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WO2018106818A1 - Methods of promoting beta cell proliferation - Google Patents

Methods of promoting beta cell proliferation Download PDF

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Publication number
WO2018106818A1
WO2018106818A1 PCT/US2017/064933 US2017064933W WO2018106818A1 WO 2018106818 A1 WO2018106818 A1 WO 2018106818A1 US 2017064933 W US2017064933 W US 2017064933W WO 2018106818 A1 WO2018106818 A1 WO 2018106818A1
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Prior art keywords
optionally substituted
alkyl
membered heterocycle
carbocycle
mmol
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Application number
PCT/US2017/064933
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French (fr)
Inventor
Tao Wu
Liansheng Li
Yi Wang
Pingda Ren
Yi Liu
Ryan Kent SNYDER
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Kura Oncology, Inc.
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Publication of WO2018106818A1 publication Critical patent/WO2018106818A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the mixed-lineage leukemia (MLL) protein is a histone methyltransferase critical for the epigenetic regulation of gene transcription.
  • the menin protein which is encoded by the Multiple Endocrine Neoplasia (MEN) gene, is a ubiquitously expressed nuclear protein that engages in interactions with DNA processing and repair proteins, chromatin modifying proteins and numerous transcription factors (Agarwal, et al.; Horm Metab Res, 2005, 37(6): 369-374).
  • MEN Multiple Endocrine Neoplasia
  • the association of menin with MLL promotes trimethylation of histone H3 on lysine 4. This association has been shown to maintain the expression of p27 Kip1 and p18 INK4C and impairs islet proliferation. Since menin levels have been shown to be correlated to pancreatic islet expression, the interaction between menin and MLL represents a potential therapeutic target.
  • Diabetes mellitus commonly referred to as diabetes, is a disease in which the body does not produce or properly respond to insulin, a hormone that is needed to convert sugar, starches and other food into energy.
  • the hallmark of diabetes is the presence of high blood sugar levels.
  • diabetes is described by its two main forms: type 1 and type 2 diabetes.
  • Type 1 diabetes which is typically diagnosed in children and young adults, is an autoimmune disease in which the body is unable to produce insulin.
  • the underlying mechanism involves an autoimmune destruction of the insulin-producing beta cells in the pancreas. Due to a breakdown of islet cells in the pancreas, the pancreas produces either very little insulin or none at all. As a consequence, the lack of insulin results in high sugar levels in the blood.
  • Type 2 diabetes which is typically diagnosed in middle-aged and older adults, is a metabolic disorder resulting from the body’s inability to make enough insulin or to properly use insulin.
  • the body’s cells are unable to absorb and use the insulin, which is commonly referred to as“insulin resistance.”
  • insulin resistance As a result of insulin resistance, elevated sugar levels are maintained in the bloodstream.
  • the present disclosure addresses a need in the art by providing methods of treating diabetes and associated diseases.
  • the methods herein may be useful for treating diseases dependent on the activity of menin, such as diabetes.
  • the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising administerin a com ound of Formula I :
  • H is selected from C 3-12 carbocycle and 3- to 12-membered heterocycle
  • A is selected from bond, C 3-12 carbocycle, and 3- to 12-membered heterocycle
  • B is selected from C 3-12 carbocycle and 3- to 12-membered heterocycle
  • C is selected from bond, C 3-12 carbocycle, and 3- to 12-membered heterocycle
  • each of L 1 , L 2 , and L 3 is independently selected from bond, -O-, -S-, -N(R 51 )-, - N(R 51 )CH 2 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 )-, - C(O)N(R 51 )C(O)-, -C(O)N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)O-, -OC(O)N(R 51 )-, -C(NR 51 )-, -N(R 51 )C(NR 51 )-, -C(NR 51 )N
  • R 50 is, at each occurrence, independently selected from:
  • R 51 is independently selected at each occurrence from:
  • R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 ;
  • each of R H , R A , and R B is, at each occurrence, independently selected from R 50 , or two R H groups, two R A groups, or two R B groups attached to the same atom or different atoms can together optionally form a bridge or ring;
  • R C is, at each occurrence, independently selected from hydrogen or R 50 , or two R C groups attached to the same atom or different atoms can together optionally form a bridge or ring; and each of m, n, p, and q is independently an integer from 0 to 12.
  • H is 5- to 12-membered heterocycle; A is 3- to 12-membered heterocycle; and B is 5- to 12-membered heterocycle or C 4- 8 carbocycle.
  • H is 6-membered to 12-membered
  • H is ; each of X 1 and X 2 is independently selected from CR 2 and N; each of X 3 and X 4 is independently selected from C and N; each of X 5 and X 6 is independently selected from CR 3 , N, NR 4 , O, and S; each of R 1 , R 2 and R 3 is independently selected at each occurrence from hydrogen and R 50 ; and R 4 is selected from R 51 .
  • X 3 and X 4 are each C.
  • X 6 is CR 3
  • R 3 is selected from hydrogen, halogen, -OR 52 , -N(R 52 ) 2 , -CN, -C(O)OR 52 , C 1-3 alkyl, and C 1-3
  • H is In some embodiments, R 2 is selected from hydrogen, halogen, -OR 52 , -NH 2 , -N(R 52 ) 2 , -CN, C 1-3 alkyl, C 1-3 alkyl-OR 52 , C 1-3 alkyl- N(R 52 ) 2 , C 1-3 haloalkyl, C 2-3 alkenyl, and C 2-3 alkynyl.
  • R 3 is selected from hydrogen, halogen, -OR 52 , -N(R 52 ) 2 , -CN, -C(O)OR 52 , C 1-3 alkyl, and C 1-3 haloalkyl.
  • R 1 is C 1-3 haloalkyl. In some embodiments, R 1 is . In some embodiments, H is thienopyrimidinyl or thienopyridinyl.
  • H is ; each of X 1 and X 2 is independently CR 2 or N; each of X 7 , X 8 , X 9 , and X 10 is independently CR 16 , CR 17 R 18 , N, NR 19 , O, or S; each of R 16 , R 17 , and R 18 is independently selected at each occurrence from hydrogen and R 50 ; and R 19 is selected from R 51 .
  • X 1 is CR 2
  • R 2 is selected from hydrogen, halogen, -OH, -OR 52 , -NH 2 , -N(R 52 ) 2 , -CN, C 1-3 alkyl, C 1-3 alkyl-OR 52 , C 1-3 alkyl- N(R 52 ) 2 , C 1-3 haloalkyl, C 2-3 alkenyl, and C 2-3 alkynyl.
  • X 2 is N.
  • H is 5- or 6-membered
  • H is ; each of Y 1 , Y 2 , and Y 4 is independently CR 2 , N, NR 21 , O, or S; Y 5 is CR 20 , N, NR 21 , O, or S; Y 6 is C or N; Y 3 is a bond, CR 22 , or N, wherein when Y 3 is CR 22 or N, then each of Y 1 , Y 2 , and Y 4 is independently CR 2 , N, or NR 21 and Y 5 is CR 20 , N, or NR 21 ; each of R 2 and R 20 is independently selected at each occurrence from hydrogen and R 50 ; and R 21 is selected from R 51 .
  • L 1 is a bond or -N(R 51 )-. In some embodiments, for a compound of Formula (I), L 1 is not a bond. In some embodiments, L 1 is - NH-.
  • L 2 is not a bond.
  • L 2 is alkylene or heteroalkylene, each of which is optionally substituted with one or more R 50 .
  • L 2 is C 1-4 alkylene, optionally substituted with one or more R 50 .
  • L 2 is selected from -CH 2 -, -N(R 51 )-, -N(R 51 )CH 2 -, -N(R 51 )C(O)-, and -N(R 51 )S(O) 2 -.
  • L 2 is - CH 2 -.
  • L 3 comprises less than 20 atoms. In m m im n L 3 i n n In m m im n L 3 i 1- lk l n i n ll
  • A is 5- to 10-membered heterocycle. In some embodiments, A is 6-membered monocyclic heterocycle. In some embodiments, A comprises at least one nitrogen atom. In some m im n A is selected from
  • A is some
  • n 0.
  • B is 6- to 12-membered bicyclic heterocycle.
  • B comprises at least one nitrogen atom.
  • B is optionally substituted with one or more R B , wherein each of E and G is inde endently N or C.
  • B is indolylene.
  • B optionally substituted with one or more R B .
  • B is phenylene.
  • R B is selected from halogen, methyl, -CN, -OR 52 , and - N(R 52 ) 2 .
  • C is 5- to 12-membered heterocycle, wherein the heterocycle comp nitrogen atom.
  • C is aromatic.
  • C is saturated.
  • C is selected from piperidinyl, piperazinyl, and morpholinyl.
  • R C is selected from C 1-3 alkyl and C 1-3 haloalkyl.
  • C is ; W 1 is C 1-4 alkylene, optionally substituted with one or more R 50 ; W 2 is selected from a bond; and C 1-4 alkylene, optionally substituted with one or more R 50 ; W 3 is selected from absent; and C 1-4 alkylene, optionally substituted with one or more R 50 ; wherein when W 3 is absent: W 1 is C 1 alkylene, W 2 is a bond, and L 3 is not a bond; W 1 is C 2-4 alkylene and W 2 is a bond; or W 1 and W 2 are each C 1 alkylene and L 3 is not a bond, wherein each C 1 alkylene is independently optionally substituted with one or more R 50 .
  • W 1 , W 2 and W 3 are each independently selected from C 1-4 alkylene, wherein each C 1-4 alkylene is optionally substituted with one or more R 50 . In some embodiments, W 1 , W 2 and W 3 are each C 1 alkylene. In some embodiments, W 1 and W 2 are each C 1 alkylene and W 3 is absent.
  • the compound is selected from Table 1-6, 9-10, 12, 14, 16, 18, or 20.
  • H is 5- to 12-membered heterocycle
  • A is piperidinylene or piperazinylene
  • B is indolylene
  • C is 5- to 6-membered heterocycle.
  • H is thienopyrimidinyl or thienopyridinyl
  • A is piperidinylene or piperazinylene
  • B is indolylene
  • C is piperidinyl, piperazinyl, or morpholinyl.
  • H is thienopyrimidinyl or thienopyridinyl; A is piperidinylene or piperazinylene; B is indolylene; and L 1 , L 2 , and L 3 are not bonds.
  • the compound has a structure of .
  • H is thienopyrimidinyl; A is 3- to 12-membered heterocycle; B is 6- to 12-membered bicyclic heterocycle; m is an integer from 0 to 3; n is an integer from 0 to 3; and p is an integer from 0 to 3.
  • H is thienopyrimidinyl
  • A is selected from piperidinylene and piperazinylene
  • L 1 and L 2 are each independently selected from -O-, -S-, -NH-, and -CH 2 -;
  • L 3 is selected from bond, -O-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, -C(O)O-, - OC(O)-, -OC(O)O-, -C(O)N(R 51 )-, -C(O)N(R 51 )C(O)-, -C(O)N(R 51 )C(O)N(R 51 )-, - N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)O-, -OC(O)N(R 51 )-, -C(NR 51 )-, - N(R 51 )C(NR 51 )-, -C(NR 51 )N(R 51 )-, -N(R 51 )C(NR 51 )N(R 51
  • heteroalkylene heteroalkenylene, and heteroalkynylene, each of which is optionally substituted with one or more R 50 , wherein two R 50 groups attached to the same atom or different atoms of L 3 can together optionally form a ring;
  • R A , R B and R C are each independently selected at each occurrence from R 50 , or two R A groups, two R B groups or two R C groups attached to the same atom or different atoms can together optionally form a ring;
  • n is an integer from 0 to 3;
  • n is an integer from 0 to 3;
  • p is an integer from 0 to 6;
  • q is an integer from 0 to 6.
  • H is thienopyrimidinyl
  • A is selected from piperidinylene and piperazinylene
  • L 1 and L 2 are each independently selected from -O-, -S-, -NH-, and -CH 2 -;
  • L 3 is selected from C 1-6 alkylene, C 2-6 alkenylene, and C 2-6 alkynylene, each of which is optionally substituted with one or more R 50 ;
  • R A , R B and R C are each independently selected at each occurrence from R 50 , or two R A groups, two R B groups or two R C groups attached to the same atom or different atoms can together optionally form a bridge or ring;
  • n is an integer from 0 to 3;
  • n is an integer from 0 to 3;
  • p is an integer from 0 to 3;
  • q is an integer from 0 to 6.
  • H is and R 2 is selected from hydrogen, halogen, -OH, -OR 52 , -NH 2 , -N(R 52 ) 2 , -CN, C 1-3 alkyl, C 1-3 alkyl-OR 52 , C 1-3 alkyl-N(R 52 ) 2 , C 1-3 haloalkyl, C 2-3 alkenyl, and C 2-3 alkynyl.
  • R 2 is selected from -NH 2 , -CH 3 , and -NHCH 3 .
  • the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprisin administerin a com ound of Formula III :
  • H is selected from C 3-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more R 50 ;
  • each of Z 1 , Z 2 , Z 3 , and Z 4 is independently selected from -C(R A1 )(R A2 )-, -C(R A1 )(R A2 )- C(R A1 )(R A2 )-, -C(O)-, and -C(R A1 )(R A2 )-C(O)-, wherein no more than one of Z 1 , Z 2 , Z 3 , and Z 4 is -C(O)- or -C(R A1 )(R A2 )-C(O)-;
  • B is selected from bond, C 3-12 carbocycle and 3- to 12-membered heterocycle
  • C is selected from bond, C 3-12 carbocycle and 3- to 12-membered heterocycle
  • L 1 , L 2 and L 3 are each independently selected from bond, -O-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 )-, -C(O)N(R 51 )C(O)-, - C(O)N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)O-, -OC(O)N(R 51 )-, - C(NR 51 )-, -N(R 51 )C(NR 51 )-, -C(NR 51 )N(R 51 )- -N(R 51 )C(NR
  • R B is independently selected at each occurrence from R 50 , or two R B groups attached to the same atom or different atoms can together optionally form a bridge or ring;
  • R C is independently selected at each occurrence from hydrogen and R 50 , or two R C groups attached to the same atom or different atoms can together optionally form a bridge or ring;
  • R A1 and R A2 are each independently selected at each occurrence from hydrogen and R 50 ; n is an integer from 0 to 6;
  • p is an integer from 1 to 6;
  • R 50 is independently selected at each occurrence from:
  • R 51 is independently selected at each occurrence from:
  • R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 .
  • the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising administering a compound of Formula (IV):
  • G a is selected from C 3-12 carbocycle and 3- to 12-membered heterocycle, each of which is substituted with -E 1 -R 4a and optionally further substituted with one or more R 50 ;
  • R 2a is selected from hydrogen, alkyl, alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, optionally substituted heteroaryl, and aralkyl;
  • R 3a and R 3b are each independently selected from hydrogen, alkyl, halo, hydroxy, cyano, amino, alkylamino, dialkylamino, haloalkyl, alkoxy, and haloalkoxy;
  • X a is selected from hydrogen, alkyl, halo, hydroxy, cyano, amino, alkylamino, dialkylamino, haloalkyl, alkoxy, and haloalkoxy;
  • Y a is selected from cyano, hydroxy, and -CH 2 R 50 ;
  • R 4a is selected from hydrogen, alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, optionally substituted heteroaryl, aralkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl;
  • R 14a is selected from hydrogen and alkyl
  • R 50 is independently selected at each occurrence from:
  • R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 .
  • the compound is provided as a substantially pure stereoisomer.
  • the stereoisomer is provided in at least 90% enantiomeric excess.
  • the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising administering a compound selected from Table 1-6, 9-10, 12, 14, 16, 18, or 20. In certain aspects, the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising administering a compound selected from Table 22 or 23. [0036] In certain aspects, the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising administering a compound described herein. In practicing any of the subject methods, the pancreatic cell may be an islet cell or a beta cell. Beta cell proliferation may be evidenced by an increase in beta cell production and/or by an increase in insulin production. A method described herein may further comprise administering a second therapeutic agent.
  • a method described herein may further comprise administering the compound to a subject.
  • the subject suffers from diabetes.
  • the diabetes may be type 1 diabetes or type 2 diabetes.
  • the subject suffers from prediabetes.
  • the subject suffers from impaired beta cell production.
  • the subject is human.
  • FIG.1 is an amino acid sequence of human menin, isoform 1 (SEQ ID NO: 1).
  • FIG.2 is an amino acid sequence of human menin, isoform 2 (SEQ ID NO: 2).
  • FIG.3 is an amino acid sequence of human menin, isoform 3 (SEQ ID NO: 3).
  • FIG.4A-4D depict confocal images of rat primary dispersed islet cells treated with Compound B-403, Compound C-35, Compound C-36, and no compound, respectively.
  • FIG.5A-5C depict the change in beta cell proliferation for rat primary dispersed islet cells treated with Compound B-403, Compound C-35, and Compound C-36, respectively.
  • C x-y or“C x -C y ” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain.
  • C x-y alkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain.
  • C x-y alkenyl and“C x-y alkynyl” refer to substituted or unsubstituted straight-chain or branched-chain unsaturated hydrocarbon groups that contain at least one double or triple bond respectively. Unless stated otherwise specifically in the specification, a C x-y alkyl, C x-y alkenyl, or C x-y alkynyl is optionally substituted by one or more substituents such as those substituents described herein.
  • Carbocycle refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is a carbon atom.
  • Carbocycle may include 3- to 10-membered monocyclic rings, 6- to 12- membered bicyclic rings, and 6- to 12-membered bridged rings.
  • Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings.
  • the carbocycle is an aryl. In some embodiments, the carbocycle is a cycloalkyl. In some embodiments, the carbocycle is a cycloalkenyl. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane,
  • cyclopentane or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, are included in the definition of carbocyclic.
  • Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Unless stated otherwise specifically in the specification, a carbocycle is optionally substituted by one or more substituents such as those substituents described herein.
  • Heterocycle refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms.
  • exemplary heteroatoms include N, O, Si, P, B, and S atoms.
  • Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings.
  • the heterocycle may be attached to the rest of the molecule through any atom of the heterocycle, valence permitting, such as a carbon or nitrogen atom of the
  • heterocycle In some embodiments, the heterocycle is a heteroaryl. In some embodiments, the heterocycle is a heterocycloalkyl. In an exemplary embodiment, a heterocycle, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene.
  • Heteroaryl refers to a 3- to 12-membered aromatic ring that comprises at least one heteroatom wherein each heteroatom may be independently selected from N, O, and S.
  • the heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems rings wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ⁇ –electron system in accordance with the Hückel theory.
  • the heteroatom(s) in the heteroaryl may be optionally oxidized.
  • One or more nitrogen atoms, if present, are optionally quaternized.
  • heteroaryl may be attached to the rest of the molecule through any atom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl.
  • heteroaryls include but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl,
  • Compounds used in the methods of the present disclosure also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.
  • the compounds used in the methods described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds used in the methods of the present disclosure whether radioactive or not, are encompassed within the scope of the present disclosure.
  • hydrogen has three naturally occurring isotopes, denoted 1 H (protium), 2 H (deuterium), and 3 H (tritium). Protium is the most abundant isotope of hydrogen in nature.
  • Enriching for deuterium may afford certain therapeutic advantages, such as increased in vivo half-life and/or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism.
  • Isotopically-enriched compounds may be prepared by conventional techniques well known to those skilled in the art.
  • Steps are isomers that differ only in the way the atoms are arranged in space.
  • Enantiomers are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “( ⁇ )” is used to designate a racemic mixture where appropriate.
  • “Diastereoisomers” or“diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S.
  • Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line.
  • Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
  • the compounds of the present methods are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers and intermediate mixtures.
  • Optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.
  • Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, chemical entities described herein for use in the subject methods are intended to include all Z-, E- and tautomeric forms as well.
  • substitution refers to moieties having substituents replacing a hydrogen on one or more carbons or heteroatoms of the structure. It will be understood that“substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term“substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen
  • Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a
  • substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH 2 O- is equivalent to -OCH 2 -.
  • salts or“pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art.
  • 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.
  • 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.
  • the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
  • the term“effective amount” or“therapeutically effective amount” refers to that amount of a compound described herein that is sufficient to affect the intended application, including but not limited to disease treatment, as defined below.
  • the therapeutically effective amount may vary depending upon the intended treatment application (in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • the term also applies to a dose that will induce a particular response in target cells, e.g., reduced histone methylation and/or increased islet expression.
  • the specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.
  • treatment refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition including but not limited to a therapeutic benefit and/or a prophylactic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject,
  • compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
  • A“therapeutic effect,” as that term is used herein, encompasses a therapeutic benefit and/or a prophylactic benefit as described above.
  • a prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
  • co-administration encompass administration of two or more agents to an animal, including humans, so that both agents and/or their metabolites are present in the subject at the same time.
  • Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.
  • the terms“antagonist” and“inhibitor” are used interchangeably, and they refer to a compound having the ability to inhibit a biological function (e.g., activity, expression, binding, protein-protein interaction) of a target protein (e.g., menin, MLL1, MLL2, and/or an MLL fusion protein). Accordingly, the terms“antagonist” and“inhibitor” are defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit a biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition. A preferred biological activity inhibited by an antagonist is associated with the proliferation of beta cells.
  • the term“agonist” as used herein refers to a compound having the ability to initiate or enhance a biological function of a target protein whether by inhibiting the activity or expression of the target protein. Accordingly, the term“agonist” is defined in the context of the biological role of the target polypeptide. While preferred agonists herein specifically interact with (e.g., bind to) the target, compounds that initiate or enhance a biological activity of the target polypeptide by interacting with other members of the signal transduction pathway of which the target polypeptide is a member are also specifically included within this definition.
  • “Signal transduction” is a process during which stimulatory or inhibitory signals are transmitted into and within a cell to elicit an intracellular response.
  • a modulator of a signal transduction pathway refers to a compound which modulates the activity of one or more cellular proteins mapped to the same specific signal transduction pathway.
  • a modulator may augment (agonist) or suppress (antagonist) the activity of a signaling molecule.
  • diabetes refers to disease conditions in which glucose metabolism is impaired. Said impairment results in hyperglycemia.
  • WHO World Health Organization
  • diabetes can be subdivided into four classes. Type 1 diabetes is caused by a lack of insulin. Insulin is produced by the so-called pancreatic islet cells. Said cells may be destroyed by an autoimmune reaction in Type 1 diabetes (Type 1a). Moreover, Type 1 diabetes also encompasses an idiopathic variant (Type 1b). Type 2 diabetes is caused by insulin resistance.
  • Type 3 diabetes according to the current classification, comprises all other specific types of diabetes mellitus.
  • the beta cells may have genetic defects affecting insulin production, insulin resistance may be caused genetically or the pancreas as such may be destroyed or impaired.
  • hormone deregulation or drugs may also cause Type 3 diabetes.
  • Type 4 diabetes may occur during pregnancy.
  • diabetes as used herein refers to Type 1 and Type 2 diabetes. Diabetes may be diagnosed either by a plasma glucose level higher than 110 mg/dL in a fasting state or higher than 220 mg/dL postprandial, or by other diagnostic methods well known in the art.
  • An“anti-diabetic agent” generally refers to an agent that lowers blood glucose levels. If blood glucose level is decreased by at least about 100 mg/dL, then the compound is considered to be a hypoglycemic agent.
  • the hypoglycemic or anti-diabetic effect can be measured by a variety of methods including, but not limited to, measuring the blood glucose levels, the rate of insulin binding to its receptor, the level of insulin secretion from pancreatic beta cells, and inhibition of glucohydrolase activity.
  • related disorders means disorders related to diabetes mellitus, which include, but are not limited to, diabetic neuropathy, diabetic diarrhea, urinary retention, gustatory swelling, papillary reflexes, cardiac autonomic disturbances, collagen disturbances, thickening of capillary basement membrane, increase in vessel wall matrix and cellular proliferation resulting in vascular complications such as lumen narrowing, early atherosclerosis, sclerosis of glomerular capillaries, retinopathy, neuropathy and peripheral vascular insufficiency.
  • Subject refers to an animal, such as a mammal, for example a human.
  • the methods described herein can be useful in both human therapeutics and veterinary applications.
  • the subject is a mammal, and in some embodiments, the subject is human.
  • “Mammal” includes humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like.
  • Prodrug is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound of the methods described herein (e.g., compound of Formula (I), (III) or (IV)).
  • a biologically active compound of the methods described herein e.g., compound of Formula (I), (III) or (IV)
  • prodrug refers to a precursor of a biologically active compound that is pharmaceutically acceptable.
  • a prodrug is inactive when administered to a subject but is converted in vivo to an active compound, for example, by hydrolysis.
  • prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp.7-9, 21-24 (Elsevier, Amsterdam); Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," (1987) A.C.S. Symposium Series, Vol.14; and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press) each of which is incorporated in full by reference herein.
  • the term“prodrug” is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of an active compound are typically prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound.
  • Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
  • prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of a hydroxy functional group, or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like.
  • in vivo refers to an event that takes place in a subject’s body.
  • in vitro refers to an event that takes places outside of a subject’s body.
  • an in vitro assay encompasses any assay run outside of a subject.
  • in vitro assays encompass cell-based assays in which cells alive or dead are employed.
  • In vitro assays also encompass a cell-free assay in which no intact cells are employed.
  • “Optional” or“optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
  • “optionally substituted aryl” means that the aryl group may or may not be substituted and that the description includes both substituted aryl groups and aryl groups having no substitution.
  • “Pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye, colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
  • the present disclosure provides methods for modulating the interaction of menin with proteins such as MLL for the treatment of a wide variety of disorders associated with impaired beta cell production, such as type 1 diabetes or type 2 diabetes.
  • the disclosure provides methods for inhibiting the interaction of menin with its upstream or downstream signaling molecules, including but not limited to MLL.
  • a method of the disclosure provides a compound that covalently binds menin and inhibits the interaction of menin with another protein such as MLL.
  • a method of the disclosure provides a compound that interacts non-covalently with menin and inhibits the interaction of menin with another protein such as MLL.
  • the present disclosure provides a method comprising a compound or salt that selectively binds to the menin protein and/or modulates the interaction of menin with an MLL protein.
  • the compound modulates the menin protein by binding to or interacting with one or more amino acids and/or one or more metal ions.
  • Certain compounds may occupy the F9 and/or P13 pocket of menin.
  • the binding of a compound disclosed in the subject methods may disrupt menin or MLL (e.g., MLL1, MLL2, or an MLL fusion protein) downstream signaling.
  • the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising administerin a com ound of Formula I :
  • H is selected from C 3-12 carbocycle and 3- to 12-membered heterocycle
  • A is selected from bond, C 3-12 carbocycle, and 3- to 12-membered heterocycle
  • B is selected from C 3-12 carbocycle and 3- to 12-membered heterocycle
  • C is selected from bond, C 3-12 carbocycle, and 3- to 12-membered heterocycle
  • each of L 1 , L 2 , and L 3 is independently selected from bond, -O-, -S-, -N(R 51 )-, - N(R 51 )CH 2 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 )-, - C(O)N(R 51 )C(O)-, -C(O)N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)O-, -OC(O)N(R 51 )-, -C(NR 51 )-, -N(R 51 )C(NR 51 )-, -C(NR 51 )N
  • R 50 is, at each occurrence, independently selected from:
  • R 51 is independently selected at each occurrence from:
  • R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 ;
  • each of R H , R A , and R B is, at each occurrence, independently selected from R 50 , or two R H groups, two R A groups, or two R B groups attached to the same atom or different atoms can together optionally form a bridge or ring;
  • R C is, at each occurrence, independently selected from hydrogen or R 50 , or two R C groups attached to the same atom or different atoms can together optionally form a bridge or ring; and each of m, n, p, and q is independently an integer from 0 to 12.
  • H is 5- to 12-membered heterocycle, such as 6- to 12-membered bicyclic heterocycle, optionally substituted with one or more R H .
  • H contains one or more heteroatoms, such as 1, 2, 3, 4, 5 or 6 ring heteroatoms.
  • H contains at least 1, 2, 3, 4 or 5 ring nitrogen atoms.
  • H is thienopyrimidinyl, optionally substituted with one or more R H .
  • H is substituted with C 1-4 haloalkyl, such as -CH 2 CF 3 .
  • H is substituted with one or more R H (e.g., by replacing a hydrogen connected to a ring atom with a bond to R H ).
  • H may be substituted with 0, 1, 2, 3, 4, 5, 6 or more R H groups.
  • H may be substituted with 1, 2, 3, 4, 5 or 6 R H groups, such as H substituted with 1 or 2 R H groups.
  • H is substituted with at least 1, 2, 3, 4, 5 or 6 R H groups.
  • H is substituted with up to 6, 5, 4, 3, 2 or 1 R H groups.
  • H is substituted with m R H groups, wherein m is an integer from 0 to 6.
  • m is 0, 1, 2, 3, 4, 5 or 6.
  • m is at least 1, 2, 3, 4, 5 or 6.
  • m is up to 6, 5, 4, 3, 2, or 1.
  • m is 0.
  • H is 6-membered to 12-membered
  • H is ; each of X 1 and X 2 is independently selected from CR 2 and N; each of X 3 and X 4 is independently selected from C and N; each of X 5 and X 6 is independently selected from CR 3 , N, NR 4 , O, and S; each of R 1 , R 2 and R 3 is independently selected at each occurrence from hydrogen and R 50 ; and R 4 is selected from R 51 .
  • X 3 and X 4 are each C.
  • X 5 is S.
  • X 6 is S.
  • at least one of X 5 and X 6 is selected from N, NR 4 , O and S.
  • X 6 is CR 3
  • R 3 is selected from hydrogen, halogen, -OR 52 , - N(R 52 ) 2 , -CN, -C(O)OR 52 , C 1-3 alkyl, and C 1-3 haloalkyl.
  • H is .
  • R 2 is selected from hydrogen, halogen, -OR 52 , -NH 2 , -N(R 52 ) 2
  • R 3 is selected from hydrogen, halogen, -OR 52 , -N(R 52 ) 2 , - CN, -C(O)OR 52 , C 1-3 alkyl, and C 1-3 haloalkyl.
  • R 1 is C 1-3 haloalkyl.
  • R 1 is .
  • H is thienopyrimidinyl or thienopyridinyl.
  • X 1 is CR 2 , X 2 is N, X 3 and X 4 are each C, X 5 is S, X 6 is CR 3 , and R 1 is selected from R 50 .
  • X 1 is CR 2 ; X 2 is N; X 3 and X 4 are each C; X 5 is S; X 6 is CH; R 1 is C 1-3 haloalkyl; and R 2 is selected from hydrogen, halogen, -OH, -NH 2 , -CN, C 1-3 alkyl, C 1-3 haloalkyl, C 2-3 alkenyl, and C 2-3 alkynyl.
  • H is selected from hydrogen, halogen, -OH, -NH 2 , -CN, C 1-3 alkyl, C 1-3 haloalkyl, C 2-3 alkenyl, and C 2-3 alkynyl.
  • H is selected from hydrogen, halogen, -OH, -NH 2 , -CN, C 1-3 alkyl
  • H is
  • R 2 is selected from hydrogen, halogen, -OH, alkoxy (e.g., -OR 52 , -OCH 3 , -OCH 2 CH 3 ), aminoalkyl, alkylamino, -N(R 52 ) 2 (e.g., - NH 2 , -NHCH 3 , -NHCH 2 CH 3 ), -N(CH 3 ) 2 , -CN, C 1-3 alkyl (e.g., -CH 3 ), cyclopropyl, C 1-3 alkyl- OR 52 (e.g., -CH 2 OH, -CH 2 OC(O)CH 3 ), C 1-3 alkyl-N(R 52 ) 2 , C 1-3 haloalkyl, C 2-3 alkenyl, and C 2-3 alkynyl.
  • R 2 is selected from hydrogen, halogen, -OH, alkoxy (e.g., -OR 52 , -OCH 3 , -OC
  • H is , wherein R 1 is selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, and haloalkyl, such as from alkyl and haloalkyl; R 2 is selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, and alkylamino, such as from H, halo, hydroxyl, and amino; and each of X 5 and X 6 is independently selected from S, CR 3 , N, NR 4 and O. In certain embodiments, up to one of X
  • H is ; each of X 1 and X 2 is independently CR 2 or N; each of X 7 , X 8 , X 9 , and X 10 is independently CR 16 , CR 17 R 18 , N, NR 19 , O, or S; each of R 16 , R 17 , and R 18 is independently selected at each occurrence from hydrogen and R 50 ; and R 19 is selected from R 51 .
  • X 1 is CR 2
  • R 2 is selected from hydrogen, halogen, -OH, -OR 52 , -NH 2 , -N(R 52 ) 2 , -CN, C 1-3 alkyl, C 1-3 alkyl-OR 52 , C 1-3 alkyl- N(R 52 ) 2 , C 1-3 haloalkyl, C 2-3 alkenyl, and C 2-3 alkynyl.
  • X 2 is N.
  • H is 5- or 6-membered
  • H is ; each of Y 1 , Y 2 , and Y 4 is independently CR 2 , N, NR 21 , O, or S; Y 5 is CR 20 , N, NR 21 , O, or S; Y 6 is C or N; Y 3 is a bond, CR 22 , or N, wherein when Y 3 is CR 22 or N, then each of Y 1 , Y 2 , and Y 4 is independently CR 2 , N, or NR 21 and Y 5 is CR 20 , N, or NR 21 ; each of R 2 and R 20 is independently selected at each occurrence from hydrogen and R 50 ; and R 21 is selected from R 51 .
  • L 1 comprises less than 20 atoms, such as less than 10 atoms. In some embodiments, L 1 comprises less than 20, 15, 10, 9, 8, 7, 6, 5, 4, or less than 3 atoms. In some embodiments, L 1 comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or at least 20 atoms. In some embodiments, L 1 comprises at least one heteroatom, such as L 1 comprises at least one nitrogen. In some embodiments, L 1 is substituted with one or more R 50 . In some embodiments, L 1 is unsubstituted.
  • L 1 is selected from bond, -O-, -S- , -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R 51 )-, -N(R 51 )C(O)-, - N(R 51 )C(O)N(R 51 )-, -S(O) 2- , -S(O)-, -N(R 51 )S(O) 2 -, -S(O) 2 N(R 51 )-, -N(R 51 )S(O) 2 N(R 51 )-, alkylene, alkenylene, heteroalkylene, and heteroalkenylene.
  • L 1 is selected from bond, -O-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R 51 )-, - N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -S(O) 2- , -S(O)-, -N(R 51 )S(O) 2 -, -S(O) 2 N(R 51 )-, - N(R 51 )S(O) 2 N(R 51 )-, C 1-6 alkylene and C 2-6 alkenylene, wherein the C 1-6 alkylene and C 2-6 alkenylene are each optionally substituted with one or more R 50 .
  • L 1 is a bond or -N(R 51 )-. In some embodiments, L 1 is not a bond. In some embodiments, L 1 is -N(R 51 )-, such as -NH-. In some embodiments, L 1 is selected from -O-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, - C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )S(O) 2 -, -S(O) 2 N(R 51 )-, C 1-4 alkylene, C 2-4 alkenylene, and C 1-4 heteroalkylene. In some embodiments, L 1 is -N(R 51 )-, wherein R 51 is selected from hydrogen and alkyl.
  • A is 3- to 12-membered heterocycle, such as 5- to 8-membered heterocycle.
  • A is 6-membered monocyclic heterocycle.
  • the heterocycle comprises at least one nitrogen atom.
  • A comprises at least one ring nitrogen.
  • A is
  • A selected from piperidinylene and piperazinylene, such as .
  • A is .
  • A is an aromatic, non-aromatic, saturated or unsaturated ring.
  • A is selected from arylene, cycloalkylene, heterocycloalkylene, N- heterocycloalkylene, heteroarylene, and N-heteroarylene.
  • A is 5- to 8- membered heterocycle, wherein the heterocycle comprises at least 1, 2, 3 or 4 ring heteroatoms selected from N, O and S.
