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WO2018165466A1 - Composés de type indole et indazole et utilisations thérapeutiques correspondantes - Google Patents

Composés de type indole et indazole et utilisations thérapeutiques correspondantes Download PDF

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Publication number
WO2018165466A1
WO2018165466A1 PCT/US2018/021600 US2018021600W WO2018165466A1 WO 2018165466 A1 WO2018165466 A1 WO 2018165466A1 US 2018021600 W US2018021600 W US 2018021600W WO 2018165466 A1 WO2018165466 A1 WO 2018165466A1
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compound
alkyl
formula
optionally substituted
carbocyclyl
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Venkatram R. Mereddy
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University of Minnesota Twin Cities
University of Minnesota System
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University of Minnesota Twin Cities
University of Minnesota System
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles

Definitions

  • Indole and indazole derivatives are provided.
  • methods of making such compounds are provided.
  • pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds to treat, prevent, alleviate or diagnose diseases, disorders, or conditions associated with cancers are provided.
  • Indole and Indazole compounds are highly valuable compounds because of their use in variety of disciplines such as organic, materials, and medicinal chemistry.
  • the development of indole and indazole compounds for the treatment of various diseases has increased the enthusiasm for these molecules as a novel class of pharmaceutical compounds.
  • New indole and indazole compounds have attracted significant attention because of their attractive therapeutic and biological profile.
  • X is CH or N; each of A 1 and A 2 is independently a C3-C7 carbocyclyl, 5-10 membered heterocyclyl, Ce-io aryl, and 5-10 membered heteroaryl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, C 1-4 alkyl, halogenCi-4 alkyl, -OR a , -CN, -NO2, -NR a R b , -C(0)NR a R b , and -NR a C(0)R b ;
  • each of M 1 and M 2 is independently selected from O and S;
  • Z is selected from the group consisting of -COOH, -COOCi-C 6 alkyl, - COOC2-C6 alkenyl, -COOC 2 -C 6 alkynyl, -COOCi-Ce heteroalkyl, -COOC3-C7 carbocyclyl optionally substituted with Ci-Ce alkyl, -COO-5-10 membered heterocyclyl optionally substituted with Ci-C 6 alkyl, -COO-C 6 -Cio aryl optionally substituted with Ci-C 6 alkyl, -COO-4-10 membered heteroaryl optionally substituted with Ci-C 6 alkyl, -CO-5-10 membered heterocyclyl optionally substituted with Ci-C 6 alkyl , and -CONR 2 (CH 2 )o-6NR 3 R 4 ;
  • each of R 2 , R 3 , and R 4 is independently selected from H, OH, halogen, -CF3, Ci-C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C 6 heteroalkyl, C3-C7 carbocyclyl, 5-10 membered heterocyclyl, C 6 -Cio aryl, 4-10 membered heteroaryl, cyano, Ci-C 6 alkoxy(Ci-C 6 )alkyl, aryloxy, sulfhydryl (mercapto), COR a , and -(CH2)i-io-R a ;
  • R 5 is selected from Ci-C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C 6 heteroalkyl, C3-C8 carbocyclyl, 5-10 membered heterocyclyl, C 6 -io aryl, and 5-10 membered heteroaryl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, C 1-4 alkyl, haloC 1-4 alkyl, -OR a , -CN, -NO2, -NR a R b , -C(0)NR a R b , and -NR a C(0)R b ;
  • each R a and R b is independently selected from -H, -CN, -NO2, -NH 2 , -OH, Ci- 4 alkyl, halogenCi-4 alkyl, C2 ioalkenyl, C2 ioalkynyl, optionally substituted C3-7 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C 6 -ioaryl, optionally substituted -NH- Ce-io aryl, and optionally substituted 5-10 membered heteroaryl.
  • X is CH or N
  • each of A 1 and A 2 is independently a C3-C7 carbocyclyl, 5-10 membered heterocyclyl, Ce-io aryl, and 5-10 membered heteroaryl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, C 1-4 alkyl, halogenCi-4 alkyl, -OR a , -CN, -NO2, -NR a R b , -C(0)NR a R b , and -NR a C(0)R b ;
  • each of M 1 and M 2 is independently selected from O and S;
  • R 1 is selected from the group consisting of H, Ci-Ce alkyl, C2-C6 alkenyl, C 2 - C 6 alkynyl, Ci-C 6 heteroalkyl, C3-C7 carbocyclyl, 5-10 membered heterocyclyl, C 6 - C10 aryl, 4-10 membered heteroaryl;
  • each of R 2 , R 3 , and R 4 is independently selected from H, OH, halogen, -CF3, Ci-C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C 6 heteroalkyl, C3-C7 carbocyclyl, 5-10 membered heterocyclyl, C 6 -Cio aryl, 4-10 membered heteroaryl, cyano, Ci-C 6 alkoxy(Ci-C 6 )alkyl, aryloxy, sulfhydryl (mercapto), COR a , and -(CH2)i-io-R a ;
  • R 5 is selected from Ci-C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C 6 heteroalkyl, C3-C8 carbocyclyl, 5-10 membered heterocyclyl, C 6 -io aryl, and 5-10 membered heteroaryl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, C 1-4 alkyl, haloCi-4alkyl, -OR a , -CN, -NO2, -NR a R b , -C(0)NR a R b , and -NR a C(0)R b ;
  • each R a and R b is independently selected from -H, -CN, -NO2, -NH 2 , -OH, Ci- 4 alkyl, halogenCi-4 alkyl, C2 ioalkenyl, C2 ioalkynyl, optionally substituted C3-7 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C 6 -ioaryl, optionally substituted -NH- C 6 -io aryl, and optionally substituted 5-10 membered heteroaryl.
