)-2-(l- methyl-2-oxo-2,3-dihydro-lH-pyrrolo[2,3-b]pyridin-5- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
(R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(5-(fluoromethoxy)-2-(4- methyl-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-7-yl)phenyl)thiazol-
2-yl)(methyl)amino)-4-oxobutanoic acid
(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro-4-(5-
(fluoromethoxy)-2-(4-methyl-3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazin-7-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
(R)-4-((5-fluoro-4-(5-(fluoromethoxy)-2-(4-methyl-3,4-dihydro-2H- pyrido [3 ,2-b] [ 1 ,4] oxazin-7-yl)phenyl)thiazo l-2-yl)(methyl)amino)-4- oxo-3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
(R)-4-(cyclopropyl(5-fluoro-4-(5-(fluoromethoxy)-2-(4-methyl-3,4- dihydro-2H-pyrido[3,2-b][l,4]oxazin-7-yl)phenyl)thiazol-2- yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
(R)-3-benzyl-4-((5-fluoro-4-(5-(fluoromethoxy)-2-(4-methyl-3,4- dihydro-2H-pyrido[3,2-b][l,4]oxazin-7-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
(R)-3-benzyl-4-(cyclopropyl(5-fluoro-4-(5-(fluoromethoxy)-2-(4- methyl-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-7-yl)phenyl)thiazol- 2-yl)amino)-4-oxobutanoic acid 578 (R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(5-(fluoromethoxy)-2-(l- methyl- 1 H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
579 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro-4-(5- (fluoromethoxy)-2-(l -methyl- 1 H-pyrrolo[2,3-b]pyridin-5- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
580 (R)-4-((5-fluoro-4-(5-(fluoromethoxy)-2-(l-methyl-lH-pyrrolo[2,3- b]pyridin-5-yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
581 (R)-4-(cyclopropyl(5-fluoro-4-(5-(fluoromethoxy)-2-(l -methyl- 1H- pyrrolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
582 (R)-3-benzyl-4-((5-fluoro-4-(5-(fluoromethoxy)-2-(l-methyl-lH- pyrrolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
583 (R)-3-benzyl-4-(cyclopropyl(5-fluoro-4-(5-(fluoromethoxy)-2-(l- methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
584 (R)-4-((4-(5-chloro-2-(8-methyl-7-oxo-5,6,7,8-tetrahydro-l,8- naphthyridin-3 -yl)phenyl)-5 -nuorothiazo l-2-yl)(methyl)amino)-3 - (cyclopentylmethyl)-4-oxobutano ic acid
585 (R)-4-((4-(5-chloro-2-(8-methyl-7-oxo-5,6,7,8-tetrahydro-l,8- naphthyridin-3 -yl)phenyl)-5 -nuorothiazo l-2-yl)(cyclopropyl)amino)- 3-(cyclopentylmethyl)-4-oxobutanoic acid
586 (R)-4-((4-(5-chloro-2-(8-methyl-7-oxo-5,6,7,8-tetrahydro-l,8- naphthyridin-3-yl)phenyl)-5-fluorothiazol-2-yl)(methyl)amino)-4-oxo-
3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
587 (R)-4-((4-(5-chloro-2-(8-methyl-7-oxo-5,6,7,8-tetrahydro-l,8- naphthyridin-3 -yl)phenyl)-5 -nuorothiazo l-2-yl)(cyclopropyl)amino)-
4- oxo-3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid (R)-3-benzyl-4-((4-(5-chloro-2-(8-methyl-7-oxo-5,6,7,8-tetrahydro- 1 , 8-naphthyridin-3 -yl)phenyl)-5 -fluorothiazo l-2-yl)(methyl)amino)-4- oxobutanoic acid
(R)-3-benzyl-4-((4-(5-chloro-2-(8-methyl-7-oxo-5,6,7,8-tetrahydro- 1 , 8-naphthyridin-3 -yl)phenyl)-5 -fluorothiazo 1-2- yl)(cyclopropyl)amino)-4-oxobutanoic acid
(R)-4-((4-(5-chloro-2-(l-methyl-2-oxo-2,3-dihydro-lH-pyrrolo[2,3- b]pyridin-5 -yl)phenyl)-5 -fluorothiazo l-2-yl)(methyl)amino)-3 - (cyclopentylmethyl)-4-oxobutano ic acid
(R)-4-((4-(5-chloro-2-(l-methyl-2-oxo-2,3-dihydro-lH-pyrrolo[2,3- b]pyridin-5-yl)phenyl)-5-fluorothiazol-2-yl)(cyclopropyl)amino)-3- (cyclopentylmethyl)-4-oxobutano ic acid
(R)-4-((4-(5-chloro-2-(l-methyl-2-oxo-2,3-dihydro-lH-pyrrolo[2,3- b]pyridin-5-yl)phenyl)-5-fluorothiazol-2-yl)(methyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
(R)-4-((4-(5-chloro-2-(l-methyl-2-oxo-2,3-dihydro-lH-pyrrolo[2,3- b]pyridin-5-yl)phenyl)-5-fluorothiazol-2-yl)(cyclopropyl)amino)-4- oxo-3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
(R)-3-benzyl-4-((4-(5-chloro-2-(l-methyl-2-oxo-2,3-dihydro-lH- pyrrolo [2,3 -b]pyridin-5 -yl)phenyl)-5 -fluorothiazo 1-2- yl)(methyl)amino)-4-oxobutano ic acid
(R)-3-benzyl-4-((4-(5-chloro-2-(l-methyl-2-oxo-2,3-dihydro-lH- pyrrolo [2,3 -b]pyridin-5 -yl)phenyl)-5 -fluorothiazo 1-2- yl)(cyclopropyl)amino)-4-oxobutanoic acid
(R)-4-((4-(5-chloro-2-(4-methyl-3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazin-7-yl)phenyl)-5-fluorothiazol-2-yl)(methyl)amino)-3- (cyclopentylmethyl)-4-oxobutano ic acid
(R)-4-((4-(5-chloro-2-(4-methyl-3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazin-7-yl)phenyl)-5-fluorothiazol-2-yl)(cyclopropyl)amino)- 3-(cyclopentylmethyl)-4-oxobutanoic acid (R)-4-((4-(5-chloro-2-(4-methyl-3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazin-7-yl)phenyl)-5-fluorothiazol-2-yl)(methyl)amino)-4- oxo-3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