  • A is substituted with one or more R A (e.g., by replacing a hydrogen connected to a ring atom with a bond to R A ).
  • A may be substituted with 0, 1, 2, 3, 4, 5, 6 or more R A groups.
  • A may be substituted with 1, 2, 3, 4, 5 or 6 R A groups, such as A substituted with 1 or 2 R A groups.
  • A is substituted with at least 1, 2, 3, 4, 5 or 6 R A groups.
  • A is unsubstituted.
  • A is substituted with n R A groups, wherein n is an integer from 0 to 6.
  • n is 0, 1, 2, 3, 4, 5 or 6.
  • n is at least 1, 2, 3, 4, 5 or 6.
  • n is up to 6, 5, 4, 3, 2, or 1.
  • n is 0.
  • R A is independently selected at each occurrence from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino,
  • heterocyclylalkylamino aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino.
  • two R A groups attached to the same atom or different atoms can together form a ring.
  • L 2 comprises less than 20 atoms, such as less than 10 atoms. In some embodiments, L 2 comprises less than 20, 15, 10, 9, 8, 7, 6, 5, 4, or less than 3 atoms. In some embodiments, L 2 comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or at least 20 atoms. In some embodiments, L 2 comprises at least one heteroatom, such as L 2 comprises at least one nitrogen. In some embodiments, L 2 is C 1-10 alkylene, such as C 1-4 alkylene, optionally substituted with one or more R 50 . In some embodiments, L 2 is substituted with one or more R 50 . In some embodiments, L 2 is unsubstituted.
  • L 2 is selected from bond, -O-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R 51 )-, -N(R 51 )C(O)-, - N(R 51 )C(O)N(R 51 )-, -S(O) 2- , -S(O)-, -N(R 51 )S(O) 2 -, -S(O) 2 N(R 51 )-, -N(R 51 )S(O) 2 N(R 51 )-, alkylene, alkenylene, heteroalkylene, and heteroalkenylene.
  • L 2 is selected from bond, -O-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R 51 )-, - N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -S(O) 2- , -S(O)-, -N(R 51 )S(O) 2 -, -S(O) 2 N(R 51 )-, - N(R 51 )S(O) 2 N(R 51 )-, C 1-6 alkylene and C 2-6 alkenylene, wherein the C 1-6 alkylene and C 2-6 alkenylene are each optionally substituted with one or more R 50 .
  • L 2 is selected from -O-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )S(O) 2 -, - S(O) 2 N(R 51 )-, C 1-4 alkylene and C 1-4 heteroalkylene.
  • L 2 is selected from - CH 2 -, -N(R 51 )-, -N(R 51 )CH 2 -, -N(R 51 )C(O)-, and -N(R 51 )S(O) 2 -.
  • L 2 is - CH 2 -.
  • B is 3- to 12-membered heterocycle, such as 6- to 12-membered bicyclic heterocycle.
  • the heterocycle comprises at least one nitrogen atom.
  • B is 6- to 12-membered heterocycle, wherein the heterocycle comprises at least 1, 2, 3 or 4 ring heteroatoms selected from N, O and S.
  • B is a 6,5- or 6,6-bicyclic heterocycle.
  • B comprises at least one ring nitrogen.
  • B is indolylene, such as optionally substituted with one or more R B .
  • B is y substituted with one or more R B , wherein each of E and G is independently N or C.
  • B is indolylene. In some embodiments, B is , optionally substituted with one or more R B . In some embodiments, B is phenylene. In some embodiments, R B is selected from halogen, methyl, -CN, -OR 52 , and -N(R 52 ) 2 .
  • B is selected
  • M 1 , M 2 , M 3 and M 4 are each independently selected from CR 7 , N and NR 9 ;
  • M 5 is selected from C and N;
  • M 6 , M 7 and M 8 are each independently selected from CR 8 , N, NR 9 , O and S;
  • M 9 , M 10 and M 11 are each independently selected from CR 10 , CR 11 R 12 , NR 13 , O and S;
  • R 7 , R 8 , R 10 , R 11 , and R 12 are each independently selected from hydrogen and R 50 ;
  • R 9 and R 13 are each independently selected from R 51 , wherein B may be connected at any ring atom to L 2 or L 3 (e.g., by replacing a hydrogen connected to a ring atom with a bond to L 2 or L 3 ).
  • B is substituted with one or more R B (e.g., by replacing a hydrogen connected to a ring atom with a b d R B ) B y be substituted with 0, 1, 2, 3, 4, 5, 6 or more R B groups.
  • B may be substituted with 1, 2, 3, 4, 5 or 6 R B groups, such as B substituted with 1 or 2 R B groups.
  • B is substituted with at least 1, 2, 3, 4, 5 or 6 R B groups.
  • B is substituted with p R B groups, wherein p is an integer from 0 to 6.
  • p is 0, 1, 2, 3, 4, 5 or 6.
  • p is at least 1, 2, 3, 4, 5 or 6.
  • p is up to 6, 5, 4, 3, 2, or 1.
  • p is an integer from 1 to 3.
  • R B is independently selected at each occurrence from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino,
  • heterocyclylalkylamino aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino.
  • R B is independently selected at each occurrence from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, heterocyclylalkyl, and heteroarylalkyl.
  • two R B groups attached to the same atom or different atoms can together form a ring.
  • L 3 comprises less than 30 atoms, such as less than 20 atoms. In some embodiments, L 3 comprises less than 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, or less than 3 atoms. In some embodiments, L 3 comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or at least 20 atoms. In some embodiments, L 3 comprises at least one heteroatom, such as L 3 comprises at least one nitrogen. In some embodiments, L 3 is C 1-10 alkylene, such as C 1-4 alkylene, optionally substituted with one or more R 50 . In some embodiments, L 3 is unsubstituted.
  • L 3 is selected from bond, -O-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, - C(O)O-, -OC(O)-, -C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -S(O) 2- , -S(O)-, - N(R 51 )S(O) 2 -, -S(O) 2 N(R 51 )-, -N(R 51 )S(O) 2 N(R 51 )-, alkylene, alkenylene, heteroalkylene, and heteroalkenylene.
  • two R 50 groups attached to the same atom or different atoms of L 3 optionally form a bridge or ring, such as a cyclopropyl ring.
  • L 3 is substituted with R 50 , wherein R 50 forms a bond to ring C.
  • L 3 is a bond.
  • L 3 is not a bond.
  • L 3 is C 1-6 alkylene, optionally substituted with one or more R 50 .
  • L 3 is selected from ,
  • L 3 comprises a stereocenter.
  • the stereocenter is in the R-configuration.
  • the stereocenter is in the S- configuration.
  • the R-isomer of L 3 is provided in at least 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% excess over the S-isomer.
  • the S-isomer of L 3 is provided in at least 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% excess over the R- isomer.
  • C is selected from C 3-12 carbocycle and 3- to 12-membered heterocycle, such as 5- to 12-membered heterocycle.
  • the heterocycle is saturated.
  • C is selected from 5- to 7- membered monocyclic heterocycle, 8- to 10-membered fused bicyclic heterocycle, and 7- to 12- membered spirocyclic heterocycle.
  • the heterocycle comprises at least one nitrogen atom, such as one or two nitrogen atoms.
  • C comprises at least one ring nitrogen.
  • C is a bond.
  • C is ; W 1 is C 1-4 alkylene, optionally substituted with one or more R 50 ; W 2 is selected from a bond; and C 1-4 alkylene, optionally substituted with one or more R 50 ; W 3 is selected from absent; and C 1-4 alkylene, optionally substituted with one or more R 50 ; wherein when W 3 is absent: W 1 is C 1 alkylene, W 2 is a bond, and L 3 is not a bond; W 1 is C 2-4 alkylene and W 2 is a bond; or W 1 and W 2 are each C 1 alkylene and L 3 is not a bond, wherein each C 1 alkylene is independently optionally substituted with one or more R 50 .
  • W 1 , W 2 and W 3 are each independently selected from C 1-4 alkylene, wherein each C 1-4 alkylene is optionally substituted with In some embodiments, W 1 , W 2 and W 3 are each C 1 alkylene. In some embodiments, W 1 and W 2 are each C 1 alkylene and W 3 is absent.
  • C is substituted with one or more R C (e.g., by replacing a hydrogen connected to a ring atom with a bond to R C ).
  • C may be substituted with 0, 1, 2, 3, 4, 5, 6 or more R C groups.
  • C may be substituted with 1, 2, 3, 4, 5 or 6 R C groups, such as C substituted with 1 or 2 R C groups.
  • C is substituted with at least 1, 2, 3, 4, 5 or 6 R C groups.
  • C is unsubstituted.
  • C is substituted with q R C groups, wherein q is an integer from 0 to 6.
  • q is 0, 1, 2, 3, 4, 5 or 6.
  • q is at least 1, 2, 3, 4, 5 or 6.
  • q is up to 6, 5, 4, 3, 2, or 1.
  • q is 1 or 2.
  • R C is selected from:
  • H is 5- to 12-membered heterocycle; A is 3- to 12-membered heterocycle; and B is 3- to 12-membered heterocycle.
  • H is 6- to 12-membered bicyclic heterocycle; A is 3- to 12-membered heterocycle; and B is 3- to 12-membered heterocycle.
  • H is 6- to 12- membered bicyclic heterocycle, optionally substituted with one or more R 50 ; A is 3- to 12- membered heterocycle; and B is 6- to 12-membered bicyclic heterocycle.
  • H is 5- to 12-membered heterocycle; A is 3- to 12-membered heterocycle; and B is 6- to 12- membered bicyclic heterocycle.
  • H is thienopyrimidinyl; A is 3- to 12- membered heterocycle; and B is 3- to 12-membered heterocycle.
  • H is 5- to 12-membered heterocycle; A is selected from piperidinylene and piperazinylene; and B is 3- to 12-membered heterocycle.
  • H is 5- to 12-membered heterocycle; A is 3- to 12-membered heterocycle; and B is indolylene.
  • H is thienopyrimidinyl; A is selected from piperidinylene and piperazinylene; and B is indolylene.
  • H is 5- to 12-membered heterocycle; A is 3- to 12-membered heterocycle; B is 3- to 12-membered heterocycle; C is 3- to 12-membered heterocycle;and m, n, p and q are each independently an integer from 0 to 3.
  • H is 6- to 12-membered bicyclic heterocycle; A is 3- to 12-membered heterocycle; B is 6- to 12-membered bicyclic heterocycle; C is 3- to 12-membered heterocycle; and m, n, p and q are each independently an integer from 0 to 3.
  • H is 5- to 12-membered heterocycle; A is 3- to 12-membered heterocycle; B is 3- to 12-membered heterocycle; and C is 3- to 12-membered heterocycle.
  • H is 6- to 12- membered bicyclic heterocycle; A is 3- to 12-membered heterocycle; B is 6- to 12-membered bicyclic heterocycle; and C is 3- to 12-membered heterocycle.
  • H is 6- to 12-membered bicyclic heterocycle; A is selected from piperidinylene and piperazinylene; B is 6- to 12-membered bicyclic heterocycle; and C is 3- to 12-membered heterocycle.
  • H is 6- to 12-membered bicyclic heterocycle
  • A is selected from piperidinylene and piperazinylene
  • B is 6- to 12-membered bicyclic heterocycle
  • m, n, p and q are each independently an integer from 0 to 3.
  • H is thienopyrimidinyl
  • A is 3- to 12-membered heterocycle
  • B is 6- to 12-membered bicyclic heterocycle.
  • H is thienopyrimidinyl; A is 3- to 12-membered heterocycle; B is 6- to 12- membered bicyclic heterocycle; and m, n, p and q are each independently an integer from 0 to 3.
  • H is 9- to 10-membered bicyclic heterocycle; A is 5- to 7-membered heterocycle; and B is 9-membered bicyclic heterocycle wherein each of said heterocycles comprises at least one nitrogen atom.
  • H is 9- to 10-membered bicyclic heterocycle; A is 5- to 7-membered heterocycle; B is 9-membered bicyclic heterocycle; and n is an integer from 0 to 3, wherein each of said heterocycles comprises at least one nitrogen atom.
  • H is thienopyrimidinyl; A is selected from piperidinylene and
  • H is thienopyrimidinyl; A is selected from piperidinylene and piperazinylene; B is indolylene; m is 1 or 2; n is an integer from 0 to 3; p is 2; and q is an integer from 0 to 4.
  • H is 6- to 12-membered bicyclic heterocycle; A is 3- to 12- membered heterocycle; B is 6- to 12-membered bicyclic heterocycle; C is a bond; and m, n, and p are each independently an integer from 0 to 3; and q is 1.
  • H is thienopyrimidinyl; A is selected from piperidinylene and piperazinylene; B is indolylene; C is a bond; and m, n, and p are each independently an integer from 0 to 3; and q is 1.
  • L 1 comprises less than 10 atoms
  • L 2 comprises less than 10 atoms
  • L 3 comprises less than 20 atoms.
  • L 1 , L 2 and L 3 each comprise at least 1 atom, such as at least 2 atoms.
  • L 1 , L 2 and L 3 are each independently selected from bond, -O-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, - C(O)O-, -OC(O)-, -C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -S(O) 2- , -S(O)-, - N(R 51 )S(O) 2 -, -S(O) 2 N(R 51 )-, -N(R 51 )S(O) 2 N(R 51 )-, alkylene, alkenylene, heteroalkylene, and heteroalkenylene.
  • L 1 , L 2 and L 3 are each independently selected from - CH 2 -, -CH 2 CH 2 -, -CH 2 CH(CH 3 )-, -N(R 51 )-, -N(R 51 )CH 2 -, -N(R 51 )C(O)-, and -N(R 51 )S(O) 2 -.
  • L 1 is selected from -O-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, -C(O)O-, - OC(O)-, -C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -S(O) 2- , -S(O)-, -N(R 51 )S(O) 2 -, - S(O) 2 N(R 51 )-, -N(R 51 )S(O) 2 N(R 51 )-, alkylene, alkenylene, heteroalkylene, and heteroalkenylene; and L 2 and L 3 are independently selected from C 1-4 alkylene, optionally substituted with one or more R 50 .
  • L 1 , L 2 and L 3 are each independently selected from -O-, -S-, - N(R 51 )-; C 1-4 alkylene and 1- to 4-membered heteroalkylene, each of which is optionally substituted with one or more R 50 .
  • L 1 is -NH-
  • L 2 is -CH 2 -
  • L 3 is C 1-4 alkylene, optionally substituted with one or more R 50 .
  • L 1 is -NH-
  • L 2 is - CH 2 -
  • L 3 is a bond.
  • L 1 and L 2 are each independently selected from bond, -O-, -S-, - N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R 51 )-, -N(R 51 )C(O)-, - N(R 51 )C(O)N(R 51 )-, -S(O) 2- , -S(O)-, -N(R 51 )S(O) 2 -, -S(O) 2 N(R 51 )-, -N(R 51 )S(O) 2 N(R 51 )-, alkylene, alkenylene, heteroalkylene, and heteroalkenylene.
  • L 1 and L 2 are each independently selected from -CH 2 -, -N(R 51 )-, -N(R 51 )CH 2 -, -N(R 51 )C(O)-, and - N(R 51 )S(O) 2 -.
  • L 1 is selected from -O-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, - C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -S(O) 2- , -S(O)-, - N(R 51 )S(O) 2 -, -S(O) 2 N(R 51 )-, -N(R 51 )S(O) 2 N(R 51 )-, alkylene, alkenylene, heteroalkylene, and heteroalkenylene; and L 2 is C 1-4 alkylene, optionally substituted with one or more R 50 .
  • L 1 and L 2 are each independently selected from -O-, -S-, -N(R 51 )-; C 1-4 alkylene and 1- to 4-membered heteroalkylene, each of which is optionally substituted with one or more R 50 .
  • L 1 is -NH-
  • L 2 is -CH 2 -.
  • the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising administerin a com ound of Formula (I):
  • H is selected from C 3-12 carbocycle and 3- to 12-membered heterocycle
  • A is selected from bond, C 3-12 carbocycle, and 3- to 12-membered heterocycle
  • B is selected from C 3-12 carbocycle and 3- to 12-membered heterocycle
  • C is selected from bond, C 3-12 carbocycle, and 3- to 12-membered heterocycle
  • each of L 1 , L 2 , and L 3 is independently selected from bond, -O-, -S-, -N(R 51 )-, - N(R 51 )CH 2 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 )-, - C(O)N(R 51 )C(O)-, -C(O)N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)O-, -OC(O)N(R 51 )-, -C(NR 51 )-, -N(R 51 )C(NR 51 )-, -C(NR 51 )N
  • R 50 is, at each occurrence, independently selected from:
  • R 51 is independently selected at each occurrence from:
  • R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 ;
  • each of R H , R A , and R B is, at each occurrence, independently selected from R 50 , or two R H groups, two R A groups, or two R B groups attached to the same atom or different atoms can together optionally form a bridge or ring;
  • R C is, at each occurrence, independently selected from hydrogen or R 50 , or two R C groups attached to the same atom or different atoms can together optionally form a bridge or ring;
  • n is an integer from 1 to 3;
  • n is an integer from 0 to 3;
  • p is an integer from 0 to 6;
  • q is an integer from 0 to 6.
  • H is thienopyrimidinyl
  • A is selected from piperidinylene and piperazinylene
  • C is selected from bond, C 3-12 carbocycle, and 3- to 12-membered heterocycle
  • L 1 and L 2 are each independently selected from -O-, -S-, -NH-, and -CH 2 -;
  • L 3 is selected from bond, -O-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, -C(O)O-, -OC(O)-, - OC(O)O-, -C(O)N(R 51 )-, -C(O)N(R 51 )C(O)-, -C(O)N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)-, - N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)O-, -OC(O)N(R 51 )-, -C(NR 51 )-, -N(R 51 )C(NR 51 )-, - C(NR 51 )N(R 51 )-, -N(R 51 )C(NR 51 )N(R 51
  • n is an integer from 1 to 3;
  • n is an integer from 0 to 3;
  • p is an integer from 0 to 6;
  • q is an integer from 0 to 6.
  • the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising administering a stereoisomer of a compound of Formula (I).
  • the stereoisomer is in enantiomeric excess.
  • the stereoisomer is provided in at least 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%, enantiomeric excess.
  • the stereoisomer is provided in greater than 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%, enantiomeric excess. In some embodiments, the stereoisomer is in greater than 95% enantiomeric excess, such as greater than 99% enantiomeric excess.
  • the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising administering a stereoisomer of a compound of Formula (I).
  • the stereoisomer is in diastereomeric excess.
  • the stereoisomer is provided in at least 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%, diastereomeric excess.
  • the stereoisomer is provided in greater than 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%, diastereomeric excess. In some embodiments, the stereoisomer is in greater than 95% diastereomeric excess, such as greater than 99%
  • the compound of Formula (I) is preferably used in the subject methods as a non-racemic mixture, wherein one enantiomer is present in excess of its
  • the compound is provided in at least 96% enantiomeric excess, meaning the compound has less than 2% of the corresponding enantiomer. In some embodiments, the compound is provided in at least 96% diastereomeric excess, meaning the compound has less than 2% of the corresponding
  • the compound of Formula (I) is preferably used in the subject methods as a non-racemic mixture wherein the (+)-isomer is the major component of the mixture.
  • such mixture will contain no more than about 10% of the (–)-isomer, meaning the ratio of (+)- to (–)-isomers is at least about 9:1, and preferably less than 5% of the (–)-isomer, meaning the ratio of (+)- to (–)-isomers is at least about 19:1.
  • the compound used has less than 2% of the (–)-isomer, meaning it has an enantiomeric excess of at least about 96%.
  • the compound has an enantiomeric excess of at least 98%.
  • the compound has an enantiomeric excess of at least 99%.
  • the compound of Formula (I) is preferably used in the subject methods as a non-racemic mixture wherein the (–)-isomer is the major component of the mixture.
  • such mixture will contain no more than about 10% of the (+)-isomer, meaning the ratio of (–)- to (+)-isomers is at least about 9:1, and preferably less than 5% of the (+)-isomer, meaning the ratio of (–)- to (+)-isomers is at least about 19:1.
  • the compound used has less than 2% of the (+)-isomer, meaning it has an enantiomeric excess of at least about 96%.
  • the compound has an enantiomeric excess of at least 98%.
  • the compound has an enantiomeric excess of at least 99%.
  • the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising administering a stereoisomer of a compound of Formula (I), wherein:
  • H is 5- to 12-membered heterocycle
  • A is 3- to 12-membered heterocycle
  • B is 3- to 12-membered heterocycle
  • C is selected from bond, C 3-12 carbocycle, and 3- to 12-membered heterocycle
  • each of L 1 , L 2 , and L 3 is independently selected from bond, -O-, -S-, -N(R 51 )-, - N(R 51 )CH 2 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 )-, - C(O)N(R 51 )C(O)-, -C(O)N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)O-, -OC(O)N(R 51 )- -C(NR 51 )- -N(R 51 )C(NR 51 )-, -C(NR 51 )C(NR
  • R 50 is, at each occurrence, independently selected from:
  • R 51 is independently selected at each occurrence from: hydrogen, -C(O)R 52 , -C(O)OR 52 , -C(O)N(R 52 ) 2 , -C(O)NR 53 R 54 ;
  • R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 ;
  • each of R H , R A , and R B is, at each occurrence, independently selected from R 50 , or two R H groups, two R A groups, or two R B groups attached to the same atom or different atoms can together optionally form a bridge or ring;
  • R C is, at each occurrence, independently selected from hydrogen or R 50 , or two R C groups attached to the same atom or different atoms can together optionally form a bridge or ring; and m is an integer from 0 to 3; and
  • each of n, p, and q is independently an integer from 0 to 12.
  • the stereoisomer of a compound of Formula (I) is provided in at least 20%, 30%, 40%, 50%, 55%, 60%, 65% 70% 75% 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%, enantiomeric excess.
  • the stereoisomer is provided in greater than 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%, enantiomeric excess.
  • the stereoisomer is in greater than 95% enantiomeric excess, such as greater than 99% enantiomeric excess.
  • a compound used in a method of the disclosure covalently binds to menin and inhibits the interaction of menin with MLL. Such bonding may lead to an increase in the affinity of the compound for menin, which is an advantageous property in many applications, including therapeutic and diagnostic uses.
  • a compound used in a method of the disclosure comprises an electrophilic group capable of reacting with a nucleophilic group present in a menin protein. Suitable electrophilic groups are described throughout the
  • nucleophilic groups include, for example, cysteine moieties present in the binding domain of a menin protein.
  • a cysteine residue in the menin binding domain may react with the electrophilic group of a compound for use in the methods of the disclosure, leading to formation of a conjugate product.
  • the compounds for use in the methods of the disclosure are capable of covalently bonding to the cysteine residue at position 329 of a menin isoform 2 (SEQ ID NO: 2) or cysteine 334 in menin isoform 1 (SEQ ID NO: 1).
  • one or more of R A , R B and R C when present, comprises a functional group that covalently reacts with one or more residues on menin.
  • the functional group covalently reacts with one or more cysteine residues on menin.
  • the functional group covalently reacts with a cysteine on menin at position 329 relative to SEQ ID NO: 2 when optimally aligned or position 334 relative to SEQ ID NO: 1 when optimally aligned.
  • the functional group covalently reacts with one or more residues on menin selected from cysteine 329, cysteine 241, and/or cysteine 230 on menin relative to SEQ ID NO: 2 when optimally aligned. In some embodiments, the functional group covalently reacts with cysteine 329 relative to SEQ ID NO: 2 when optimally aligned.
  • one or more of R A , R B and R C when present, comprises a moiety that covalently reacts with one or more residues on menin.
  • one or more of R A , R B and R C when present, comprises a moiety that covalently reacts with one or more isoforms of menin, for example, isoform 1 (SEQ ID NO: 1), isoform 2 (SEQ ID NO: 2) or isoform 3 (SEQ ID NO: 3) of menin.
  • one or more of R A , R B and R C when present, comprises a moiety that covalently reacts with menin, wherein the menin protein shares 60% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or 99% or more sequence identity with isoform 1 (SEQ ID NO: 1), isoform 2 (SEQ ID NO: 2) or isoform 3 (SEQ ID NO: 3).
  • one or more of R A , R B and R C when present, comprises an electrophilic group that is susceptible to nuclephilic attack from a residue on menin.
  • one or more of R A , R B and R C when present, comprises a moiety other than an electrophile, wherein the moiety is capable of binding to or covalently reacting with a residue on menin.
  • a compound or salt of Formula (I) is capable of (a) binding covalently to menin and (b) inhibiting the interaction of menin and MLL.
  • R C comprises a functional group that covalently reacts with one or more residues on menin.
  • the functional group covalently reacts with one or more cysteine residues on menin.
  • the functional group covalently reacts with a cysteine on menin at position 329 relative to SEQ ID NO: 2 when optimally aligned or position 334 relative to SEQ ID NO: 1 when optimally aligned.
  • R C is a moiety comprising an alpha, beta-unsaturated carbonyl; an alpha, beta-unsaturated sulfonyl; an epoxide; an aldehyde; sulfonyl fluoride; a halomethylcarbonyl, a dihalomethylcarbonyl, or a trihalomethylcarbonyl.
  • R C is selected from:
  • L 5 is selected from a bond; and C 1-6 alkylene, C 1-6 heteroalkylene, C 2-6 alkenylene, and C 2-6 alkynylene, each of which is independently optionally substituted with one or more R 32 ;
  • R 22 and R 23 are each independently selected from:
  • each C 3-10 carbocycle and 3- to 10-membered heterocycle of R 22 and R 23 is independently optionally substituted with one or more substituents selected from halogen, -OR 20 , -SR 20 , -N(R 20 ) 2 , - N(R 20 )C(O)R 20
  • R 24 is selected from:
  • each C 3-10 carbocycle and 3- to 10-membered heterocycle of R 24 is independently optionally substituted with one or more substituents selected from halogen, -OR 20 , -SR 20 , -N(R 20 ) 2 , - N(R 20 )C(O)R 20
  • R 20 is independently selected at each occurrence from R 52 ;
  • R 32 is independently selected at each occurrence from R 50 .
  • R 23 is selected from:
  • each C 3-10 carbocycle and 3- to 10-membered heterocycle is independently optionally substituted with one or more substituents selected from halogen, -OR 20 , -SR 20 , -N(R 20 ) 2 , -N(R 20 )C(O)R 20
  • R 23 is selected from:
  • 3- to 10-membered heterocycle optionally substituted with one or more substituents selected from halogen, -OR 20 , -SR 20 , -N(R 20 ) 2 , -N(R 20 )C(O)R 20
  • R 22 is selected from:
  • each C 3-10 carbocycle and 3- to 10-membered heterocycle is independently optionally substituted with one or more substituents selected from halogen, -OR 20 , -SR 20 , -N(R 20 ) 2 , -N(R 20 )C(O)R 20
  • R 22 is selected from hydrogen, -CN; and C 1-6 alkyl optionally substituted with one or more substituents selected from halogen, -OR 20 , -SR 20 , and -N(R 20 ) 2 .
  • R 22 and R 23 together with the carbon atoms to which they are attached, form a 5-, 6-, or 7-membered carbocyclic ring.
  • the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprisin administerin a com ound of Formula III :
  • H is selected from C 3-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more R 50 ;
  • each of Z 1 , Z 2 , Z 3 , and Z 4 is independently selected from -C(R A1 )(R A2 )-, -C(R A1 )(R A2 )- C(R A1 )(R A2 )-, -C(O)-, and -C(R A1 )(R A2 )-C(O)-, wherein no more than one of Z 1 , Z 2 , Z 3 , and Z 4 is -C(O)- or -C(R A1 )(R A2 )-C(O)-;
  • B is selected from bond, C 3-12 carbocycle and 3- to 12-membered heterocycle
  • C is selected from bond, C 3-12 carbocycle and 3- to 12-membered heterocycle
  • L 1 , L 2 and L 3 are each independently selected from bond, -O-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 )-, -C(O)N(R 51 )C(O)-, - C(O)N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)O-, -OC(O)N(R 51 )-, - C(NR 51 )-, -N(R 51 )C(NR 51 )-, -C(NR 51 )N(R 51 )-, -N(R 51 )C(
  • R B is independently selected at each occurrence from R 50 , or two R B groups attached to the same atom or different atoms can together optionally form a bridge or ring;
  • R C is independently selected at each m hydrogen and R 50 , or two R C groups attached to the same atom or different atoms can together optionally form a bridge or ring;
  • R A1 and R A2 are each independently selected at each occurrence from hydrogen and R 50 ;
  • n is an integer from 0 to 6;
  • p is an integer from 1 to 6;
  • R 50 is independently selected at each occurrence from:
  • R 51 is independently selected at each occurrence from:
  • R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 .
  • a compound of Formula (III) may be represented by:
  • R 1 , R 2 and R 3 are each independently selected at each occurrence from hydrogen and R 50 .
  • R 1 is selected from R 50 .
  • R 1 is C 1-3 haloalkyl, such as -CH 2 CF 3 .
  • R 2 is selected from hydrogen and R 50 .
  • R 2 is selected from hydrogen, halogen, -OH, -OR 52 , -NH 2 , -N(R 52 ) 2 , -CN, C 1-3 alkyl, C 1-3 alkyl-OR 52 , C 1-3 alkyl-N(R 52 ) 2 , C 1-3 haloalkyl, C 2-3 alkenyl, and C 2-3 alkynyl.
  • R 2 is selected from halogen, -OH, -OR 52 , -NH 2 , -N(R 52 ) 2 , -CN, C 1-3 alkyl, - CH 2 OH, -CH 2 OR 52 , -CH 2 NH 2 , -CH 2 N(R 52 ) 2 , C 1-3 alkyl-N(R 52 ) 2 , C 1-3 haloalkyl, C 2-3 alkenyl, and C 2-3 alkynyl, such as R 2 is selected from -OH, -OR 52 , -NH 2 , -N(R 52 ) 2 , -CN, and C 1-2 alkyl.
  • R 2 is selected from -NH 2 , -CH 3 , -OCH 3 , -CH 2 OH, and -NHCH 3 .
  • R 3 is selected from hydrogen, halogen, -OH, -N(R 52 ) 2 , -CN, -C(O)OR 52 , C 1-3 alkyl, and C 1-3 haloalkyl.
  • R 52 is selected from selected from hydrogen and alkyl, such as R 52 is hydrogen.
  • A is selected from
  • the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising administering a compound of Formula (IV):
  • G a is selected from C 3-12 carbocycle and 3- to 12-membered heterocycle, each of which is substituted with -E 1 -R 4a and optionally further substituted with one or more R 50 ;
  • R 2a is selected from hydrogen, alkyl, alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, optionally substituted heteroaryl, and aralkyl;
  • R 3a and R 3b are each independently selected from hydrogen, alkyl, halo, hydroxy, cyano, amino, alkylamino, dialkylamino, haloalkyl, alkoxy, and haloalkoxy;
  • X a is selected from hydrogen, alkyl, halo, hydroxy, cyano, amino, alkylamino, dialkylamino, haloalkyl, alkoxy, and haloalkoxy;
  • Y a is selected from cyano, hydroxy, and -CH 2 R 50 ;
  • R 4a is selected from hydrogen, alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, optionally substituted heteroaryl, aralkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl;
  • R 14a is selected from hydrogen and alkyl
  • R 50 is independently selected at each occurrence from:
  • R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 .
  • G a is piperidinyl.
  • a compound of Formula (IV) is represented by:
  • R 17a and R 18a is independently selected from hydrogen and R 50 ;
  • R 24a is selected from hydrogen and fluoro.
  • R 3a and R 3b are independently selected from hydrogen and halo.
  • X a and Y a do not form a chemical bond, and X a is hydrogen.
  • R 4a is selected from hydrogen; and alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclo, heteroaryl, aralkyl, (heterocyclo)alkyl, and
  • R 4a is R 50 -substituted heterocyclo.
  • reaction times and conditions are intended to be approximate, e.g., taking place at about atmospheric pressure within a temperature range of about -10 °C to about 110 °C over a period of about 1 to about 24 hours; reactions left to run overnight average a period of about 16 hours.
  • a compound of the present disclosure for use in the subject methods for example, a compound of a formula given in Table 1-6, 9-10, 12, 14, 16, 18, 20, 22 or 23, is synthesized according to one of the general routes described herein, or by methods generally known in the art.
  • exemplary compounds for use in the subject methods may include, but are not limited to, a compound or salt thereof selected from Table 1-6, 9-10, 12, 14, 16, 18, 20, 22 or 23.
  • Table 1 Structures and activities for thienopyrimidine class of compounds measured by FP and HTRF. NA– no activity, NS - no saturation on titration curve. IC 50 values ⁇ 100 ⁇ M are in bold.
  • Table 2 Structures and activities for thienopyrimidine class of compounds. NA– no activity, NS - no saturation on titration curve. IC 50 values ⁇ 100 ⁇ M are in bold.
  • Table 3 Structures and activities for benzodiazepine class of compounds measured by FP and HTRF. NA– no activity, ND– not determined, IC 50 values ⁇ 100 ⁇ M are in bold.
  • Table 4 Structures and activities of hits from MFL and 6G10 analogues measured by FP and HTRF. NA– no activity, ND– not determined. [0147] Table 5
  • Boc- intermediate was dissolved in 4M HCl in dioxane (40 mL) and stirred for 2 h. Solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and saturated sodium carbonate solution. The organic layer was washed with brine, dried over MgSO 4 and evaporated to afford N-(piperidin-4-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3- d]pyrimidin-4-amine (5.3 g), which was used in later steps without purification.
  • reaction mixture was cooled in an ice-water bath and concentrated ammonia in water (40 mL) was added dropwise. The heterogeneous mixture was stirred for another 3 h and filtered off to obtain the carboxamide.
  • Methanesulfonic anhydride (Ms 2 O) (662 mg, 3.81 mmol) was slowly added to a solution of 5-formyl-1-(2-hydroxyethyl)-4-methyl-1H-indole-2-carbonitrile (290 mg, 1.27 mmol) and DIPEA (1.1 mL) in THF (6.3 mL). After stirring for 10 minutes, the mixture was diluted with saturated bicarbonate solution and stirred for 20 minutes, and the product was filtered off and thoroughly dried.
  • reaction mixture was purified using preparative thin-layer chromatography (pTLC) eluting with
  • Compound 24 was synthesized starting with tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate. Compound 24 was converted to its hydrochloride salt by dissolving it in methanol (0.1 mL), adding 1 equivalent of 1M HCl in water and evaporating.
  • Compound 28 was synthesized starting with tert-butyl azetidin-3-ylcarbamate. Compound 28 was converted to its hydrochloride salt by dissolving it in methanol (0.1 mL), adding 1 equivalent of 1M HCl in water and evaporating.
  • Compound 32 was synthesized starting with tert-butyl (R)-pyrrolidin-3-ylcarbamate. Compound 32 was converted to its hydrochloride salt by dissolving it in methanol (0.1 mL), adding 1 equivalent of 1M HCl in water and evaporating.
  • the mesylate intermediate was dissolved in DMF (0.5 mL) and 5- formyl-4-methyl-1H-indole-2-carbonitrile (50 mg, 0.27 mmol) and cesium carbonate (265 mg, 0.81 mmol) were added. After stirring for 3 h at 60 °C, TLC showed consumption of aldehyde.
  • the reaction mixture was diluted with water (20 mL) and extracted with DCM (2 x 25 mL). The organic phase was evaporated with silica gel and loaded on a silica gel column.
  • reaction mixture was transferred to a separatory funnel and washed with 1M NaOH (10 mL).
  • the organic phase was evaporated with silica gel and loaded on a silica gel column.