  • Some embodiments relate to a compound having the structure of Formula (A-II)
  • Some embodiments relate to a compound having the structure of Formula (A-III)
  • Z, R 3 , R 4 , R 5 , and X are as defined in Formula (A).
  • R 1 , R 3 , R 4 , R 5 , M 1 , M 2 , and X are as defined in Formula (I).
  • R 1 , R 3 , R 4 , R 5 , and X are as defined in Formula (I).
  • Figures 1A -1C show the Systemic Toxicity of Compound 1 in CD-I Mice: Figure 1A shows the results for compound 1 ; Figure IB shows the results for compound 4; and Figure 1C shows the results for compound 5.
  • Figures 2A-2B show the anti-tumor efficacy of the compound 5 using WiDr Tumor Xenograft Study in Athymic Nude Mice: Figures 2 A shows the effect of Compound 5 on tumor volume compared to the control group; Figure 2B shows the effect of Compound 5 on tumor weight compared to the control group.
  • Figures 3A and 3B show test results in 4T1 Tumor Syngraft Study using compound 5 in BALB/c Mice: Figures 3A shows the effect of Compound 5 on tumor volume compared to the control group; Figure 3B shows the effect of Compound 5 on tumor weight compared to the control group.
  • Figures 4A and 4B show the anti-tumor efficacy of the compound 1 when tested using WiDr Tumor Xenograft Study in Athymic Nude Mice: Figures 4A and 4B respectively showed the average tumor weight and tumor volume during the study.
  • Figures 5A and 5B show the anti-tumor efficacy of the compound 4 was tested using WiDr Tumor Xenograft Study in Athymic Nude Mice: Figures 5 A and 5B respectively showed the average tumor weight and tumor volume during the study. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
  • Solvate refers to the compound formed by the interaction of a solvent and a compound described herein or salt thereof. Suitable solvates are pharmaceutically acceptable solvates including hydrates.
  • pharmaceutically acceptable salt refers to salts that retain the biological effectiveness and properties of a compound and, which are not biologically or otherwise undesirable for use in a pharmaceutical. In many cases, the compounds disclosed herein are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in WO 87/05297, Johnston et al., published September 11 , 1987 (incorporated by reference herein in its entirety).
  • C a to C b or "C a -b” in which "a” and “b” are integers refer to the number of carbon atoms in the specified group. That is, the group can contain from “a” to "b", inclusive, carbon atoms.
  • a “Ci to C 4 alkyl” or “Ci- 4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, (CH 3 ) 2 CH-, CH 3 CH 2 CH 2 CH 2 -, CH 3 CH 2 CH(CH 3 )- and (CH 3 ) 3 C-.
  • halogen or “halo,” as used herein, means any one of the radio- stable atoms of column 7 of the Periodic Table of the Elements, e.g. , fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being preferred.
  • alkyl refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., contains no double or triple bonds).
  • the alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., "1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated).
  • the alkyl group may also be a medium size alkyl having 1 to 9 carbon atoms.
  • the alkyl group could also be a lower alkyl having 1 to 4 carbon atoms.
  • the alkyl group may be designated as "C 1-4 alkyl" or similar designations.
  • C 1-4 alkyl indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec -butyl, and t-butyl.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.
  • alkoxy refers to the formula -OR wherein R is an alkyl as is defined above, such as “C1-9 alkoxy”, including but not limited to methoxy, ethoxy, n- propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy, and the like.
  • alkylthio refers to the formula -SR wherein R is an alkyl as is defined above, such as “C1-9 alkylthio” and the like, including but not limited to methylmercapto, ethylmercapto, n-propylmercapto, 1-methylethylmercapto (isopropylmercapto), n-butylmercapto, iso-butylmercapto, sec-butylmercapto, tert- butylmercapto, and the like.
  • alkenyl refers to a straight or branched hydrocarbon chain containing one or more double bonds.
  • the alkenyl group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term "alkenyl” where no numerical range is designated.
  • the alkenyl group may also be a medium size alkenyl having 2 to 9 carbon atoms.
  • the alkenyl group could also be a lower alkenyl having 2 to 4 carbon atoms.
  • the alkenyl group may be designated as "C2-4 alkenyl" or similar designations.
  • C2-4 alkenyl indicates that there are two to four carbon atoms in the alkenyl chain, i.e., the alkenyl chain is selected from the group consisting of ethenyl, propen-l-yl, propen-2-yl, propen-3-yl, buten-l-yl, buten-2-yl, buten-3-yl, buten- 4-yl, 1-methyl-propen-l-yl, 2-methyl-propen-l-yl, 1-ethyl-ethen-l-yl, 2-methyl-propen-3-yl, buta-l,3-dienyl, buta-l ,2,-dienyl, and buta-l ,2-dien-4-yl.
  • Typical alkenyl groups include, but are in no way limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl, and the like.
  • alkynyl refers to a straight or branched hydrocarbon chain containing one or more triple bonds.
  • the alkynyl group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term "alkynyl” where no numerical range is designated.
  • the alkynyl group may also be a medium size alkynyl having 2 to 9 carbon atoms.
  • the alkynyl group could also be a lower alkynyl having 2 to 4 carbon atoms.
  • the alkynyl group may be designated as "C2-4 alkynyl" or similar designations.
  • C2-4 alkynyl indicates that there are two to four carbon atoms in the alkynyl chain, i.e., the alkynyl chain is selected from the group consisting of ethynyl, propyn-l-yl, propyn-2-yl, butyn-l-yl, butyn-3-yl, butyn-4-yl, and 2-butynyl.
  • Typical alkynyl groups include, but are in no way limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl, and the like.
  • aromatic refers to a ring or ring system having a conjugated pi electron system and includes both carbocyclic aromatic (e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine).