(R)-4-((4-(5-chloro-2-(4-methyl-3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazin-7-yl)phenyl)-5-fluorothiazol-2-yl)(cyclopropyl)amino)- 4-oxo-3-((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
(R)-3-benzyl-4-((4-(5-chloro-2-(4-methyl-3,4-dihydro-2H-pyrido[3,2 b][l,4]oxazin-7-yl)phenyl)-5-fluorothiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
(R)-3-benzyl-4-((4-(5-chloro-2-(4-methyl-3,4-dihydro-2H-pyrido[3,2 b][l,4]oxazin-7-yl)phenyl)-5-fluorothiazol-2-yl)(cyclopropyl)amino)- 4-oxobutanoic acid
(R)-4-((4-(5-chloro-2-(l-methyl-lH-pyrrolo[2,3-b]pyridin-5- yl)phenyl)-5 -fluorothiazo l-2-yl)(methyl)amino)-3 - (cyclopentylmethyl)-4-oxobutano ic acid
(R)-4-((4-(5-chloro-2-(l-methyl-lH-pyrrolo[2,3-b]pyridin-5- yl)phenyl)-5-fluorothiazol-2-yl)(cyclopropyl)amino)-3- (cyclopentylmethyl)-4-oxobutano ic acid
(R)-4-((4-(5-chloro-2-(l-methyl-lH-pyrrolo[2,3-b]pyridin-5- yl)phenyl)-5-fluorothiazol-2-yl)(methyl)amino)-4-oxo-3-((tetrahydro 2H-pyran-4-yl)methyl)butanoic acid
(R)-4-((4-(5-chloro-2-(l-methyl-lH-pyrrolo[2,3-b]pyridin-5- yl)phenyl)-5-fluorothiazol-2-yl)(cyclopropyl)amino)-4-oxo-3-
((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
(R)-3 -benzyl-4-((4-(5 -chloro-2-( 1 -methyl- 1 H-pyrrolo [2 ,3 -b]pyridin-f yl)phenyl)-5-fluorothiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
(R)-3 -benzyl-4-((4-(5 -chloro-2-( 1 -methyl- 1 H-pyrrolo [2 ,3 -b]pyridin-f yl)phenyl)-5-fluorothiazol-2-yl)(cyclopropyl)amino)-4-oxobutanoic acid (R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(2-(8-methyl-7-oxo-5,6,7,8- tetrahydro- 1 , 8-naphthyridin-3 -yl)phenyl)thiazo l-2-yl)(methyl)amino)- 4-oxobutanoic acid
(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro-4-(2-(8-methyl-7- oxo-5,6,7,8 -tetrahydro -1,8 -naphthyridin-3 -y l)pheny l)thiazo 1-2- yl)amino)-4-oxobutanoic acid
(R)-4-((5-fluoro-4-(2-(8-methyl-7-oxo-5,6,7,8-tetrahydro-l,8- naphthyridin-3-yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
(R)-4-(cyclopropyl(5-fluoro-4-(2-(8-methyl-7-oxo-5,6,7,8-tetrahydro- 1 , 8-naphthyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4-oxo-3 - ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
(R)-3-benzyl-4-((5-fluoro-4-(2-(8-methyl-7-oxo-5,6,7,8-tetrahydro- 1 , 8-naphthyridin-3 -yl)phenyl)thiazo l-2-yl)(methyl)amino)-4- oxobutanoic acid
(R)-3-benzyl-4-(cyclopropyl(5-fluoro-4-(2-(8-methyl-7-oxo-5,6,7,8- tetrahydro- 1 , 8-naphthyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4- oxobutanoic acid
(R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(2-(l-methyl-2-oxo-2,3- dihydro-lH-pyrrolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro-4-(2-(l-methyl-2- oxo-2,3 -dihydro- 1 H-pyrrolo [2,3 -b]pyridin-5 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
(R)-4-((5-fluoro-4-(2-(l-methyl-2-oxo-2,3-dihydro-lH-pyrrolo[2,3- b]pyridin-5-yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
(R)-4-(cyclopropyl(5-fluoro-4-(2-(l-methyl-2-oxo-2,3-dihydro-lH- pyrrolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid (R)-3-benzyl-4-((5-fluoro-4-(2-(l-methyl-2-oxo-2,3-dihydro-lH- pyrTolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
(R)-3-benzyl-4-(cyclopropyl(5-fluoro-4-(2-(l-methyl-2-oxo-2,3- dihydro-lH-pyrrolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
(R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(2-(4-methyl-3,4-dihydro- 2H-pyrido [3 ,2-b] [ 1 ,4]oxazin-7-yl)phenyl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro-4-(2-(4-methyl- 3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-7-yl)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid
(R)-4-((5-fluoro-4-(2-(4-methyl-3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazin-7-yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
(R)-4-(cyclopropyl(5-fluoro-4-(2-(4-methyl-3,4-dihydro-2H- pyrido[3,2-b][l,4]oxazin-7-yl)phenyl)thiazol-2-yl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
(R)-3-benzyl-4-((5-fluoro-4-(2-(4-methyl-3,4-dihydro-2H-pyrido[3,2- b] [ 1 ,4] oxazin-7-yl)phenyl)thiazo l-2-yl)(methyl)amino)-4-oxobutanoic acid
(R)-3-benzyl-4-(cyclopropyl(5-fluoro-4-(2-(4-methyl-3,4-dihydro-2H- pyrido[3,2-b][l,4]oxazin-7-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
(R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(2-(l -methyl- 1 H- pyrTolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2-yl)(methyl)amino)-4- oxobutanoic acid
(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro-4-(2-(l-methyl- lH-pyrrolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid 628 (R)-4-((5-fluoro-4-(2-(l-methyl-lH-pyrrolo[2,3-b]pyridin-5- yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
629 (R)-4-(cyclopropyl(5-fluoro-4-(2-(l-methyl-lH-pyrrolo[2,3-b]pyridin- 5 -yl)phenyl)thiazo l-2-yl)amino)-4-oxo-3 -((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