  • the product was eluted with DCM:MeOH:NH 3 *H 2 O (starting from 40:1:0.1 and decreasing to 20:1:0.1). Evaporation of solvent gave the trityl protected intermediate (25 mg) that was dissolved in chloroform (1 mL) and trifluoroacetic acid (0.5 mL). After 5 minutes, the reaction mixture was quenched with saturated sodium carbonate solution and extracted with ethyl dichloromethane.
  • Trifluoromethanesulfonic anhydride (2.6 mL, 15 mmol) was added to a solution of 4-nitrophenyl-2-ethanol (1.67 g, 10 mmol) and 2,6-lutidine (2.1 mL, 18 mmol) in DCM (50 mL) at -50 °C. The reaction mixture allowed to warm to room temperature and then washed with NaHCO 3 , followed by 4% citric acid solution, and finally with brine. The reaction mixture was dried over Na 2 SO 4 . After concentration, the 4-nitrophenethyl trifluoromethanesulfonate
  • Th ti i ture was slowly warmed to room temperature, evaporated with silica gel at room temperature, loaded on a column, and eluted with DCM:MeOH:NH 3 -H 2 O (starting with 15:1:0.1 and decreasing to 10:1:0.1) to isolate N-(4-(2-(2- cyano-4-methyl-5-((4-(6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-ylamino)piperidin-1- yl)methyl)-1H-indol-1-yl)ethyl)phenyl)acrylamide with a minor impurity of the starting material.
  • N-(4-(2-(2-Cyano-4-methyl-5-((4-(6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4- ylamino)piperidin-1-yl)methyl)-1H-indol-1-yl)ethyl)phenyl)acrylamide was recrystallized from MeOH to afford pure product (510 mg).
  • 2-(6-nitropyridin-3-yl)ethyl trifluoromethanesulfonate was synthesized from 2-(6-nitropyridin-3-yl)ethanol (840 mg, 5 mmol).
  • reaction mixture was slowly warmed to room temperature, evaporated with silica gel at room temperature, loaded on a column, eluted with DCM:MeOH:NH 3 -H 2 O (starting with 15:1:0.1 and decreasing to 10:1:0.1), and recrystallized from MeOH to afford N-(5-(2-(2-cyano-4-methyl-5-((4-(6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-1H-indol-1- yl)ethyl)pyridin-2-yl)acrylamide (470 mg).
  • III-3-2 500 mg, 1.53 mmol
  • wet Pd/C (10%) in MeOH (10 mL) was stirred under H 2 atmosphere at room temperature overnight.
  • the reaction mixture was filtered over celite and the cake was washed with MeOH and ethyl acetate.
  • the filtrate was concentrated to give III-3-3 (334 mg, yield: 92%) as a colorless oil.
  • III-3-3 360 mg, 1.42 mmol
  • tert-butyl 4-amino-3,3-difluoropiperidine-1- carboxylate 334 mg, 1.42 mmol
  • isopropanol 10 ml
  • III-3-4 (110 mg, 0.24 mmol), in HCl/MeOH (4N) (10 mL) was stirred at room temperature for 2 hours. The mixture was concentrated to give 100 mg of III-3-5
  • V-1-2 130 mg, 0.31mmol
  • HCl/MeOH 10 mL
  • the mixture was concentrated to give V-1-3 hydrochloride crude (98 mg, yield: 89%) as a white solid.
  • V-1-1 125 mg, 0.5 mmol
  • Zn(CN) 2 60 mg, 0.5 mmol
  • Pd 2 (dba) 3 5 mg, 0.005 mmol
  • Zn 3 mg, 0.05 mmol
  • Pd(dppf)Cl 2 4 mg, 0.005 mmol
  • NMP 5 ml
  • TLC TLC showed that the reaction was complete.
  • V-3-1 500 mg, 2 mmol
  • 20 mL of about 10 N H 2 SO 4 aqueous solution was stirred at 100 o C for 6 hours. TLC showed that the reaction was complete.
  • the reaction mixture was extracted by EA, dired over Na 2 SO 4 . Solvent was removed under vacuum to V-3-2 crude as a brown solid (200 mg, 40%), which was used in next step without further purifications.
  • V-3-4 120 mg, 0.3 mmol
  • HCl/MeOH 8 ml
  • Solvent was removed under vacuum and the residue was diluted with DCM and washed with NaHCO 3 .
  • the organic solution was washed with brine, dired over Na 2 SO 4 and concentrated to give V-3-5 crude as a yellow oil (120 mg).
  • Step A Preparation of Compound 3-2: To a solution of 3-1 (6 g, 25 mmol) in THF (100 mL) was added LiAlH 4 (1.5 g, 37 mol) in small portions at 0 °C. The reaction was stirred until the TLC showed that the reaction was complete (about 2h). The reaction mixture was quenched by addition of EtOAc and partitioned between EtOAc and H 2 O. The organic layer was washed with brine and dried over Na 2 SO 4 . Solvent was removed under vacuum to give 3-2 as a yellow solid (5.2 g, yield: 97%).
  • Step B Preparation of Compound 3-4: To a solution of 3-2 (800 mg, 3.7 mmol) and Et 3 N (740 mg, 7.4 mmol) in CH 2 Cl 2 (10 mL) was added MsCl (428 mg, 4.4 mmol) at 0 °C. The reaction was stirred at room temperature for 30 min, then quenched by addition of NaHCO 3 , washed with brine and dried over Na 2 SO 4 . Solvent was removed under vacuum to give 3-3, which was used in the next step without further purification.
  • Step C Preparation of Compound 3-5: A mixture of 3-4 (2.2 g, 5.8 mmol), 6-(2,2,2- trifluoroethyl)-N-(piperidin-4-yl)thieno-[2, amine (2.3 g, 6.9 mmol) and Et 3 N (3.5 g, 34 mmol) in CH 2 Cl 2 (50 mL) was stirred at room temperature for 1 hour before NaBH(OAc) 3 (7.3 g, 34 mmol) was added to the reaction. The reaction mixture was stirred at room temperature overnight. The reaction mixture was then partitioned between CH 2 Cl 2 and NaHCO 3. The organic layer was washed with brine and dried over Na 2 SO 4 . Solvent was removed under vacuum and the residue was purified by silica gel column chromatography
  • Step A Preparation of Compound 29-2: To a solution of 29-1 (200 mg, 1.0 mmol) and Et 3 N (202 mg, 2.0 mmol) in CH 2 Cl 2 (10 mL) was added MsCl (172 mg, 1.5 mmol) at 0 °C. The reaction mixture was stirred at room temperature overnight before water was added to the reaction. The solution mixture was extracted with CH 2 Cl 2 3 times. The organic layer was washed with brine and dried over Na 2 SO 4 . The solution was filtered and concentrated to give 29-2 as a white solid (250 mg, yield: 90%).
  • Step B Preparation of Compound 29-3: A mixture of 29-2 (250 mg, 0.9 mmol), 5- formyl-4-methyl-1H-indole-2-carbonitrile (82 mg, 0.45 mmol) and Cs 2 CO 3 (438 mg, 1.35mmol) in DMF (6 mL) was stirred at 60 °C for 6 hours before water (15 mL) was added. The reaction mixture was extracted with ethyl acetate (20 mL x 3). The combined organic solution was washed with brine and dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by silica gel column chromatography (33% EtOAc in pet. ether to 50% EtOAc in pet. ether) to give 29-3 as a yellow solid (110 mg, yield: 33%).
  • Step C Preparation of Compound 29-4: A mixture of 29-3 (110 mg, 0.3 mmol), 6-(2,2,2- trifluoroethyl)-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine hydrochloride (116 mg, 0.3 mmol) and Et 3 N (185 mg, 1.8 mmol) in CH 2 Cl 2 (20 mL) was stirred at room temperature for 1 hour before NaBH(OAc) 3 (381 mg, 1.8 mmol) was added to the reaction under ice bath. The reaction mixture was stirred at room temperature overnight. Solvent was removed by vacuum and the residue was purified by silica gel column chromatography (2.5% MeOH in CH 2 Cl 2 ) to give 29-4 as a solid (180 mg, yield: 90%).
  • Step D Preparation of Compound 29-5: A solution of tert-butyl carbamate 29-4 (180 mg, 0.27 mmol) in HCl/MeOH (10 mL) was stirred at room temperature for 2 hours. Solvent was removed and a solution of NH 3 (7N) in MeOH (10 mL) was added. The reaction mixture was stirred for 10 minutes before solvent was removed and the residue purified by silica gel column chromatography (10% MeOH in CH 2 Cl 2 ) to give 29-5 as an oil (100 mg, yield:65%).
  • Step E Preparation of Compound 29: To a mixture of 29-5 (100 mg, 0.17 mmol) and Et 3 N (27 mg, 0.26 mmol) in CH 2 Cl 2 /THF (10 mL, 1:1) was add slowly acryloyl chloride (19 mg, 0.21 mmol) at -78 °C under N 2 . The mixture was stirred at room temperature for 15 min, then NH 3 ⁇ MeOH was added. Solvent was removed and the residue was purified by silica gel column chromatography (10% MeOH in CH 2 Cl 2 ) to give final product 29 as a solid (78 mg, yield: 71 %).
  • Step C Preparation of Compound 10-3: To a solution of 10-2 (230 mg, 1.01 mmol) in CH 2 Cl 2 was added Et 3 N (0.42 mL, 3.03 mmol) at 0 °C, followed by methanesulfonyl chloride (231 mg, 2.02 mmol). The resulting mixture was stirred at room temperature for 1h. CH 2 Cl 2 was added, the mixture was washed with NaHCO 3 , and the organic layer was washed with brine and dried over Na 2 SO 4 . Solvent was removed to give 10-3 (330 mg) as a brown oil.
  • Step A Preparation of Compound 12-1: A mixture of 3-3 and Bu 4 CN (3.5 g, 13 mmol) in CH 3 CN (30 mL) was stirred under reflux for 10 h until TLC showed that the reaction was complete. Solvent was removed and the residue was purified by silica gel column
  • Step B Preparation of Compound 12-2: To a solution of 12-1 (460 mg, 2 mmol) in CH 2 Cl 2 was added DIBAL-H (6 mmol) dropwise at -78 °C and the reaction mixture stirred at the same temperature for 2 h. The reaction was quenched with NH 4 Cl and dried over Na 2 SO 4.
  • Step C Preparation of Compound 12-3: To a solution of 12-2 (200 mg, 1 mmol) in THF was added BH 3 /THF (4 mmol) dropwise at -78 °C. The reaction was stirred for 10 h before it was quenched by MeOH. Solvent was removed under vacuum to give 12-3 as a white solid (200 mg, yield: 99%), used in the next step without further purifications.
  • Step D Preparation of Compound 12-5: To a solution of 12-3 (120 mg, 0.54 mmol) and Et 3 N (109 mg, 1.0 mmol) in CH 2 Cl 2 (10 mL) was added MsCl (73 mg, 0.63 mmol) at 0 °C. The reaction was stirred at room temperature for 30 min. The reaction was quenched by NaHCO 3 , washed with brine and dried over Na 2 SO 4 . Solvent was removed under vacuum to give crude 12- 4, used in the next step without further purification.
  • Step E Preparation of Compound 12-6: A mixture of 12-5 (30 mg, 0.1 mmol), 6-(2,2,2- trifluoroethyl)-N-(piperidin-4-yl)thieno-[2,3-d]pyrimidin-4-amine (50 mg, 0.12 mmol) and Et 3 N (60 mg, 0.6 mmol) in CH 2 Cl 2 (10 mL) was stirred at room temperature for 1 hour before
  • Step F Preparation of Compound 11: To a solution of 12-6 (130 mg, 0.19 mmol) in CH 2 Cl 2 (3 mL) was added TFA (2 mL). The reaction was stirred for 4h at room temperature. Solvent was removed under vacuum to give a residue, which was diluted with CH 2 Cl 2 and washed with NaHCO 3 . The organic layer was washed with brine and dried over Na 2 SO 4 . Solvent was removed under vacuum to give compound 11 as a yellow foam (100 mg, crude).
  • Step A Preparation of Compound 18-2: A mixture of 18-1 and Et 3 N (600 mg, 6 mmol) in CH 2 Cl 2 was stirred at 0 °C before MsCl (460 mg, 4 mmol) was added slowly. The reaction mixture was stirred at 0 °C under N 2 for 2 hr. TLC showed that the reaction was complete. The reaction mixture was partitioned between CH 2 Cl 2 and H 2 O, and the organic layer was washed with brine and dried over Na 2 SO 4 . Solvent was removed under vacuum and the resulting compound (18-2) was used without further purification as a light yellow oil (460 mg, yield: 99%).
  • Step C Preparation of Compound 18-4: A mixture of 18-3 (280 mg, 0.87 mmol), N- (piperidin-4-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-amine hydrochloride (435 mg, 1.35 mmol) and Et 3 N (400 mg, 4 mmol) in CH 2 Cl 2 (30 mL) was stirred at room temperature for 2 hours before NaBH(OAc) 3 (570 mg, 2.7 mmol) was added with ice bath cooling. The reaction mixture was stirred at room temperature overnight. The reaction was partitioned between CH 2 Cl 2 and NaHCO 3 , and the organic layer was washed by brine and dried over Na 2 SO 4 . Solvent was removed under vacuum to give a residue, which was purified by silica gel column
  • Step D Preparation of Compound 20: To a solution of 18-4 (180 mg, 0.3 mmol) in water (4 mL) and THF (10 mL) was added LiOH (24 mg, 0.6 mmol). The reaction was stirred at room temperature for 16 h. TLC showed that the reaction was complete. The pH of the mixture was adjusted to pH 4 with HCl (a.q., 1N). The reaction mixture was diluted with EtOAc and the organic layer was dried over Na 2 SO 4 . Solvent was removed under vacuum to give compound 20, which was used without further purification as a yellow solid (130 mg, yield: 75%)
  • Step E Preparation of Compound 18: A mixture of crude compound 20 (40 mg, 0.07 mmol), methylamine hydrochloride (30 mg, 0.44 mmol), EDCI (40 mg, 0.28 mmol), HOBT (15 mg, 0.11 mmol) and Et 3 N (50 mg, 0.5 mmol) in CH 2 Cl 2 (10 mL) was stirred at room temperature for 40 hours. The reaction mixture was partitioned between CH 2 Cl 2 and NaHCO 3 , and the organic layer was washed by brine and dried over Na 2 SO 4 .
  • Step A Preparation of Compound 33-1: A mixture of compound 13 (190 mg, 0.33 mmol), 2-(tert-butoxycarbonyl)acetic acid (79 mg, 0.43 mmol), benzotriazol-1- yloxytris(dimethylamino)-phosphonium hexafluorophosphate (229 mg, 0.5 mmol), and iPr 2 NEt (0.3 mL,1.65 mmol) in CH 2 Cl 2 (10 mL) was stirred at room temperature for 30 min. Water was added and the resulting mixture was extracted with CH 2 Cl 2 .
  • Step B Preparation of Compound 17: A mixture of 33-1 (230 mg, 0.34 mmol) in CH 2 Cl 2 (5 mL) and trifluoroacetic acid (5 mL) was stirred at room temperature for 2h. The reaction mixture was concentrated to dryness and the residue was dissolved in NH 3 /MeOH (7N). The mixture was concentrated to dryness. The residue was purified by silica gel column to give compound 17 as a yellow solid (210 mg, yield: 83%). ESI-MS m/z: 637 (M+H).
  • Step C Preparation of Compound 33: A mixture of compound 17 (50 mg, 0.08 mmol), formic acid (8 mg, 0.16 mmol), benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (52 mg, 0.12 mmol), and iPr 2 NEt (0.07 mL, 0.4 mmol) in CH 2 Cl 2 (5 mL) was stirred at room temperature for 30 min. Water was added and the resulting reaction mixture was extracted with CH 2 Cl 2 .
  • the methods of the present disclosure may be utilized to treat an individual in need thereof.
  • the individual is a mammal such as a human, or a non-human mammal.
  • the composition or the compound of the subject methods is preferably administered as a pharmaceutical composition comprising, for example, a compound or salt of Formula (I), (III) or (IV) and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is formulated for oral
  • the pharmaceutical composition is formulated for injection.
  • the pharmaceutical compositions comprise a compound as disclosed herein and an additional therapeutic agent (e.g., anticancer agent).
  • additional therapeutic agent e.g., anticancer agent
  • Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration.
  • parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
  • the present disclosure provides a method comprising
  • compositions of a compound or salt of Formula (I), (III) or (IV) in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation.
  • long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • a compound or salt of Formula (I), (III) or (IV) is delivered in a targeted drug delivery system, for example, in a liposome coated with organ-specific antibody.
  • the liposomes are targeted to and taken up selectively by the organ.
  • the composition is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.
  • the composition is administered topically.
  • the compound of Formula (I), (III) or (IV) for use in the subject methods may be effective over a wide dosage range.
  • dosages from 0.01 to 1000 mg per day, from 0.5 to 100 mg per day, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used.
  • the exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.
  • a compound or salt of Formula (I), (III) or (IV) for use in the subject methods is administered in a single dose.
  • a single dose of a compound or salt of Formula (I), (III) or (IV) is used for treatment of an acute condition.
  • a compound or salt of Formula (I), (III) or (IV) for use in the subject methods is administered in multiple doses.
  • dosing is about once, twice, three times, four times, five times, six times, or more than six times per day.
  • dosing is about once a month, once every two weeks, once a week, or once every other day.
  • a compound or salt of Formula (I), (III) or (IV) and another agent are administered together about once per day to about 6 times per day.
  • the administration of a compound or salt of Formula (I), (III) or (IV) and an agent continues for less than about 7 days.
  • the administration continues for more than about 6 days, more than about 10 days, more than about 14 days, more than about 28 days, more than about two months, more than about six months, or one year or more. In some cases, continuous dosing is achieved and maintained as long as necessary.
  • a compound or salt of Formula (I), (III) or (IV) may continue as long as necessary.
  • a compound of the disclosure is administered for more than 1, more than 2, more than 3, more than 4, more than 5, more than 6, more than 7, more than 14, or more than 28 days.
  • a compound of the disclosure is administered 28 days or less, 14 days or less, 7 days or less, 6 days or less, 5 days or less, 4 days or less, 3 days or less, 2 days or less, or 1 day or a part thereof.
  • a compound or salt of Formula (I), (III) or (IV) is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects.
  • a compound or salt of Formula (I), (III) or (IV) is administered in dosages. It is known in the art that due to intersubject variability in compound pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. Dosing for a compound or salt of Formula (I), (III) or (IV) may be found by routine experimentation in light of the instant disclosure.
  • a compound or salt of Formula (I), (III) or (IV) is formulated into pharmaceutical compositions for use in the subject methods.
  • pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
  • compositions comprising a compound or salt of Formula (I), (III) or (IV) and a pharmaceutically acceptable diluent(s), excipient(s), or carrier(s).
  • the compounds or salts described are administered as pharmaceutical
  • compositions in which a compound or salt of Formula (I), (III) or (IV) is mixed with other active ingredients, as in combination therapy are all combinations of active ingredients set forth in the combination therapies section below and throughout this disclosure.
  • the pharmaceutical compositions include one or more compounds of Formula (I), (III) or (IV), or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition refers to a mixture of a compound or salt of Formula (I), (III) or (IV) with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • the pharmaceutical composition facilitates administration of the compound to an organism.
  • therapeutically effective amounts of a compound or salt of Formula (I), (III) or (IV) are administered in a pharmaceutical composition to a mammal having a disease, disorder or medical condition to be treated.
  • the mammal is a human.
  • therapeutically effective amounts vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors.
  • a compound or salt of Formula (I), (III) or (IV) may be used singly or in combination with one or more therapeutic agents as components of mixtures.
  • a compound or salt of Formula (I), (III) or (IV) is formulated in an aqueous solution.
  • the aqueous solution is selected from, by way of example only, a physiologically compatible buffer, such as Hank’s solution, Ringer’s solution, or physiological saline buffer.
  • a compound or salt of Formula (I), (III) or (IV) is formulated for transmucosal administration.
  • transmucosal formulations include penetrants that are appropriate to the barrier to be permeated.
  • appropriate formulations include aqueous or nonaqueous solutions.
  • such solutions include physiologically compatible buffers and/or excipients.
  • a compound or salt of Formula (I), (III) or (IV) is formulated for oral administration.
  • a compound or salt of Formula (I), (III) or (IV) may be formulated by combining the active compounds with, e.g., pharmaceutically acceptable carriers or excipients.
  • a compound or salt of Formula (I), (III) or (IV) is formulated in oral dosage forms that include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like.
  • pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with a compound or salt of Formula (I), (III) or (IV), optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.
  • disintegrating agents are optionally added. Disintegrating agents include, by way of example only, cross-linked croscarmellose sodium,
  • polyvinylpyrrolidone agar, or alginic acid or a salt thereof such as sodium alginate.
  • dosage forms such as dragee cores and tablets, are provided with one or more suitable coating.
  • concentrated sugar solutions are used for coating the dosage form.
  • the sugar solutions optionally contain additional components, such as by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs and/or pigments are also optionally added to the coatings for identification purposes. Additionally, the dyestuffs and/or pigments are optionally utilized to characterize different combinations of active compound doses.
  • Oral dosage forms include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • push-fit capsules contain the active ingredients in admixture with one or more filler. Fillers include, by way of example only, lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • soft capsules contain one or more active compound that is dissolved or suspended in a suitable liquid.
  • suitable liquids include, by way of example only, one or more fatty oil, liquid paraffin, or liquid polyethylene glycol.
  • stabilizers are optionally added.
  • a therapeutically effective amount of a compound or salt of Formula (I), (III) or (IV) is formulated for buccal or sublingual administration.
  • Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, lozenges, or gels.
  • a compound or salt of Formula (I), (III) or (IV) is formulated for parental injection, including formulations suitable for bolus injection or continuous infusion.
  • formulations for injection are presented in unit dosage form (e.g., in ampoules) or in multi-dose containers. Preservatives are, optionally, added to the injection formulations.
  • the pharmaceutical compositions are formulated in a form suitable for parenteral injection as sterile suspensions, solutions or emulsions in oily or aqueous vehicles.
  • Parenteral injection formulations optionally contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form.
  • a suspension of a compound or salt of Formula (I), (III) or (IV) is prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • aqueous injection suspensions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension contains suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active agent is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a compound or salt of Formula (I), (III) or (IV) may be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments.
  • Such pharmaceutical compositions optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • a compound or salt of Formula (I), (III) or (IV) is formulated for transdermal administration.
  • Transdermal formulations may employ transdermal delivery devices and transdermal delivery patches and can be lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive.
  • patches are constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • the transdermal delivery of a compound or salt of Formula (I), (III) or (IV) is accomplished by means of iontophoretic patches and the like.
  • transdermal patches provide controlled delivery of a compound or salt of Formula (I), (III) or (IV).
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing a compound or salt of Formula (I), (III) or (IV), optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • a compound or salt of Formula (I), (III) or (IV) is formulated for administration by inhalation.
  • Various forms suitable for administration by inhalation include, but are not limited to, aerosols, mists or powders.
  • Pharmaceutical compositions of a compound or salt of Formula (I), (III) or (IV) are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas).
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit of a pressurized aerosol is determined by providing a valve to deliver a metered amount.
  • capsules and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufflator are formulated containing a powder mix of a compound or salt of Formula (I), (III) or (IV) and a suitable powder base such as lactose or starch.
  • a compound or salt of Formula (I), (III) or (IV) is formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like.
  • a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted.
  • compositions are formulated in any conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients may be optionally used as suitable.
  • Pharmaceutical compositions comprising a compound or salt of Formula (I), (III) or (IV) are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
  • compositions for use in the subject methods include at least one pharmaceutically acceptable carrier, diluent or excipient and a compound or salt of Formula (I), (III) or (IV), sometimes referred to herein as an active agent or ingredient.
  • the active ingredient may be in free-acid or free-base form, or in a pharmaceutically acceptable salt form.
  • a compound or salt of Formula (I), (III) or (IV) may be in unsolvated or solvated forms with pharmaceutically acceptable solvents such as water and ethanol.
  • pharmaceutical compositions optionally include other medicinal or pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, buffers, and/or other therapeutically valuable substances.
  • Methods of the present disclosure may include a compound or salt of Formula (I), (III) or (IV) formulated with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid.
  • Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound or salt of Formula (I), (III) or (IV).
  • Semi-solid compositions include, but are not limited to, gels, suspensions and creams.
  • compositions of a compound or salt of Formula (I), (III) or (IV) include liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions also optionally contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so forth.
  • a pharmaceutical composition comprising a compound or salt of Formula (I), (III) or (IV) takes the form of a liquid where the agents are present in solution, in suspension or both. Typically when the composition is administered as a solution or suspension a first portion of the agent is present in solution and a second portion of the agent is present in particulate form, in suspension in a liquid matrix.
  • a liquid composition includes a gel formulation. In other embodiments, the liquid composition is aqueous.
  • aqueous suspensions contain one or more polymers as suspending agents.
  • Polymers include water-soluble polymers such as cellulosic polymers, e.g., hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl- containing polymers.
  • Certain pharmaceutical compositions described herein comprise a mucoadhesive polymer, selected for example from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.
  • compositions also, optionally, include solubilizing agents to aid in the solubility of a compound described herein.
  • solubilizing agent generally includes agents that result in formation of a micellar solution or a true solution of the agent.
  • Certain acceptable nonionic surfactants for example polysorbate 80, are useful as solubilizing agents, as can ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers.
  • compositions optionally include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride.
  • acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids
  • bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane
  • buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride.
  • acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.
  • useful compositions also, optionally, include one or more salts in an amount required to bring osmolality of the composition into an acceptable range.
  • salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.
  • compositions optionally include one or more preservatives to inhibit microbial activity.
  • Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.
  • compositions may include one or more surfactants to enhance physical stability or for other purposes.
  • Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40.
  • compositions may include one or more antioxidants to enhance chemical stability where required.
  • Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.
  • aqueous suspension compositions are packaged in single-dose non-reclosable containers.
  • multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.
  • delivery systems for hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also employed.
  • a compound or salt of Formula (I), (III) or (IV) is delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials may be used herein. In some embodiments, sustained-release capsules release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization are employed.
  • the formulations described herein comprise one or more antioxidants, metal chelating agents, thiol containing compounds and/or other general stabilizing agents.
  • stabilizing agents include, but are not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05% w/v.
  • polysorbate 20 (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.
  • the concentration of a compound or salt of Formula (I), (III) or (IV) provided in a pharmaceutical composition for use in the subject methods is less than about:100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v or
  • the concentration of a compound or salt of Formula (I), (III) or (IV) provided in a pharmaceutical composition for use in the subject methods is greater than about: 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25%, 15%, 14.75%, 14.50%, 14.25%, 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25%, 11%, 10.75%, 10.50%, 10.25%, 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25%, 8%, 7.75%, 7.50%, 7.25%, 7%
  • the concentration of a compound or salt of Formula (I), (III) or (IV) in a pharmaceutical composition for use in the subject methods is in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40 %, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately 1% to approximately 10% w/w, w/v or v/v.
  • the concentration of a compound or salt of Formula (I), (III) or (IV) in a pharmaceutical composition for use in the subject methods is in the range from approximately 0.001% to approximately 10%, approximately 0.01% to approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1%, approximately 0.1% to approximately 0.9% w/w, w/v or v/v.
  • the amount of a compound or salt of Formula (I), (III) or (IV) in a pharmaceutical composition for use in the subject methods is equal to or less than about: 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.
  • the amount of a compound or salt of Formula (I), (III) or (IV) in a pharmaceutical composition for use in the subject methods is more than about: 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g
  • the amount of one or more compounds of the disclosure in a pharmaceutical composition for use in the subject methods is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.
  • kits and articles of manufacture are also provided.
  • such kits comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein.
  • Suitable containers include, for example, bottles, vials, syringes, and test tubes.
  • the containers are formed from a variety of materials such as glass or plastic.
  • the articles of manufacture provided herein contain packaging materials.
  • Packaging materials for use in packaging pharmaceutical products include those found in, e.g., U.S. Pat. Nos.5,323,907, 5,052,558 and 5,033,252.
  • Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
  • the container(s) includes a compound or salt of Formula (I), (III) or (IV), optionally in a composition or in combination with another agent as disclosed herein.
  • the container(s) optionally have a sterile access port (for example the container is an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
  • a sterile access port for example the container is an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle.
  • kits optionally comprising a compound with an identifying description or label or instructions relating to its use in the methods described herein.
  • a kit typically includes one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and/or devices) desirable from a commercial and user standpoint for use of a compound described herein.
  • materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and/or tube labels listing contents and/or instructions for use, and package inserts with instructions for use.
  • a set of instructions will also typically be included.
  • a label is optionally on or associated with the container.
  • a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself, a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert.
  • a label is used to indicate that the contents are to be used for a specific therapeutic application.
  • the label indicates directions for use of the contents, such as in the methods described herein.
  • the pharmaceutical composition is presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein.
  • the pack for example, contains metal or plastic foil, such as a blister pack.
  • the pack or dispenser device is accompanied by instructions for administration.
  • the pack or dispenser is
  • compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • the present disclosure provides a method of promoting beta cell proliferation.
  • the method comprises contacting menin with an effective amount of a compound of Formula (I), (III) or (IV).
  • the compound inhibits the interaction of menin and MLL. Inhibition of the menin/MLL interaction can be assessed by a wide variety of techniques known in the art.
  • Non-limiting examples include a showing of (a) a decrease in menin binding to MLL, or a peptide fragment thereof; (b) a decrease in p27 Kip1 and/or p18 INK4C mRNA levels; (c) a decrease in p27 Kip1 and/or p18 INK4C protein levels; (d) a decrease in the levels of downstream targets of MLL; (e) an increase in beta cells; and/or (f) an increase in pancreatic islet cell proliferation. Kits and commercially available assays can be utilized for determining one or more of the above.
  • the promoted beta cell proliferation is evidenced by an increase in insulin production.
  • contacting menin comprises contacting a cell that expresses menin.
  • the contacting step may take place in vivo or in vitro.
  • the promoted beta cell proliferation may be evidenced by an increase in beta cell production.
  • the number of beta cells in a treated islet increases by at least 1.1-fold, at least 1.2-fold, at least 1.3- fold, at least 1.4-fold, at least 1.5-fold, at least 1.6-fold, at least 1.7-fold, at least 1.8-fold, at least 1.9-fold, at least 2-fold, at least 2.5-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 7.5-fold, or at least 10-fold relative to the number of beta cells in an islet treated with vehicle only.
  • Beta cell proliferation may be assessed using methods known in the art.
  • beta cell proliferation can be assessed using quantitative-stereological methods or by immunohistochemistry imaging methods, either using manual or automated image processing.
  • suitable methods are described in Noorafshan, A.; et al. J. Pancreas 2012, 13, 427-432; Chen, H.; et al. Frontiers in Physiology 2013, 3, 1-9; and Kilimnik, G.; et al. Islets 2012, 4, 167-172.
  • the present disclosure provides a method of increasing the size of a pancreatic islet, comprising administering an effective amount of a compound described herein to a subject in need thereof.
  • the average size of treated pancreatic islets increases by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, or at least 60% relative to the average size of pancreatic islets treated with vehicle only.
  • pancreatic islets may be expressed in any unit commonly used in the art, such as area (e.g., mm 2 ) or volume (e.g., mm 3 ), and can be assessed using methods known in the art.
  • pancreatic islet size can be assessed using quantitative-stereological methods or by immunohistochemistry imaging methods, either using manual or automated image processing.
  • suitable methods are described in Noorafshan, A.; et al. J. Pancreas 2012, 13, 427-432; Chen, H.; et al. Frontiers in Physiology 2013, 3, 1-9; and Kilimnik, G.; et al. Islets 2012, 4, 167-172.
  • the present disclosure provides a method of increasing the average beta cell number per islet, comprising administering an effective amount of a compound described herein to a subject in need thereof.
  • the average beta cell number per islet of treated islets increases by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, or at least 40% relative to the average beta cell number per islet of islets treated with vehicle only.
  • the average beta cell number per islet can be assessed using methods known in the art. For example, average beta cell number per islet can be assessed using quantitative-stereological methods or by immunohistochemistry imaging methods, either using manual or automated image processing.
  • Non-limiting examples of suitable methods are described in Noorafshan, A.; et al. J. Pancreas 2012, 13, 427-432; Chen, H.; et al. Frontiers in Physiology 2013, 3, 1-9; and Kilimnik, G.; et al. Islets 2012, 4, 167-172.
  • the present disclosure provides a method of improving islet transplantation, comprising contacting an islet cell with an effective amount of a compound described herein.
  • the contacting takes place prior to transplantation of the islet into a recipient.
  • the contacting takes place after transplantation of the islet into a recipient.
  • the contacting may take place in vivo, ex vivo or in vitro.
  • the present disclosure provides a method of treating a disease or condition in a subject having impaired beta cell production, comprising administering to the subject an effective amount of a compound of Formula (I), (III) or (IV).
  • the disease or condition may comprise diabetes, such as type 1 diabetes or type 2 diabetes.
  • the disease or condition is characterized by impaired glucose metabolism and/or hyperglycemia.
  • the treated subject may exhibit decreased plasma glucose levels.
  • plasma glucose levels may be reduced by at least 10 mg/dL, 20 mg/dL, 30 mg/dL, 40 mg/dL, 50 mg/dL, 60 mg/dL, 70 mg/dL, 80 mg/dL, 90 mg/dL, or at least 100 mg/dL relative to plasma glucose levels measured before the administering the effective amount of the compound of Formula (I), (III) or (IV).
  • a fasting plasma glucose level of the treated subject may be less than 150 mg/dL, such as less than 140 mg/dL, 130 mg/dL, 120 mg/dL, 110 mg/dL, 100 mg/dL, 90 mg/dL, or less than 80 mg/dL.
  • the present disclosure provides a method of treating impaired glucose metabolism, comprising administering an effective amount of a compound or salt of Formula (I), (III) or (IV) to a subject in need thereof.
  • Subjects that can be treated according the subject methods include, for example, subjects that have been diagnosed as having impaired glucose tolerance, hyperglycemia, impaired glucose metabolism, diabetes, type 1 diabetes, or type 2 diabetes, or subjects suffering from a disease associated with reduced beta cell number and/or impaired beta-cell function, for example but not limited to one of the diseases for which a pro-proliferative effect on pancreatic beta cells and/or an anti-apoptotic/pro-survival effect on pancreatic beta cells and/or a beta cell neogenesis- promoting effect would be beneficial: Type I diabetes: new onset, established, prevention in high-risk patients (identified e.g.
  • LADA new onset and established
  • Type II diabetes when loss of beta cell mass occurs
  • MODY Modaturity Onset Diabetes of the Young, all forms
  • Gestational diabetes Islet+duct cell transplantation-treatment of recipients before or after transplantation
  • Treatment of islets before transplantation/during pre- transplantation culture Treatment of islets before transplantation/during pre- transplantation culture; and Pancreatitis-associated beta cell loss.
  • the methods described herein may be used to treat diabetes type I, LADA or prognosed diabetes type II, but also used preventively on subjects at risk to develop complete beta-cell degeneration, like for example but not limited to patients suffering from diabetes type II or LADA and type I diabetes in early stages, or other types of diseases as indicated above.
  • the methods may also be used to prevent or ameliorate diabetes in patients at risk for type I diabetes or LADA (identified e.g. by screening for autoantibodies, genetic predisposition, impaired glucose tolerance or combinations thereof.
  • the present disclosure also provides methods for combination therapies in which an agent known to modulate other pathways, or other components of the same pathway, or even overlapping sets of target enzymes are used in combination with a compound or salt of Formula (I), (III) or (IV).
  • such therapy includes but is not limited to the combination of one or more compounds of the disclosure with anti-diabetic agents to provide a synergistic or additive therapeutic effect.
  • the compounds described herein are formulated or administered in conjunction with liquid or solid tissue barriers also known as lubricants.