  • carbocyclic aromatic e.g., phenyl
  • heterocyclic aromatic groups e.g., pyridine
  • the term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of atoms) groups provided that the entire ring system is aromatic.
  • aryl refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent carbon atoms) containing only carbon in the ring backbone. When the aryl is a ring system, every ring in the system is aromatic.
  • the aryl group may have 6 to 18 carbon atoms, although the present definition also covers the occurrence of the term "aryl” where no numerical range is designated. In some embodiments, the aryl group has 6 to 10 carbon atoms.
  • the aryl group may be designated as "C 6 -io aryl,” “C 6 or Cio aryl,” or similar designations.
  • aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.
  • aryloxy and arylthio refers to RO- and RS-, in which R is an aryl as is defined above, such as “C 6 -io aryloxy” or “C 6 -io arylthio” and the like, including but not limited to phenyloxy.
  • an "aralkyl” or “arylalkyl” is an aryl group connected, as a substituent, via an alkylene group, such as "C7-14 aralkyl” and the like, including but not limited to benzyl, 2- phenylethyl, 3-phenylpropyl, and naphthylalkyl.
  • the alkylene group is a lower alkylene group (i.e., a C1-4 alkylene group).
  • heteroaryl refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent atoms) that contain(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the ring backbone.
  • heteroaryl is a ring system, every ring in the system is aromatic.
  • the heteroaryl group may have 5-18 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term "heteroaryl" where no numerical range is designated.
  • the heteroaryl group has 5 to 10 ring members or 5 to 7 ring members.
  • the heteroaryl group may be designated as "5-7 membered heteroaryl,” "5-10 membered heteroaryl,” or similar designations.
  • heteroaryl rings include, but are not limited to, furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinlinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and benzothienyl.
  • a “heteroaralkyl” or “heteroarylalkyl” is heteroaryl group connected, as a substituent, via an alkylene group. Examples include but are not limited to 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazollylalkyl, and imidazolylalkyl.
  • the alkylene group is a lower alkylene group (i.e., a C 1-4 alkylene group).
  • carbocyclyl means a non-aromatic cyclic ring or ring system containing only carbon atoms in the ring system backbone.
  • carbocyclyl is a ring system, two or more rings may be joined together in a fused, bridged or spiro-connected fashion.
  • Carbocyclyls may have any degree of saturation provided that at least one ring in a ring system is not aromatic.
  • carbocyclyls include cycloalkyls, cycloalkenyls, and cycloalkynyls.
  • the carbocyclyl group may have 3 to 20 carbon atoms, although the present definition also covers the occurrence of the term "carbocyclyl” where no numerical range is designated.
  • the carbocyclyl group may also be a medium size carbocyclyl having 3 to 10 carbon atoms.
  • the carbocyclyl group could also be a carbocyclyl having 3 to 6 carbon atoms.
  • the carbocyclyl group may be designated as "C3-6 carbocyclyl" or similar designations.
  • carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicycle[2.2.2]octanyl, adamantyl, and spiro[4.4]nonanyl.
  • a "(carbocyclyl)alkyl” is a carbocyclyl group connected, as a substituent, via an alkylene group, such as "C4 10 (carbocyclyl)alkyl” and the like, including but not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like.
  • the alkylene group is a lower alkylene group.
  • cycloalkyl means a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • heterocyclyl means a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring backbone. Heterocyclyls may be joined together in a fused, bridged or spiro-connected fashion. Heterocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic. The heteroatom(s) may be present in either a non-aromatic or aromatic ring in the ring system.
  • the heterocyclyl group may have 3 to 20 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term "heterocyclyl” where no numerical range is designated.
  • the heterocyclyl group may also be a medium size heterocyclyl having 3 to 10 ring members.
  • the heterocyclyl group could also be a heterocyclyl having 3 to 6 ring members.
  • the heterocyclyl group may be designated as "3-6 membered heterocyclyl" or similar designations.
  • the heteroatom(s) are selected from one up to three of O, N or S, and in preferred five membered monocyclic heterocyclyls, the heteroatom(s) are selected from one or two heteroatoms selected from O, N, or S.
  • heterocyclyl rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrohdinyl, pyrrohdonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1 ,4- dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl, 1 ,4-oxathiinyl, 1,4-oxathianyl, 2H- 1 ,2-oxazinyl, trioxany
  • a "(heterocyclyl)alkyl” is a heterocyclyl group connected, as a substituent, via an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.
  • Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acryl.
  • R is selected from hydrogen, Ci- 6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C 6 -io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • a "cyano" group refers to a "-CN” group.
  • a “sulfonyl” group refers to an "-SO2R” group in which R is selected from hydrogen, C 1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C 6 -io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • S-sulfonamido refers to a "-S0 2 NR A RB” group in which R A and RB are each independently selected from hydrogen, C 1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C 6 -io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • N-sulfonamido refers to a "-N(RA)S02RB” group in which RA and Rb are each independently selected from hydrogen, C 1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C 6 -io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • An “amino” group refers to a "-NR A RB” group in which R A and RB are each independently selected from hydrogen, C 1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C 6 -io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • R A and RB are each independently selected from hydrogen, C 1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C 6 -io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • a non-limiting example includes free amino (i.e., -NH 2 ).
  • aminoalkyl refers to an amino group connected via an alkylene group.
  • alkoxyalkyl refers to an alkoxy group connected via an alkylene group, such as a “C2-8 alkoxyalkyl” and the like.
  • a substituted group is derived from the unsubstituted parent group in which there has been an exchange of one or more hydrogen atoms for another atom or group.