630 (R)-3 -benzyl-4-((5 - fluoro-4-(2-( 1 -methyl- 1 H-pyrrolo [2 ,3 -b]pyridin-5 - yl)phenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
631 (R)-3-benzyl-4-(cyclopropyl(5-fluoro-4-(2-(l-methyl-lH-pyrrolo[2,3- b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
632 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-( 1 -methyl- 1 H- pyrrolo[3,2-b]pyridin-6-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
633 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(l-methyl-2-oxo-2,3- dihydro-lH-imidazo[4,5-b]pyridin-6-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
634 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(l-methyl-2-oxo- 1,2,3 ,4-tetrahydropyrido [3 ,2-d]pyrimidin-7-yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
635 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(l-methyl-2-oxo-2,3- dihydro-lH-pyrrolo[3,2-b]pyridin-6-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
636 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-methyl-5-oxo- 5,6,7,8 -tetrahydro - 1 , 6-naphthyridin-3 -y l)pheny l)thiazo 1-2-y l)amino)- 4-oxobutanoic acid
637 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(l,3-dimethyl-2-oxo- 1,2,3 ,4-tetrahydropyrido [3 ,2-d]pyrimidin-7-yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
638 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(7-methyl-8-oxo- 5,6,7,8 -tetrahydro - 1 , 7-naphthyridin-3 -y l)pheny l)thiazo 1-2-y l)amino)- 4-oxobutanoic acid 639 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-methyl-5-oxo-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
640 (R)-4-((4-(2-(5-chloro-6-(2-oxopyrrolidin-l-yl)pyridin-3- yl)phenyl)thiazol-2-yl)(cyclopropyl)amino)-3-(cyclopentylmethyl)-4- oxobutanoic acid
641 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(3-methyl-3H- imidazo[4,5-b]pyridin-6-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
642 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(l-methyl-2,3- dihydro-lH-pyrido[2,3-b][l,4]oxazin-7-yl)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid
643 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(3-methyl-2-oxo-2,3- dihydro-lH-imidazo[4,5-b]pyridin-6-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
644 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(7-methyl-6-oxo- 5,6,7,8 -tetrahydro - 1 , 7-naphthyridin-3 -y l)pheny l)thiazo 1-2-y l)amino)- 4-oxobutanoic acid
645 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-methyl-7-oxo-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
646 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(l,3-dimethyl-2-oxo- 2,3-dihydro-lH-imidazo[4,5-b]pyridin-6-yl)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid
647 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-( 1 -methyl- 1 H- imidazo[4,5-b]pyridin-6-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
648 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(5-fluoro-6-(2- oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(l-methyl-2-oxo- l,2,3,4-tetrahydro-l,5-naphthyridin-7-yl)phenyl)thiazol-2-yl)amino)- 4-oxobutanoic acid
(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(3-methyl-2-oxo- 1,2,3 ,4-tetrahydropyrido [3 ,2-d]pyrimidin-7-yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
(R)-4-(cyclopropyl(5-fluoro-4-(5-methyl-2-(6-(2-oxopyrrolidin- 1 - yl)pyridin-3-yl)furan-3-yl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro- 2H-pyran-4-yl)methyl)butano ic acid
(R)-4-(cyclopropyl(4-(5-methyl-2-(6-(2-oxopyrrolidin-l-yl)pyridin-3- yl)furan-3-yl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
(R)-4-((5-fluoro-4-(5-methyl-2-(6-(2-oxopyrrolidin-l-yl)pyridin-3- yl)furan-3-yl)thiazol-2-yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
(R)-4-(methyl(4-(5-methyl-2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3- yl)furan-3-yl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(5-fluoro-4-(5-methyl-2-(6- (2-oxopyrrolidin-l-yl)pyridin-3-yl)furan-3-yl)thiazol-2-yl)amino)-4- oxobutanoic acid
(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5-methyl-2-(6-(2- oxopyrrolidin- 1 -yl)pyridin-3-yl)furan-3-yl)thiazol-2-yl)amino)-4- oxobutanoic acid
(R)-3-(cyclopentylmethyl)-4-((5-fluoro-4-(5-methyl-2-(6-(2- oxopyrrolidin- 1 -yl)pyridin-3-yl)furan-3-yl)thiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
(R)-3-(cyclopentylmethyl)-4-(methyl(4-(5-methyl-2-(6-(2- oxopyrrolidin- 1 -yl)pyridin-3-yl)furan-3-yl)thiazol-2-yl)amino)-4- oxobutanoic acid 659 (R)-3-benzyl-4-(cyclopropyl(5-fluoro-4-(5-methyl-2-(6-(2- oxopyrrolidin- 1 -yl)pyridin-3-yl)furan-3-yl)thiazol-2-yl)amino)-4- oxobutanoic acid
660 (R)-3-benzyl-4-(cyclopropyl(4-(5-methyl-2-(6-(2-oxopyrrolidin- 1 - yl)pyridin-3-yl)furan-3-yl)thiazol-2-yl)amino)-4-oxobutanoic acid
661 (R)-3-benzyl-4-((5-fluoro-4-(5-methyl-2-(6-(2-oxopyrrolidin-l- yl)pyridin-3-yl)furan-3-yl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid
662 (R)-3-benzyl-4-(methyl(4-(5-methyl-2-(6-(2-oxopyrrolidin- 1 - yl)pyridin-3-yl)furan-3-yl)thiazol-2-yl)amino)-4-oxobutanoic acid
663 (R)-3-benzyl-4-(methyl(3-(2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3- yl)phenyl)- 1 ,2,4-thiadiazol-5-yl)amino)-4-oxobutanoic acid
664 (R)-3 -benzyl-4-(cy clopropyl(3 -(2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3 - yl)phenyl)- 1 ,2,4-thiadiazol-5-yl)amino)-4-oxobutanoic acid
665 (R)-3-(cyclopentylmethyl)-4-(methyl(3-(2-(6-(2-oxopyrrolidin- 1 - yl)pyridin-3-yl)phenyl)-l,2,4-thiadiazol-5-yl)amino)-4-oxobutanoic acid
666 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(3-(2-(6-(2-oxopyrrolidin- 1 - yl)pyridin-3-yl)phenyl)-l,2,4-thiadiazol-5-yl)amino)-4-oxobutanoic acid
667 (R)-4-(methyl(3-(2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)- l,2,4-thiadiazol-5-yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-4- yl)methyl)butanoic acid
668 (R)-4-(cyclopropyl(3-(2-(6-(2-oxopyrrolidin-l-yl)pyridin-3- yl)phenyl)-l,2,4-thiadiazol-5-yl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
669 (3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2,5-dimethyl-4-(6-(2- oxopyrrolidin- 1 -yl)pyridin-3-yl)furan-3-yl)-5-fluorothiazol-2- yl)amino)-4-oxobutanoic acid 670 (3R)-3-(cyclopentylmethyl)-4-((4-(2,5-dimethyl-4-(6-(2- oxopyrrolidin- 1 -yl)pyridin-3-yl)furan-3-yl)-5-fluorothiazol-2- yl)(methyl)amino)-4-oxobutano ic acid
671 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2,5-dimethyl-4-(6-(2- oxopyrrolidin- 1 -yl)pyridin-3-yl)furan-3-yl)thiazol-2-yl)amino)-4- oxobutanoic acid
672 (R)-3-(cyclopentylmethyl)-4-((4-(2,5-dimethyl-4-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3 -yl)furan-3 -yl)thiazo l-2-yl)(methyl)amino)-4- oxobutanoic acid
673 (3R)-4-(cyclopropyl(4-(2,5-dimethyl-4-(6-(2-oxopyrrolidin-l- yl)pyridin-3 -yl)furan-3 -yl)-5 -fluorothiazo l-2-yl)amino)-4-oxo-3 - ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
674 (3R)-4-((4-(2,5-dimethyl-4-(6-(2-oxopyrrolidin-l-yl)pyridin-3- yl)furan-3-yl)-5-fluorothiazol-2-yl)(methyl)amino)-4-oxo-3- ((tetrahydro-2H-pyran-4-yl)methyl)butanoic acid
675 (R)-4-(cyclopropyl(4-(2,5-dimethyl-4-(6-(2-oxopyrrolidin- 1 - yl)pyridin-3-yl)furan-3-yl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro- 2H-pyran-4-yl)methyl)butano ic acid
676 (R)-4-((4-(2,5-dimethyl-4-(6-(2-oxopyrrolidin-l-yl)pyridin-3- yl)furan-3-yl)thiazol-2-yl)(methyl)amino)-4-oxo-3-((tetrahydro-2H- pyran-4-yl)methyl)butanoic acid
677 (3R)-3-benzyl-4-(cyclopropyl(4-(2,5-dimethyl-4-(6-(2-oxopyrrolidin- l-yl)pyridin-3-yl)furan-3-yl)-5-fluorothiazol-2-yl)amino)-4- oxobutanoic acid
678 (3R)-3-benzyl-4-((4-(2,5-dimethyl-4-(6-(2-oxopyrrolidin-l-yl)pyridin- 3 -yl)furan-3 -yl)-5 -fluorothiazo l-2-yl)(methyl)amino)-4-oxobutanoic acid
679 (R)-3-benzyl-4-(cyclopropyl(4-(2,5-dimethyl-4-(6-(2-oxopyrrolidin-l- yl)pyridin-3-yl)furan-3-yl)thiazol-2-yl)amino)-4-oxobutanoic acid
680 (R)-3-benzyl-4-((4-(2,5-dimethyl-4-(6-(2-oxopyrrolidin- 1 -yl)pyridin- 3 -yl)furan-3 -yl)thiazo l-2-yl)(methyl)amino)-4-oxobutano ic acid (3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(l-methyl-6- oxopiperidin-3 -yl)pyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4- oxobutanoic acid
(3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(l-methyl-2- oxopiperidin-4-yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
(3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(3-methyl-2- oxoimidazolidin-4-yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(N- methylacetamido)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(l,3-dimethyl-2- oxohexahydropyrimidin-5 -yl)pyridin-3 -yl)phenyl)thiazo l-2-yl)amino)- 4-oxobutanoic acid
(3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(5-oxopyrrolidin- 3-yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid (3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(l-methyl-2- oxoimidazolidin-4-yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(pyrrolidin- 1 - yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid (3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(2- oxoimidazolidin-4-yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
(3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(l-methyl-5- oxopyrrolidin-2-yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(4-methyl-3- oxopiperazin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(4-methyl-2,5- dioxopiperazin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- (dimethylcarbamoyl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
(3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(3-methyl-2- oxohexahydropyrimidin-4-yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino) 4-oxobutanoic acid
(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-isopropoxypyridin-
3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