  • tissue barriers include, but are not limited to, polysaccharides, polyglycans, seprafilm, interceed and hyaluronic acid.
  • medicaments which are administered in conjunction with the compounds described herein include any suitable drugs usefully delivered by inhalation for example, analgesics, e.g., codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations, e.g., diltiazem; antiallergics, e.g., cromoglycate, ketotifen or nedocromil; anti- infectives, e.g., cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines or pentamidine; antihistamines, e.g., methapyrilene; anti-inflammatories, e.g., beclomethasone, flunisolide, budesonide, tipredane, triamcinolone acetonide or fluticasone; antitussives, e.g., noscapine
  • analgesics
  • the medicaments are used in the form of salts (e.g., as alkali metal or amine salts or as acid addition salts) or as esters (e.g., lower alkyl esters) or as solvates (e.g., hydrates) to optimize the activity and/or stability of the medicament.
  • salts e.g., as alkali metal or amine salts or as acid addition salts
  • esters e.g., lower alkyl esters
  • solvates e.g., hydrates
  • exemplary therapeutic agents useful for a combination therapy include but are not limited to agents as described above, hormone antagonists, hormones and their releasing factors, thyroid and antithyroid drugs, estrogens and progestins, androgens, adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogs; inhibitors of the synthesis and actions of adrenocortical hormones, insulin, oral hypoglycemic agents, and the pharmacology of the endocrine pancreas, agents affecting calcification and bone turnover: calcium, phosphate, parathyroid hormone, vitamin D, calcitonin, vitamins such as water-soluble vitamins, vitamin B complex, ascorbic acid, fat-soluble vitamins, vitamins A, K, and E, growth factors, cytokines, chemokines, muscarinic receptor agonists and antagonists; anticholinesterase agents; agents acting at the neuromuscular junction and/or autonomic ganglia; catecholamines,
  • sympathomimetic drugs and adrenergic receptor agonists or antagonists
  • 5- hydroxytryptamine (5-HT, serotonin) receptor agonists and antagonists 5- hydroxytryptamine
  • Therapeutic agents can also include agents for pain and inflammation such as histamine and histamine antagonists, bradykinin and bradykinin antagonists, 5-hydroxytryptamine
  • lipid substances that are generated by biotransformation of the products of the selective hydrolysis of membrane phospholipids, eicosanoids, prostaglandins, thromboxanes, leukotrienes, aspirin, nonsteroidal anti-inflammatory agents, analgesic-antipyretic agents, agents that inhibit the synthesis of prostaglandins and thromboxanes, selective inhibitors of the inducible cyclooxygenase, selective inhibitors of the inducible cyclooxygenase-2, autacoids, paracrine hormones, somatostatin, gastrin, cytokines that mediate interactions involved in humoral and cellular immune responses, lipid-derived autacoids, eicosanoids, ⁇ -adrenergic agonists, ipratropium, glucocorticoids, methylxanthines, sodium channel blockers, opioid receptor agonists, calcium channel blockers, membrane stabilizers and leukotriene inhibitors.

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Abstract

The present disclosure provides methods of promoting proliferation of a pancreatic cell. The methods are useful for the treatment of diabetes and other diseases characterized by impaired glucose tolerance.

Description

METHODS OF PROMOTING BETA CELL PROLIFERATION CROSS-REFERENCE
[0001] This application claims the benefit of U.S. Provisional Application No.62/431,412, filed December 7, 2016, incorporated herein by reference in its entirety. BACKGROUND OF THE INVENTION
[0002] The mixed-lineage leukemia (MLL) protein is a histone methyltransferase critical for the epigenetic regulation of gene transcription. The menin protein, which is encoded by the Multiple Endocrine Neoplasia (MEN) gene, is a ubiquitously expressed nuclear protein that engages in interactions with DNA processing and repair proteins, chromatin modifying proteins and numerous transcription factors (Agarwal, et al.; Horm Metab Res, 2005, 37(6): 369-374). The association of menin with MLL promotes trimethylation of histone H3 on lysine 4. This association has been shown to maintain the expression of p27Kip1 and p18INK4C and impairs islet proliferation. Since menin levels have been shown to be correlated to pancreatic islet expression, the interaction between menin and MLL represents a potential therapeutic target.
[0003] Diabetes mellitus, commonly referred to as diabetes, is a disease in which the body does not produce or properly respond to insulin, a hormone that is needed to convert sugar, starches and other food into energy. The hallmark of diabetes is the presence of high blood sugar levels. Generally, diabetes is described by its two main forms: type 1 and type 2 diabetes.
[0004] Type 1 diabetes, which is typically diagnosed in children and young adults, is an autoimmune disease in which the body is unable to produce insulin. The underlying mechanism involves an autoimmune destruction of the insulin-producing beta cells in the pancreas. Due to a breakdown of islet cells in the pancreas, the pancreas produces either very little insulin or none at all. As a consequence, the lack of insulin results in high sugar levels in the blood.
[0005] Type 2 diabetes, which is typically diagnosed in middle-aged and older adults, is a metabolic disorder resulting from the body’s inability to make enough insulin or to properly use insulin. In type 2 diabetes, the body’s cells are unable to absorb and use the insulin, which is commonly referred to as“insulin resistance.” As a result of insulin resistance, elevated sugar levels are maintained in the bloodstream.
[0006] As of 2015, approximately 415 million people have diabetes worldwide. Of all diabetes cases, type 1 diabetes accounts for approximately 5% to 10%, and type 2 diabetes makes up about 90%. Currently, the global cost of diabetes is now approximately $825 billion per year.
[0007] Current treatments for diabetes suffer from a number of profound drawbacks. Amongst them include the inconvenience in continuously monitoring blood sugar levels and administering treatments, the limitations in maintaining long term efficacy, the increased risk for side effects, and the difficulties in maintaining patient compliance. As such, there remains considerable need for alternative therapeutics for treatment. SUMMARY OF THE INVENTION
[0008] The present disclosure addresses a need in the art by providing methods of treating diabetes and associated diseases. The methods herein may be useful for treating diseases dependent on the activity of menin, such as diabetes.
[0009] In one aspect, the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising administerin a com ound of Formula I :
Figure imgf000003_0001
or a pharmaceutically acceptable salt thereof, wherein:
H is selected from C3-12 carbocycle and 3- to 12-membered heterocycle;
A is selected from bond, C3-12 carbocycle, and 3- to 12-membered heterocycle;
B is selected from C3-12 carbocycle and 3- to 12-membered heterocycle;
C is selected from bond, C3-12 carbocycle, and 3- to 12-membered heterocycle;
each of L1, L2, and L3 is independently selected from bond, -O-, -S-, -N(R51)-, - N(R51)CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R51)-, - C(O)N(R51)C(O)-, -C(O)N(R51)C(O)N(R51)-, -N(R51)C(O)-, -N(R51)C(O)N(R51)-, -N(R51)C(O)O-, -OC(O)N(R51)-, -C(NR51)-, -N(R51)C(NR51)-, -C(NR51)N(R51)-, - N(R51)C(NR51)N(R51)-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, - N(R51)S(O)2-, -S(O)2N(R51)-, -N(R51)S(O)-, -S(O)N(R51)-, -N(R51)S(O)2N(R51)-, and -N(R51)S(O)N(R51)- or from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is optionally substituted with one or more R50, wherein two R50 groups attached to the same atom or different atoms of any one of L1, L2, or L3 can together optionally form a bridge or ring;
R50 is, at each occurrence, independently selected from:
halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, - S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, - NR52S(=O) 3
2NR5 R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, - OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52 NR52C(O)N(R52)2, - NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, - P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52);
C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, - S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, - NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, - OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), - P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; and
C3-12 carbocycle and 3- to 12-membered heterocycle,
wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R50 is independently optionally substituted with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, - S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, - NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, - P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), - P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;
R51 is independently selected at each occurrence from:
hydrogen, -C(O)R52, -C(O)OR52, -C(O)N(R52)2, -C(O)NR53R54;
C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, - S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, - NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, - OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, - NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, - P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C3-12 carbocycle and 3- to 12-membered heterocycle; and
C3-12 carbocycle and 3- to 12-membered heterocycle,
wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R51 is independently optionally substituted with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, - S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, - NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, - P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), - P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;
R52 is independently selected at each occurrence from hydrogen; and C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, 1- to 6-membered heteroalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -NO2, -NH2, -NHCH3, - NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C3-12 carbocycle, or 3- to 6-membered heterocycle;
R53 and R54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R50;
each of RH, RA, and RB is, at each occurrence, independently selected from R50, or two RH groups, two RA groups, or two RB groups attached to the same atom or different atoms can together optionally form a bridge or ring;
RC is, at each occurrence, independently selected from hydrogen or R50, or two RC groups attached to the same atom or different atoms can together optionally form a bridge or ring; and each of m, n, p, and q is independently an integer from 0 to 12.
[0010] In some embodiments, for a compound of Formula (I), H is 5- to 12-membered heterocycle; A is 3- to 12-membered heterocycle; and B is 5- to 12-membered heterocycle or C4- 8 carbocycle.
[0011] In some embodiments, for a compound of Formula (I), H is 6-membered to 12-membered
bicyclic heterocycle. In some embodiments, H is
Figure imgf000005_0001
; each of X1 and X2 is independently selected from CR2 and N; each of X3 and X4 is independently selected from C and N; each of X5 and X6 is independently selected from CR3, N, NR4, O, and S; each of R1, R2 and R3 is independently selected at each occurrence from hydrogen and R50; and R4 is selected from R51. In some embodiments, X3 and X4 are each C. In some embodiments, X6 is CR3, and R3 is selected from hydrogen, halogen, -OR52, -N(R52)2, -CN, -C(O)OR52, C1-3 alkyl, and C1-3
haloalkyl. In some embodiments, H is In some embodiments, R2 is selected
Figure imgf000005_0002
from hydrogen, halogen, -OR52, -NH2, -N(R52)2, -CN, C1-3 alkyl, C1-3 alkyl-OR52, C1-3 alkyl- N(R52)2, C1-3 haloalkyl, C2-3 alkenyl, and C2-3 alkynyl. In some embodiments, R3 is selected from hydrogen, halogen, -OR52, -N(R52)2, -CN, -C(O)OR52, C1-3 alkyl, and C1-3 haloalkyl. In some
CF3
embodiments, R1 is C1-3 haloalkyl. In some embodiments, R1 is . In some embodiments, H is thienopyrimidinyl or thienopyridinyl.
[0012] In some embodiments, for a compound of Formula (I), H is
Figure imgf000006_0001
; each of X1 and X2 is independently CR2 or N; each of X7, X8, X9, and X10 is independently CR16, CR17R18, N, NR19, O, or S; each of R16, R17, and R18 is independently selected at each occurrence from hydrogen and R50; and R19 is selected from R51.
[0013] In some embodiments, for a compound of Formula (I), X1 is CR2, and R2 is selected from hydrogen, halogen, -OH, -OR52, -NH2, -N(R52)2, -CN, C1-3 alkyl, C1-3 alkyl-OR52, C1-3 alkyl- N(R52)2, C1-3 haloalkyl, C2-3 alkenyl, and C2-3 alkynyl.
[0014] In some embodiments, for a compound of Formula (I), X2 is N.
[0015] In some embodiments, for a compound of Formula (I), H is 5- or 6-membered
monocyclic heterocycle. In some embodiments, H is
Figure imgf000006_0002
; each of Y1, Y2, and Y4 is independently CR2, N, NR21, O, or S; Y5 is CR20, N, NR21, O, or S; Y6 is C or N; Y3 is a bond, CR22, or N, wherein when Y3 is CR22 or N, then each of Y1, Y2, and Y4 is independently CR2, N, or NR21 and Y5 is CR20, N, or NR21; each of R2 and R20 is independently selected at each occurrence from hydrogen and R50; and R21 is selected from R51.
[0016] In some embodiments, for a compound of Formula (I), L1 is a bond or -N(R51)-. In some embodiments, for a compound of Formula (I), L1 is not a bond. In some embodiments, L1 is - NH-.
[0017] In some embodiments, for a compound of Formula (I), L2 is not a bond. In some embodiments, L2 is alkylene or heteroalkylene, each of which is optionally substituted with one or more R50. In some embodiments, L2 is C1-4 alkylene, optionally substituted with one or more R50. In some embodiments, L2 is substituted with =O. In some embodiments, L2 is selected from -CH2-, -N(R51)-, -N(R51)CH2-, -N(R51)C(O)-, and -N(R51)S(O)2-. In some embodiments, L2 is - CH2-.
[0018] In some embodiments, for a compound of Formula (I), L3 comprises less than 20 atoms. In m m im n L3 i n n In m m im n L3 i 1- lk l n i n ll
Figure imgf000007_0001
one or more R50.
[0019] In some embodiments, for a compound of Formula (I), A is 5- to 10-membered heterocycle. In some embodiments, A is 6-membered monocyclic heterocycle. In some embodiments, A comprises at least one nitrogen atom. In some m im n A is selected from
piperidinylene and piperazinylene. In some embodiments, A is
Figure imgf000007_0002
some
embodiments, n is 0.
[0020] In some embodiments, for a compound of Formula (I), B is 6- to 12-membered bicyclic heterocycle. In some embodiments, B comprises at least one nitrogen atom. In some
embodiments, B is
Figure imgf000007_0004
optionally substituted with one or more RB, wherein each of E and G is inde endently N or C. In some embodiments, B is indolylene. In some embodiments, B
Figure imgf000007_0003
optionally substituted with one or more RB. In some embodiments, B is phenylene. In some embodiments, RB is selected from halogen, methyl, -CN, -OR52, and - N(R52)2.
[0021] In some embodiments, for a compound of Formula (I), C is 5- to 12-membered heterocycle, wherein the heterocycle comp nitrogen atom. In some embodiments, C is aromatic. In some embodiments, C is saturated. In some embodiments, C is selected from piperidinyl, piperazinyl, and morpholinyl. In some embodiments, RC is selected from C1-3 alkyl and C1-3 haloalkyl.
[0022] In some embodiments, C is
Figure imgf000008_0001
; W1 is C1-4 alkylene, optionally substituted with one or more R50; W2 is selected from a bond; and C1-4 alkylene, optionally substituted with one or more R50; W3 is selected from absent; and C1-4 alkylene, optionally substituted with one or more R50; wherein when W3 is absent: W1 is C1 alkylene, W2 is a bond, and L3 is not a bond; W1 is C2-4 alkylene and W2 is a bond; or W1 and W2 are each C1 alkylene and L3 is not a bond, wherein each C1 alkylene is independently optionally substituted with one or more R50. In some embodiments, W1, W2 and W3 are each independently selected from C1-4 alkylene, wherein each C1-4 alkylene is optionally substituted with one or more R50. In some embodiments, W1, W2 and W3 are each C1 alkylene. In some embodiments, W1 and W2 are each C1 alkylene and W3 is absent.
[0023] In some embodiments, RC is selected from -N(R52)2, -NR53R54, -NR52S(=O)2R52, - C(O)R52, -C(O)OR52, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, - NR52C(O)NR53R54, -C(O)N(R52)2, and -C(O)NR53R54.
[0024] In some embodiments, for a compound of Formula (I), the compound is selected from Table 1-6, 9-10, 12, 14, 16, 18, or 20.
[0025] In some embodiments, for a compound of Formula (I), H is 5- to 12-membered heterocycle; A is piperidinylene or piperazinylene; B is indolylene; and C is 5- to 6-membered heterocycle.
[0026] In some embodiments, for a compound of Formula (I), H is thienopyrimidinyl or thienopyridinyl; A is piperidinylene or piperazinylene; B is indolylene; and C is piperidinyl, piperazinyl, or morpholinyl.
[0027] In some embodiments, for a compound of Formula (I), H is thienopyrimidinyl or thienopyridinyl; A is piperidinylene or piperazinylene; B is indolylene; and L1, L2, and L3 are not bonds.
[0028] In some embodiments, for a compound of Formula (I), the compound has a structure of
Figure imgf000009_0001
.
[0029] In some embodiments, for a compound of Formula (I), H is thienopyrimidinyl; A is 3- to 12-membered heterocycle; B is 6- to 12-membered bicyclic heterocycle; m is an integer from 0 to 3; n is an integer from 0 to 3; and p is an integer from 0 to 3.
[0030] In some embodiments, for a compound of Formula (I),
H is thienopyrimidinyl;
A is selected from piperidinylene and piperazinylene;
B is indolylene;
L1 and L2 are each independently selected from -O-, -S-, -NH-, and -CH2-;
L3 is selected from bond, -O-, -S-, -N(R51)-, -N(R51)CH2-, -C(O)-, -C(O)O-, - OC(O)-, -OC(O)O-, -C(O)N(R51)-, -C(O)N(R51)C(O)-, -C(O)N(R51)C(O)N(R51)-, - N(R51)C(O)-, -N(R51)C(O)N(R51)-, -N(R51)C(O)O-, -OC(O)N(R51)-, -C(NR51)-, - N(R51)C(NR51)-, -C(NR51)N(R51)-, -N(R51)C(NR51)N(R51)-, -S(O)2-, -OS(O)-, -S(O)O-, - S(O)-, -OS(O)2-, -S(O)2O-, -N(R51)S(O)2-, -S(O)2N(R51)-, -N(R51)S(O)-, -S(O)N(R51)-, - N(R51)S(O)2N(R51)-, -N(R51)S(O)N(R51)-; alkylene, alkenylene, alkynylene,
heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is optionally substituted with one or more R50, wherein two R50 groups attached to the same atom or different atoms of L3 can together optionally form a ring;
RA, RB and RC are each independently selected at each occurrence from R50, or two RA groups, two RB groups or two RC groups attached to the same atom or different atoms can together optionally form a ring;
m is an integer from 0 to 3;
n is an integer from 0 to 3;
p is an integer from 0 to 6; and
q is an integer from 0 to 6.
In some embodiments, for a compound of Formula (I), H is thienopyrimidinyl;
A is selected from piperidinylene and piperazinylene;
B is indolylene;
L1 and L2 are each independently selected from -O-, -S-, -NH-, and -CH2-;
L3 is selected from C1-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene, each of which is optionally substituted with one or more R50;
RA, RB and RC are each independently selected at each occurrence from R50, or two RA groups, two RB groups or two RC groups attached to the same atom or different atoms can together optionally form a bridge or ring;
m is an integer from 0 to 3;
n is an integer from 0 to 3;
p is an integer from 0 to 3; and
q is an integer from 0 to 6.
[0031] In some embodiments, for a compound of Formula (I), H is
Figure imgf000010_0001
and R2 is selected from hydrogen, halogen, -OH, -OR52, -NH2, -N(R52)2, -CN, C1-3 alkyl, C1-3 alkyl-OR52, C1-3 alkyl-N(R52)2, C1-3 haloalkyl, C2-3 alkenyl, and C2-3 alkynyl. In some embodiments, R2 is selected from -NH2, -CH3, and -NHCH3.
[0032] In certain aspects, the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprisin administerin a com ound of Formula III :
Figure imgf000010_0002
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
H is selected from C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more R50;
Figure imgf000010_0003
each of Z1, Z2, Z3, and Z4 is independently selected from -C(RA1)(RA2)-, -C(RA1)(RA2)- C(RA1)(RA2)-, -C(O)-, and -C(RA1)(RA2)-C(O)-, wherein no more than one of Z1, Z2, Z3, and Z4 is -C(O)- or -C(RA1)(RA2)-C(O)-;
B is selected from bond, C3-12 carbocycle and 3- to 12-membered heterocycle;
C is selected from bond, C3-12 carbocycle and 3- to 12-membered heterocycle;
L1, L2 and L3 are each independently selected from bond, -O-, -S-, -N(R51)-, -N(R51)CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R51)-, -C(O)N(R51)C(O)-, - C(O)N(R51)C(O)N(R51)-, -N(R51)C(O)-, -N(R51)C(O)N(R51)-, -N(R51)C(O)O-, -OC(O)N(R51)-, - C(NR51)-, -N(R51)C(NR51)-, -C(NR51)N(R51)- -N(R51)C(NR51)N(R51)-, -S(O)2-, -OS(O)-, - S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R51)S(O)2-, -S(O)2N(R51)-, -N(R51)S(O)-, -S(O)N(R51)-, -N(R51)S(O)2N(R51)-, -N(R51)S(O)N(R51)-; alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is optionally substituted with one or more R50, wherein two R50 groups attached to the same atom or different atoms of any one of L1, L2 or L3 can together optionally form a bridge or ring;
RB is independently selected at each occurrence from R50, or two RB groups attached to the same atom or different atoms can together optionally form a bridge or ring;
RC is independently selected at each occurrence from hydrogen and R50, or two RC groups attached to the same atom or different atoms can together optionally form a bridge or ring;
RA1 and RA2 are each independently selected at each occurrence from hydrogen and R50; n is an integer from 0 to 6;
p is an integer from 1 to 6;
R50 is independently selected at each occurrence from:
halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, - S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, - NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, - OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, - NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, - P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), - P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52);
C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl, each of which is
independently optionally substituted at each occurrence with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, - NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, - OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, - NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, - P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), - P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; and
C3-12 carbocycle and 3- to 12-membered heterocycle, wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R50 is independently optionally substituted with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, - S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54 -NR52S(=O)2R52, - NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, - OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, - NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, - P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), - P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;
R51 is independently selected at each occurrence from:
hydrogen, -C(O)R52, -C(O)OR52, -C(O)N(R52)2, -C(O)NR53R54;
C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, - S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, - NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, - OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, - NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, - P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), - P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C3-12 carbocycle and 3- to 12- membered heterocycle; and
C3-12 carbocycle and 3- to 12-membered heterocycle, wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R51 is independently optionally substituted with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, - S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, - NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, - OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, - NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, - P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), - P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;
R52 is independently selected at each occurrence from hydrogen; and C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, 1- to 6-membered heteroalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -NO2, -NH2, -NHCH3, - NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C3-12 carbocycle, or 3- to 6-membered heterocycle; and
R53 and R54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R50.
[0033] In certain aspects, the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising administering a compound of Formula (IV):
Figure imgf000013_0001
or a ph cally acceptable salt or prodrug thereof, wherein:
Figure imgf000013_0002
fused thienyl or fused phenyl group;
Ga is selected from C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is substituted with -E1-R4a and optionally further substituted with one or more R50;
R2a is selected from hydrogen, alkyl, alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, optionally substituted heteroaryl, and aralkyl;
R3a and R3b are each independently selected from hydrogen, alkyl, halo, hydroxy, cyano, amino, alkylamino, dialkylamino, haloalkyl, alkoxy, and haloalkoxy;
Xa-Ya is selected from -N(R52)-C(=O)-, -C(=O)-O-, -C(=O)-N(R52)-, -CH2N(R52)-CH2-, - C(=O)N(R52)-CH2-, -CH2CH2-N(R52)-, -CH2N(R52)-C(=O)-, and–CH2O-CH2-; or
Xa and Ya do not form a chemical bond, wherein:
Xa is selected from hydrogen, alkyl, halo, hydroxy, cyano, amino, alkylamino, dialkylamino, haloalkyl, alkoxy, and haloalkoxy; and
Ya is selected from cyano, hydroxy, and -CH2R50;
E1 is selected from absent, -C(=O)-, -C(=O)N(R52)-, -[C(R14a)2]1-5O-, -[C(R14a)2]1-5NR52-, -[C(R14a)2]1-5-, -CH2(=O)-, and -S(=O)2-;
R4a is selected from hydrogen, alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, optionally substituted heteroaryl, aralkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl;
R14a is selected from hydrogen and alkyl;
R50 is independently selected at each occurrence from:
halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, - S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, - NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, - OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, - NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, - P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), - P(O)(NR52)(OR52), -P(O)(N N(R52); C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl, each of which is
independently optionally substituted at each occurrence with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, - NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, - OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, - NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, - P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), - P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; and
C3-12 carbocycle and 3- to 12-membered heterocycle, wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R50 is independently optionally substituted with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, - S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, - NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, - OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, - NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, - P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), - P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;
R52 is independently selected at each occurrence from hydrogen; and C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, 1- to 6-membered heteroalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -NO2, -NH2, -NHCH3, - NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C3-12 carbocycle, or 3- to 6-membered heterocycle; and
R53 and R54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R50.
[0034] In some embodiments, for a method disclosed herein, the compound is provided as a substantially pure stereoisomer. In some embodiments, the stereoisomer is provided in at least 90% enantiomeric excess.
[0035] In one aspect, the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising administering a compound selected from Table 1-6, 9-10, 12, 14, 16, 18, or 20. In certain aspects, the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising administering a compound selected from Table 22 or 23. [0036] In certain aspects, the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising administering a compound described herein. In practicing any of the subject methods, the pancreatic cell may be an islet cell or a beta cell. Beta cell proliferation may be evidenced by an increase in beta cell production and/or by an increase in insulin production. A method described herein may further comprise administering a second therapeutic agent. A method described herein may further comprise administering the compound to a subject. In some embodiments, the subject suffers from diabetes. The diabetes may be type 1 diabetes or type 2 diabetes. In some embodiments, the subject suffers from prediabetes. In some embodiments, the subject suffers from impaired beta cell production. In some embodiments, the subject is human. INCORPORATION BY REFERENCE
[0037] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS
[0038] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:
[0039] FIG.1 is an amino acid sequence of human menin, isoform 1 (SEQ ID NO: 1).
[0040] FIG.2 is an amino acid sequence of human menin, isoform 2 (SEQ ID NO: 2).
[0041] FIG.3 is an amino acid sequence of human menin, isoform 3 (SEQ ID NO: 3).
[0042] FIG.4A-4D depict confocal images of rat primary dispersed islet cells treated with Compound B-403, Compound C-35, Compound C-36, and no compound, respectively.
[0043] FIG.5A-5C depict the change in beta cell proliferation for rat primary dispersed islet cells treated with Compound B-403, Compound C-35, and Compound C-36, respectively. DETAILED DESCRIPTION OF THE INVENTION
[0044] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.
[0045] The term“Cx-y” or“Cx-Cy” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain. For example, the term“Cx-y alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain. The terms“Cx-y alkenyl” and“Cx-y alkynyl” refer to substituted or unsubstituted straight-chain or branched-chain unsaturated hydrocarbon groups that contain at least one double or triple bond respectively. Unless stated otherwise specifically in the specification, a Cx-y alkyl, Cx-y alkenyl, or Cx-y alkynyl is optionally substituted by one or more substituents such as those substituents described herein.
[0046]“Carbocycle” refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is a carbon atom. Carbocycle may include 3- to 10-membered monocyclic rings, 6- to 12- membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. In some
embodiments, the carbocycle is an aryl. In some embodiments, the carbocycle is a cycloalkyl. In some embodiments, the carbocycle is a cycloalkenyl. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane,
cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, are included in the definition of carbocyclic. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Unless stated otherwise specifically in the specification, a carbocycle is optionally substituted by one or more substituents such as those substituents described herein.
[0047]“Heterocycle” refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings. The heterocycle may be attached to the rest of the molecule through any atom of the heterocycle, valence permitting, such as a carbon or nitrogen atom of the
heterocycle. In some embodiments, the heterocycle is a heteroaryl. In some embodiments, the heterocycle is a heterocycloalkyl. In an exemplary embodiment, a heterocycle, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene.
[0048] "Heteroaryl" refers to a 3- to 12-membered aromatic ring that comprises at least one heteroatom wherein each heteroatom may be independently selected from N, O, and S. As used herein, the heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems rings wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) π–electron system in accordance with the Hückel theory. The heteroatom(s) in the heteroaryl may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl may be attached to the rest of the molecule through any atom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl. Examples of heteroaryls include but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl,
benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl,
1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H- benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10- hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,
1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a- octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,
phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9- tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5- c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryls as defined above which are optionally substituted by one or more substituents such as those substituents described herein.
[0049] Compounds used in the methods of the present disclosure also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.
[0050] The compounds used in the methods described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds used in the methods of the present disclosure whether radioactive or not, are encompassed within the scope of the present disclosure. For example, hydrogen has three naturally occurring isotopes, denoted 1H (protium), 2H (deuterium), and 3H (tritium). Protium is the most abundant isotope of hydrogen in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increased in vivo half-life and/or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism. Isotopically-enriched compounds may be prepared by conventional techniques well known to those skilled in the art.
[0051] "Isomers" are different compounds that have the same molecular formula.
"Stereoisomers" are isomers that differ only in the way the atoms are arranged in space.
"Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(±)" is used to designate a racemic mixture where appropriate. "Diastereoisomers" or“diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The compounds of the present methods are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers and intermediate mixtures. Optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.
[0052] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, chemical entities described herein for use in the subject methods are intended to include all Z-, E- and tautomeric forms as well.
[0053] The term“substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or heteroatoms of the structure. It will be understood that“substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term“substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms such as nitrogen may have hydrogen
substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, a carbocycle, a heterocycle, a cycloalkyl, a heterocycloalkyl, an aromatic and heteroaromatic moiety. In some embodiments, substituents may include any substituents described herein, for example: halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazino (=N- NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, - Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, - Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or
2), -Rb-S(O)tORa (where t is 1 or 2), and -Rb-S(O)tN(Ra)2 (where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, hydroxy, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazine (=N-NH2), - Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, - Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, - Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2); wherein each Ra is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl,
heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each Ra, valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazine (=N-NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, - Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra )C(O)Ra, -Rb-N(Ra)S(O)tRa (where t is 1 or 2) -Rb-S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2); and wherein each Rb is independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each Rc is a straight or branched alkylene, alkenylene or alkynylene chain.
[0054] It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as“unsubstituted,” references to chemical moieties herein are understood to include substituted variants. For example, reference to a “heteroaryl” group or moiety implicitly includes both substituted and unsubstituted variants.
[0055] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.
[0056] The term“salt” or“pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. 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. 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. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
[0057] The term“effective amount” or“therapeutically effective amount” refers to that amount of a compound described herein that is sufficient to affect the intended application, including but not limited to disease treatment, as defined below. The therapeutically effective amount may vary depending upon the intended treatment application (in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells, e.g., reduced histone methylation and/or increased islet expression. The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.
[0058] As used herein,“treatment” or“treating” refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition including but not limited to a therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject,
notwithstanding that the subject may still be afflicted with the underlying disorder. In certain embodiments, for prophylactic benefit, the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
[0059] A“therapeutic effect,” as that term is used herein, encompasses a therapeutic benefit and/or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
[0060] The term“co-administration,”“administered in combination with,” and their grammatical equivalents, as used herein, encompass administration of two or more agents to an animal, including humans, so that both agents and/or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.
[0061] The terms“antagonist” and“inhibitor” are used interchangeably, and they refer to a compound having the ability to inhibit a biological function (e.g., activity, expression, binding, protein-protein interaction) of a target protein (e.g., menin, MLL1, MLL2, and/or an MLL fusion protein). Accordingly, the terms“antagonist” and“inhibitor” are defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit a biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition. A preferred biological activity inhibited by an antagonist is associated with the proliferation of beta cells.
[0062] The term“agonist” as used herein refers to a compound having the ability to initiate or enhance a biological function of a target protein whether by inhibiting the activity or expression of the target protein. Accordingly, the term“agonist” is defined in the context of the biological role of the target polypeptide. While preferred agonists herein specifically interact with (e.g., bind to) the target, compounds that initiate or enhance a biological activity of the target polypeptide by interacting with other members of the signal transduction pathway of which the target polypeptide is a member are also specifically included within this definition.
[0063]“Signal transduction” is a process during which stimulatory or inhibitory signals are transmitted into and within a cell to elicit an intracellular response. A modulator of a signal transduction pathway refers to a compound which modulates the activity of one or more cellular proteins mapped to the same specific signal transduction pathway. A modulator may augment (agonist) or suppress (antagonist) the activity of a signaling molecule.
[0064] The term“diabetes” or“diabetes mellitus”, as used herein, refers to disease conditions in which glucose metabolism is impaired. Said impairment results in hyperglycemia. According to the World Health Organization (WHO), diabetes can be subdivided into four classes. Type 1 diabetes is caused by a lack of insulin. Insulin is produced by the so-called pancreatic islet cells. Said cells may be destroyed by an autoimmune reaction in Type 1 diabetes (Type 1a). Moreover, Type 1 diabetes also encompasses an idiopathic variant (Type 1b). Type 2 diabetes is caused by insulin resistance. Type 3 diabetes, according to the current classification, comprises all other specific types of diabetes mellitus. For example, the beta cells may have genetic defects affecting insulin production, insulin resistance may be caused genetically or the pancreas as such may be destroyed or impaired. Moreover, hormone deregulation or drugs may also cause Type 3 diabetes. Type 4 diabetes may occur during pregnancy. Preferably, diabetes as used herein refers to Type 1 and Type 2 diabetes. Diabetes may be diagnosed either by a plasma glucose level higher than 110 mg/dL in a fasting state or higher than 220 mg/dL postprandial, or by other diagnostic methods well known in the art.
[0065] An“anti-diabetic agent” generally refers to an agent that lowers blood glucose levels. If blood glucose level is decreased by at least about 100 mg/dL, then the compound is considered to be a hypoglycemic agent. The hypoglycemic or anti-diabetic effect can be measured by a variety of methods including, but not limited to, measuring the blood glucose levels, the rate of insulin binding to its receptor, the level of insulin secretion from pancreatic beta cells, and inhibition of glucohydrolase activity. As used herein the term, "related disorders" means disorders related to diabetes mellitus, which include, but are not limited to, diabetic neuropathy, diabetic diarrhea, urinary retention, gustatory swelling, papillary reflexes, cardiac autonomic disturbances, collagen disturbances, thickening of capillary basement membrane, increase in vessel wall matrix and cellular proliferation resulting in vascular complications such as lumen narrowing, early atherosclerosis, sclerosis of glomerular capillaries, retinopathy, neuropathy and peripheral vascular insufficiency.
[0066]“Subject” refers to an animal, such as a mammal, for example a human. The methods described herein can be useful in both human therapeutics and veterinary applications. In some embodiments, the subject is a mammal, and in some embodiments, the subject is human.
“Mammal” includes humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like.
[0067]“Prodrug” is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound of the methods described herein (e.g., compound of Formula (I), (III) or (IV)). Thus, the term "prodrug" refers to a precursor of a biologically active compound that is pharmaceutically acceptable. In some aspects, a prodrug is inactive when administered to a subject but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp.7-9, 21-24 (Elsevier, Amsterdam); Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," (1987) A.C.S. Symposium Series, Vol.14; and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press) each of which is incorporated in full by reference herein. The term“prodrug” is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound are typically prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of a hydroxy functional group, or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like.
[0068] The term“in vivo” refers to an event that takes place in a subject’s body.
[0069] The term“in vitro” refers to an event that takes places outside of a subject’s body. For example, an in vitro assay encompasses any assay run outside of a subject. In vitro assays encompass cell-based assays in which cells alive or dead are employed. In vitro assays also encompass a cell-free assay in which no intact cells are employed.
[0070]“Optional” or“optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example,“optionally substituted aryl” means that the aryl group may or may not be substituted and that the description includes both substituted aryl groups and aryl groups having no substitution.
[0071]“Pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye, colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
[0072] The present disclosure provides methods for modulating the interaction of menin with proteins such as MLL for the treatment of a wide variety of disorders associated with impaired beta cell production, such as type 1 diabetes or type 2 diabetes. In certain embodiments, the disclosure provides methods for inhibiting the interaction of menin with its upstream or downstream signaling molecules, including but not limited to MLL. In certain embodiments, a method of the disclosure provides a compound that covalently binds menin and inhibits the interaction of menin with another protein such as MLL. In certain embodiments, a method of the disclosure provides a compound that interacts non-covalently with menin and inhibits the interaction of menin with another protein such as MLL.