  • substituents independently selected from Ci-C 6 alkyl, Ci-C 6 alkenyl, Ci-C 6 alkynyl, Ci-C 6 heteroalkyl, C3-C7 carbocyclyl (optionally substituted with halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, and Ci-C 6 haloalkoxy), C 3 - C 7 -carbocyclyl-Ci-C6-alkyl (optionally substituted with halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci- C 6 haloalkyl, and Ci-C 6 haloalk
  • radical naming conventions can include either a mono-radical or a di-radical, depending on the context. For example, where a substituent requires two points of attachment to the rest of the molecule, it is understood that the substituent is a di-radical.
  • a substituent identified as alkyl that requires two points of attachment includes di-radicals such as -CH2-, -CH2CH2-, -CH2CH(CH 3 )CH2-, and the like.
  • Other radical naming conventions clearly indicate that the radical is a di-radical such as "alkylene” or "alkenylene.”
  • a substituent is depicted as a di-radical (i.e., has two points of attachment to the rest of the molecule), it is to be understood that the substituent can be attached in any directional configuration unless otherwise indicated.
  • Subject as used herein, means a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate.
  • mammal is used in its usual biological sense. Thus, it specifically includes, but is not limited to, primates, including simians (chimpanzees, apes, monkeys) and humans, cattle, horses, sheep, goats, swine, rabbits, dogs, cats, rodents, rats, mice guinea pigs, or the like.
  • primates including simians (chimpanzees, apes, monkeys) and humans, cattle, horses, sheep, goats, swine, rabbits, dogs, cats, rodents, rats, mice guinea pigs, or the like.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated.
  • various adjuvants such as are commonly used in the art may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press.
  • a therapeutic effect relieves, to some extent, one or more of the symptoms of a disease or condition, and includes curing a disease or condition. "Curing” means that the symptoms of a disease or condition are eliminated; however, certain long-term or permanent effects may exist even after a cure is obtained (such as extensive tissue damage).
  • Treatment refers to administering a compound or pharmaceutical composition to a subject for prophylactic and/or therapeutic purposes.
  • prophylactic treatment refers to treating a subject who does not yet exhibit symptoms of a disease or condition, but who is susceptible to, or otherwise at risk of, a particular disease or condition, whereby the treatment reduces the likelihood that the patient will develop the disease or condition.
  • therapeutic treatment refers to administering treatment to a subject already suffering from a disease or condition.
  • the compounds disclosed herein may exist as individual enantiomers and diastereomers or as mixtures of such isomers, including racemates. Separation of the individual isomers or selective synthesis of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art. Unless otherwise indicated, all such isomers and mixtures thereof are included in the scope of the compounds disclosed herein. Furthermore, compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms are included in the scope of the compounds disclosed herein including any polymorphic forms. In addition, some of the compounds disclosed herein may form solvates with water (i.e., hydrates) or common organic solvents. Unless otherwise indicated, such solvates are included in the scope of the compounds disclosed herein.
  • Isotopes may be present in the compounds described. Each chemical element as represented in a compound structure may include any isotope of said element.
  • a hydrogen atom may be explicitly disclosed or understood to be present in the compound.
  • the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen- 1 (protium) and hydrogen-2 (deuterium).
  • reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.
  • Some embodiments disclosed herein relate to a compound of formula (A) as described above or a pharmaceutically acceptable salt thereof. [0062] Some embodiments disclosed herein relate to a compound of formula (I) as described above or a pharmaceutically acceptable salt thereof.
  • Some embodiments disclosed herein relate to a compound of formula (II) as described above or a pharmaceutically acceptable salt thereof.
  • Some embodiments disclosed herein relate to a compound of formula (III) as described above or a pharmaceutically acceptable salt thereof.
  • R 3 and R 4 are hydrogen.
  • X is CH. In some embodiments, X is N.
  • R 5 is selected from C 6 -io aryl, C3-C8 carbocyclyl, 5-10 membered heterocyclyl, and 5-10 membered heteroaryl, each optionally substituted with one or more substituents selected from halogen, C1-10 alkyl, halo C1-10 alkyl, -OR a , -CN, -NO2, -NR a R b , -C(0)NR a R b , and -NR a C(0)R b .
  • R 5 is phenyl.
  • R 5 is phenyl substituted with CF3 and CI.
  • R 5 is cyclohexyl.
  • R 1 is methyl.
  • R 1 is H.
  • R 1 is selected from the group consisting of H, Ci-C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C 6 heteroalkyl, C3-C7 carbocyclyl, 5-10 membered heterocyclyl, C 6 -Cio aryl, 4-10 membered heteroaryl
  • Z is — CONH(CH 2 )2N(CH 3 )2. In some embodiments, Z is -CONR 2 (CH2)o-eNR 3 R 4 . In some embodiments, Z is -CO-C 3 -Cs carbocyclyl optionally substituted with Ci-C 6 alkyl. In some embodiments, Z is -CO-3-10 membered hetrocyclyl optionally substituted with Ci-C 6 alkyl. In some embodiments, Z is . In some embodiments, Z is COOR 1 .
  • the compound of formula (I), (II), or (III) can have
  • the compound of formula A), (A-I), or (A-II) can be any compound of formula A), (A-I), or (A-II).
  • compositions comprising: (a) a safe and therapeutically effective amount of a compound described herein (including enantiomers, diastereoisomers, tautomers, polymorphs, and solvates thereof), or pharmaceutically acceptable salts thereof; and (b) a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
  • a daily dose for most of the compounds described herein is from about 0.25 mg/kg to about 120 mg/kg or more of body weight, from about 0.5 mg/kg or less to about 70 mg/kg, from about 1.0 mg/kg to about 50 mg/kg of body weight, or from about 1.5 mg/kg to about 10 mg/kg of body weight.
  • the dosage range would be from about 17 mg per day to about 8000 mg per day, from about 35 mg per day or less to about 7000 mg per day or more, from about 70 mg per day to about 6000 mg per day, from about 100 mg per day to about 5000 mg per day, or from about 200 mg to about 3000 mg per day.