(3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(l-methyl-6- oxopiperidin-2-yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
(3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(l-methyl-5- oxopyrrolidin-3 -yl)pyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4- oxobutanoic acid
(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(3-methyl-2- oxotetrahydropyrimidin- 1 (2H)-yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(2- oxotetrahydropyrimidin- 1 (2H)-yl)pyridin-3 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
(3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(l,3-dimethyl-2- oxoimidazolidin-4-yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
(3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(l,3-dimethyl-2- oxohexahydropyrimidin-4-yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)
4- oxobutanoic acid 702 (3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(l-methyl-2- oxohexahydropyrimidin-4-yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)- 4-oxobutanoic acid
703 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(N- methylcyclopropanecarboxamido)pyridin-3 -yl)phenyl)thiazo 1-2- yl)amino)-4-oxobutanoic acid
704 (3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(l-methyl-2- oxopyrrolidin-3 -yl)pyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4- oxobutanoic acid
705 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- (cyclopropylmethoxy)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
706 (3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin-
3- yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
707 (3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(l-methyl-2- oxopiperidin-3 -yl)pyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4- oxobutanoic acid
708 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- (methoxymethyl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
709 (3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(l-methyl-2- oxohexahydropyrimidin-5 -yl)pyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-
4- oxobutanoic acid
710 (3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(5-oxopyrrolidin- 2-yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
711 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 - yl)pyridin-3 -yl)-5 -(trifluoromethyl)phenyl)thiazo l-2-yl)amino)-4- oxobutanoic acid
712 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(5-(fluoromethoxy)-2-(6- (2-oxopyrrolidin- 1 -yl)pyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4- oxobutanoic acid 713 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 - yl)pyridin-3-yl)-5-(trifluoromethoxy)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
714 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-(pyridin-2-ylmethyl)butanoic acid
715 (R)-2-(2-(carboxymethyl)-3-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 - yl)pyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-3 -oxopropyl)pyridine 1 - oxide
716 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-(((R)-tetrahydro-2H-pyran-2- yl)methyl)butanoic acid
717 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-(pyrimidin-2- ylmethyl)butanoic acid
718 (S)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-(thiophen-2-ylmethyl)butanoic acid
719 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-(((S)-tetrahydrofuran-2- yl)methyl)butanoic acid
720 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-(((S)-tetrahydro-2H-pyran-3- yl)methyl)butanoic acid
721 (3R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-3-(((2S)-2-methyltetrahydro-2H-pyran- 4-yl)methyl)-4-oxobutanoic acid
722 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-(((R)-tetrahydro-2H-pyran-3- yl)methyl)butanoic acid 723 (3R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin-l-yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-3-(((3R,5S)-3,5-dimethyltetrahydro- 2H-pyran-4-yl)methyl)-4-oxobutanoic acid
724 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-3-(((2R,3R)-2-methyltetrahydro-2H- pyran-3-yl)methyl)-4-oxobutanoic acid
725 (3R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin-l-yl)pyridin-3- yl)phenyl)thiazo l-2-yl)amino)-3 -(((3 S)-3 -methyltetrahydro-2H-pyran- 4-yl)methyl)-4-oxobutanoic acid
726 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-(((S)-tetrahydro-2H-pyran-2- yl)methyl)butanoic acid
727 (R)-3-(benzofuran-2-ylmethyl)-4-(cyclopropyl(4-(2-(6-(2- oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
728 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-(((R)-tetrahydrofuran-2- yl)methyl)butanoic acid
729 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3- yl)phenyl)thiazo l-2-yl)amino)-3 -((5 -methylfuran-2-yl)methyl)-4- oxobutanoic acid