[0073] In some aspects, the present disclosure provides a method comprising a compound or salt that selectively binds to the menin protein and/or modulates the interaction of menin with an MLL protein. In certain embodiments, the compound modulates the menin protein by binding to or interacting with one or more amino acids and/or one or more metal ions. Certain compounds may occupy the F9 and/or P13 pocket of menin. The binding of a compound disclosed in the subject methods may disrupt menin or MLL (e.g., MLL1, MLL2, or an MLL fusion protein) downstream signaling.
[0074] In certain aspects, the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising administerin a com ound of Formula I :
Figure imgf000024_0001
or a pharmaceutically acceptable salt thereof, wherein:
H is selected from C3-12 carbocycle and 3- to 12-membered heterocycle;
A is selected from bond, C3-12 carbocycle, and 3- to 12-membered heterocycle;
B is selected from C3-12 carbocycle and 3- to 12-membered heterocycle; C is selected from bond, C3-12 carbocycle, and 3- to 12-membered heterocycle;
each of L1, L2, and L3 is independently selected from bond, -O-, -S-, -N(R51)-, - N(R51)CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R51)-, - C(O)N(R51)C(O)-, -C(O)N(R51)C(O)N(R51)-, -N(R51)C(O)-, -N(R51)C(O)N(R51)-, -N(R51)C(O)O-, -OC(O)N(R51)-, -C(NR51)-, -N(R51)C(NR51)-, -C(NR51)N(R51)-, - N(R51)C(NR51)N(R51)-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, - N(R51)S(O)2-, -S(O)2N(R51)-, -N(R51)S(O)-, -S(O)N(R51)-, -N(R51)S(O)2N(R51)-, and -N(R51)S(O)N(R51)- or from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is optionally substituted with one or more R50, wherein two R50 groups attached to the same atom or different atoms of any one of L1, L2, or L3 can together optionally form a bridge or ring;
R50 is, at each occurrence, independently selected from:
halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, - S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, - NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, - OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, - NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, - P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52);
C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, - S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, - NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, - OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), - P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; and
C3-12 carbocycle and 3- to 12-membered heterocycle,
wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R50 is independently optionally substituted with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, - S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52 -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, - NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, - P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), - P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;
R51 is independently selected at each occurrence from:
hydrogen, -C(O)R52, -C(O)OR52, -C(O)N(R52)2, -C(O)NR53R54;
C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, - S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, - NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, - OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, - NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, - P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C3-12 carbocycle and 3- to 12-membered heterocycle; and
C3-12 carbocycle and 3- to 12-membered heterocycle,
wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R51 is independently optionally substituted with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, - S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, - NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, - P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), - P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;
R52 is independently selected at each occurrence from hydrogen; and C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, 1- to 6-membered heteroalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -NO2, -NH2, -NHCH3, - NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C3-12 carbocycle, or 3- to 6-membered heterocycle;
R53 and R54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R50;
each of RH, RA, and RB is, at each occurrence, independently selected from R50, or two RH groups, two RA groups, or two RB groups attached to the same atom or different atoms can together optionally form a bridge or ring;
RC is, at each occurrence, independently selected from hydrogen or R50, or two RC groups attached to the same atom or different atoms can together optionally form a bridge or ring; and each of m, n, p, and q is independently an integer from 0 to 12.
[0075] In some embodiments, for a compound of Formula (I), H is 5- to 12-membered heterocycle, such as 6- to 12-membered bicyclic heterocycle, optionally substituted with one or more RH. In some embodiments, H contains one or more heteroatoms, such as 1, 2, 3, 4, 5 or 6 ring heteroatoms. In some embodiments, H contains at least 1, 2, 3, 4 or 5 ring nitrogen atoms. In some embodiments, H is thienopyrimidinyl, optionally substituted with one or more RH. In some embodiments, H is substituted with C1-4 haloalkyl, such as -CH2CF3. In some embodiments, H is substituted with one or more RH (e.g., by replacing a hydrogen connected to a ring atom with a bond to RH). H may be substituted with 0, 1, 2, 3, 4, 5, 6 or more RH groups. H may be substituted with 1, 2, 3, 4, 5 or 6 RH groups, such as H substituted with 1 or 2 RH groups. In some embodiments, H is substituted with at least 1, 2, 3, 4, 5 or 6 RH groups. In some embodiments, H is substituted with up to 6, 5, 4, 3, 2 or 1 RH groups. In some embodiments, H is substituted with m RH groups, wherein m is an integer from 0 to 6. In some embodiments, m is 0, 1, 2, 3, 4, 5 or 6. In some embodiments, m is at least 1, 2, 3, 4, 5 or 6. In some embodiments, m is up to 6, 5, 4, 3, 2, or 1. In some embodiments, m is 0.
[0076] In some embodiments, for a compound of Formula (I), H is 6-membered to 12-membered
bicyclic heterocycle. In some embodiments, H is
Figure imgf000027_0001
; each of X1 and X2 is independently selected from CR2 and N; each of X3 and X4 is independently selected from C and N; each of X5 and X6 is independently selected from CR3, N, NR4, O, and S; each of R1, R2 and R3 is independently selected at each occurrence from hydrogen and R50; and R4 is selected from R51. In some embodiments, X3 and X4 are each C. In some embodiments, X5 is S. In some embodiments, X6 is S. In some embodiments, at least one of X5 and X6 is selected from N, NR4, O and S. In some embodiments, X6 is CR3, and R3 is selected from hydrogen, halogen, -OR52, - N(R52)2, -CN, -C(O)OR52, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, H is
Figure imgf000027_0002
. In some embodiments, R2 is selected from hydrogen, halogen, -OR52, -NH2, -N(R52) 2
2, -CN, C1-3 alkyl, C1-3 alkyl-OR5 , C1-3 alkyl-N(R52)2, C1-3 haloalkyl, C2-3 alkenyl, and C2-3 alkynyl. In some embodiments, R3 is selected from hydrogen, halogen, -OR52, -N(R52)2, - CN, -C(O)OR52, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R1 is C1-3 haloalkyl. In some embodiments, R1 is
Figure imgf000027_0003
. In some embodiments, H is thienopyrimidinyl or thienopyridinyl.
[0077] In some embodiments, X1 is CR2, X2 is N, X3 and X4 are each C, X5 is S, X6 is CR3, and R1 is selected from R50. In some embodiments, X1 is CR2; X2 is N; X3 and X4 are each C; X5 is S; X6 is CH; R1 is C1-3 haloalkyl; and R2 is selected from hydrogen, halogen, -OH, -NH2, -CN, C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, and C2-3 alkynyl. In some embodiments, H is
. In some embodiments, H is
Figure imgf000028_0003
haloalkyl, C2-3 alkenyl, and C2-3 alkynyl. In some embodiments, R2 is selected from hydrogen, halogen, -OH, alkoxy (e.g., -OR52, -OCH3, -OCH2CH3), aminoalkyl, alkylamino, -N(R52)2 (e.g., - NH2, -NHCH3, -NHCH2CH3), -N(CH3)2, -CN, C1-3 alkyl (e.g., -CH3), cyclopropyl, C1-3 alkyl- OR52 (e.g., -CH2OH, -CH2OC(O)CH3), C1-3 alkyl-N(R52)2, C1-3 haloalkyl, C2-3 alkenyl, and C2-3 alkynyl.
[0078] In some embodiments, for a compound of Formula (I), H is
Figure imgf000028_0001
, wherein R1 is selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, and haloalkyl, such as from alkyl and haloalkyl; R2 is selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, and alkylamino, such as from H, halo, hydroxyl, and amino; and each of X5 and X6 is independently selected from S, CR3, N, NR4 and O. In certain embodiments, up to one of X5 and X6 is O or S.
[0079] In some embodiments, for a compound of Formula (I), H is
Figure imgf000028_0002
; each of X1 and X2 is independently CR2 or N; each of X7, X8, X9, and X10 is independently CR16, CR17R18, N, NR19, O, or S; each of R16, R17, and R18 is independently selected at each occurrence from hydrogen and R50; and R19 is selected from R51.
[0080] In some embodiments, for a compound of Formula (I), X1 is CR2, and R2 is selected from hydrogen, halogen, -OH, -OR52, -NH2, -N(R52)2, -CN, C1-3 alkyl, C1-3 alkyl-OR52, C1-3 alkyl- N(R52)2, C1-3 haloalkyl, C2-3 alkenyl, and C2-3 alkynyl. [0081] In some embodiments, for a compound of Formula (I), X2 is N.
[0082] In some embodiments, for a compound of Formula (I), H is 5- or 6-membered
monocyclic heterocycle. In some embodiments, H is
Figure imgf000029_0001
; each of Y1, Y2, and Y4 is independently CR2, N, NR21, O, or S; Y5 is CR20, N, NR21, O, or S; Y6 is C or N; Y3 is a bond, CR22, or N, wherein when Y3 is CR22 or N, then each of Y1, Y2, and Y4 is independently CR2, N, or NR21 and Y5 is CR20, N, or NR21; each of R2 and R20 is independently selected at each occurrence from hydrogen and R50; and R21 is selected from R51.
[0083] In some embodiments, for a compound of Formula (I), L1 comprises less than 20 atoms, such as less than 10 atoms. In some embodiments, L1 comprises less than 20, 15, 10, 9, 8, 7, 6, 5, 4, or less than 3 atoms. In some embodiments, L1 comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or at least 20 atoms. In some embodiments, L1 comprises at least one heteroatom, such as L1 comprises at least one nitrogen. In some embodiments, L1 is substituted with one or more R50. In some embodiments, L1 is unsubstituted. In some embodiments, L1 is selected from bond, -O-, -S- , -N(R51)-, -N(R51)CH2-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R51)-, -N(R51)C(O)-, - N(R51)C(O)N(R51)-, -S(O)2-, -S(O)-, -N(R51)S(O)2-, -S(O)2N(R51)-, -N(R51)S(O)2N(R51)-, alkylene, alkenylene, heteroalkylene, and heteroalkenylene. In some embodiments, L1 is selected from bond, -O-, -S-, -N(R51)-, -N(R51)CH2-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R51)-, - N(R51)C(O)-, -N(R51)C(O)N(R51)-, -S(O)2-, -S(O)-, -N(R51)S(O)2-, -S(O)2N(R51)-, - N(R51)S(O)2N(R51)-, C1-6 alkylene and C2-6 alkenylene, wherein the C1-6 alkylene and C2-6 alkenylene are each optionally substituted with one or more R50. In some embodiments, L1 is a bond or -N(R51)-. In some embodiments, L1 is not a bond. In some embodiments, L1 is -N(R51)-, such as -NH-. In some embodiments, L1 is selected from -O-, -N(R51)-, -N(R51)CH2-, -C(O)-, - C(O)N(R51)-, -N(R51)C(O)-, -N(R51)S(O)2-, -S(O)2N(R51)-, C1-4 alkylene, C2-4 alkenylene, and C1-4 heteroalkylene. In some embodiments, L1 is -N(R51)-, wherein R51 is selected from hydrogen and alkyl.
[0084] In some embodiments, for a compound of Formula (I), A is 3- to 12-membered heterocycle, such as 5- to 8-membered heterocycle. In some embodiments, A is 6-membered monocyclic heterocycle. In some embodiments, the heterocycle comprises at least one nitrogen atom. In some embodiments, A comprises at least one ring nitrogen. In some embodiments, A is
selected from piperidinylene and piperazinylene, such as
Figure imgf000029_0002
. In some embodiments, A is
Figure imgf000030_0002
. In some embodiments, A is an aromatic, non-aromatic, saturated or unsaturated ring. In some embodiments, A is selected from arylene, cycloalkylene, heterocycloalkylene, N- heterocycloalkylene, heteroarylene, and N-heteroarylene. In some embodiments, A is 5- to 8- membered heterocycle, wherein the heterocycle comprises at least 1, 2, 3 or 4 ring heteroatoms selected from N, O and S.
Figure imgf000030_0001
[0086] In some embodiments, A is substituted with one or more RA (e.g., by replacing a hydrogen connected to a ring atom with a bond to RA). A may be substituted with 0, 1, 2, 3, 4, 5, 6 or more RA groups. A may be substituted with 1, 2, 3, 4, 5 or 6 RA groups, such as A substituted with 1 or 2 RA groups. In some embodiments, A is substituted with at least 1, 2, 3, 4, 5 or 6 RA groups. In some embodiments, A is unsubstituted. In some embodiments, A is substituted with n RA groups, wherein n is an integer from 0 to 6. In some embodiments, n is 0, 1, 2, 3, 4, 5 or 6. In some embodiments, n is at least 1, 2, 3, 4, 5 or 6. In some embodiments, n is up to 6, 5, 4, 3, 2, or 1. In some embodiments, n is 0.
[0087] In some embodiments, RA is independently selected at each occurrence from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino,
heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino. In some embodiments, two RA groups attached to the same atom or different atoms can together form a ring.
[0088] In some embodiments, for a compound of Formula (I), L2 comprises less than 20 atoms, such as less than 10 atoms. In some embodiments, L2 comprises less than 20, 15, 10, 9, 8, 7, 6, 5, 4, or less than 3 atoms. In some embodiments, L2 comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or at least 20 atoms. In some embodiments, L2 comprises at least one heteroatom, such as L2 comprises at least one nitrogen. In some embodiments, L2 is C1-10 alkylene, such as C1-4 alkylene, optionally substituted with one or more R50. In some embodiments, L2 is substituted with one or more R50. In some embodiments, L2 is unsubstituted. In some embodiments, L2 is selected from bond, -O-, -S-, -N(R51)-, -N(R51)CH2-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R51)-, -N(R51)C(O)-, - N(R51)C(O)N(R51)-, -S(O)2-, -S(O)-, -N(R51)S(O)2-, -S(O)2N(R51)-, -N(R51)S(O)2N(R51)-, alkylene, alkenylene, heteroalkylene, and heteroalkenylene. In some embodiments, L2 is selected from bond, -O-, -S-, -N(R51)-, -N(R51)CH2-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R51)-, - N(R51)C(O)-, -N(R51)C(O)N(R51)-, -S(O)2-, -S(O)-, -N(R51)S(O)2-, -S(O)2N(R51)-, - N(R51)S(O)2N(R51)-, C1-6 alkylene and C2-6 alkenylene, wherein the C1-6 alkylene and C2-6 alkenylene are each optionally substituted with one or more R50. In some embodiments, L2 is selected from -O-, -N(R51)-, -N(R51)CH2-, -C(O)N(R51)-, -N(R51)C(O)-, -N(R51)S(O)2-, - S(O)2N(R51)-, C1-4 alkylene and C1-4 heteroalkylene. In some embodiments, L2 is selected from - CH2-, -N(R51)-, -N(R51)CH2-, -N(R51)C(O)-, and -N(R51)S(O)2-. In some embodiments, L2 is - CH2-.
[0089] In some embodiments, for a compound of Formula (I), B is 3- to 12-membered heterocycle, such as 6- to 12-membered bicyclic heterocycle. In some embodiments, the heterocycle comprises at least one nitrogen atom. In some embodiments, B is 6- to 12-membered heterocycle, wherein the heterocycle comprises at least 1, 2, 3 or 4 ring heteroatoms selected from N, O and S. In some embodiments, B is a 6,5- or 6,6-bicyclic heterocycle. In some embodiments, B comprises at least one ring nitrogen. In some embodiments, B is indolylene, such as
Figure imgf000031_0001
optionally substituted with one or more RB. In some embodiments, B is
Figure imgf000032_0001
y substituted with one or more RB, wherein each of E and G is independently N or C. In some
embodiments, B is indolylene. In some embodiments, B is
Figure imgf000032_0002
, optionally substituted with one or more RB. In some embodiments, B is phenylene. In some embodiments, RB is selected from halogen, methyl, -CN, -OR52, and -N(R52)2.
[0090] In some embodiments, B is selected
Figure imgf000032_0003
and
Figure imgf000032_0004
, wherein M1, M2, M3 and M4 are each independently selected from CR7, N and NR9; M5 is selected from C and N; M6, M7 and M8 are each independently selected from CR8, N, NR9, O and S; M9, M10 and M11 are each independently selected from CR10, CR11R12, NR13, O and S; R7, R8, R10, R11, and R12 are each independently selected from hydrogen and R50; and R9 and R13 are each independently selected from R51, wherein B may be connected at any ring atom to L2 or L3 (e.g., by replacing a hydrogen connected to a ring atom with a bond to L2 or L3).
Figure imgf000032_0005
,
Figure imgf000033_0001
[0092] In some embodiments, B is substituted with one or more RB (e.g., by replacing a hydrogen connected to a ring atom with a b d RB) B y be substituted with 0, 1, 2, 3, 4, 5, 6 or more RB groups. B may be substituted with 1, 2, 3, 4, 5 or 6 RB groups, such as B substituted with 1 or 2 RB groups. In some embodiments, B is substituted with at least 1, 2, 3, 4, 5 or 6 RB groups. In some embodiments, B is substituted with p RB groups, wherein p is an integer from 0 to 6. In some embodiments, p is 0, 1, 2, 3, 4, 5 or 6. In some embodiments, p is at least 1, 2, 3, 4, 5 or 6. In some embodiments, p is up to 6, 5, 4, 3, 2, or 1. In some embodiments, p is an integer from 1 to 3.
[0093] In some embodiments, RB is independently selected at each occurrence from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino,
heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino. In some embodiments, RB is independently selected at each occurrence from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, heterocyclylalkyl, and heteroarylalkyl. In some embodiments, two RB groups attached to the same atom or different atoms can together form a ring.
[0094] In some embodiments, for a compound of Formula (I), L3 comprises less than 30 atoms, such as less than 20 atoms. In some embodiments, L3 comprises less than 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, or less than 3 atoms. In some embodiments, L3 comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or at least 20 atoms. In some embodiments, L3 comprises at least one heteroatom, such as L3 comprises at least one nitrogen. In some embodiments, L3 is C1-10 alkylene, such as C1-4 alkylene, optionally substituted with one or more R50. In some embodiments, L3 is unsubstituted. In some embodiments, L3 is selected from bond, -O-, -S-, -N(R51)-, -N(R51)CH2-, -C(O)-, - C(O)O-, -OC(O)-, -C(O)N(R51)-, -N(R51)C(O)-, -N(R51)C(O)N(R51)-, -S(O)2-, -S(O)-, - N(R51)S(O)2-, -S(O)2N(R51)-, -N(R51)S(O)2N(R51)-, alkylene, alkenylene, heteroalkylene, and heteroalkenylene. In some embodiments, two R50 groups attached to the same atom or different atoms of L3 optionally form a bridge or ring, such as a cyclopropyl ring. In some embodiments, L3 is substituted with R50, wherein R50 forms a bond to ring C. In some embodiments, L3 is a bond. In some embodiments, L3 is not a bond. In some embodiments, L3 is C1-6 alkylene, optionally substituted with one or more R50. In some embodiments, L3 is selected from ,
Figure imgf000034_0001
Figure imgf000035_0001
wherein any one of which is optionally substituted with one or more R50. In some embodiments,
Figure imgf000035_0002
nally substituted with one or more R50.
[0095] In some embodiments, L3 comprises a stereocenter. In some embodiments, the stereocenter is in the R-configuration. In some embodiments, the stereocenter is in the S- configuration. In some embodiments, the R-isomer of L3 is provided in at least 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% excess over the S-isomer. In some embodiments, the S-isomer of L3 is provided in at least 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% excess over the R- isomer.
[0096] In some embodiments, for a compound of Formula (I), C is selected from C3-12 carbocycle and 3- to 12-membered heterocycle, such as 5- to 12-membered heterocycle. In some embodiments, the heterocycle is saturated. In some embodiments, C is selected from 5- to 7- membered monocyclic heterocycle, 8- to 10-membered fused bicyclic heterocycle, and 7- to 12- membered spirocyclic heterocycle. In some embodiments, the heterocycle comprises at least one nitrogen atom, such as one or two nitrogen atoms. In some embodiments, C comprises at least one ring nitrogen. In some embodiments, C is a bond.
[0097] In some embodiments, C is
Figure imgf000035_0003
; W1 is C1-4 alkylene, optionally substituted with one or more R50; W2 is selected from a bond; and C1-4 alkylene, optionally substituted with one or more R50; W3 is selected from absent; and C1-4 alkylene, optionally substituted with one or more R50; wherein when W3 is absent: W1 is C1 alkylene, W2 is a bond, and L3 is not a bond; W1 is C2-4 alkylene and W2 is a bond; or W1 and W2 are each C1 alkylene and L3 is not a bond, wherein each C1 alkylene is independently optionally substituted with one or more R50. In some embodiments, W1, W2 and W3 are each independently selected from C1-4 alkylene, wherein each C1-4 alkylene is optionally substituted with In some embodiments, W1, W2 and W3 are each C1 alkylene. In some embodiments, W1 and W2 are each C1 alkylene and W3 is absent.
[0098] In some embodiments, for a compound of Formula (I), C is substituted with one or more RC (e.g., by replacing a hydrogen connected to a ring atom with a bond to RC). C may be substituted with 0, 1, 2, 3, 4, 5, 6 or more RC groups. C may be substituted with 1, 2, 3, 4, 5 or 6 RC groups, such as C substituted with 1 or 2 RC groups. In some embodiments, C is substituted with at least 1, 2, 3, 4, 5 or 6 RC groups. In some embodiments, C is unsubstituted. In some embodiments, C is substituted with q RC groups, wherein q is an integer from 0 to 6. In some embodiments, q is 0, 1, 2, 3, 4, 5 or 6. In some embodiments, q is at least 1, 2, 3, 4, 5 or 6. In some embodiments, q is up to 6, 5, 4, 3, 2, or 1. In some embodiments, q is 1 or 2.
[0099] In some embodiments, for a compound of Formula (I), RC is selected from:
halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, - S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, - C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, - NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, - C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, =O, =S, and =N(R52); and
C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -NO2, -CN, - OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, - NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, - NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, =O, =S, =N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle;
wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in RC is independently optionally substituted with one or more substituents selected from halogen, -NO2, -CN, -OR52, - SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, - NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, - NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, =O, =S, =N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl.
[0100] In some embodiments, RC is selected from -N(R52)2, -NR53R54, -NR52S(=O)2R52, - C(O)R52, -C(O)OR52, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, - NR52C(O)NR53R54, -C(O)N(R52)2, and -C(O)NR53R54. In some embodiments, RC is selected from -N(R52)2, -NR53R54, -NR52S(=O)2R52, -C(O)R52, -C(O)OR52, -NR52C(O)R52, -NR52C(O)OR52, - NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2 -C(O)NR53R54, C1-6 alkyl, and C1-6 alkyl substituted with -N(R52)2, -NR53R54, -NR52S(=O)2R52, -C(O)R52, -C(O)OR52, -NR52C(O)R52, - NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, or -C(O)NR53R54.
[0101] In some embodiments, for a compound of Formula (I), H is 5- to 12-membered heterocycle; A is 3- to 12-membered heterocycle; and B is 3- to 12-membered heterocycle. In some embodiments, H is 6- to 12-membered bicyclic heterocycle; A is 3- to 12-membered heterocycle; and B is 3- to 12-membered heterocycle. In some embodiments, H is 6- to 12- membered bicyclic heterocycle, optionally substituted with one or more R50; A is 3- to 12- membered heterocycle; and B is 6- to 12-membered bicyclic heterocycle. In some embodiments, H is 5- to 12-membered heterocycle; A is 3- to 12-membered heterocycle; and B is 6- to 12- membered bicyclic heterocycle. In some embodiments, H is thienopyrimidinyl; A is 3- to 12- membered heterocycle; and B is 3- to 12-membered heterocycle. In some embodiments, H is 5- to 12-membered heterocycle; A is selected from piperidinylene and piperazinylene; and B is 3- to 12-membered heterocycle. In some embodiments, H is 5- to 12-membered heterocycle; A is 3- to 12-membered heterocycle; and B is indolylene. In some embodiments, H is thienopyrimidinyl; A is selected from piperidinylene and piperazinylene; and B is indolylene.
[0102] In some embodiments, for a compound of Formula (I), H is 5- to 12-membered heterocycle; A is 3- to 12-membered heterocycle; B is 3- to 12-membered heterocycle; C is 3- to 12-membered heterocycle;and m, n, p and q are each independently an integer from 0 to 3. In some embodiments, H is 6- to 12-membered bicyclic heterocycle; A is 3- to 12-membered heterocycle; B is 6- to 12-membered bicyclic heterocycle; C is 3- to 12-membered heterocycle; and m, n, p and q are each independently an integer from 0 to 3. In some embodiments, H is 5- to 12-membered heterocycle; A is 3- to 12-membered heterocycle; B is 3- to 12-membered heterocycle; and C is 3- to 12-membered heterocycle. In some embodiments, H is 6- to 12- membered bicyclic heterocycle; A is 3- to 12-membered heterocycle; B is 6- to 12-membered bicyclic heterocycle; and C is 3- to 12-membered heterocycle. In some embodiments, H is 6- to 12-membered bicyclic heterocycle; A is selected from piperidinylene and piperazinylene; B is 6- to 12-membered bicyclic heterocycle; and C is 3- to 12-membered heterocycle. In some embodiments, H is 6- to 12-membered bicyclic heterocycle; A is selected from piperidinylene and piperazinylene; B is 6- to 12-membered bicyclic heterocycle; and m, n, p and q are each independently an integer from 0 to 3. In some embodiments, H is thienopyrimidinyl; A is 3- to 12-membered heterocycle; and B is 6- to 12-membered bicyclic heterocycle. In some
embodiments, H is thienopyrimidinyl; A is 3- to 12-membered heterocycle; B is 6- to 12- membered bicyclic heterocycle; and m, n, p and q are each independently an integer from 0 to 3. In some embodiments, H is 9- to 10-membered bicyclic heterocycle; A is 5- to 7-membered heterocycle; and B is 9-membered bicyclic heterocycle wherein each of said heterocycles comprises at least one nitrogen atom. In some embodiments, H is 9- to 10-membered bicyclic heterocycle; A is 5- to 7-membered heterocycle; B is 9-membered bicyclic heterocycle; and n is an integer from 0 to 3, wherein each of said heterocycles comprises at least one nitrogen atom. In some embodiments, H is thienopyrimidinyl; A is selected from piperidinylene and
piperazinylene; B is indolylene; m is 1 or 2; n is 0 or 1; p is 2 or 3; and q is an integer from 0 to 4. In some embodiments, H is thienopyrimidinyl; A is selected from piperidinylene and piperazinylene; B is indolylene; m is 1 or 2; n is an integer from 0 to 3; p is 2; and q is an integer from 0 to 4. In some embodiments, H is 6- to 12-membered bicyclic heterocycle; A is 3- to 12- membered heterocycle; B is 6- to 12-membered bicyclic heterocycle; C is a bond; and m, n, and p are each independently an integer from 0 to 3; and q is 1. In some embodiments, H is thienopyrimidinyl; A is selected from piperidinylene and piperazinylene; B is indolylene; C is a bond; and m, n, and p are each independently an integer from 0 to 3; and q is 1.
[0103] In some embodiments, for a compound of Formula (I), L1 comprises less than 10 atoms, L2 comprises less than 10 atoms, and L3 comprises less than 20 atoms. In some embodiments, L1, L2 and L3 each comprise at least 1 atom, such as at least 2 atoms. In some embodiments, L1, L2 and L3 are each independently selected from bond, -O-, -S-, -N(R51)-, -N(R51)CH2-, -C(O)-, - C(O)O-, -OC(O)-, -C(O)N(R51)-, -N(R51)C(O)-, -N(R51)C(O)N(R51)-, -S(O)2-, -S(O)-, - N(R51)S(O)2-, -S(O)2N(R51)-, -N(R51)S(O)2N(R51)-, alkylene, alkenylene, heteroalkylene, and heteroalkenylene. In some embodiments, L1, L2 and L3 are each independently selected from - CH2-, -CH2CH2-, -CH2CH(CH3)-, -N(R51)-, -N(R51)CH2-, -N(R51)C(O)-, and -N(R51)S(O)2-. In some embodiments, L1 is selected from -O-, -S-, -N(R51)-, -N(R51)CH2-, -C(O)-, -C(O)O-, - OC(O)-, -C(O)N(R51)-, -N(R51)C(O)-, -N(R51)C(O)N(R51)-, -S(O)2-, -S(O)-, -N(R51)S(O)2-, - S(O)2N(R51)-, -N(R51)S(O)2N(R51)-, alkylene, alkenylene, heteroalkylene, and heteroalkenylene; and L2 and L3 are independently selected from C1-4 alkylene, optionally substituted with one or more R50. In some embodiments, L1, L2 and L3 are each independently selected from -O-, -S-, - N(R51)-; C1-4 alkylene and 1- to 4-membered heteroalkylene, each of which is optionally substituted with one or more R50. In some embodiments, L1 is -NH-, L2 is -CH2-, and L3 is C1-4 alkylene, optionally substituted with one or more R50. In some embodiments, L1 is -NH-, L2 is - CH2-, and L3 is a bond.
[0104] In some embodiments, L1 and L2 are each independently selected from bond, -O-, -S-, - N(R51)-, -N(R51)CH2-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R51)-, -N(R51)C(O)-, - N(R51)C(O)N(R51)-, -S(O)2-, -S(O)-, -N(R51)S(O)2-, -S(O)2N(R51)-, -N(R51)S(O)2N(R51)-, alkylene, alkenylene, heteroalkylene, and heteroalkenylene. In some embodiments, L1 and L2 are each independently selected from -CH2-, -N(R51)-, -N(R51)CH2-, -N(R51)C(O)-, and - N(R51)S(O)2-. In some embodiments, L1 is selected from -O-, -S-, -N(R51)-, -N(R51)CH2-, - C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R51)-, -N(R51)C(O)-, -N(R51)C(O)N(R51)-, -S(O)2-, -S(O)-, - N(R51)S(O)2-, -S(O)2N(R51)-, -N(R51)S(O)2N(R51)-, alkylene, alkenylene, heteroalkylene, and heteroalkenylene; and L2 is C1-4 alkylene, optionally substituted with one or more R50. In some embodiments, L1 and L2 are each independently selected from -O-, -S-, -N(R51)-; C1-4 alkylene and 1- to 4-membered heteroalkylene, each of which is optionally substituted with one or more R50. In some embodiments, L1 is -NH-, and L2 is -CH2-.
[0105] In certain aspects, the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising administerin a com ound of Formula (I):
Figure imgf000039_0001
(I);
or a pharmaceutically acceptable salt thereof, wherein:
H is selected from C3-12 carbocycle and 3- to 12-membered heterocycle;
A is selected from bond, C3-12 carbocycle, and 3- to 12-membered heterocycle;
B is selected from C3-12 carbocycle and 3- to 12-membered heterocycle;
C is selected from bond, C3-12 carbocycle, and 3- to 12-membered heterocycle;
each of L1, L2, and L3 is independently selected from bond, -O-, -S-, -N(R51)-, - N(R51)CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R51)-, - C(O)N(R51)C(O)-, -C(O)N(R51)C(O)N(R51)-, -N(R51)C(O)-, -N(R51)C(O)N(R51)-, -N(R51)C(O)O-, -OC(O)N(R51)-, -C(NR51)-, -N(R51)C(NR51)-, -C(NR51)N(R51)-, - N(R51)C(NR51)N(R51)-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, - N(R51)S(O)2-, -S(O)2N(R51)-, -N(R51)S(O)-, -S(O)N(R51)-, -N(R51)S(O)2N(R51)-, and -N(R51)S(O)N(R51)- or from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is optionally substituted with one or more R50, wherein two R50 groups attached to the same atom or different atoms of any one of L1, L2, or L3 can together optionally form a bridge or ring;
R50 is, at each occurrence, independently selected from:
halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, - S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, - NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, - OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, - NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, - P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52);
C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, - S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, - NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, - OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), - P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; and
C3-12 carbocycle and 3- to 12-membered heterocycle,
wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R50 is independently optionally substituted with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, - S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, - NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, - P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), - P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;
R51 is independently selected at each occurrence from:
hydrogen, -C(O)R52, -C(O)OR52, -C(O)N(R52)2, -C(O)NR53R54;
C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, - S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, - NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, - OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, - NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, - P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C3-12 carbocycle and 3- to 12-membered heterocycle; and
C3-12 carbocycle and 3- to 12-membered heterocycle,
wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R51 is independently optionally substituted with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, - S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, - NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, - P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), - P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;
R52 is independently selected at each occurrence from hydrogen; and C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, 1- to 6-membered heteroalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -NO2, -NH2, -NHCH3, - NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C3-12 carbocycle, or 3- to 6-membered heterocycle;
R53 and R54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R50;
each of RH, RA, and RB is, at each occurrence, independently selected from R50, or two RH groups, two RA groups, or two RB groups attached to the same atom or different atoms can together optionally form a bridge or ring;
RC is, at each occurrence, independently selected from hydrogen or R50, or two RC groups attached to the same atom or different atoms can together optionally form a bridge or ring;
m is an integer from 1 to 3;
n is an integer from 0 to 3;
p is an integer from 0 to 6; and
q is an integer from 0 to 6.
[0106] In certain aspects, for a compound of Formula (I):
H is thienopyrimidinyl;
A is selected from piperidinylene and piperazinylene;
B is indolylene;
C is selected from bond, C3-12 carbocycle, and 3- to 12-membered heterocycle;
L1 and L2 are each independently selected from -O-, -S-, -NH-, and -CH2-;
L3 is selected from bond, -O-, -S-, -N(R51)-, -N(R51)CH2-, -C(O)-, -C(O)O-, -OC(O)-, - OC(O)O-, -C(O)N(R51)-, -C(O)N(R51)C(O)-, -C(O)N(R51)C(O)N(R51)-, -N(R51)C(O)-, - N(R51)C(O)N(R51)-, -N(R51)C(O)O-, -OC(O)N(R51)-, -C(NR51)-, -N(R51)C(NR51)-, - C(NR51)N(R51)-, -N(R51)C(NR51)N(R51)-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R51)S(O)2-, -S(O)2N(R51)-, -N(R51)S(O)-, -S(O)N(R51)-, -N(R51)S(O)2N(R51)-, - N(R51)S(O)N(R51)-; alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is optionally substituted with one or more R50, wherein two R50 groups attached to the same atom or different atoms of L3 can together optionally form a ring; RA, RB and RC are each independently selected at each occurrence from R50, or two RA groups, two RB groups or two RC groups attached to the same atom or different atoms can together optionally form a ring;
m is an integer from 1 to 3;
n is an integer from 0 to 3;
p is an integer from 0 to 6; and
q is an integer from 0 to 6.
1 In m m im n f r mpound of Formula (I), the compound has a structure of
Figure imgf000042_0001
.
[0108] In certain aspects, the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising administering a stereoisomer of a compound of Formula (I). In some embodiments, the stereoisomer is in enantiomeric excess. In some embodiments, the stereoisomer is provided in at least 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%, enantiomeric excess. In some embodiments, the stereoisomer is provided in greater than 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%, enantiomeric excess. In some embodiments, the stereoisomer is in greater than 95% enantiomeric excess, such as greater than 99% enantiomeric excess.
[0109] In certain aspects, the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising administering a stereoisomer of a compound of Formula (I). In some embodiments, the stereoisomer is in diastereomeric excess. In some embodiments, the stereoisomer is provided in at least 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%, diastereomeric excess. In some embodiments, the stereoisomer is provided in greater than 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%, diastereomeric excess. In some embodiments, the stereoisomer is in greater than 95% diastereomeric excess, such as greater than 99%
diastereomeric excess. [0110] In certain embodiments, the compound of Formula (I) is preferably used in the subject methods as a non-racemic mixture, wherein one enantiomer is present in excess of its
corresponding enantiomer. Typically, such mixture will contain a mixture of the two isomers in a ratio of at least about 9:1, preferably at least 19:1. In some embodiments, the compound is provided in at least 96% enantiomeric excess, meaning the compound has less than 2% of the corresponding enantiomer. In some embodiments, the compound is provided in at least 96% diastereomeric excess, meaning the compound has less than 2% of the corresponding
diastereomer.