  • the amount of active compound administered will, of course, be dependent on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician.
  • Administration of the compounds disclosed herein or the pharmaceutically acceptable salts thereof can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, or intraocularly. Oral and parenteral administrations are customary in treating the indications that are the subject of the preferred embodiments.
  • compositions containing a pharmaceutically-acceptable carrier include compositions containing a pharmaceutically-acceptable carrier.
  • pharmaceutically-acceptable carrier means one or more compatible solid or liquid filler diluents or encapsulating substances, which are suitable for administration to a mammal.
  • compatible means that the components of the composition are capable of being commingled with the subject compound, and with each other, in a manner such that there is no interaction, which would substantially reduce the pharmaceutical efficacy of the composition under ordinary use situations.
  • Pharmaceutically-acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration preferably to an animal, preferably a mammal, being treated.
  • substances which can serve as pharmaceutically- acceptable carriers or components thereof, are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyr
  • compositions described herein are preferably provided in unit dosage form.
  • a "unit dosage form” is a composition containing an amount of a compound that is suitable for administration to an animal, preferably mammal subject, in a single dose, according to good medical practice.
  • the preparation of a single or unit dosage form does not imply that the dosage form is administered once per day or once per course of therapy.
  • Such dosage forms are contemplated to be administered once, twice, thrice or more per day and may be administered as infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours), or administered as a continuous infusion, and may be given more than once during a course of therapy, though a single administration is not specifically excluded.
  • the skilled artisan will recognize that the formulation does not specifically contemplate the entire course of therapy and such decisions are left for those skilled in the art of treatment rather than formulation.
  • compositions useful as described above may be in any of a variety of suitable forms for a variety of routes for administration, for example, for oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intra-arterial, intravenous, intramuscular, or other parental routes of administration.
  • routes for administration for example, for oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intra-arterial, intravenous, intramuscular, or other parental routes of administration.
  • oral and nasal compositions include compositions that are administered by inhalation, and made using available methodologies.
  • a variety of pharmaceutically-acceptable carriers well-known in the art may be used.
  • Pharmaceutically-acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropies, surface-active agents, and encapsulating substances.
  • Optional pharmaceutically-active materials may be included, which do not substantially interfere with the inhibitory activity of the compound.
  • the amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
  • Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow- inducing agents, and melting agents.
  • Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.
  • the pharmaceutically-acceptable carriers suitable for the preparation of unit dosage forms for peroral administration is well-known in the art.
  • Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc.
  • Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture.
  • Coloring agents such as the FD&C dyes, can be added for appearance.
  • Sweeteners and flavoring agents such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets.
  • Capsules typically comprise one or more solid diluents disclosed above. The selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical, and can be readily made by a person skilled in the art.
  • Peroral compositions also include liquid solutions, emulsions, suspensions, and the like.
  • the pharmaceutically-acceptable carriers suitable for preparation of such compositions are well known in the art.
  • Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water.
  • typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591 , tragacanth and sodium alginate;
  • typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate.
  • Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above.
  • compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject compound is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action.
  • dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac.
  • compositions described herein may optionally include other drug actives.
  • compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms.
  • Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.
  • Preservatives that may be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate.
  • a useful surfactant is, for example, Tween ® 80.
  • various useful vehicles may be used in the ophthalmic preparations disclosed herein. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water.
  • Topical formulations may generally be comprised of a pharmaceutical carrier, co-solvent, emulsifier, penetration enhancer, preservative system, and emollient.
  • the compounds and compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent, such as a saline or dextrose solution.
  • a pharmaceutically acceptable diluent such as a saline or dextrose solution.
  • Suitable excipients may be included to achieve the desired pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HC1, and citric acid.
  • the pH of the final composition ranges from 2 to 8, or preferably from 4 to 7.
  • Antioxidant excipients may include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylate, thiourea, and EDTA.
  • excipients found in the final intravenous composition may include sodium or potassium phosphates, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran. Further acceptable excipients are described in Powell, et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-31 1 and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287-332, both of which are incorporated herein by reference in their entirety.
  • Antimicrobial agents may also be included to achieve a bacteriostatic or fungistatic solution, including but not limited to phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.
  • compositions for intravenous administration may be provided to caregivers in the form of one more solids that are reconstituted with a suitable diluent such as sterile water, saline or dextrose in water shortly prior to administration.
  • a suitable diluent such as sterile water, saline or dextrose in water shortly prior to administration.
  • the compositions are provided in solution ready to administer parenterally.
  • the compositions are provided in a solution that is further diluted prior to administration.
  • the combination may be provided to caregivers as a mixture, or the caregivers may mix the two agents prior to administration, or the two agents may be administered separately.
  • Some embodiments described herein relate to a method of treating or inhibiting progression of cancer, which can include administering a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to a subject.
  • the methods include identifying a subject at risk for or having cancer and administering a compound to the subject in an effective amount for therapeutic treatment or prophylactic treatment of cancer.
  • the cancer is breast cancer, including triple negative breast cancer, estrogen receptor +, progesterone receptor+, HER2- breast cancer.
  • the cancer is pancreatic cancer.
  • the cancer is prostate cancer.
  • the cancer is a glioma.
  • the cancer is pancreatic cancer.
  • the cancer is colorectal adenocarcinoma.
  • the subject is a human.
  • therapeutically effective amount refers to an amount of a compound sufficient to cure, ameliorate, slow progression of, prevent, or reduce the likelihood of onset of the identified disease or condition, or to exhibit a detectable therapeutic, prophylactic, or inhibitory effect.
  • the effect can be detected by, for example, the assays disclosed in the following examples.
  • the precise effective amount for a subject will depend upon the subject's body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration.
  • Therapeutically and prophylactically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.