730 (3R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin-l-yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-3- yl)methyl)butanoic acid
731 (3R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin-l-yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-3-(((2R,6S)-2,6-dimethyltetrahydro- 2H-pyran-4-yl)methyl)-4-oxobutanoic acid
732 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-3-(furan-2-ylmethyl)-4-oxobutanoic acid 733 (3R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin-l-yl)pyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxo-3-((tetrahydro-2H-pyran-2- yl)methyl)butanoic acid
734 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
735 (R)-4-((4-(5-chloro-2-(6-methoxypyridin-3-yl)phenyl)thiazol-2- yl)(cyclopropyl)amino)-3-(cyclopentylmethyl)-4-oxobutanoic acid
736 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin-l-yl)pyridin-3- yl)phenyl)thiazo l-2-yl)amino)-3 -(oxetan-3 -ylmethyl)-4-oxobutanoic acid
737 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(oxetan-3- yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
738 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin-l-yl)pyridin-3- yl)phenyl)thiazo l-2-yl)amino)-3 -(oxetan-3 -ylmethyl)-4-oxobutanoic acid
739 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(3-methyloxetan-3- yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
740 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3- yl)phenyl)thiazo l-2-yl)amino)-3 -(oxetan-3 -ylmethyl)-4-oxobutanoic acid
741 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(3-fluorooxetan-3- yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
742 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3- yl)phenyl)thiazo l-2-yl)amino)-3 -((3 -methyloxetan-3 -yl)methyl)-4- oxobutanoic acid
743 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(oxetan-3- yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
744 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3- yl)phenyl)thiazo l-2-yl)amino)-3 -((3 -methyloxetan-3 -yl)methyl)-4- oxobutanoic acid 745 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(3-methyloxetan-3- yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
746 (R)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3- yl)phenyl)thiazo l-2-yl)amino)-3 -((3 -methyloxetan-3 -yl)methyl)-4- oxobutanoic acid
747 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(3-fluorooxetan-3- yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
748 (S)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3- yl)phenyl)thiazo l-2-yl)amino)-3 -((3 -fluorooxetan-3 -yl)methyl)-4- oxobutanoic acid
749 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(oxetan-3- yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
750 (S)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin-l-yl)pyridin-3- yl)phenyl)thiazo l-2-yl)amino)-3 -((3 -fluorooxetan-3 -yl)methyl)-4- oxobutanoic acid
751 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(3-methyloxetan-3- yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid
752 (S)-4-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin-l-yl)pyridin-3- yl)phenyl)thiazo l-2-yl)amino)-3 -((3 -fluorooxetan-3 -yl)methyl)-4- oxobutanoic acid
753 (R)-3 -(eye lopentylmethyl)-4-(cyclopropyl(4-(2-(6-(3 -fluorooxetan-3 - yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid and pharmaceutically acceptable salts, and solvates thereof, for use in the treatment and /or prevention of inflammatory diseases.
11. The compound according to any one of the preceeding claims for use in delaying in a patient the onset of an inflammatory disease.
12. The compound according to any one of the preceeding claims, wherein the inflammatory disease is selected from the group consisting of rheumatoid arthritis; inflammatory bowel disease (IBD) including but not limited to Crohn's disease, ulcerative colitis and colitis; Pagets disease; osteoporosis; multiple myeloma; uveitilis; acute and chronic myelogenous leukemia; pancreatic β cell destruction; rheumatoid spondylitis; osteoarthritis; gouty arthritis and other arthritis conditions; gout; adult respiratory distress syndrome (ARDS); chronic pulmonary inflammation diseases; silicosis; pulmonary sarcoidosis; psoriasis; allergic rhinitis; anaphylaxis; contact dermatitis; pancreatitis; asthma; muscle degeneration; cachexia such as cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome; Reiter's syndrome; type I diabetes; bone resorption disease; graft vs. host reaction; ischemia reperfusion injury; brain trauma; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; endotoxic shock; gram negative sepsis; fever and myalgias due to infection such as influenza; pyrosis.
13. The compound according to any one of the preceeding claims, wherein the inflammatory diseases are TNF, IL-1, IL-6, and/or IL-8 mediated diseases or disease states.