[0111] In certain embodiments, the compound of Formula (I) is preferably used in the subject methods as a non-racemic mixture wherein the (+)-isomer is the major component of the mixture. Typically, such mixture will contain no more than about 10% of the (–)-isomer, meaning the ratio of (+)- to (–)-isomers is at least about 9:1, and preferably less than 5% of the (–)-isomer, meaning the ratio of (+)- to (–)-isomers is at least about 19:1. In some embodiments, the compound used has less than 2% of the (–)-isomer, meaning it has an enantiomeric excess of at least about 96%. In some embodiments, the compound has an enantiomeric excess of at least 98%. In some embodiments, the compound has an enantiomeric excess of at least 99%.
[0112] In certain embodiments, the compound of Formula (I) is preferably used in the subject methods as a non-racemic mixture wherein the (–)-isomer is the major component of the mixture. Typically, such mixture will contain no more than about 10% of the (+)-isomer, meaning the ratio of (–)- to (+)-isomers is at least about 9:1, and preferably less than 5% of the (+)-isomer, meaning the ratio of (–)- to (+)-isomers is at least about 19:1. In some embodiments, the compound used has less than 2% of the (+)-isomer, meaning it has an enantiomeric excess of at least about 96%. In some embodiments, the compound has an enantiomeric excess of at least 98%. In some embodiments, the compound has an enantiomeric excess of at least 99%.
[0113] In certain aspects, the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising administering a stereoisomer of a compound of Formula (I), wherein:
H is 5- to 12-membered heterocycle;
A is 3- to 12-membered heterocycle;
B is 3- to 12-membered heterocycle;
C is selected from bond, C3-12 carbocycle, and 3- to 12-membered heterocycle;
each of L1, L2, and L3 is independently selected from bond, -O-, -S-, -N(R51)-, - N(R51)CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R51)-, - C(O)N(R51)C(O)-, -C(O)N(R51)C(O)N(R51)-, -N(R51)C(O)-, -N(R51)C(O)N(R51)-, -N(R51)C(O)O-, -OC(O)N(R51)- -C(NR51)- -N(R51)C(NR51)-, -C(NR51)N(R51)-, - N(R51)C(NR51)N(R51)-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, - N(R51)S(O)2-, -S(O)2N(R51)-, -N(R51)S(O)-, -S(O)N(R51)-, -N(R51)S(O)2N(R51)-, and -N(R51)S(O)N(R51)- or from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is optionally substituted with one or more R50, wherein two R50 groups attached to the same atom or different atoms of any one of L1, L2, or L3 can together optionally form a bridge or ring;
R50 is, at each occurrence, independently selected from:
halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, - S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, - NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, - OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, - NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, - P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52);
C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, - S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, - NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, - OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), - P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; and
C3-12 carbocycle and 3- to 12-membered heterocycle,
wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R50 is independently optionally substituted with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, - S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, - NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, - P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), - P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;
R51 is independently selected at each occurrence from: hydrogen, -C(O)R52, -C(O)OR52, -C(O)N(R52)2, -C(O)NR53R54;
C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, - S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, - NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, - OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, - NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, - P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C3-12 carbocycle and 3- to 12-membered heterocycle; and
C3-12 carbocycle and 3- to 12-membered heterocycle,
wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R51 is independently optionally substituted with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, - S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, - NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, - P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), - P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;
R52 is independently selected at each occurrence from hydrogen; and C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, 1- to 6-membered heteroalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -NO2, -NH2, -NHCH3, - NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C3-12 carbocycle, or 3- to 6-membered heterocycle;
R53 and R54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R50;
each of RH, RA, and RB is, at each occurrence, independently selected from R50, or two RH groups, two RA groups, or two RB groups attached to the same atom or different atoms can together optionally form a bridge or ring;
RC is, at each occurrence, independently selected from hydrogen or R50, or two RC groups attached to the same atom or different atoms can together optionally form a bridge or ring; and m is an integer from 0 to 3; and
each of n, p, and q is independently an integer from 0 to 12.
[0114] In some embodiments, the stereoisomer of a compound of Formula (I) is provided in at least 20%, 30%, 40%, 50%, 55%, 60%, 65% 70% 75% 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%, enantiomeric excess. In some embodiments, the stereoisomer is provided in greater than 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%, enantiomeric excess. In some embodiments, the stereoisomer is in greater than 95% enantiomeric excess, such as greater than 99% enantiomeric excess.
[0115] Any combination of the groups described above for the various variables of a compound of Formula (I) is contemplated herein for the stereoisomer of a compound of Formula (I).
[0116] In certain aspects, a compound used in a method of the disclosure covalently binds to menin and inhibits the interaction of menin with MLL. Such bonding may lead to an increase in the affinity of the compound for menin, which is an advantageous property in many applications, including therapeutic and diagnostic uses. In some embodiments, a compound used in a method of the disclosure comprises an electrophilic group capable of reacting with a nucleophilic group present in a menin protein. Suitable electrophilic groups are described throughout the
application, while suitable nucleophilic groups include, for example, cysteine moieties present in the binding domain of a menin protein. Without wishing to be bound by theory, a cysteine residue in the menin binding domain may react with the electrophilic group of a compound for use in the methods of the disclosure, leading to formation of a conjugate product. In some embodiments, the compounds for use in the methods of the disclosure are capable of covalently bonding to the cysteine residue at position 329 of a menin isoform 2 (SEQ ID NO: 2) or cysteine 334 in menin isoform 1 (SEQ ID NO: 1).
[0117] In some embodiments, for a compound of Formula (I), one or more of RA, RB and RC, when present, comprises a functional group that covalently reacts with one or more residues on menin. In some embodiments, the functional group covalently reacts with one or more cysteine residues on menin. In some embodiments, the functional group covalently reacts with a cysteine on menin at position 329 relative to SEQ ID NO: 2 when optimally aligned or position 334 relative to SEQ ID NO: 1 when optimally aligned. In some embodiments, the functional group covalently reacts with one or more residues on menin selected from cysteine 329, cysteine 241, and/or cysteine 230 on menin relative to SEQ ID NO: 2 when optimally aligned. In some embodiments, the functional group covalently reacts with cysteine 329 relative to SEQ ID NO: 2 when optimally aligned.
[0118] In some embodiments, for a compound of Formula (I), one or more of RA, RB and RC, when present, comprises a moiety that covalently reacts with one or more residues on menin. In some embodiments, one or more of RA, RB and RC, when present, comprises a moiety that covalently reacts with one or more isoforms of menin, for example, isoform 1 (SEQ ID NO: 1), isoform 2 (SEQ ID NO: 2) or isoform 3 (SEQ ID NO: 3) of menin. In certain embodiments, one or more of RA, RB and RC, when present, comprises a moiety that covalently reacts with menin, wherein the menin protein shares 60% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or 99% or more sequence identity with isoform 1 (SEQ ID NO: 1), isoform 2 (SEQ ID NO: 2) or isoform 3 (SEQ ID NO: 3).
[0119] In some embodiments, for a compound of Formula (I), one or more of RA, RB and RC, when present, comprises an electrophilic group that is susceptible to nuclephilic attack from a residue on menin. Any suitable electrophilic moiety known to one of skill in the art to bind to nuclephilic residues, for example, any electrophilic moiety known to bind to cysteine residues, is contemplated herein. In some embodiments, one or more of RA, RB and RC, when present, comprises a moiety other than an electrophile, wherein the moiety is capable of binding to or covalently reacting with a residue on menin. In some embodiments, a compound or salt of Formula (I) is capable of (a) binding covalently to menin and (b) inhibiting the interaction of menin and MLL.
[0120] In some embodiments, for a compound of Formula (I), RC comprises a functional group that covalently reacts with one or more residues on menin. In some embodiments, the functional group covalently reacts with one or more cysteine residues on menin. In some embodiments, the functional group covalently reacts with a cysteine on menin at position 329 relative to SEQ ID NO: 2 when optimally aligned or position 334 relative to SEQ ID NO: 1 when optimally aligned.
[0121] In some embodiments, for a compound of Formula (I), RC is a moiety comprising an alpha, beta-unsaturated carbonyl; an alpha, beta-unsaturated sulfonyl; an epoxide; an aldehyde; sulfonyl fluoride; a halomethylcarbonyl, a dihalomethylcarbonyl, or a trihalomethylcarbonyl.
[0122] In some embodiments, for a compound of Formula (I), RC is selected from:
Figure imgf000047_0001
, , , , ;
wherein:
L5 is selected from a bond; and C1-6 alkylene, C1-6 heteroalkylene, C2-6 alkenylene, and C2-6 alkynylene, each of which is independently optionally substituted with one or more R32;
R22 and R23 are each independently selected from:
hydrogen, ha R20, -N(R20)2, -N(R20)C(O)R20
, - C(O)R20, -C(O)OR20, -C(O)N(R20)2, -OC(O)R20, -S(O)2R20, - S(O)2N(R20)2, -N(R20)S(O)2R20, -NO2, =O, =S, =N(R20), -P(O)(OR20)2, - P(O)(R20)2, -OP(O)(OR20)2, and -CN;
C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -OR20, -SR20, -N(R20)2, - N(R20)C(O)R20
, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -OC(O)R20, - S(O)2R20, -S(O)2N(R20)2, -N(R20)S(O)2R20, -NO2, =O, =S,
=N(R20), -P(O)(OR20)2, -P(O)(R20)2, -OP(O)(OR20)2, -CN, C3-10 carbocycle, and 3- to 10-membered heterocycle; and
C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle and 3- to 10-membered heterocycle of R22 and R23 is independently optionally substituted with one or more substituents selected from halogen, -OR20, -SR20, -N(R20)2, - N(R20)C(O)R20
, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -OC(O)R20, - S(O)2R20, -S(O)2N(R20)2, -N(R20)S(O)2R20, -NO2, =O, =S,
=N(R20), -P(O)(OR20)2, -P(O)(R20)2, -OP(O)(OR20)2, -CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl; or R22 and R23, together with the carbon atoms to which they are attached, form a carbocyclic ring;
R24 is selected from:
hydrogen, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -OC(O)R20, - S(O)2R20, and -S(O)2N(R20)2;
C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -OR20, -SR20, -N(R20)2, - N(R20)C(O)R20
, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -OC(O)R20, - S(O)2R20, -S(O)2N(R20)2, -N(R20)S(O)2R20, -NO2, =O, =S, =N(R20), - P(O)(OR20)2, -P(O)(R20)2, -OP(O)(OR20)2, -CN, C3-10 carbocycle, and 3- to 10-membered heterocycle; and
C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle and 3- to 10-membered heterocycle of R24 is independently optionally substituted with one or more substituents selected from halogen, -OR20, -SR20, -N(R20)2, - N(R20)C(O)R20
, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -OC(O)R20, - S(O)2R20, -S(O)2N(R20)2 -N(R20)S(O)2R20, -NO2, =O, =S, =N(R20), -P(O)(OR20)2, -P(O)(R20)2, -OP(O)(OR20)2, -CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
R20 is independently selected at each occurrence from R52; and
R32 is independently selected at each occurrence from R50.
[0123] In some embodiments, L5 is a bond. In some embodiments, L5 is optionally substituted C1-6 alkylene. In some embodiments, L5 is selected from methylene, ethylene or propylene. In some embodiments, L5 is substituted with one or more substituents selected from halogen, -NO2, =O, =S, -OR20, -SR20, and -N(R20)2.
[0124] In some embodiments, R23 is selected from:
hydrogen;
C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -OR20, -SR20, -N(R20)2, -N(R20)C(O)R20
, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, - OC(O)R20, -S(O)2R20, -S(O)2N(R20)2, -N(R20)S(O)2R20, -NO2, =O, =S, =N(R20), - P(O)(OR20)2, -P(O)(R20)2, -OP(O)(OR20)2, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle; and
C3-10 carbocycle, and 3- to 10-membered heterocycle,
wherein each C3-10 carbocycle and 3- to 10-membered heterocycle is independently optionally substituted with one or more substituents selected from halogen, -OR20, -SR20, -N(R20)2, -N(R20)C(O)R20
, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, - OC(O)R20, -S(O)2R20, -S(O)2N(R20)2, -N(R20)S(O)2R20, -NO2, =O, =S,
=N(R20), -P(O)(OR20)2, -P(O)(R20)2, -OP(O)(OR20)2, -CN, C1-6 alkyl, C2-6 alkenyl, and C2- 6 alkynyl.
[0125] In some embodiments, R23 is selected from:
hydrogen;
C1-6 alkyl optionally substituted with one or more substituents selected from halogen, -OR20, -SR20, -N(R20)2, =O, =S, =N(R20), and–CN; and
3- to 10-membered heterocycle optionally substituted with one or more substituents selected from halogen, -OR20, -SR20, -N(R20)2, -N(R20)C(O)R20
, - C(O)R20, -C(O)OR20, -C(O)N(R20)2, -OC(O)R20, -S(O)2R20, -S(O)2N(R20)2, - N(R20)S(O)2R20, -NO2, =O, =S, =N(R20), -P(O)(OR20)2, -P(O)(R20)2, -OP(O)(OR20)2, - CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl.
[0126] In some embodiments, R23 is selected from hydrogen and C1-6 alkyl optionally substituted with one or more substituents selected from halogen, -OR20, -SR20, -N(R20)2, =O, =S, =N(R20), and -CN. [0127] In some embodiments, R22 is selected from:
hydrogen and–CN;
C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -OR20, -SR20, -N(R20)2, -N(R20)C(O)R20
, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, - OC(O)R20, -S(O)2R20, -S(O)2N(R20)2, -N(R20)S(O)2R20, -NO2, =O, =S, =N(R20), - P(O)(OR20)2, -P(O)(R20)2, -OP(O)(OR20)2, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle; and
C3-10 carbocycle and 3- to 10-membered heterocycle,
wherein each C3-10 carbocycle and 3- to 10-membered heterocycle is independently optionally substituted with one or more substituents selected from halogen, -OR20, -SR20, -N(R20)2, -N(R20)C(O)R20
, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, - OC(O)R20, -S(O)2R20, -S(O)2N(R20)2, -N(R20)S(O)2R20, -NO2, =O, =S, =N(R20), - P(O)(OR20)2, -P(O)(R20)2, -OP(O)(OR20)2, -CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl.
[0128] In some embodiments, R22 is selected from hydrogen, -CN; and C1-6 alkyl optionally substituted with one or more substituents selected from halogen, -OR20, -SR20, and -N(R20)2.
[0129] In some embodiments, R22 and R23, together with the carbon atoms to which they are attached, form a 5-, 6-, or 7-membered carbocyclic ring.
[0130] In some embodiments, R24 is selected from hydrogen and C1-6 alkyl optionally substituted with one or more substituents selected from halogen, -OR20, -SR20, -N(R20)2, -NO2, =O, and– CN.
Figure imgf000050_0001
and
Figure imgf000051_0001
[0132] In certain aspects, the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprisin administerin a com ound of Formula III :
Figure imgf000051_0002
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
H is selected from C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more R50;
Figure imgf000051_0003
each of Z1, Z2, Z3, and Z4 is independently selected from -C(RA1)(RA2)-, -C(RA1)(RA2)- C(RA1)(RA2)-, -C(O)-, and -C(RA1)(RA2)-C(O)-, wherein no more than one of Z1, Z2, Z3, and Z4 is -C(O)- or -C(RA1)(RA2)-C(O)-;
B is selected from bond, C3-12 carbocycle and 3- to 12-membered heterocycle;
C is selected from bond, C3-12 carbocycle and 3- to 12-membered heterocycle;
L1, L2 and L3 are each independently selected from bond, -O-, -S-, -N(R51)-, -N(R51)CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R51)-, -C(O)N(R51)C(O)-, - C(O)N(R51)C(O)N(R51)-, -N(R51)C(O)-, -N(R51)C(O)N(R51)-, -N(R51)C(O)O-, -OC(O)N(R51)-, - C(NR51)-, -N(R51)C(NR51)-, -C(NR51)N(R51)-, -N(R51)C(NR51)N(R51)-, -S(O)2-, -OS(O)-, - S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R51)S(O)2-, -S(O)2N(R51)-, -N(R51)S(O)-, -S(O)N(R51)-, -N(R51)S(O)2N(R51)-, -N(R51)S(O)N(R51)-; alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is optionally substituted with one or more R50, wherein two R50 groups attached to the same atom or different atoms of any one of L1, L2 or L3 can together optionally form a bridge or ring;
RB is independently selected at each occurrence from R50, or two RB groups attached to the same atom or different atoms can together optionally form a bridge or ring;
RC is independently selected at each m hydrogen and R50, or two RC groups attached to the same atom or different atoms can together optionally form a bridge or ring; RA1 and RA2 are each independently selected at each occurrence from hydrogen and R50; n is an integer from 0 to 6;
p is an integer from 1 to 6;
R50 is independently selected at each occurrence from:
halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, - S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, - NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, - OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, - NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, - P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), - P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52);
C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl, each of which is
independently optionally substituted at each occurrence with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, - NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, - OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, - NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, - P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), - P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; and
C3-12 carbocycle and 3- to 12-membered heterocycle, wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R50 is independently optionally substituted with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, - S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, - NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, - OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, - NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, - P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), - P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;
R51 is independently selected at each occurrence from:
hydrogen, -C(O)R52, -C(O)OR52 -C(O)N(R52)2, -C(O)NR53R54; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, - S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, - NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, - OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, - NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, - P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), - P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C3-12 carbocycle and 3- to 12- membered heterocycle; and
C3-12 carbocycle and 3- to 12-membered heterocycle, wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R51 is independently optionally substituted with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, - S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, - NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, - OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, - NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, - P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), - P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;
R52 is independently selected at each occurrence from hydrogen; and C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, 1- to 6-membered heteroalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -NO2, -NH2, -NHCH3, - NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C3-12 carbocycle, or 3- to 6-membered heterocycle; and
R53 and R54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R50.
[0133] In certain aspects, a compound of Formula (III) may be represented by:
Figure imgf000054_0001
wherein R1, R2 and R3 are each independently selected at each occurrence from hydrogen and R50. In some embodiments, R1 is selected from R50. In some embodiments, R1 is C1-3 haloalkyl, such as -CH2CF3. In some embodiments, R2 is selected from hydrogen and R50. In some embodiments, R2 is selected from hydrogen, halogen, -OH, -OR52, -NH2, -N(R52)2, -CN, C1-3 alkyl, C1-3 alkyl-OR52, C1-3 alkyl-N(R52)2, C1-3 haloalkyl, C2-3 alkenyl, and C2-3 alkynyl. In some embodiments, R2 is selected from halogen, -OH, -OR52, -NH2, -N(R52)2, -CN, C1-3 alkyl, - CH2OH, -CH2OR52, -CH2NH2, -CH2N(R52)2, C1-3 alkyl-N(R52)2, C1-3 haloalkyl, C2-3 alkenyl, and C2-3 alkynyl, such as R2 is selected from -OH, -OR52, -NH2, -N(R52)2, -CN, and C1-2 alkyl.
Optionally, R2 is selected from -NH2, -CH3, -OCH3, -CH2OH, and -NHCH3. In some
embodiments, R3 is selected from hydrogen, halogen, -OH, -N(R52)2, -CN, -C(O)OR52, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R52 is selected from selected from hydrogen and alkyl, such as R52 is hydrogen.
[0134] In some embodiments, for a compound of Formula (III), A is selected from
Figure imgf000054_0002
.
[0135] In certain aspects, the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising administering a compound of Formula (IV):
Figure imgf000054_0003
or a pharmaceutically acceptable salt or prodrug thereof, wherein: is a fused thienyl or fused phenyl group;
Ga is selected from C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is substituted with -E1-R4a and optionally further substituted with one or more R50;
R2a is selected from hydrogen, alkyl, alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, optionally substituted heteroaryl, and aralkyl;
R3a and R3b are each independently selected from hydrogen, alkyl, halo, hydroxy, cyano, amino, alkylamino, dialkylamino, haloalkyl, alkoxy, and haloalkoxy;
Xa-Ya is selected from -N(R52)-C(=O)-, -C(=O)-O-, -C(=O)-N(R52)-, -CH2N(R52)-CH2-, - C(=O)N(R52)-CH2-, -CH2CH2-N(R52)-, -CH2N(R52)-C(=O)-, and–CH2O-CH2-; or
Xa and Ya do not form a chemical bond, wherein:
Xa is selected from hydrogen, alkyl, halo, hydroxy, cyano, amino, alkylamino, dialkylamino, haloalkyl, alkoxy, and haloalkoxy; and
Ya is selected from cyano, hydroxy, and -CH2R50;
E1 is selected from absent, -C(=O)-, -C(=O)N(R52)-, -[C(R14a)2]1-5O-, -[C(R14a)2]1-5NR52-, -[C(R14a)2]1-5-, -CH2(=O)-, and -S(=O)2-;
R4a is selected from hydrogen, alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, optionally substituted heteroaryl, aralkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl;
R14a is selected from hydrogen and alkyl;
R50 is independently selected at each occurrence from:
halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, - S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, - NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, - OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, - NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, - P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), - P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52);
C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl, each of which is
independently optionally substituted at each occurrence with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, - NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, - OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, - NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, - P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), - P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; and C3-12 carbocycle and 3- to 12-membered heterocycle,
wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R50 is independently optionally substituted with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, - S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, - NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, - OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, - NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, - P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), - P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;
R52 is independently selected at each occurrence from hydrogen; and C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, 1- to 6-membered heteroalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -NO2, -NH2, -NHCH3, - NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C3-12 carbocycle, or 3- to 6-membered heterocycle; and
R53 and R54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R50.
[0136] In some embodiments, for a compound of Formula (IV), Ga is piperidinyl. In some embodiments, a compound of Formula (IV) is represented by:
Figure imgf000056_0001
Figure imgf000057_0001
wherein R17a and R18a is independently selected from hydrogen and R50; and
R24a is selected from hydrogen and fluoro.
[0137] In some embodiments, for a compound of Formula (IV), R3a and R3b are independently selected from hydrogen and halo. In some embodiments, Xa and Ya do not form a chemical bond, and Xa is hydrogen. In some embodiments, R4a is selected from hydrogen; and alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclo, heteroaryl, aralkyl, (heterocyclo)alkyl, and
(heteroaryl)alkyl, each of which is optionally substituted with one or more substituents selected from R50. In some embodiments, R4a is R50-substituted heterocyclo.
[0138] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof can be chosen to provide stable moieties and compounds.
[0139] The chemical entities described herein for use in the subject methods can be synthesized according to one or more illustrative schemes herein and/or techniques known in the art.
Materials used herein are either commercially available or prepared by synthetic methods generally known in the art. These schemes are not limited to the compounds listed in the examples or by any particular substituents, which are employed for illustrative purposes.
Although various steps are described and depicted herein, the steps in some cases may be performed in a different order than the order shown. Various modifications to these synthetic reaction schemes may be made and will be suggested to one skilled in the art having referred to the disclosure contained in this Application. Numberings or R groups in each scheme do not necessarily correspond to that of the claims or other schemes or tables herein.
[0140] Unless specified to the contrary, the reactions described herein take place at atmospheric pressure, generally within a temperature range from -10 °C to 200 °C. Further, except as otherwise specified, reaction times and conditions are intended to be approximate, e.g., taking place at about atmospheric pressure within a temperature range of about -10 °C to about 110 °C over a period of about 1 to about 24 hours; reactions left to run overnight average a period of about 16 hours.
[0141] In some embodiments, a compound of the present disclosure for use in the subject methods, for example, a compound of a formula given in Table 1-6, 9-10, 12, 14, 16, 18, 20, 22 or 23, is synthesized according to one of the general routes described herein, or by methods generally known in the art. In some embodiments, exemplary compounds for use in the subject methods may include, but are not limited to, a compound or salt thereof selected from Table 1-6, 9-10, 12, 14, 16, 18, 20, 22 or 23.
[0142] Table 1. Structures and activities for thienopyrimidine class of compounds measured by FP and HTRF. NA– no activity, NS - no saturation on titration curve. IC50 values < 100 μM are in bold.
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0002
[0143] Table 2. Structures and activities for thienopyrimidine class of compounds. NA– no activity, NS - no saturation on titration curve. IC50 values < 100 μM are in bold.
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
[0144] Scheme 1. Synthetic scheme for thienopyrimidine compounds.
Figure imgf000065_0001
[0145] Table 3. Structures and activities for benzodiazepine class of compounds measured by FP and HTRF. NA– no activity, ND– not determined, IC50 values < 100 µM are in bold.
Figure imgf000066_0001
Figure imgf000067_0001
[0146] Table 4. Structures and activities of hits from MFL and 6G10 analogues measured by FP and HTRF. NA– no activity, ND– not determined.
Figure imgf000068_0001
Figure imgf000069_0001
[0147] Table 5
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0002
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
[0148] Table 6
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
[0149] Table 7: IC50 values for Table 6 inhibitors of menin
Figure imgf000189_0001
[00151] Schemes for preparing compounds of the disclosure
[00152] Compounds and salts described herein may be prepared according to the following general schemes.
Scheme 1:
Figure imgf000190_0001
Scheme 2:
Figure imgf000191_0001
Representative rocedure for s nthesis of com ounds C-3 C-8, and C-20
Figure imgf000192_0001
O
[00153] 4,4,4-trifluorobuteraldehyde (5 g, 39.6 mmol), cyanoacetamide (3.36 g, 39.6 mmol) and sulfur (1.28 g, 39.6 mmol) were stirred in N, N-dimethylformamide (DMF) (40mL) in the presence of triethylamine (6.7 mL) for 24 h. Solvent was evaporated under reduced pressure and the residue was loaded on a silica gel column and eluted with pure ethyl acetate to afford 2- amino-5-(2,2,2-trifluoroethyl)thiophene-3-carboxamide (8.4 g).1H NMR CDCl3 (300MHz): 7.97 (s, 1H), 6.76 (s, 1H), 3.59 (br, 2H), 3.35 (q, 2H, J 10.3 Hz), 2.98 (s, 1H), 2.88 (s, 1H).13C NMR CDCl3 (75MHz): 168.6, 125.6, 124.3, 111.7, 107.3, 36.8, 34.7 (q, J 31.4 Hz).
Figure imgf000192_0002
[00154] 2-Amino-5-(2,2,2-trifluoroethyl)thiophene-3-carboxamide (8.4 g) was refluxed in a mixture of triethylorthoformate (28 mL) and acetic acid (20 mL) for 4 h. Solvents were removed under reduced pressure and the residue was triturated in a hexane-ethyl acetate mixture (1:1). The solid was filtered off to afford 6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4(3H)-one (5.7 g).1H NMR MeOH-d4 (300MHz): 12.6 (br, 1H), 8.14 (s, 1H), 7.42 (s, 1H), 4.07 (q, 2H, J 11.0 Hz).13C NMR MeOH-d4 (75MHz): 164.5, 157.01, 146.1, 128.4, 124.6, 123.5, 33.6 (q, J 31.5 Hz).
Figure imgf000192_0003
[00155] 6-(2,2,2-Trifluoroethyl)thieno[2,3-d]pyrimidin-4(3H)-one (5.7 g) was added to POCl3 (16 mL) with one drop of DMF. The heterogeneous mixture was refluxed for 3 h, and the solvent was evaporated. The residue was quenched with ice and saturated ammonia solution and extracted with chloroform. Combined extracts were evaporated with silica gel and loaded on a short silica gel column. The column was eluted with hexane-ethyl acetate (5:1) to afford 4- chloro-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine (5.9 g).1H NMR CDCl3 (300MHz): 8.86 (s, 1H), 7.39 (s, 1H), 3.76 (q, 2H, J 9.9 Hz).13C NMR CDCl3 (75MHz): 169.0, 154.7, 153.2, 129.9, 125.3, 123.5, 121.3, 35.9 (q, J 33.0 Hz).
Figure imgf000193_0001
[00156] 4-Chloro-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine (4.8 g, 19 mmol) was added to a stirred solution (95 mL) of N,N-diisopropylethylamine (7.4 g, 57 mmol) and 4-amino-N-Boc- piperidine (4.56 g, 22.8 mmol) and was heated at reflux overnight. In the morning, the reaction mixture was evaporated with silica gel and loaded on a column. The product was eluted with hexane-ethyl acetate (increasing from 1:1 to 1:5) yielding the boc-derivative (7.42 g). Boc- intermediate was dissolved in 4M HCl in dioxane (40 mL) and stirred for 2 h. Solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and saturated sodium carbonate solution. The organic layer was washed with brine, dried over MgSO4 and evaporated to afford N-(piperidin-4-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3- d]pyrimidin-4-amine (5.3 g), which was used in later steps without purification.1H NMR (600 MHz, CDCl3): δ 8.47 (s, 1H), 7.13 (s, 1H), 5.32 (d, 1H, J=7.7Hz), 4.32 (m, 1H), 3.64 (q, 2H, 10Hz), 3.19 (m, 2H), 2.83 (m, 2H), 2.57 (br, 1H), 2.14 (m, 2H), 1.55 (m, 2H).13C NMR (150 MHz, CDCl3): δC 166.85, 155.96, 154.33, 128.12, 126.62, 118.66, 116.48, 47.98, 45.32, 35.56 (q, J=31.5Hz), 33.10. ESI MS [MH+]: 317.2.
Figure imgf000193_0002
[00157] 3-Bromo-2-methylbenzoic acid (30 g, 139 mmol) was dissolved in tetrahydrofuran (THF) (180 mL) and cooled to 0 °C. Lithium aluminium hydride (9.5 g, 250 mmol) was added in small portions. After stirring for 3 h, no starting material was observed by TLC. The reaction mixture was carefully quenched with ethyl acetate (20 mL) and water (20 mL). Silica gel was added and the mixture was evaporated to dryness and loaded on a small silica gel column. The product was eluted with hexane:ethyl acetate (1:1) resulting in the pure alcohol (3-bromo-2- methylphenyl)methanol (24 g) after evaporation.1H NMR (600 MHz, CDCl3): 7.50 (d, 1H, J=8.1Hz), 7.29 (d, 1H, J=8.1Hz), 7.04 (t, 1H, J=8.1Hz), 4.68 (s, 2H), 2.40 (s, 3H), 1.90 (br s, 1H).13C NMR (150 MHz, CDCl3): 140.60, 135.84, 132.03, 127.12, 126.70, 126.05.
Figure imgf000193_0003
[00158] (3-Bromo-2-methylphenyl)methanol (24 g, 119 mmol) was dissolved in
dichloromethane (240 mL) and manganese (IV) oxide (103 g, 1.2 mol) was added. After stirring overnight, TLC showed no starting materia re was evaporated with silica gel and loaded on a small silica gel column. The product was eluted with hexane:ethyl acetate (10:1) to afford the pure aldehyde 3-bromo-2-methylbenzaldehyde (18.6 g) after evaporation.1H NMR (600 MHz, CDCl3): 10.25 (s, 1H), 7.78 (m, 2H), 7.23 (t, 1H, J=7.7Hz), 2.75 (s, 3H).13C NMR (150 MHz, CDCl3): 191.84, 137.72, 130.93, 130.20, 127.61, 127.37, 126.82, 18.13.
Figure imgf000194_0001
[00159] To the mixture of 3-bromo-2-methylbenzaldehyde (18.6 g, 93 mmol) and methyl azidoacetate (26.8 g, 233 mmol) in MeOH (130 mL) was added 5.4 M MeONa (43 mL) over 30 min at -10 °C. After addition, the mixture was stirred for additional hour at the same temperature and then transferred to a cold room (4 °C) and stirred overnight. In the morning, the reaction mixture was poured into a mixture of ice and concentrated ammonium chloride solution (1 L), stirred for 10 minutes and filtered off. The solid was washed with plenty of ice cold water and then air dried for 1 hr at ambient temperature. Then the solid was dissolved in dichloromethane (DCM) (100 mL), dried over magnesium sulfate and passed through a short silica gel plug.
Evaporation of solvent produced methyl (E)-2-azido-3-(3-bromo-2-methylphenyl)acrylate (21.1 g), that was used in the next step without further purification.1H NMR (600 MHz, CDCl3): 7.72 (d, 1H, J=7.7Hz), 7.53 (d, 1H, J=7.7Hz), 7.10 (s, 1H), 7.07 (t, 1H, J=7.7Hz), 3.93 (s, 3H), 2.42 (s, 3H).13C NMR (150 MHz, CDCl3): 163.61, 136.65, 133.94, 133.09, 129.25, 128.76, 126.78, 125.81, 123.64, 53.10, 20.04.
Figure imgf000194_0002
[00160] Methyl (E)-2-azido-3-(3-bromo-2-methylphenyl)acrylate (21.1 g, 71 mmol) was dissolved in xylene (700 mL). The mixture was refluxed for 10 minutes. Reaction mixture was cooled to room temperature (RT) and kept in a -20 °C freezer overnight. The precipitated product was filtered off and dried on a funnel to produce methyl 5-bromo-4-methyl-1H-indole-2- carboxylate (10.0 g).1H NMR (600 MHz, CDCl3): 8.98 (br s, 1H), 7.44 (d, 1H, J=8.4Hz), 7.24 (s, 1H), 7.14 (d, 1H, J=8.4Hz), 3.96 (s, 3H), 2.60 (s, 3H).13C NMR (150 MHz, CDCl3): 162.12, 135.38, 131.56, 129.52, 128.98, 127.36, 115.92, 110.82, 107.70, 52.15, 18.97.
Figure imgf000194_0003
[00161] Methyl 5-bromo-4-methyl-1H-indole-2-carboxylate (10.0 g, 38 mmol) was refluxed in solution of KOH (10.6 g, 190 mmol) in methanol (130 mL) for 1 hr. The reaction mixture was then concentrated and acidified with 12 M HCl in water. The precipitated product was filtered off. After drying, the 5-bromo-4-methyl-1H-indole-2-carboxylic acid was added to a solution of oxalyl chloride (6.5 mL, 76 mmol) in dichloromethane (200 mL) with DMF (0.6 mL). After stirring for 1 hr, the reaction mixture was cooled in an ice-water bath and concentrated ammonia in water (40 mL) was added dropwise. The heterogeneous mixture was stirred for another 3 h and filtered off to obtain the carboxamide. A mixture of 5-bromo-4-methyl-1H-indole-2- carboxamide, phosphorus oxychloride (36 mL, 380 mmol) and chloroform (120 mL) was refluxed for 5 h. Then reaction mixture was evaporated to dryness and quenched with ice and concentrated ammonia (about 40 mL). The formed precipitate was filtered off, washed with plenty of water and dissolved in THF (100mL). The solution was evaporated with silica gel and loaded on a medium silica gel column. The product was eluted in hexane:ethyl acetate (2:1) affording the pure carbonitrile (7.4 g) after evaporation..1H NMR (600 MHz, Me2CO-d6): 11.42 (br s, 1H), 7.49 (d, 1H, J=8.8Hz), 7.42 (s, 1H), 7.32 (d, 1H, J=8.4Hz), 2.59 (s, 3H).13C NMR (150 MHz, Me2CO-d6): 137.48, 131.99, 130.95, 129.33, 117.21, 114.93, 113.71, 112.95, 108.51, 19.59.