  • the therapeutically or prophylactically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs.
  • the animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.
  • Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population).
  • the dose ratio between therapeutic and toxic effects is the therapeutic index, and it can be expressed as the ratio, ED50/LD50.
  • Pharmaceutical compositions that exhibit large therapeutic indices are preferred. However, pharmaceutical compositions that exhibit narrow therapeutic indices are also within the scope of the invention.
  • the data obtained from cell culture assays and animal studies may be used in formulating a range of dosage for human use.
  • the dosage contained in such compositions is preferably within a range of circulating concentrations that include an EDso with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.
  • the exact dosage will be determined by the practitioner, in light of factors related to the subject that requires treatment. Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.
  • treating a condition described herein results in an increase in average survival time of a population of treated subjects in comparison to a population of untreated subjects.
  • the average survival time is increased by more than about 30 days; more preferably, by more than about 60 days; more preferably, by more than about 90 days; and even more preferably by more than about 120 days.
  • An increase in survival time of a population may be measured by any reproducible means.
  • an increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound.
  • an increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.
  • treating a condition described herein results in a decrease in the mortality rate of a population of treated subjects in comparison to a population of subjects receiving carrier alone.
  • treating a condition described herein results in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population.
  • treating a condition described herein results a decrease in the mortality rate of a population of treated subjects in comparison to a population receiving monotherapy with a drug that is not a compound of the embodiments, or a pharmaceutically acceptable salt, metabolite, analog or derivative thereof.
  • the mortality rate is decreased by more than about 2%; more preferably, by more than about 5%; more preferably, by more than about 10%; and most preferably, by more than about 25%.
  • a decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means.
  • a decrease in the mortality rate of a population may be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with an active compound.
  • a decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease related deaths per unit time following completion of a first round of treatment with an active compound.
  • treating a condition described herein results in a reduction in the rate of cellular proliferation.
  • the rate of cellular proliferation is reduced by at least about 5%; more preferably, by at least about 10%; more preferably, by at least about 20%; more preferably, by at least about 30%; more preferably, by at least about 40%; more preferably, by at least about 50%; even more preferably, by at least about 60%; and most preferably, by at least about 75%.
  • the rate of cellular proliferation may be measured by any reproducible means of measurement.
  • the rate of cellular proliferation is measured, for example, by measuring the number of dividing cells in a tissue sample per unit time.
  • treating a condition described herein results in a reduction in the proportion of proliferating cells.
  • the proportion of proliferating cells is reduced by at least about 5%; more preferably, by at least about 10%; more preferably, by at least about 20%; more preferably, by at least about 30%; more preferably, by at least about 40%; more preferably, by at least about 50%; even more preferably, by at least about 60%; and most preferably, by at least about 75%.
  • the proportion of proliferating cells may be measured by any reproducible means of measurement.
  • the proportion of proliferating cells is measured, for example, by quantifying the number of dividing cells relative to the number of nondividing cells in a tissue sample.
  • the proportion of proliferating cells is equivalent to the mitotic index.
  • treating a condition described herein results in a decrease in size of an area or zone of cellular proliferation.
  • size of an area or zone of cellular proliferation is reduced by at least 5% relative to its size prior to treatment; more preferably, reduced by at least about 10%; more preferably, reduced by at least about 20% ; more preferably, reduced by at least about 30% ; more preferably, reduced by at least about 40%; more preferably, reduced by at least about 50%; even more preferably, reduced by at least about 60%; and most preferably, reduced by at least about 75%.
  • Size of an area or zone of cellular proliferation may be measured by any reproducible means of measurement. In a preferred aspect, size of an area or zone of cellular proliferation may be measured as a diameter or width of an area or zone of cellular proliferation.
  • the methods described herein may include identifying a subject in need of treatment.
  • the methods include identifying a mammal in need of treatment.
  • the methods include identifying a human in need of treatment. Identifying a subject in need of treatment may be accomplished by any means that indicates a subject who may benefit from treatment. For example, identifying a subject in need of treatment may occur by clinical diagnosis, laboratory testing, or any other means known to one of skill in the art, including any combination of means for identification.
  • the compounds described herein may be formulated in pharmaceutical compositions, if desired, and can be administered by any route that permits treatment of the disease or condition.
  • a preferred route of administration is oral administration. Administration may take the form of single dose administration, or the compound of the embodiments can be administered over a period of time, either in divided doses or in a continuous-release formulation or administration method (e.g., a pump). However the compounds of the embodiments are administered to the subject, the amounts of compound administered and the route of administration chosen should be selected to permit efficacious treatment of the disease condition.
  • a combination can include a compound, composition, pharmaceutical composition described herein with an additional medicament.
  • the additional medicament is a chemotherapeutic agent.
  • the additional chemotherapeutic agent can be an antineoplastic agent.
  • antineoplastic agents include but are not limited to paclitaxel, docetaxel, doxorubicin, etoposide, carboplatin, cisplatin, topotecan, gemcitabine, tamoxifen, 5- fluorouracil, adriamycin, daunorubicin, vincristine, nedaplatin, oxaliplatin, satraplatin, triplatin tetranitrate, and vinblastine.
  • Some embodiments include co-administering a compound, composition, and/or pharmaceutical composition described herein, with an additional medicament.
  • co-administration it is meant that the two or more agents may be found in the patient's bloodstream at the same time, regardless of when or how they are actually administered.
  • the agents are administered simultaneously.
  • administration in combination is accomplished by combining the agents in a single dosage form.
  • the agents are administered sequentially.
  • the agents are administered through the same route, such as orally.
  • the agents are administered through different routes, such as one being administered orally and another being administered i.v.
  • the combination of active ingredients may be: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by any other combination therapy regimen known in the art.