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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014175832A1 (en) * 2013-04-26 2014-10-30 Agency For Science, Technology And Research Wnt pathway modulators
US10710986B2 (en) 2018-02-13 2020-07-14 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10774071B2 (en) 2018-07-13 2020-09-15 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
CN112209922A (en) * 2019-07-12 2021-01-12 湖南大学 Ferulamide derivatives and their medicinal uses and crystal structures
US10899735B2 (en) 2018-04-19 2021-01-26 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
WO2021160109A1 (en) * 2020-02-13 2021-08-19 劲方医药科技(上海)有限公司 Dihydronaphthyridinone compound, and preparation method therefor and medical use thereof
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
RU2809869C1 (en) * 2020-02-13 2023-12-19 Генфлит Терапьютикс (Шанхай) Инк. Compound based on dihydronapthyridinone, method of its obtaining, and its use in medicine
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US12157731B2 (en) 2020-03-03 2024-12-03 PIC Therapeutics, Inc. EIF4E inhibitors and uses thereof
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US12234231B2 (en) 2021-08-25 2025-02-25 PIC Therapeutics, Inc. EIF4E inhibitors and uses thereof

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07149745A (en) * 1993-11-30 1995-06-13 Hisamitsu Pharmaceut Co Inc New 2-aminothiazole derivative
WO1996033176A1 (en) 1995-04-18 1996-10-24 The Du Pont Merck Pharmaceutical Company Novel hydroxamic acid and amino-carboxylate compounds as metalloprotease and tnf inhibitors
WO2000026202A1 (en) * 1998-10-30 2000-05-11 Pharmacia & Upjohn S.P.A. 2-amino-thiazole derivatives, process for their preparation, and their use as antitumor agents
WO2003006443A2 (en) * 2001-07-11 2003-01-23 Boehringer Ingelheim Pharma Gmbh & Co. Kg 2- 4-(naphtalin-2-yl)-thiazol-2-ylaminocarbonyl benzoic acid and 2- 4-(naphtalin-2-yl)-pyrimidin-2-ylaminocarbonyl benzoic acid and additional compounds serving as telomerase inhibitors for use in tumor therapy
WO2004041813A1 (en) * 2002-10-30 2004-05-21 Vertex Pharmaceuticals Incorporated Compositions useful as inhibitors of rock and other protein kinases
WO2004085388A2 (en) * 2003-03-24 2004-10-07 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
WO2005026137A2 (en) * 2003-09-06 2005-03-24 Vertex Pharmaceuticals Incorporated Modulators of atp-binding cassette transporters
US20050143384A1 (en) * 2003-10-30 2005-06-30 Eric Sartori Amide thiadiazole inhibitors of plasminogen activator inhibitor-1
WO2005103022A1 (en) * 2004-04-20 2005-11-03 Transtech Pharma, Inc. Substituted thiazole and pyrimidine derivatives as melanocortin receptor modulators
WO2007117494A1 (en) * 2006-04-05 2007-10-18 Vertex Pharmaceuticals Incorporated Deazapurines useful as inhibitors of janus kinases
WO2009044250A1 (en) * 2007-10-02 2009-04-09 Palobiofarma, S.L. New compounds as adenosine a1 receptor antagonists
WO2010066682A1 (en) * 2008-12-08 2010-06-17 Euroscreen S.A. Compounds, pharmaceutical composition and methods for use in treating metabolic disorders

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07149745A (en) * 1993-11-30 1995-06-13 Hisamitsu Pharmaceut Co Inc New 2-aminothiazole derivative
WO1996033176A1 (en) 1995-04-18 1996-10-24 The Du Pont Merck Pharmaceutical Company Novel hydroxamic acid and amino-carboxylate compounds as metalloprotease and tnf inhibitors
WO2000026202A1 (en) * 1998-10-30 2000-05-11 Pharmacia & Upjohn S.P.A. 2-amino-thiazole derivatives, process for their preparation, and their use as antitumor agents
WO2003006443A2 (en) * 2001-07-11 2003-01-23 Boehringer Ingelheim Pharma Gmbh & Co. Kg 2- 4-(naphtalin-2-yl)-thiazol-2-ylaminocarbonyl benzoic acid and 2- 4-(naphtalin-2-yl)-pyrimidin-2-ylaminocarbonyl benzoic acid and additional compounds serving as telomerase inhibitors for use in tumor therapy
WO2004041813A1 (en) * 2002-10-30 2004-05-21 Vertex Pharmaceuticals Incorporated Compositions useful as inhibitors of rock and other protein kinases