Figure imgf000195_0001
[00162] 5-Bromo-4-methyl-1H-indole-2-carbonitrile (2.35 g, 10 mmol) was dissolved in THF (100 mL). The flask was flushed with argon and potassium hydride (3.2 g) was added (30% suspension in oil, 24 mmol). After stirring for 5 minutes, the reaction mixture was cooled to -90 °C (internal temperature, ethanol/N2(liq.)) and tert-butyl lithium (11.8 mL, 20 mmol) was slowly added to maintain the temperature in the range between -95 °C and -90 °C. After stirring for 1 h, DMF (3.8 ml, 50 mmol) was added dropwise and the reaction mixture was allowed to warm to - 70 °C and kept for 30 minutes at that temperature. The reaction mixture was quenched with acetic acid (2.9mL, 50 mmol) and warmed to room temperature. After the addition of brine (100 mL), the organic phase was separated, evaporated with silica gel and loaded on a medium silica gel column. Elution started with pure hexane and then product was washed out with hexane:THF (1:1). After evaporation of the product-containing fractions, the pure aldehyde (1.11 g) was obtained.1H NMR (600 MHz, CD3CN): 10.39 (s, 1H), 7.82 (d, 1H, J=8.4Hz), 7.51 (s, 1H), 7.43 (d, 1H, J=8.4Hz), 2.86 (s, 3H).13C NMR (150 MHz, CD3CN): 191.15, 138.90, 137.17, 127.26, 126.94, 126.55, 113.70, 113.11, 109.97, 107.19, 13.39.
Figure imgf000196_0001
[00163] Tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (1 g, 4.3 mmol) and triethyl amine (0.89 mL, 6.5 mmol) were dissolved in DCM (14 mL). MsCl (0.4 mL, 5.2 mmol) was added slowly and the reaction was stirred for 2 h. The reaction mixture was washed with brine, dried over anhydrous sodium sulfate and evaporated. The intermediate was dissolved in DMF (4 mL) and 5-formyl-4-methyl-1H-indole-2-carbonitrile (368 mg, 2 mmol) and cesium carbonate (2 g, 6 mmol) was added. After stirring for 18 h, TLC showed consumption of aldehyde. The reaction mixture was diluted with water (50 mL) and extracted with DCM (2 x 50 mL). The organic phase was evaporated with silica gel and loaded on a silica gel column. The product was eluted with hexane-ethyl acetate (1:1) to afford tert-butyl 4-(2-(2-cyano-5-formyl-4-methyl-1H- indol-1-yl)ethyl)piperazine-1-carboxylate (240 mg). HR MS (ESI): C22H28N4O3 + H+ calculated 397.2234; found 397.2239.
Figure imgf000196_0002
[00164] Tert-butyl 4-(2-(2-cyano-5-formyl-4-methyl-1H-indol-1-yl)ethyl)piperazine-1- carboxylate (120mg, 0.3 mmol), N-(piperidin-4-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3- d]pyrimidin-4-amine hydrochloride (126 mg, 0.36 mmol), and triethylamine (0.06 mL, 0.45 mmol) were mixed in dry dichloromethane (3 mL). Sodium triacetoxyborohydride (97 mg, 0.45 mmol) was added to the mixture in one portion. After stirring overnight, TLC showed absence of starting aldehyde and the reaction mixture was transferred to a separatory funnel and washed with 1M NaOH (20 mL). The organic phase was evaporated with silica gel and loaded on a silica gel column. The product was eluted starting from DCM:MeOH:NH3*H2O 40:1:0.1 and decreasing to 20:1:0.1. Evaporation of solvent gave tert-butyl 4-(2-(2-cyano-4-methyl-5-((4-((6- (2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indol-1- yl)ethyl)piperazine-1-carboxylate (180 mg) HR MS (ESI) C35H43F3N8O2S + H+ calculated 697.3255; found 697.3259.
Figure imgf000197_0001
[00165] Tert-butyl 4-(2-(2-cyano-4-methyl-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indol-1-yl)ethyl)piperazine-1-carboxylate (180 mg, 0.26 mmol) was dissolved in acetonitrile (ACN) (2.6 mL) and SnCl4 (0.3 mL, 2.6 mmol) was added. The homogenous reaction mixture was stirred for 1 h and then volatiles were removed in vacuo. The residue was quenched with ammonia and extracted with ethyl acetate. Combined organic fractions were dried over MgSO4 and concentrated. The residue was purified using preparative TLC to afford 4-methyl-1-(2-(piperazin-1-yl)ethyl)-5-((4-((6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2- carbonitrile (88 mg).1H NMR (600 MHz, CDCl3): 8.46 (s, 1H), 7.35 (d, 1H, J=8.4Hz), 7.17 (s, 1H), 7.15 (d, 1H, J=8.4Hz), 7.10 (s, 1H), 5.20 (d, 1H, J=7.7Hz), 4.32 (m, 2H), 4.22 (m, 1H), 3.63 (q, 2H, J=10.5Hz), 3.60 (s, 2H), 2.91, (m, 6H), 2.69 (m, 2H), 2.54 (s, 3H), 2.50 (m, 4H), 2.26 (t, 2H, J=10.6Hz), 2.09 (d, 2H, J=10.3Hz), 1.58 (d, 2H, J=9.9Hz).13C NMR (150 MHz, CDCl3): 166.79, 156.09, 154.36, 136.37, 131.18, 128.97, 128.65, 127.33, 125.61, 118.62, 116.43, 114.03, 111.64, 109.76, 107.23, 60.14, 57.80, 57.80, 53.86, 52.36, 51.34, 48.05, 45.48, 43.34, 35.53 (q, J=32Hz), 32.39, 15.06. HR MS (ESI): C30H35F3N8S + H+ calculated 597.2730; found 597.2727.
Figure imgf000197_0002
[00166] To a mixture of 4-methyl-1-(2-(piperazin-1-yl)ethyl)-5-((4-((6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2- carbonitrile (520 mg, 0.87 mmol) and N,N-diisopropylethylamine (DIPEA) (0.23 mL, 1.3mmol) in DCM (17 mL) was added 2-chloroethanesulfonyl chloride (0.1 mL, 0.96 mmol) with external cooling of ice water. After stirring for 15 minutes, the reaction mixture was loaded directly on a column and eluted with DCM-MeOH (10:1) and then purified again in a column using Hexane- Ethyl Acetate-Methanol (1:1:0.2). Evaporating the product-containing fractions resulted in 4- methyl-1-(2-(4-vinylsulfonylpiperazin-1-yl)ethyl)-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile (Compound 3) (308 mg). Compound 3 was converted to its hydrochloride salt by dissolving it in methanol (4 mL), adding 1M HCl in water (0.55 mL) and evaporating.1H NMR (600 MHz, CD3OD): 8.35 (s, 1H), 7.59 (m, 3H), 7.43 (s, 1H), 6.61 (dd, J=16.5, 10.3Hz, 1H), 6.14 (m, 2H), 4.54 (m, 2H), 4.46 (s, 2H), 3.86 (q, 2H, J=10.5Hz), 3.63 (m, 2H), 3.50 (m, 1H), 3.34 (m, 2H), 3.10 (m, 4H), 2.79 (m, 2H), 2.69 (s, 3H), 2.56 (m, 4H), 2.35 (m, 2H), 1.99 (m, 2H).13C NMR (150 MHz, CD3OD): 167.02, 157.69, 154.84, 138.70, 135.10133.74, 130.56, 129.96, 129.77, 126.60 (q, J=289.5Hz), 121.74, 121.01, 118.18, 114.62, 113.18, 112.65, 100.44, 58.59, 58.05, 53.85, 52.94, 47.11, 46.72, 44.46, 35.63 (q, J=32Hz), 30.92, 30.01, 15.80. HR MS (ESI): C32H37F3N8O2S2 + H+ calculated 687.2506; found 687.2505.
[00167] Following the same general procedures for preparing Compound 3, Compound 8 was synthesized starting with the tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate.1H NMR (600 MHz, CD3OD): 8.36 (s, 1H), 7.59 (m, 3H), 7.47 (s, 1H), 6.60 (dd, J=16.5, 9.9Hz, 1H), 6.12 (m, 2H), 4.54 (m, 2H), 4.42 (s, 2H), 3.86 (q, 2H, J=10.5Hz), 3.64 (m, 2H), 3.45 (m, 1H), 3.33 (m, 2H), 3.10 (m, 4H), 2.69 (s, 3H), 2.61 (m, 2H), 2.35 (m, 2H), 1.84 (m, 3H), 1.44 (m, 1H), 1.32 (m, 3H).13C NMR (150 MHz, CD3OD): 166.69, 157.70, 154.70, 138.80, 135.23, 134.19, 130.71, 129.09, 128.74, 126.53 (q, J=289.5Hz), 121.74, 120.99, 118.21, 114.26, 113.64, 111.43, 110.41, 58.91, 52.95, 46.94, 44.29, 37.47, 35.54 (q, J=32Hz), 34.18, 32.71, 30.77, 30.00, 27.33, 15.79. HR MS (ESI): C33H38F3N7O2S2 + H+ calculated 686.2553; found 687.2556.
[00168] Following the same general procedures for preparing Compound 3, Compound 20 was synthesized starting with 4-methyl-1-(2-(piperidin-1-yl)ethyl)-5-((4-((6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2- carbonitrile.1H NMR (600 MHz, CD3OD): 8.36 (s, 1H), 7.63 (m, 1H), 7.55 (m, 2H)7.48 (s, 1H), 6.60 (dd, J=16.9, 10.6Hz, 1H), 6.18 (dd, J=16.7, 1.7Hz, 1H), 5.74 (dd, J=10.6, 1.7Hz, 1H), 4.57 (m, 3H), 4.44 (m, 1H), 4.42 (s, 2H), 4.12 (m, 1H), 3.88 (q, 2H, J=10.5Hz), 3.64 (m, 2H), 3.33 (m, 2H), 3.12 (m, 1H), 2.72 (s, 3H), 2.66 (m, 1H), 2.34 (m, 2H), 2.05 (m, 2H), 1.84 (m, 4H), 1.65 (m, 1H), 1.23 (m, 2H).13C NMR (150 MHz, CD3OD): 167.45, 167.07, 157.72, 154.87, 138.79, 135.18, 130.77, 129.66, 129.23, 128.71, 128.28, 126.53 (q, J=289.5Hz), 121.87, 121.15, 118.20, 114.32, 113.65, 111.35, 110.40, 58.82, 52.93, 47.20, 44.29, 43.37, 37.61, 35.68 (q, J=32Hz), 34.81, 33.83, 32.88, 29.99, 15.85. HR MS (ESI): C34H38F3N7OS + H+ calculated 650.2884; found 650.2881. Representative procedure for synthesis of compounds C-17, C-18, C-22-C-25, C-27-C-29, C-31 and C-32
Figure imgf000199_0001
[00169] Monosilylated ethylene glycol (704 mg, 4 mmol) and triethylamine (0.89 mL, 6 mmol) were dissolved in DCM (10 mL). Ms2O (835 mg, 4.8 mmol) was added slowly and the reaction was stirred for 2 h. The reaction mixture was washed with brine, dried over anhydrous sodium sulfate and evaporated. The reaction intermediate was dissolved in DMF (5.3 mL) and 5-formyl- 4-methyl-1H-indole-2-carbonitrile (490.6 mg, 2.67 mmol) and cesium carbonate (2.6 g, 8 mmol) were added. After stirring for 4 h at 50 °C, TLC showed consumption of the aldehyde. The reaction mixture was diluted with water (50 mL) and extracted with diethyl ether (2 x 50 mL). The organic phase was evaporated and dissolved in acetonitrile (4 mL). Et3N-3HF (0.7 mL) was added and mixture was stirred for 1 h at 50 °C. Reaction mixture was concentrated and purified using column chromatography eluting with hexane-ethyl acetate (1:1) to afford pure 5-formyl-1- (2-hydroxyethyl)-4-methyl-1H-indole-2-carbonitrile (369 mg).1H NMR (600 MHz, CD3OD): 10.38 (s, 1H), 7.84 (d, 1H, J=8.4Hz), 7.53 (s, 1H), 7,47 (d, 1H, J=8.4Hz), 4.40 (m, 2H), 3.85 (m, 2H), 3.07 (m, 1H), 2.86 (s, 3H).
Figure imgf000199_0002
[00170] Methanesulfonic anhydride (Ms2O) (662 mg, 3.81 mmol) was slowly added to a solution of 5-formyl-1-(2-hydroxyethyl)-4-methyl-1H-indole-2-carbonitrile (290 mg, 1.27 mmol) and DIPEA (1.1 mL) in THF (6.3 mL). After stirring for 10 minutes, the mixture was diluted with saturated bicarbonate solution and stirred for 20 minutes, and the product was filtered off and thoroughly dried.1H NMR (600 MHz, CD3CN): 10.39 (s, 1H), 7.88 (d, 1H, J=8.4Hz), 7.59 (s, 1H), 7,49 (d, 1H, J=8.4Hz), 4.66 (m, 2H), 4.53 (m, 2H), 2.86 (m, 6H). The mesylated derivative (130 mg, 0.42 mmol) was dissolved in DMF (2 mL) and tert-butyl 2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (166 mg, 0.84 mmol) and potassium carbonate (86 mg, 0.63 mmol) were added. The mixture was heated at 85 °C for 1 h, cooled down, diluted with water, and extracted with DCM. The crude fied on silica gel column to produce tert-butyl 5-(2-(2-cyano-5-formyl-4-methyl-1H-indol-1-yl)ethyl)-2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate (10 mg). HR MS (ESI): C23H28N4O3 + H+ calculated 409.2234; found 409.2232.
Figure imgf000200_0001
[00171] Tert-butyl 5-(2-(2-cyano-5-formyl-4-methyl-1H-indol-1-yl)ethyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (10 mg, 0.025 mmol), N-(piperidin-4-yl)-6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidin-4-amine hydrochloride (126 mg, 0.038 mmol), and triethylamine (0.01 mL, 0.045 mmol) were mixed in dry dichloromethane (0.3 mL). Sodium triacetoxyborohydride (10 mg, 0.045 mmol) was added to it in one portion. After stirring overnight, TLC showed absence of starting aldehyde in reaction mixture. Reaction mixture was purified using preparative thin-layer chromatography (pTLC) eluting with
DCM:MeOH:NH3*H2O (20:1:0.1). After washing the product from silica gel with methanol, it was dissolved in acetonitrile (0.5 mL) and tin chloride (0.03 mL, 0.26 mmol). After strirring for 15 minutes, volatiles were removed in vacuo. The residue was quenched with ammonia and extracted with ethyl acetate. Combined organic fractions were dried over MgSO4 and
concentrated. The residue was purified using preparative TLC to afford 1-(2-(2,5- diazabicyclo[2.2.1]heptan-2-yl)ethyl)-4-methyl-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile (10 mg).
Figure imgf000200_0002
[00172] To a mixture of 1-(2-(2,5-diazabicyclo[2.2.1]heptan-2-yl)ethyl)-4-methyl-5-((4-((6- (2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2- carbonitrile (10 mg, 0.016 mmol) and DIPEA (0.011 mL, 0.066 mmol) in DCM (0.32mL) was added 2-chloroethanesulfonyl chloride (0.002 mL, 0.02 mmol) with external cooling of ice water. After stirring for 15 minutes, the reaction mixture was purified using pTLC and eluted with DCM-MeOH (15:1). The product was washed off from silica gel with methanol affording after evaporation 4-methyl-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)methyl)-1-(2-(5-(vinylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2- yl)ethyl)-1H-indole-2-carbonitrile (Compound 17) (0.7 mg). HR MS (ESI): C33H37F3N8O2S2 + H+ calculated 699.2506; found 699.2508.
Figure imgf000201_0001
[00173] Following the same general procedures for preparing Compound 17, Compound 18 was synthesized starting with tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate. Compound 18 was converted to its hydrochloride salt by dissolving it in methanol (0.1 mL), adding 1 equivalent of 1M HCl in water and evaporating.1H NMR (600 MHz, CD3OD): 8.35 (s, 1H), 7.53 (m, 3H), 7.44 (s, 1H), 6.57 (m, 1H), 6.08 (m, 1H), 5.96 (m, 1H), 4.43 (m, 5H), 3.86 (m, 2H), 3.58 (m, 2H), 3.35 (m, 2H), 3.16 (m, 2H), 3.06 (m, 2H), 2.82 (m, 2H), 2.69 (s, 3H), 2.32 (m, 2H), 1.88 (m, 4H), 1.71 (m, 2H).13C NMR (150 MHz, CD3OD, not all signals reported because of low conc.): 167.10, 157.76, 154.89, 138.74, 133.84, 130.37, 128.94, 128.82, 114.81, 113.06, 61.33, 54.03, 52.54, 46.60, 26.25, 15.73. HR MS (ESI): M + H+ calculated 713.2662; found 713.2664.
Figure imgf000201_0002
[00174] Following the same general procedures for preparing Compound 17, Compound 22 was synthesized starting with tert-butyl (R)-2-methylpiperazine-1-carboxylate. Compound 22 was converted to its hydrochloride salt by dissolving it in methanol (0.1 mL), adding 1 equivalent of 1M HCl in water and evaporating.1H NMR (600 MHz, CD3OD): 8.37 (s, 1H), 7.59 (m, 3H), 7.47 (s, 1H), 6.63 (m, 1H), 6.13 (m, 1H), 5.98 (m, 1H), 4.55 (m, 2H), 4.48 (m, 3H), 3.88 (m, 2H), 3.63 (m, 2H), 3.41 (m, 1H), 3.25 (m, 1H), 2.94 (m, 1H), 2.77 (m, 1H), 2.72 (s, 3H), 2.38 (m, 4H),2.15 (m, 1H), 2.04 (m, 2H), 1.09 (m, 3H).13C NMR (150 MHz, CD3OD): 167.09, 157.74, 154.89, 138.90, 137.71, 134.99, 130.47, 129.97, 128.76, 126.64 (q, J=289.5Hz), 121.83, 121.20, 118.21, 114.70, 113.19, 112.48, 110.57, 60.33, 58.54, 53.84, 50.79, 44.63, 41.41, 35.66 (q, J=32Hz), 16.34, 15.79. HR MS (ESI): C33H39F3N8O2S2 + H+ calculated 701.2662; found 701.2669.
[00175] Following the same general procedures for preparing Compound 17, Compound 23 was synthesized starting with tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate. Compound 23 was converted to its hydrochloride salt by dissolving it in methanol (0.1 mL), adding 1 equivalent of 1M HCl in water and evaporating.1H NMR (600 MHz, CD3OD): 8.38 (s, 1H), 7.59 (m, 3H), 7.50 (s, 1H), 6.65 (m, 1H), 6.19 (m, 1H), 5.96 (m, 1H), 4.56 (m, 2H), 4.47 (m, 3H), 3.97 (m, 2H), 3.89 (m, 2H), 3.64 (m, 2H), 2.88 (m, 2H), 2.73 (s, 3H), 2.64 (m, 2H), 2.40 (m, 4H), 2.02 (m, 2H), 1.72 (m, 4H), 1.32 (m, 2H).13C NMR (150 MHz, CD3OD): 167.10, 157.74, 154.89, 139.01, 137.36, 135.10, 130.53, 130.01, 128.75, 127.72, 126.64 (q, J=289.5Hz), 121.79, 121.16, 118.21, 114.66, 113.42, 112.07, 110.6860.92, 58.54, 57.14, 44.75, 35.66 (q, J=32Hz), 28.91, 15.80. HR MS (ESI): M + H+ calculated 713.2662; found 713.2661.
Figure imgf000202_0001
[00176] Following the same general procedures for preparing Compound 17, Compound 24 was synthesized starting with tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate. Compound 24 was converted to its hydrochloride salt by dissolving it in methanol (0.1 mL), adding 1 equivalent of 1M HCl in water and evaporating.1H NMR (600 MHz, CD3OD): 8.38 (s, 1H), 7.62 (m, 3H), 7.52 (s, 1H), 6.65 (m, 1H), 6.28 (m, 1H), 5.76 (m, 1H), 4.58 (m, 5H), 3.88 (m, 2H), 3.66 (m, 2H), 2.88 (m, 2H), 2.73 (s, 3H), 2.64 (m, 2H), 2.38 (m, 4H), 2.02 (m, 2H), 1.83 (m, 2H), 1.71 (m, 2H), 1.31 (m, 2H).13C NMR (150 MHz, CD3OD): 166.71, 164.31, 157.69, 154.71, 139.05, 135.19, 130.63, 130.12, 129.07, 128.77, 126.63 (q, J=289.5Hz), 121.79, 121.07, 118.19, 114.62, 113.53, 112.07, 110.72, 60.88, 59.35, 58.86, 57.20, 56.71, 53.87, 52.93, 47.14, 35.65 (q, J=32Hz), 30.80, 29.98, 29.00, 27.27, 15.82. HR MS (ESI): M + H+ calculated
677.2992; found 677.2994.
Figure imgf000202_0002
[00177] Following the same general procedures for preparing Compound 17, Compound 25 was synthesized starting with tert-butyl piperidi Compound 25 was converted to its hydrochloride salt by dissolving it in methanol (0.1 mL), adding 1 equivalent of 1M HCl in water and evaporating.1H NMR (600 MHz, CD3OD): 8.34 (s, 1H), 7.57 (m, 3H), 7.43, (s, 1H), 6.21 (m, 2H), 5.61 (m, 1H), 4.46 (m, 5H), 3.86 (q, 2H, J=10.5Hz), 3.72 (m, 1H), 3.57 (m, 2H), 3.25 (m, 2H), 2.89 (m, 2H), 2.79 (m, 2H), 2.69 (s, 3H), 2.28 (m, 4H), 2.01 (m, 2H), 1.84 (m, 2H), 1.54 (m, 2H).13C NMR (150 MHz, CD3OD): 167.43, 167.06, 157.74, 154.88, 138.72, 134.83, 132.10, 130.57, 129.92, 128.77, 126.70, 126.63 (q, J=289.5Hz), 121.85, 118.20, 114.42, 113.26, 112.24, 110.32, 58.91, 58.17, 53.85, 52.75, 47.77, 44.46, 35.66 (q, J=32Hz), 32.50, 30.72, 15.77. HR MS (ESI): M + H+ calculated 665.2992; found 665.2997.
Figure imgf000203_0001
[00178] Following the same general procedures for preparing Compound 17, Compound 28 was synthesized starting with tert-butyl azetidin-3-ylcarbamate. Compound 28 was converted to its hydrochloride salt by dissolving it in methanol (0.1 mL), adding 1 equivalent of 1M HCl in water and evaporating.1H NMR (600 MHz, CD3OD): 8.35 (s, 1H), 7.58 (m, 3H), 7.49, (s, 1H), 6.20 (m, 2H), 5.66 (m, 1H), 4.46 (m, 6H), 3.86 (q, 2H, J=10.5Hz), 3.76 (m, 2H), 3.60 (m, 2H), 3.21 (m, 2H), 3.12 (m, 2H), 2.89 (m, 2H), 2.69 (s, 3H), 2.31 (m, 2H), 2.01 (m, 2H).13C NMR (150 MHz, CD3OD): 167.67, 167.09, 157.74, 154.89, 139.01, 135.09, 131.54, 130.83, 129.97, 128.76, 127.46, 126.65 (q, J=289.5Hz), 21.85, 118.21, 114.27, 113.99, 111.76, 110.36, 62.42, 58.80, 55.87, 44.64, 43.84, 41.58, 35.66 (q, J=32Hz), 18.74, 17.31, 15.78, 14.59, 13.21. M + H+ calculated 637.2679; found 635.2683.
Figure imgf000203_0002
[00179] Following the same general procedures for preparing Compound 17, Compound 32 was synthesized starting with tert-butyl (R)-pyrrolidin-3-ylcarbamate. Compound 32 was converted to its hydrochloride salt by dissolving it in methanol (0.1 mL), adding 1 equivalent of 1M HCl in water and evaporating.1H NMR (600 MHz, CD3OD): 8.35 (s, 1H), 7.56 (m, 3H), 7.47, (s, 1H), 6.21 (m, 2H), 5.64 (m, 1H), 4.51 (m, 4H), 4.34 (m, 1H), 3.86 (q, 2H, J=10.5Hz), 3.86 (m, 2H), 3.59 (m, 2H), 3.01 (m, 2H), 2.93 (m, 2H), 2.69 (s, 3H), 2.31 (m, 2H), 2.01 (m, 2H), 1.74 (m, 1H).13C NMR (150 MHz, CD3OD): 167.75, 167.09, 157.74, 154.88, 138.87, 135.04, 131.87, 130.72, 129.96, 128.77, 126.92, 126.64 (q, J=289.5Hz), 121.81, 118.21, 114.42, 113.74, 111.95, 110.35, 61.20, 55.87, 54.36, 45.29, 35.66 (q, J=32Hz), 32.10, 30.50, 15.77. HR MS M + H+ calculated 651.2836; found 651.2838. Representative procedure for the synthesis of compounds C-30 and C-34
Figure imgf000204_0001
[00180] Ethyl 2-(2-aminothiazol-4-yl)acetate (0.93 g, 5 mmol) and trityl chloride (0.167 g, 0.6 mmol) were dissolved in DCM (8 mL). Triethyl amine (0.9 mL, 0.7 mmol) was added and mixture was stirred for 30 minutes. Then the reaction mixture was washed with water, washed with brine, dried over sodium sulfate and concentrated. The residue was dissolved in THF (50 mL) and a solution of 4 M lithium aluminum hydride (LAH) in ether (1.25 mL) was added slowly. After 30 minutes, the reaction was carefully quenched with ethyl acetate (10 mL) and then with water (4 mL). After stirring for 5 minutes, the mixture was evaporated with silica gel. Product was eluted with hexane-ethyl acetate mixture (1:1) resulting in 2-(2-(tritylamino)thiazol- 4-yl)ethan-1-ol (1.5 g) after concentration.1H NMR (600 MHz, CDCl3): 7.30 (m, 15H), 6.51 (s, 1H), 5.97 (s, 1H), 3.73 (m, 2H), 3.47 (br s, 1H), 2.65 (m, 2H).13C NMR (150 MHz, CDCl3): 167.88, 149.46, 143.77, 129.17, 128.10, 127.37, 103.25, 72.21, 61.87, 33.52.
Figure imgf000204_0002
[00181] 2-(2-(Tritylamino)thiazol-4-yl)ethan-1-ol (640 mg, 1.65 mmol) and triethyl amine (0.7 mL) were dissolved in DCM (8.3 mL). Ms2O (574 mg, 3.3 mmol) was added in small portions with cooling of reaction mixture in an ice water bath. After 5 minutes of stirring, the mixture was quenched with saturated sodium bicarbonate solution, washed with brine, dried over sodium sulfate and concentrated. The mesylate intermediate was dissolved in DMF (0.5 mL) and 5- formyl-4-methyl-1H-indole-2-carbonitrile (50 mg, 0.27 mmol) and cesium carbonate (265 mg, 0.81 mmol) were added. After stirring for 3 h at 60 °C, TLC showed consumption of aldehyde. The reaction mixture was diluted with water (20 mL) and extracted with DCM (2 x 25 mL). The organic phase was evaporated with silica gel and loaded on a silica gel column. The product was eluted with hexane-ethyl acetate (1:1) to afford 5-formyl-4-methyl-1-(2-(2-tritylthiazol-4- yl)ethyl)-1H-indole-2-carbonitrile (50 mg).1H NMR (600 MHz, CDCl3): 10.42 (s, 1H), 7.78 (m, 1H), 7.38 (m, 1H), 7.20 (s, 1H), 6.57 (s, 1H), 4.48 (m, 2H), 3.06 (m, 2H), 2.89 (s, 3H), 1.62 (s, 9H).
Figure imgf000205_0001
[00182] 5-formyl-4-methyl-1-(2-(2-tritylthiazol-4-yl)ethyl)-1H-indole-2-carbonitrile (50 mg, 0.09 mmol), N-(piperidin-4-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-amine hydrochloride (57 mg, 0.15 mmol), and triethylamine (0.0125 mL, 0.36 mmol) were mixed in dry dichloromethane (1 mL). Sodium triacetoxyborohydride (42 mg, 0.2 mmol) was added to the mixture in one portion. After stirring overnight, TLC showed absence of starting aldehyde in reaction mixture. The reaction mixture was transferred to a separatory funnel and washed with 1M NaOH (10 mL). The organic phase was evaporated with silica gel and loaded on a silica gel column. The product was eluted with DCM:MeOH:NH3*H2O (starting from 40:1:0.1 and decreasing to 20:1:0.1). Evaporation of solvent gave the trityl protected intermediate (25 mg) that was dissolved in chloroform (1 mL) and trifluoroacetic acid (0.5 mL). After 5 minutes, the reaction mixture was quenched with saturated sodium carbonate solution and extracted with ethyl dichloromethane. The organic phase was evaporated and purified using pTLC to obtain 1- (2-(2-aminothiazol-4-yl)ethyl)-4-methyl-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile (Compound 30) (10 mg).1H NMR (600 MHz, CDCl3): 8.46 (s, 1H), 7.31 (d, 1H, J=8.4Hz), 7.16 (s, 1H), 7.13 (d, 1H, J=8.4Hz), 7.07 (s, 1H), 5.92 (s, 1H), 5.19 (br s, 2H), 512, (br s, 1H), 4.53 (m, 2H), 4.22 (m, 1H), 3.60 (m, 4H), 3.00 (m, 2H), 2.89 (m, 2H), 2.53 (s, 3H), 2.25 (m, 2H), 2.13 (m, 2H), 2.08 (m, 2H), 1.58 (m, 2H).13C NMR (150 MHz, CDCl3): 168.04, 166.76, 156.07, 154.34, 148.10, 136.50, 130.98, 128.96, 128.47, 128.09, 127.16, 126.64 (q, J=289.5Hz), 118.48, 166.43, 113.72, 111.92, 108.97, 107.92, 107.38, 104.99, 104.94, 52.31, 50.77, 48.09, 45.00, 35.54 (q, J=32Hz), 32.39, 32.32, 15.06. HR MS (ESI): M + H+ calculated 611.1981; found 611.1987.
Figure imgf000206_0001
[00183] To a mixture of 1-(2-(2-aminothiazol-4-yl)ethyl)-4-methyl-5-((4-((6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2- carbonitrile (11.5 mg, 0.018 mmol) and DIPEA (0.0063 mL, 0.036 mmol) in DCM (0.2 mL) was added acryloyl chloride (0.00153 mL, 0.18 mmol) with external cooling of ice water. After stirring for 15 minutes, the reaction mixture was purified using pTLC and developed with DCM- MeOH (10:1) to isolate N-(4-(2-(2-cyano-4-methyl-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indol-1-yl)ethyl)thiazol-2-yl)acrylamide (Compound 34) (3 mg).1H NMR (600 MHz, CD3CN): 10.07 (br s, 1H), 8.33 (s, 1H), 7.35 (s, 1H), 7.29, (d, 1H, J=8.4Hz), 7.26 (s, 1H), 7.19 (d, 1H, J=8.4Hz), 6.44 (m, 3H), 6.19 (br d, 1H), 5.86 (m, 1H), 4.56 (m, 2H), 4.14 (m, 1H), 3.81 (q, 2H, J=10.5Hz), 3.60 (s, 1H), 3.13 (m, 2H), 2.88 (m, 2H), 2.52 (s, 3H), 1.98 (m, 2H), 1.59 (m, 2H).13C NMR (150 MHz, CD3CN): 168.04, 164.40, 159.15, 157.80, 155.70, 149.28, 138.12, 132.38, 130.76, 130.47, 130.31, 128.99, 128.53, 126.92 (q, J=289.5Hz), 121.94117.90, 114.95, 113.24, 111.64, 110.49, 109.23, 61.05, 53.68, 49.57, 46.48, 36.01 (q, J=32Hz), 33.16, 32.96, 30.49, 15.68. HR MS (ESI): M + H+ calculated 65.2087; found 665.2081. Representative procedure for the synthesis of compound C-81
Figure imgf000206_0002
[00184] Trifluoromethanesulfonic anhydride (Tf2O) (2.6 mL, 15 mmol) was added to a solution of 4-nitrophenyl-2-ethanol (1.67 g, 10 mmol) and 2,6-lutidine (2.1 mL, 18 mmol) in DCM (50 mL) at -50 °C. The reaction mixture allowed to warm to room temperature and then washed with NaHCO3, followed by 4% citric acid solution, and finally with brine. The reaction mixture was dried over Na2SO4. After concentration, the 4-nitrophenethyl trifluoromethanesulfonate
uantitative ield was used immediatel in the next ste .
Figure imgf000207_0001
[00185] NaH (120 mg, 3 mmol) was added to a solution of 5-formyl-4-methyl-1H-indole-2- carbonitrile (368 mg, 2 mmol) in THF (4 mL) at room temperature and then cooled to -78 °C.4- Nitrophenethyl trifluoromethanesulfonate was dissolved in THF (4 mL) and transferred via syringe to the precooled flask containing the sodium salt of 5-formyl-4-methyl-1H-indole-2- carbonitrile. After stirring for 30 min, the reaction mixture was allowed to warm to room temperature and quenched with 7 M NH3 in MeOH (2 mL). The reaction mixture was evaporated with silica gel and eluted starting with hexane:THF (4:1), then with hexane:THF (1:1), and finally with pure THF.5-Formyl-4-methyl-1-(4-nitrophenethyl)-1H-indole-2-carbonitrile (1.4 g) (MW = 333) was isolated.1H NMR (600 MHz, CDCl3): 10.42 (s, 1H), 8.10 (d, J = 8.44 Hz, 2H), 7.87 (d, J = 8.44 Hz, 1H), 7.33 (s, 1H), 7.18 (m, 3H), 4.58 (t, J = 7.2 Hz, 2H), 3.28 (t, J = 7.2 Hz, 2H), 2.9 (s, 3H).13C NMR (150 MHz, CDCl3): 191.1, 147.3, 144.2, 139.0, 138.1, 129.8, 127.9, 127.3, 124.1, 113.6, 112.5, 110.8, 108.1, 46.6, 36.1, 14.6.
Figure imgf000207_0002
[00186] Following a similar general procedure as for preparing Compound 3, 4-methyl-1-(4- nitrophenethyl)-5-((4-(6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-ylamino)piperidin-1- yl)methyl)-1H-indole-2-carbonitrile was synthesized from 5-Formyl-4-methyl-1-(4- nitrophenethyl)-1H-indole-2-carbonitrile (666 mg, 2 mmol) and N-(piperidin-4-yl)-6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidin-4-amine hydrochloride (934 mg). The product was purified by column chromatography on silica gel and l t d ith DCM:MeOH:NH3-H2O (15:1:0.1). Evaporation of solvent gave 4-methyl-1-(4-nitrophenethyl)-5-((4-(6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile (1070 mg).
Figure imgf000208_0001
[00187] A mixture of 4-methyl-1-(4-nitrophenethyl)-5-((4-(6-(2,2,2-trifluoroethyl)thieno[2,3- d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile (1.2 g, 1.7 mmol), ammonium chloride (3.6 g, 68 mmol), and Zn powder (2.2 g, 34 mmol) were stirred in acetone- water (6:1 v/v) (40 mL). After stirring for 2 h, the mixture was concentrated, diluted with 1 M NaOH and EtOAc, and filtered through celite. The organic fraction was evaporated with silica gel, loaded on a column, and eluted with DCM:MeOH:NH3-H2O (starting with 20:10:0.1 and decreasing to 10:1:0.1).1-(4-Aminophenethyl)-4-methyl-5-((4-(6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile (910 mg) was isolated.1H NMR (600 MHz, CDCl3): 8.47 (s, 1H), 7.32 (d, J = 8.44 Hz), 7.15 (s, 1H), 7.10 (d, J = 8.44 Hz), 7.06 (s, 1H), 6.87 (d, J = 8.07 Hz, 2H), 6.59 (d, J = 8.07 Hz, 2H), 5.11 (br d), 4.39 (t, J = 7.5 Hz, 2H), 4.23 (m, 1H), 3.63 (m, 4H), 2.98 (t, J = 7.5 Hz, 2H), 2.92 (m, 2H), 2.54 (s, 3H), 2.27 (m, 2H), 2.09 (m, 2H), 1.60 (m, 2H).13C NMR (150 MHz, CDCl3): 166.8, 156.1, 154.3, 145.3, 136.3, 131.1, 129.7, 129.0.127.3, 127.2, 124.7 (q, J = 277 Hz), 118.5, 116.4, 115.4, 113.7, 111.6, 109.1, 107.3, 60.1, 52.2, 50.8, 48.0, 47.6, 35.8, 35.6 (q, J = 32 Hz), 32.3, 15.1.