  • the methods described herein may comprise administering or delivering the active ingredients sequentially, e.g., in separate solution, emulsion, suspension, tablets, pills or capsules, or by different injections in separate syringes.
  • an effective dosage of each active ingredient is administered sequentially, i.e., serially
  • simultaneous therapy effective dosages of two or more active ingredients are administered together.
  • Various sequences of intermittent combination therapy may also be used. Synthesis
  • Formula III-B, III-C, III-D, and III can be prepared using the steps shown in Scheme 1 above.
  • X is CH or N
  • R 1 is selected from the group consisting of H, Ci-C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C 6 heteroalkyl, C3-C7 carbocyclyl, 5-10 membered heterocyclyl, C 6 -Cio aryl, 4-10 membered heteroaryl
  • each R 3 , and R 4 is independently selected from H, OH, halogen, -CF3, Ci-C 6 alkyl, C2-C6 alkenyl, C2- C 6 alkynyl, Ci-C 6 heteroalkyl, C3-C7 carbocyclyl, 5-10 membered heterocyclyl, C 6 -Cio aryl, 4-10 membered heteroaryl, cyano, Ci-C 6 alkoxy(Ci-C 6 )alky
  • the corresponding indazole based urea derivative can be prepared by using an indazole as the starting material; for the indole based formula shown in Scheme 1, the corresponding indole based urea derivative can also be prepared by using an indole as the starting material.
  • Formula A-I can be prepared using the steps shown in Scheme 2 above.
  • X is CH or N; each R a and R b is independently selected from the group consisting of H, Ci-C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C 6 heteroalkyl, C3-C7 carbocyclyl, 5-10 membered heterocyclyl, C 6 -Cio aryl, 4-10 membered heteroaryl, or (CH2)o- 6 NR 3 R 4 ; or R a and R b form an optionally substituted 3-10 membered heterocyclyl ring; each R 3 , and R 4 is independently selected from H, OH, halogen, -CF3, Ci-C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C 6 heteroalkyl, C3-C7 carbocyclyl, 5-10 membered heterocyclyl, C 6 -C
  • R 3 and R 4 can be both hydrogen, and R 5 can be phenyl substituted with CF3 and CI.
  • compound (III) reacts with NHR a R b , the -OR 1 group is replaced by -NR a R b to form Compound (A-I).
  • the corresponding indazole based urea derivative can be prepared by using an indazole as the starting material; for the indole based formula shown in Scheme 2, the corresponding indole based urea derivative can also be prepared by using an indole as the starting material.
  • Some embodiments relate to a method of making a compound of Formula
  • the method comprising:
  • X is CH or N
  • R 1 is selected from the group consisting of H, Ci-C 6 alkyl, C2-C6 alkenyl, C2- C 6 alkynyl, Ci-C 6 heteroalkyl, C3-C7 carbocyclyl, 5-10 membered heterocyclyl, C 6 - C10 aryl, 4-10 membered heteroaryl;
  • each R 3 , and R 4 is independently selected from H, OH, halogen, -CF3, Ci-C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C 6 heteroalkyl, C3-C7 carbocyclyl, 5-10 membered heterocyclyl, C 6 -Cio aryl, 4-10 membered heteroaryl, cyano, Ci-C 6 alkoxy(Ci-C 6 )alkyl, aryloxy, sulfhydryl (mercapto), COR a , and -(CH2)i-io-R a ; and
  • R 5 is selected from Ci-C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C 6 heteroalkyl, C3-C8 carbocyclyl, 5-10 membered heterocyclyl, C 6 -io aryl, and 5-10 membered heteroaryl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, C 1-4 alkyl, haloC 1-4 alkyl, -OR a , -CN, -NO2, -NR a R b , -C(0)NR a R b , and -NR a C(0)R b .
  • X is N.
  • R 1 is methyl
  • R 3 and R 4 are hydrogen.
  • R 5 is selected from C 6 -io aryl, C3-C8 carbocyclyl, 5- 10 membered heterocyclyl, and 5-10 membered heteroaryl, each optionally substituted with one or more substituents selected from halogen, C1-10 alkyl, halo C1-10 alkyl, -OR a , -CN, - N0 2 , -NR a R b , -C(0)NR a R b , and -NR a C(0)R b .
  • R 5 is phenyl.
  • R 5 is phenyl substituted with CF3 and CI.
  • R 5 is cyclohexyl.
  • the compound of Formula (III) has the structure of
  • X is CH or N
  • Z is -CONR a R b ;
  • each R a and R b is independently selected from the group consisting of H, Ci- C 6 alkyl, and (CH 2 )o- 6 NR 3 R 4 ; or
  • R a and R b together form a 3-10 membered heterocyclyl optionally substituted with Ci-Ce alkyl
  • each R 3 , and R 4 is independently selected from H, OH, halogen, -CF3, Ci-C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C 6 heteroalkyl, C3-C7 carbocyclyl, 5-10 membered heterocyclyl, C 6 -Cio aryl, 4-10 membered heteroaryl, cyano, Ci-C 6 alkoxy(Ci-C 6 )alkyl, aryloxy, sulfhydryl (mercapto), COR 1 , and -(CH2)i-io-R 2 ;
  • R 5 is selected from Ci-C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C 6 heteroalkyl, C3-C8 carbocyclyl, 5-10 membered heterocyclyl, C 6 -io aryl, and 5-10 membered heteroaryl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-4 alkyl, haloCi-4alkyl, -OR a , -CN, -NO2, -NR X R 2 , -C(0)NR 1 R 2 , and -NR 1 C(0)R 2 ; and
  • each R 1 and R 2 is independently selected from the group consisting of H and Ci-Ce alkyl.
  • X is N.
  • Z is CO-3-10 membered heterocyclyl optionally substituted with Ci-C 6 alkyl or - CONR 2 (CH 2 )o- 6 NR 1 R 2 .