WO2004085388A2 (en) * 2003-03-24 2004-10-07 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
WO2005026137A2 (en) * 2003-09-06 2005-03-24 Vertex Pharmaceuticals Incorporated Modulators of atp-binding cassette transporters
US20050143384A1 (en) * 2003-10-30 2005-06-30 Eric Sartori Amide thiadiazole inhibitors of plasminogen activator inhibitor-1
WO2005103022A1 (en) * 2004-04-20 2005-11-03 Transtech Pharma, Inc. Substituted thiazole and pyrimidine derivatives as melanocortin receptor modulators
WO2007117494A1 (en) * 2006-04-05 2007-10-18 Vertex Pharmaceuticals Incorporated Deazapurines useful as inhibitors of janus kinases
WO2009044250A1 (en) * 2007-10-02 2009-04-09 Palobiofarma, S.L. New compounds as adenosine a1 receptor antagonists
WO2010066682A1 (en) * 2008-12-08 2010-06-17 Euroscreen S.A. Compounds, pharmaceutical composition and methods for use in treating metabolic disorders

Non-Patent Citations (41)

* Cited by examiner, † Cited by third party
Title
"groups or molecules which have chemical and physical similarities producing similar biological effects", CHEM. SOC. REV., vol. 8, 1979, pages 563
ARIENTI ET AL., J. MED. CHEM., vol. 48, no. 6, 2005, pages 1882
ATKINSON ET AL., J. ORG. CHEM., vol. 64, 1999, pages 3467
BARTOLI ET AL., J. MED. CHEM., vol. 41, 1998, pages 1855 - 68
C.G. WERMUTH: "The Practice of Medicinal Chemistry"
CHANDRASEKHAR ET AL., CLINICAL IMMUNOL IMMUNOPATHOL., vol. 55, 1990, pages 382
CHEM. RES. TOXICOL., 2007, pages 1954 - 1965
CLAREMON ET AL., TET. LETT., vol. 28, 1988, pages 2155
COVINGTON ET AL., BIOCHEMICAL SOCIETY TRANSACTION, vol. 34, 2006, pages 770 - 773
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 12 May 1984 (1984-05-12), CHERNYKH, V. P. ET AL: "Synthesis and interactions of heteroamides of ethylenedicarboxylic acids and their esters", XP002599069, retrieved from STN Database accession no. 1983:53789 *
DATABASE WPI Week 199533, Derwent World Patents Index; AN 1995-248282, XP002599068 *
DINARELLO, EUR. CYTOKINES NETW., vol. 5, 1994, pages 517 - 531
DRYSDALE ET AL., J. MED. CHEM., vol. 35, 1992, pages 2573 - 2581
E. L. ELIEL; S. H. WILEN; L. N. MANDER: "Stereochemistry of Organic Compounds", 1994, WILEY- INTERSCIENCE
EVANS ET AL., J. ORG. CHEM., vol. 64, 1999, pages 6411 - 6417
FARMATSEVTICHNII ZHURNAL (KIEV) , (5), 64-5 CODEN: FRZKAP; ISSN: 0367-3057, 1982 *
FELDMANN ET AL., IMMUNOLOGICAL REVIEWS, 1995, pages 195 - 223
FIRESTEIN, AM. J. PATHOL., vol. 140, 1992, pages 1309
FLEURSTEIN, STROKE, vol. 25, 1994, pages 1481
FUSS, CURR DRUG TARGETS INFLAMM ALLERGY, vol. 2, 2003, pages 101 - 112
H.L. FRIEDMAN: "Symposium on Chemical-Biological correlations", 1951, NATIONAL COUNCIL PUBLICATION
I. LANGMUIR, J. AM. CHEM. SOC., vol. 41, 1919, pages 1549
J. AM. CHEM. SOC., vol. 120, 1998, pages 12459
LAROCK, R. C.: "Comprehensive Org Transf", 1999, WILEY, pages: 709 - 719
LE POUL ET AL., J. BIOL CHEM., vol. 278, 2003, pages 25481 - 489
LE POUL ET AL., J. BIOL. CHEM., vol. 278, 2003, pages 25481 - 25489
LILJEBRIS ET AL., J. MED. CHEM., vol. 45, 2002, pages 1785 - 1798
MASLOWSKI ET AL., NATURE, vol. 461, no. 7268, 2009, pages 1282 - 1286
MASLOWSKI KENDLE M ET AL: "Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43", NATURE (LONDON), vol. 461, no. 7268, October 2009 (2009-10-01), pages 1282, XP002599070, ISSN: 0028-0836 *
MATTHEWS ET AL., J. COMB. CHEM., vol. 2, 2000, pages 19 - 23
PERETTO ET AL., J. MED. CHEM., vol. 48, 2005, pages 5705 - 5720
RAYASAM ET AL., EXPERT OPINION ON THERAPEUTIC TARGETS, vol. 11, 2007, pages 661 - 671
RODRIGUEZ ET AL., TETRAHEDRON, vol. 38, no. 24, 1997, pages 4221
RUDOLPH, J., TETRAHEDRON, vol. 56, 2000, pages 3161
SENGA ET AL., BLOOD, vol. 101, 2003, pages 1185 - 1187
SWAIN ET AL., J. MED. CHEM., vol. 34, 1991, pages 140 - 151
TARAROV ET AL., J. CHEM. SOC. PERKIN TRANS., vol. 1, 1997, pages 3101 - 3106
TEDELIND ET AL., WORLD J GASTROENTEROL, vol. 13, no. 20, 2007, pages 2826 - 2832
TETRAHEDRON, vol. 1, 1957, pages 9635
WALLACE ET AL., ORG. PROC. RES.& DEV., vol. 8, 2004, pages 738 - 743
WHITE ET AL., J. MED. CHEM., vol. 39, 1996, pages 4382 - 95

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