  • R 3 and R 4 are hydrogen.
  • R 5 is selected from C 6 -io aryl, C3-C8 carbocyclyl, 5-10 membered heterocyclyl, and 5-10 membered heteroaryl, each optionally substituted with one or more substituents selected from halogen, Ci-10 alkyl, halo C1-10 alkyl, -OR 1 , -CN, -NO2, -NR X R 2 , -C(0)NR 1 R 2 , and -NR 1 C(0)R 2 .
  • R 5 is phenyl.
  • R 5 is phenyl substituted with CF3 and CI.
  • the compound of Formula (IV) has the structure
  • Compounds 1 , 2, and 3 were prepared using the synthesis route shown below.
  • Compound A3 was prepared by reacting compound Al with 4-fluronitrobenzene and K2CO3 in DMSO at lOOC for 3 hours. The nitro group in compound A3 was reduced to the amine group in compound A4 by reacting with ammonium formate and Pd and carbon catalyst at reflux for 4 hours.
  • Compound A7 was prepared by reacting compound A6 with an aminobenzoic acid compound A5 in THF at room temperature for about 1-2 h.
  • Compounds 1, 2, and 3 were made by reacting compound A4 with A7 in EDQHOBT (1: 1) and DMF at 50°C overnight.
  • R is a phenyl, l-chloro-2-(trifluoromethyl)benzene, and cyclohexyl, respectively.
  • Cell line MDA-MB-231 human triple negative breast cancer cell line
  • cell line MCF-7 estrogen receptor positive human breast cancer cell line
  • cell line MIAPaCa-2 pancreatic cancer cell line
  • cell line GL261-luc2 glioma cell line
  • cell line 4T1 metalstatic murine breast cancer cell line
  • Compounds 4 and 5 were prepared using the synthesis route shown below.
  • Compound B-3 was prepared by reacting compound B- 1 with 4-fluronitrobenzene B-2 and K2CO3 in DMSO at 100°C for 3 hours. The nitro group in compound B-3 was reduced to the amine group in compound B-4 by reacting with ammonium formate and Pd and carbon catalyst at reflux for 4 hours.
  • Compound B-7 was prepared by reacting compound B-6 with an aminobenzoic acid compound in THF at room temperature for about 1-2 h.
  • Compound B- 5 was made by reacting compound B-4 with B-7 in EDC:HOBT (1 : 1) and DMF at 50°C overnight.
  • Compound B-7 was reacted with B-8 NHR'R" to produce compound B.
  • R -chloro-2-(trifluoromethyl)benzene, and R'R" is NH(CH2) 2 N(CH3)2 for compound 4 and for compound 5.
  • MDA-MB-231 human TNBC cell line
  • MCF-7 human ER+/PR+ breast cancer cell line
  • MIAPaCa-2 human pancreatic cancer cell line
  • WiDr human colorectal adenocarcinoma cell line Example 3.
  • Compound 4 was also tested in 4T1 Tumor Syngraft Study in BALB/c Mice. The results are shown in Figure 3, In Figures 3 A and 3B, compound 4 showed significant 48% tumor growth inhibition compared to the control group. Doxorubicin exhibited only 4% tumor growth inhibition as measured by tumor weights.
  • a group of items linked with the conjunction 'and' should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as 'and/or' unless expressly stated otherwise.
  • a group of items linked with the conjunction 'or' should not be read as requiring mutual exclusivity among that group, but rather should be read as 'and/or' unless expressly stated otherwise.

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Abstract

La présente invention concerne des composés dérivés d'indole-urée et d'indazole-urée, des procédés pour leur préparation et des méthodes de traitement du cancer.
PCT/US2018/021600 2017-03-10 2018-03-08 Composés de type indole et indazole et utilisations thérapeutiques correspondantes Ceased WO2018165466A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040249185A1 (en) * 1999-03-30 2004-12-09 Hubert Barth Process for the arylation of aza-heterocycles with activated aromatics in presence of caesium carbonate
WO2007022380A2 (fr) * 2005-08-15 2007-02-22 Amgen Inc. Composes bis-aryl amide et procedes d'utilisation
WO2011048018A1 (fr) * 2009-10-19 2011-04-28 Boehringer Ingelheim International Gmbh Dérivés de cyclopentanecarboxamide, médicaments contenant ces composés et leur utilisation
WO2011109441A1 (fr) * 2010-03-01 2011-09-09 Myrexis, Inc. Composés et utilisations thérapeutiques associées
WO2012177782A1 (fr) * 2011-06-20 2012-12-27 Myrexis, Inc. Composés et ses utilisations thérapeutiques
CN106008371A (zh) * 2016-06-24 2016-10-12 谢阳 1-芳基脲基环烷基-1-甲酰胺类化合物及其药物组合物和应用

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040249185A1 (en) * 1999-03-30 2004-12-09 Hubert Barth Process for the arylation of aza-heterocycles with activated aromatics in presence of caesium carbonate
WO2007022380A2 (fr) * 2005-08-15 2007-02-22 Amgen Inc. Composes bis-aryl amide et procedes d'utilisation
WO2011048018A1 (fr) * 2009-10-19 2011-04-28 Boehringer Ingelheim International Gmbh Dérivés de cyclopentanecarboxamide, médicaments contenant ces composés et leur utilisation
WO2011109441A1 (fr) * 2010-03-01 2011-09-09 Myrexis, Inc. Composés et utilisations thérapeutiques associées
WO2012177782A1 (fr) * 2011-06-20 2012-12-27 Myrexis, Inc. Composés et ses utilisations thérapeutiques
CN106008371A (zh) * 2016-06-24 2016-10-12 谢阳 1-芳基脲基环烷基-1-甲酰胺类化合物及其药物组合物和应用

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