Figure imgf000208_0002
[00188] Acryloyl chloride (0.135 mL, 1.7 mmol) was added dropwise to a solution of 1-(4- aminophenethyl)-4-methyl-5-((4-(6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4- ylamino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile (917 mg, 1.5 mmol) and Et3N (0.46 mL, 3.3 mmol) in THF (30 mL) at -78 °C. Th ti i ture was slowly warmed to room temperature, evaporated with silica gel at room temperature, loaded on a column, and eluted with DCM:MeOH:NH3-H2O (starting with 15:1:0.1 and decreasing to 10:1:0.1) to isolate N-(4-(2-(2- cyano-4-methyl-5-((4-(6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-ylamino)piperidin-1- yl)methyl)-1H-indol-1-yl)ethyl)phenyl)acrylamide with a minor impurity of the starting material. N-(4-(2-(2-Cyano-4-methyl-5-((4-(6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4- ylamino)piperidin-1-yl)methyl)-1H-indol-1-yl)ethyl)phenyl)acrylamide was recrystallized from MeOH to afford pure product (510 mg).1H NMR (600 MHz, CD3OD): 8.33 (s, 1H), 7.57 (s, 1H), 7.41 (m, 3H), 7.35 (s, 1H), 7.26 (d, J = 8.44 Hz, 1H), 6.89 (d, J = 8.07 Hz, 2H), 6.35 (m, 1H), 6.24 (d, J = 16.87 Hz, 1H), 5.62 (d, J = 10.27 Hz, 1H), 4.54 (t, J = 7.5 Hz, 2H), 4.35 (m, 3H), 3.85 (q, J = 10.5 Hz, 2H), 3.46 (m, 2H), 3.13 (m, 2H), 3.09 (m, 2H), 2.26 (m, 2H), 1.98 (m, 2H).13C NMR (150 MHz, CD3OD): 167.1, 166.0, 157.8, 155.0, 147.5, 139.0, 138.7, 135.1, 134.5, 132.6, 130.7, 130.6, 128.6, 127.8, 126.7 (q, J = 277 Hz), 122.0, 121.4, 118.2, 116.9, 114.3, 113.5, 113.3, 111.3, 110.4, 59.1, 52.8, 37.0, 36.8, 35.7 (q, J = 32 Hz), 30.2, 15.8. HRMS (ESI): M + H+ calculated 658.2570; found 658.2572. Representative procedure for the synthesis of compound C-100
Figure imgf000209_0001
[00189] NaH (800 mg, 20 mmol) was added in small portions to a solution of tert-butyl ethyl malonate (3.8 mL, 20 mmol) in DMSO (10 mL). After 5 minutes, 5-bromo-2-nitropyridine (2.03 g, 10 mmol) was added, and the reaction mixture was sealed and heated at 80 °C for 5 h. Then the reaction mixture was diluted with saturated ammonium chloride solution and extracted with diethyl ether. Organic fractions were evaporated, purified by column chromatography, eluted with Hexane:EtOAc (4:1), and dissolved in trifluoroacetic acid (TFA) (30 mL). The reaction mixture was concentrated to dryness, dissolved in EtOAc and washed with saturated NaHCO3. Organic fractions were evaporated with silica gel and purified by silica gel column
chromatography, eluting with Hexane:EtOAc (2:1) to afford ethyl 2-(6-nitropyridin-3-yl)acetate (1.3 g).1H NMR (600 MHz, CDCl3): 8.25 (s, 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.00 (m, 1H), 4.21 (q, J = 7.3 Hz, 2H), 3.79 (s, 2H), 1.28 (t, J = 7.3 Hz, 3H).13C NMR (150 MHz, CDCl3): 169.3, 155.9, 149.5, 140.7, 136.4, 117.8, 61.8, 38.0, 14.1.
Figure imgf000210_0001
[00190] Ethyl 2-(6-nitropyridin-3-yl)acetate (1.4 g, 6.2 mmol) was dissolved in 1 M BH3-THF complex in THF (19 mL). The mixture was heated at 60 °C for 0.5 h. Then the reaction mixture was concentrated to dryness, carefully quenched with 1 M NaOH and extracted with EtOAc. Organic fractions were evaporated with silica gel and purified by silica gel column
chromatography, eluting with Hexane:EtOAc:MeOH (1:1:0.1) to afford 2-(6-nitropyridin-3- yl)ethanol (850 mg).
Figure imgf000210_0002
[00191] Following the same general procedure for synthesizing 4-nitrophenethyl
trifluoromethanesulfonate, 2-(6-nitropyridin-3-yl)ethyl trifluoromethanesulfonate was synthesized from 2-(6-nitropyridin-3-yl)ethanol (840 mg, 5 mmol). Following the same general procedure for synthesizing 5-Formyl-4-methyl-1-(4-nitrophenethyl)-1H-indole-2-carbonitrile, 5- formyl-4-methyl-1-(2-(6-nitropyridin-3-yl)ethyl)-1H-indole-2-carbonitrile was synthesized from 5-formyl-4-methyl-1H-indole-2-carbonitrile (460 mg, 2.5 mmol) and 2-(6-nitropyridin-3-yl)ethyl trifluoromethanesulfonate. After reaction was complete, the reaction mixture was quenched with AcOH (2 mL) and carefully concentrated to dryness. The residue was suspended in water (50 mL), sonicated and filtered to afford crude 5-formyl-4-methyl-1-(2-(6-nitropyridin-3-yl)ethyl)- 1H-indole-2-carbonitrile, used as is in the next step.1H NMR (600 MHz, Me2CO): 10.41, (s, 1H), 8.32 (s, 1H), 8.17 (d, J = 8.07 Hz, 1H), 7.98 (m, 1H), 7.83 (d, J = 8.80 Hz, 1H), 7.64 (s, 1H), 7.57 (d, J = 8.80 Hz, 1H), 4.82 (t, J = 6.97 Hz, 2H), 3.49 (t, J = 6.97 Hz, 2H), 2.90 (s, 3H). 13C NMR (150 MHz, Me2CO): 150.2, 141.8, 141.4, 140.3, 138.5, 128.8, 128.2, 128.1, 126.2, 118.7, 114.7, 113.4, 111.8, 110.0, 47.1, 33.7, 14.6.
Figure imgf000211_0001
[00192] Following the same general procedure as described for the preparation of Compound 3, 1-(2-(6-aminopyridin-3-yl)ethyl)-4-methyl-5-((4-(6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin- 4-ylamino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile was synthesized from 5-formyl-4- methyl-1-(2-(6-nitropyridin-3-yl)ethyl)-1H-indole-2-carbonitrile and N-(piperidin-4-yl)-6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidin-4-amine hydrochloride.1-(2-(6-Aminopyridin-3-yl)ethyl)- 4-methyl-5-((4-(6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-ylamino)piperidin-1- yl)methyl)-1H-indole-2-carbonitrile (1080 mg) was isolated.1H NMR (600 MHz, CDCl3): 8.47 (s, 1H), 7.63 (s, 1H), 7.34 (d, J = 8.44 Hz, 1H), 7.15 (m, 2H), 7.08 (d, J = 8.80 Hz, 1H), 7.05 (s, 1H), 6.42 (d, J = 8.44 Hz, 1H), 5.00 (br d), 4.40 (t, J = 7.34 Hz, 2H), 4.27 (s, 2H), 4.22 (m, 1H), 3.63 (m 4H), 2.98 (t, J = 7.34 Hz, 2H), 2.88 (m, 2H), 2.54 (s, 3H), 2.25 (m, 2H), 2.09 (m, 2H), 1.56 (m, 2H).13C NMR (150 MHz, CDCl3): 166.8, 157.5, 156.0, 154.4, 147.9, 138.4, 136.2, 131.2, 129.0, 128.7, 127.3, 126.7 (q, J = 277 Hz), 122.5, 118.3, 116.4, 113.6, 111.8, 109.0, 108.6, 107.1, 60.2, 52.3, 48.1, 47.0, 35.5 (q, J = 32 Hz), 32.8, 32.5, 15.0.
Figure imgf000211_0002
[00193] Acryloyl chloride was added dropwise to a solution of 1-(2-(6-aminopyridin-3- yl)ethyl)-4-methyl-5-((4-(6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-ylamino)piperidin-1- yl)methyl)-1H-indole-2-carbonitrile (1.03 g) and Et3N in THF at -78 °C. The reaction mixture was slowly warmed to room temperature, evaporated with silica gel at room temperature, loaded on a column, eluted with DCM:MeOH:NH3-H2O (starting with 15:1:0.1 and decreasing to 10:1:0.1), and recrystallized from MeOH to afford N-(5-(2-(2-cyano-4-methyl-5-((4-(6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-1H-indol-1- yl)ethyl)pyridin-2-yl)acrylamide (470 mg).1H NMR (600 MHz, CD3OD for HCl salt): 8.35 (s, 1H), 7.93 (d, J = 8.44 Hz, 1H), 7.83 (s, 1H), 7.54 (s, 1H), 7.40 (m, 2H), 7.30 (m, 2H), 6.41 (m, 1H), 6.30 (m, 1H), 5.67 (m, 1H), 4.62 (m, 3H) 439 (m 2H), 3.86 (q, J = 10.5 Hz, 2H), 3.45 (m, 2H), 3.17 (m, 2H), 2.64 (s, 3H), 2.26 (m, 2H), 2.15 (m, 2H), 1.91 (m, 2H).13C NMR (150 MHz, CD3OD): 167.2, 166.2, 157.9, 155.0, 152.1, 149.4, 140.1, 139.0, 135.0, 132.3, 131.0, 130.6, 130.1, 128.8, 128.6, 126.8 (q, J = 277 Hz), 121.9, 118.3, 115.5, 114.1, 113.8, 111.5, 110.6, 47.8, 35.7 (q, J = 32 Hz), 34.0, 15.8. HRMS (ESI): M + H+ calculated 659.2523; found 659.2523.
Figure imgf000212_0001
NO 2
[00194] Ethyl 2-(4-aminophenyl)acetate (5.3g, 29.6mmol) was dissolved in 20 mL of acetonitrile, followed by the addition of NaHCO3 (5 g, 59.2 mmol) and 50 mL of water. The reaction mixture was cooled to 0 oC, iodine (7.8 g, 29.6 mmol) was added slowly. The black reaction mixture was stirred at room temperature overnight. TLC showed the reaction was completed and water was added. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium thiosulfate solution and brine, dried over anhydrous Na2SO4, filtered, concentrated and purified by silica gel column chromatography (eluted with petroleum) to give ethyl 2-(4-amino-3-iodophenyl)acetate as a solid (5.3g, yield: 58%), 305.9(M+H)+.
Figure imgf000212_0002
[00195] To a mixture of ethyl 2-(4-amino-3-iodophenyl)acetate (3.05 g, 10 mmol) in 30 mL of dioxane was added dimethylphosphine oxide (860 mg, 11mmol), Pd2(dba)3 (460 mg, 0.50 mmol), xantphos (580 mg, 1 mmol), Cs2CO3 (6.5 g, 20 mmol). The resulting mixture was stirred at 90 oC overnight. LCMS showed the reaction was completed. The reaction mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography (eluted 5% methanol in dichloromethane) to give ethyl 2-(4-amino-3- (dimethylphosphoryl) phenyl)acetate as a solid (1.8 g, yield: 70%).256(M+H)+.
Figure imgf000212_0003
[00196] To a mixture of 2-(4-amino-3-(dimethylphosphoryl)phenyl)acetate (1.8 g, 7.0 mmol), 4-methoxybenzaldehyde (1.44 g, 10.5 mmol) in dichloromethane was added NaBH(OAc)3 at room temperature. Then the reaction was stirred at room temperature overnight. TLC test indicated that reaction was complete. Water was added, and the reaction mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated and purified by silica gel column chromatography (eluted 5% methanol in dichloromethane) to give ethyl 2-(4-(4-methoxybenzylamino)-3-
Figure imgf000213_0001
[00197] To a solution of 2-(4-(4-methoxybenzylamino) -3-(dimethylphosphoryl)phenyl) acetate (1.9 g, 5.0 mmol) in 20 mL of ethanol was added NaBH4 (960 mg, 25 mmol) at 0 oC. The mixture was stirred at room temperature overnight. LCMS showed that the reaction was complete. Water was added and the reaction mixture was extracted with ethyl acetate, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography (eluted 5% methanol in dichloromethane) to give 2-(4-(4- methoxybenzylamino)-3-(dimethylphosphoryl) phenyl)ethanol as a solid (1.21 g, yield: 72%). 334(M+H)+.
Figure imgf000213_0002
[00198] To a mixture of 5-formyl-4-methyl-1H-indole-2-carbonitrile (728 mg, 3.95 mmol) , 2- (4-(4-methoxybenzylamino)-3-(dimethylphosphoryl)phenyl)ethanol (878 mg, 2.63 mmol) in 40 mL of anhydrous THF was added diisopropyl azodicarboxylateDiisopropyl azodicarboxylate (1.06 g, 5.3 mmol) under argon. The reaction mixture was stirred room temperature overnight. LCMS showed that the reaction was complete. Water was added, the reaction mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column (eluted with 2% of methanol in dichloromethane) to give 1-(4-(4-methoxybenzylamino) -3- (dimethylphosphoryl)phenethyl)-5-formyl-4-methyl-1H-indole-2-carbonitrile as a solid (450 mg, yield: 34%).500(M+H)+.
Figure imgf000214_0001
[00199] To a mixture of 1-(4-(4-methoxybenzylamino)-3-(dimethylphosphoryl)phenethyl) -5- formyl-4-methyl-1H-indole-2-carbonitrile (450 mg, 0.9 mmol) and N-(piperidin-4-yl)-6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidin-4-amine (313 mg, 1.0 mmol) in dichloromethane was added TEA (273 mg, 2.7 mmol), followed by NaBH(OAc)3 (573 mg, 2.7 mmol). The reaction mixture was stirred at room temperature overnight. LCMS showed that the reaction was complete. Water was added, and the reaction mixture was extracted with dichloromethane, washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column (eluted with 10% of methanol in dichloromethane) to give 1-(4-(4- methoxybenzylamino)-3-(dimethylphosphoryl)phenethyl)-4-methyl-5-((4-(6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile as a solid (180 mg, 25%).800(M+H)+.
Figure imgf000214_0002
[00200] A mixture of 1-(4-(4-methoxybenzylamino)-3-(dimethylphosphoryl)phenethyl) -4- methyl-5-((4-(6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)- 1H-indole-2-carbonitrile (100 mg, 0.125 mmol) in 10 mL of trifluoroacetic acid was stirred at reflux overnight. The reaction mixture was then concentrated to dryness.7 N NH3 in methanol was added to neutralize the residue acid and the reaction mixture was concentrated again. The residue was purified by silica gel column (eluted with 10% of methanol in dichloromethane) to give 1-(4-amino-3-(dimethylphosphoryl)phenethyl)-4-methyl-5-((4-(6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile as a solid (48 mg, yield:56%).680(M+H)+.
Figure imgf000214_0003
[00201] To a solution of 1-(4-amino-3-(dimethylphosphoryl)phenethyl)-4-methyl -5-((4-(6- (2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-1H-indole-2- carbonitrile (48 mg, 0.07 mmol) in 10 mL of dichloromethane was added TEA (14 mg, 0.14 mmol) at -78 oC, followed by acryloyl chloride (7 mg, 0.08 mmol), then the reaction was stirred at -78 oC for 30 min. A TLC test indicated that the reaction was complete. Dichloromethane was added, the reaction mixture was washed with saturated sodium hydrogen carbonate, brine. The organic solution was dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column (eluted with 10% of methanol in dichloromethane) to give
Compound 199 as a solid (46 mg, yield: 88%).734(M+H)+.1HNMR (400MHz, CDCl3): 11.46 (s, 1H), 8.54 (dd, J = 4.0, 8.8 Hz, 1H), 8.38 (s, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.03-7.08 (m, 3H), 6.84 (d, J = 8.4 Hz, 1H), 6.46 (d, J = 10 Hz, 1H), 6.29 (dd, J = 2.4, 17.2 Hz, 1H), 6.09-6.16 (m, 1H), 5.20 (dd, J = 1.1, 10 Hz, 1H), 5.23 (s, 1H), 4.41 (t, J = 6.4 Hz, 2H), 3.52-3.60 (m, 4H), 3.04 (t, J = 6.4 Hz, 2H), 2.87 (br, 2H), 2.44 (s, 3H), 2.26 (t, J = 10.8 Hz, 2H), 2.03 (d, J = 10.4 Hz, 2H), 1.52 (s, 3H), 1.50 (s, 3H).
Re resentative rocedure for synthesis of compound C-196
Figure imgf000215_0001
[00202] A mixture of 1-bromo-4-nitrobenzene (2 g, 9.9 mmol), 4,4,5,5-tetramethyl-2- (prop-1- en-2-yl)-1,3,2-dioxaborolane (3.3 g, 19.8 mmol), K2CO3 (4.14 g, 29.7 mmol) and Pd(dppf)Cl2 (365 mg, 0.5 mmol) in dioxane (20 mL) was stirred at 110 oC under N2 overnight. TLC test showed that the reaction was completed. The solid was removed by filtration and the solvent was evaporated under vacuum. The resulting residue was purified by silica gel column
chromatography (eluted with petroleum) to give 1-nitro-4-(prop-1-en-2-yl)benzene as a yellow solid (1.6 g, yield: 99%).
Figure imgf000215_0002
[00203] To a mixture of 1-nitro-4-(prop-1-en-2-yl)benzene (1.4 g, 8.6 mmol) in 20 mL of dichloromethane was added mCPBA (2.22 g, 12.9 mmol) at 0 oC and the reaction mixture was stirred overnight. TLC showed that the reacti l ted. Saturated NaHCO3 aqueous was added to the reaction mixture, the organic layer was separated and washed with brine, dried over anhydrous Na2SO4. Solid was filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluted with petroleum) to give 2-methyl-2-(4- nitro hen l oxirane as a solid 1.1 ield:71% .
Figure imgf000216_0001
[00204] A mixture of 2-methyl-2-(4-nitrophenyl)oxirane (1.1 g, 6.1 mmol), 5-formyl-4-methyl- 1H-indole-2-carbonitrile (1.13 g, 6.1 mmol) and K2CO3 (1.7 g, 12.2 mmol) in 15 mL of DMF was stirred at 90 oC for 5-6 hours. The solid was removed by filtration. Water and ethyl acetate were added to the filtrate, the organic layer was collected, washed with brine, dried over anhydrous Na2SO4. The dried organic solution was filtered and concentrated. The resulting residue was purified by silica gel column chromatography (eluted with 50% ethyl acetate in petroleum) to give 5-formyl-1-(2-hydroxy-2-(4-nitrophenyl)propyl)-4-methyl-1H-indole-2- carbonitrile as a solid (2.0 g, yield: 89%).
ESI-MSm/z :363.05 (M+H).
Figure imgf000216_0002
[00205] A mixture of 5-formyl-1-(2-hydroxy-2-(4-nitrophenyl)propyl)-4-methyl-1H- indole-2- carbonitrile (320 mg, 0.88 mmol), 6-(2,2,2-trifluoroethyl)-N-(piperidin-4-yl) thieno-[2,3- d]pyrimidin-4-amine (411 mg, 1.05 mmol) and TEA (534 mg, 5.29 mmol) in 15 mL of DCM was stirred at room temperature for 1 hours, then NaBH(OAc)3 (1.12 g, 5.29 mmol) was added to the reaction under ice bath, the mixture reaction was stirred at room temperature overnight. The solvent was evaporated under vacuum and the residue was purified by silica gel column chromatography (eluted with 5% MeOH in dichloromethane) to give 5-((4-(6-(2,2,2- trifluoroethyl)thieno[2,3-d] pyrimidin-4-ylamino)piperidin-1-yl)methyl)-1-(2-hydroxy-2-(4- nitrophenyl)propyl)-4-methyl-1H-indole-2-carbonitrile as a solid (150 mg, yield:26%).
Figure imgf000217_0001
[00206] To a mixture of 5-((4-(6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-ylamino) piperidin-1-yl)methyl)-1-(2-hydroxy-2-(4-nitrophenyl)propyl)-4-methyl-1H-indole-2-carbonitrile (1.0 g, 1.51 mmol), NH4Cl (3.23 mg, 60.3 mmol) and H2O (5.9 g, 332 mmol) in 15 mL of acetone was add Zn dust (2.0 g, 30.2 mmol) and the mixture was stirred at room temperature for 2 hours. Then the solid was removed by filtration, the solvent was removed and the residue was purified by silica gel column chromatography (eluted with 6% MeOH in dichloromethane) to give 5-((4-(6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-1- (2-(4-aminophenyl)-2-hydroxypropyl)-4-methyl-1H-indole-2-carbonitrile as a solid (330 mg, yield:35%).
ESI-MSm/z :634.35 (M+H).
Figure imgf000217_0002
[00207] To a mixture of 5-((4-(6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-ylamino) piperidin-1-yl)methyl)-1-(2-(4-aminophenyl)-2-hydroxypropyl)-4-methyl-1H-indole-2- carbonitrile (100 mg, 0.16 mmol) and TEA (32 mg, 0.32 mmol) in 10 mL of THF was add slowly acryloyl chloride (16 mg, 0.17 mmol) in dry THF at -78oC under N2. The mixture was stirred at room temperature for 2 hours before NH3/MeOH was added. Solvent was removed and the residue was purified by silica gel column chromatography (eluted with 5% MeOH in dichloromethane) to give Compound 196 as a solid (48 mg, yield:44%).1H NMR (400
MHz, DMSO) δ: 10.13 (s, 1H), 8.33 (s, 1H), 7.80 (s, 1H),7.65 (s, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.47 (s, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.32 (br,1H), 7.19 (br, 1H),6.38-6.45 (m, 1H),6.25- 6.20 (m, 1H), 5.70 (dd, J = 2.0, 10 Hz, 1H), 5.45 (s, 1H), 4.38-4.41 (m, 1H), 4.28-4.29 (m, 1H), 4.02-4.11 (m, 3H),3.60 (m, 1H), 3.50-3.52 ,2H), 2.05-2.08 (m, 3H), 1.91(br, 2H), 1.76 (m, 1H), 1.55-1.52 (br, 2H), 1.47(s, 3H). ESI-MSm/z: 688.40 (M+H). Representative procedure for synthesis of compound C-174
Figure imgf000218_0001
[00208] A mixture of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (200 mg, 1.01 mmol), 2-bromoethanol (251 mg, 2.02 mmol), and K2CO3 (558 mg, 4.04 mmol) in 30 mL of CH3CN was stirred at 90 oC under N2 overnight. TLC test showed that the reaction was completed. Solid was removed by filtration and solvent was removed under vacuum. The resulting residue was purified by silica gel column chromatography (eluted with 2.5% MeOH in dichloromethane) to give tert-butyl 6-(2-hydroxyethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate as a yellow oil (193 mg, yield: 80%).
Figure imgf000218_0002
[00209] To a mixture of tert-butyl 6-(2-hydroxyethyl)-2,6-diazaspiro[3.3]heptane- 2- carboxylate (193 mg, 0.8 mmol) and Et3N (161 mg, 1.60 mmol) in 20 mL of dichloromethane was added MsCl (136 mg, 1.20 mmol) at 0 oC. The reaction mixture was stirred for 1h. TLC test showed that the reaction was completed. Saturated NaHCO3 aqueous was added to the reaction mixture. Organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. Solvent was removed and the resulting residue was purified by silica gel column chromatography (eluted with petroleum) to give tert-butyl 6-(2-((methylsulfonyl)oxy)ethyl)-2,6- diazaspiro [3.3]heptane-2-carboxylate as an oil (193 mg, yield: 75%).
Figure imgf000218_0003
[00210] A mixture of tert-butyl 6-(2-((methylsulfonyl)oxy)ethyl)-2,6-diazaspiro[3.3] heptane-2- carboxylate (193 mg, 0.6 mmol), 5-formyl-4 methyl 1H indole -2-carbonitrile (92 mg, 0.5 mmol) and Cs2CO3 (328 mg, 1.0 mmol) in 10 mL of DMF was stirred at 60 oC for 4 hours. The solid was removed by filtered and water and ethyl acetate were added to the filtrate, the organic layer was collected, washed with brine, dried over anhydrous Na2SO4, filtered, concentrated and purified by silica gel column chromatography (eluted 20% ethyl acetate in petroleum) to give tert-butyl 6-(2-(2-cyano-5-formyl-4-methyl-1H-indol-1-yl)ethyl)-2,6-diazaspiro[3.3] heptane-2- carboxylate as an oil (99 mg, yield: 40%). ESI-MS m/z: 408.51 (M+H).
Figure imgf000219_0001
[00211] A mixture of tert-butyl 6-(2-(2-cyano-5-formyl-4-methyl-1H-indol-1-yl) ethyl)-2,6- diazaspiro[3.3]heptane-2-carboxylate (99 mg, 0.243 mmol), N- (piperidin-4-yl)-6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidin-4-amine (115 mg, 0.364 mmol) and Et3N (147 mg, 1.456 mmol) in 20 mL of DCM was stirred at room temperature for 1 hour, then NaBH(OAc)3 (309 mg, 1.456 mmol) was added to the reaction under ice bath. The reaction mixture was stirred at room temperature overnight. Solvent was removed under vacuum and the residue was purified by silica gel column chromatography (eluted with 2.5% MeOH in dichloromethane) to give tert- butyl 6-(2-(2-cyano-4-methyl-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d] pyrimidin-4- yl)amino)piperidin-1-yl)methyl)-1H-indol-1-yl)ethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate as an oil (18 mg, yield: 10%). ESI-MSm/z: 708.84 (M+H).
Figure imgf000219_0002
[00212] To a solution of tert-butyl 6-(2-(2-cyano-4-methyl-5-((4-((6-(2,2,2-trifluoroethyl) thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indol-1-yl)ethyl)-2,6- diazaspiro[3.3]heptane-2-carboxylate (18 mg, 0.025 mmol) in 15 mL of DCM was added 5 mL of TFA. The reaction was stirred at room temperature for 2 hours. Then the reaction mixture was concentrated to dryness before 10 mL of 7 N NH3 in MeOH solution was added. Solvent was removed and the resulting residue was purified by silica gel column chromatography (eluted with 10% MeOH in dichloromethane) to give 1-(2-(2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-4-methyl-5- ((4-((6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H- indole-2-carbonitrile as an oil (11 mg, yield: 71%). ESI-MSm/z: 608.71 (M+H).
Figure imgf000220_0001
[00213] To a mixture of 1-(2-(2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-4-methyl -5-((4-((6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2- carbonitrile (11 mg, 0.018 mmol) and Et3N (4 mg, 0.036 mmol) in 10 mL of DCM was slowly added acryloyl chloride (1.6 mg, 0.17 mmol) in dry THF at -78 oC under N2. The reaction mixture was stirred at room temperature for 2 hours, then NH3/MeOH was added. Solvent was removed and the resulting residue was purified by silica gel column chromatography (eluted with 10% MeOH in dichloromethane) to give Compound 174 as a solid (3 mg, yield: 25%).1H NMR (400 MHz, DMSO) δ: 8.33 (s, 1H), 7.55~7.40 (m, 4H), 6.32~6.17 (m, 2H), 5.72~5.69 (m, 1H), 4.34~4.29 (m, 5H), 4.06~4.02 (m, 4H), 3.90~3.82 (m, 2H), 3.39~3.32 (m, 4H), 3.27~3.22 (m, 2H), 2.91~2.88 (m, 2H), 2.73~2.67 (m, 2H), 2.63 (s, 3H), 2.16~2.13 (m, 2H), 1.84~1.82(m, 2H); ESI-MSm/z :663.35 (M+H).
Representative procedure for synthesis of compound 210
Figure imgf000220_0002
[00214] To a suspension of trimethylsulfoxonium iodide (1.2 g, 5.6 mmol) in DMSO at 0 oC was added NaH (250 mg, 6.1 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 1h. Then tert-butyl 4-formylpiperidine-1-carboxylate (1.0 g, 4.7 mmol) was added. The reaction was stirred at room temperature under N2 overnight. TLC test showed that the reaction was completed. The reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was washed by brine, dried over Na2SO4. Solvent was removed under vacuum and the resulting residue was used without further purification as yellow oil (1.0 g, yield: 99%).
Figure imgf000221_0001
[00215] A mixture of tert-butyl 4-(oxiran-2-yl)piperidine-1-carboxylate (3.0 g, 13.2 mmol), 5- formyl-4-methyl-1H-indole-2-carbonitrile (1.2 g, 6.5 mmol) and K2CO3 (2.7 g, 19.5 mmol) in 30 mL of DMF was stirred at 120 oC for 10 hours. The reaction mixture was cooled to room temperature before solid was removed by filtration. The reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was washed by brine, dried over Na2SO4. Solvent was removed under vacuum to get the residue, which was purified by silica gel column chromatography (PE: ethyl acetate =10:1~5:1) to give tert-butyl 4-(2-(2-cyano-5-formyl-4- methyl-1H-indol-1-yl) -1-hydroxyethyl)piperidine-1-carboxylate as a yellow solid (800 mg, yield: 30%).
ESI-MS m/z: 434.15 (M+Na), 312.15 (M-100+H).
Figure imgf000221_0002
[00216] A mixture of tert-butyl 4-(2-(2-cyano-5-formyl-4-methyl-1H-indol-1-yl)-1- hydroxyethyl)piperidine-1-carboxylate (500 mg, 1.2 mmol), 6-(2,2,2-trifluoroethyl) -N- (piperidin-4-yl)thieno -[2,3-d]pyrimidin-4-amine (455 mg, 1.4 mmol) and triethylamine (727 mg, 7.2 mmol) in DCM (30 mL) was stirred at room temperature for 1 hour. NaBH(OAc)3 (1.5 g, 7.2 mmol) was added with ice bath cooling. The reaction mixture was stirred at room
temperature overnight before partitioned between DCM and NaHCO3 (sat.). Organic layer was washed by brine, dried over Na2SO4. Solvent was removed under vacuum to get the residue, which was purified by silica gel column chromatography (DCM: MeOH = 50:1 ~ 30:1) to give tert-butyl 4-(2-(2-cyano-4-methyl-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)methyl)-1H-indol-1-yl)-1-hydroxyethyl)piperidine-1-carboxylate as a yellow solid (500 mg, yield: 60%). ESI-MS m/z: 712.55 (M+H).
Figure imgf000222_0001
[00217] To a solution of tert-butyl 4-(2-(2-cyano-4-methyl-5-((4-((6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indol-1-yl)-1- hydroxyethyl)piperidine-1-carboxylate (150 mg, 0.21 mmol) in 3 mL of DCM was added 2 mL of TFA. The reaction mixture was stirred for 4 hours. Solvent was removed under vacuum to get the residue, which was diluted with DCM and washed with NaHCO3 (sat.). The organic layer was washed by brine, dried over Na2SO4. Then solvent was removed under vacuum to get the residue, which was used without further purification as a yellow foam (100 mg, yield: 99%).
Figure imgf000222_0002
[00218] A mixture of acrylic acid (8.6 mg, 0.12 mmol), BOP (66 mg, 0.15 mmol) and DIEA (65 mg, 0.5 mmol) in DCM (10 mL) was stirred at room temperature for 2 hours, before 1-(2- hydroxy-2-(piperidin-4-yl)ethyl)-4-methyl-5-((4-((6-(2,2,2- trifluoroethyl)thieno[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile (70 mg, 0.1 mmol) was added under ice bath cooling. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between DCM and NaHCO3 (sat.), and the organic layer was washed by brine, dried over Na2SO4. Solvent was removed under vacuum to get the residue, which was purified by Prep-TLC (DCM:MeOH=15:1) to give Compound 210 as a white solid (10 mg, yield: 20%).1HNMR (400 MHz, DMSO) δ: 10.40 (br, 1H), 8.96 (br, 1H), 8.35 (m, 1H), 8.11-8.12 (m, 1H), 7.71 (s, 1H), 7.60 (s, 1H), 7.52 (s, 1H), 6.80-6.87 (m, 1H), 6.09 (dd, J = 2.4, 16.8 Hz, 1H), 5.66 (dd, J = 2.4, 10.8 Hz, 1H), 5.05 (d, J = 5.2 Hz, 1H), 4.04-4.49 (m, 8H), 3.57~3.63 (m, 3H), 3.12~3.30 (m, 4H), 2.64 (s, 3H), 1.86-2.13 (m, 7H), 1.30-1.36 (m, 2H). ESI- MS m/z: 666.15 (M+H). Representative procedure for synthesis of compound C-216
Figure imgf000223_0001
[00219] To a solution of tert-butyl ethyl malonate (37.64 g, 200 mmol) in DMSO (100 mL) was added NaH (8 g, 200 mmol) at 0 oC. The reaction was stirred at room temperature for 0.5 hour before 5-bromo-2-nitropyridine (20.3 g, 100 mmol) was added. The reaction was stirred at 80 oC for 5h.100 mL of saturated NH3Cl aqueous solution was added and 1000 mL of ethyl acetate was added. The organic solution was washed with H2O, brine and dried over Na2SO4. Solvent was evaporated to give 1-(tert-butyl) 3-ethyl 2-(6-nitropyridin-3-yl)malonate as a solid (23 mg, yield: 74%).
ESI-MSm/z: 310.33 (M+H).
Figure imgf000223_0002
[00220] A solution of 1-(tert-butyl) 3-ethyl 2-(6-nitropyridin-3-yl)malonate (23 g, 74.2 mmol) in 40 mL of TFA was stirred at room temperature for 1 hour. Then the reaction was concentrated and 500 mL of ethyl acetate was added. Then, the solution was washed with NaHCO3 and H2O and brine and died over Na2SO4.The solution was filtered and concentrated. The residue was purified by silica gel column chromatography (eluted 20% ethyl acetate in PE) to give ethyl 2-(6- nitropyridin-3-yl)acetate as a solid (14.9 g, yield: 95%). ESI-MSm/z: 210.19 (M+H).
Figure imgf000223_0003
[00221] To a solution of ethyl 2-(6-nitropyridin-3-yl)acetate (14.9 g, 70.9 mmol) in 50 mL of EtOH was added catalytical amount of Pd/C. The reaction mixture was stirred at room
temperature for 4 hours under H2. TLC showed the reaction was completed. Then the reaction was filtered and concentrated to give ethyl 2-(6-aminopyridin-3-yl)acetate as a solid (12.5 g, yield: 98%).
ESI-MSm/z :180.23 (M+H).
Figure imgf000224_0001
[00222] To a mixture of ethyl 2-(6-aminopyridin-3-yl)acetate (12.5 g, 69.4 mmol) in 50 mL of CHCl3 were added Et3N (19.07 g, 189 mmol) and TrtCl (24.1 g, 86.7 mmol) at room
temperature. The reaction mixture was stirred at the same temperature overnight. TLC test showed that the reaction was completed. Then the reaction mixture was concentrated and the resulting residue was purified by silica gel column chromatography (eluted 20% ethyl acetate in PE) to give ethyl 2-(6-(tritylamino)pyridin-3-yl)acetate as a solid (25.6 g, yield: 87%). ESI- MSm/z: 422.57 (M+H).
Figure imgf000224_0002
[00223] A mixture of ethyl 2-(6-(tritylamino)pyridin-3-yl)acetate (6 g, 14.2 mmol), K2CO3 (3.92 g, 28.4 mmol), Benzyltriethylammonium chloride (0.324 g, 1.42 mmol) in 30 mL of toluene was degassed and then paraformaldehyde (2.56 g, 85.3 mol) was added in portions to the mixture. The reaction mixture was heated with stirring at 80 °C overnight. The resulting mixture was cooled to room temperature and solvent was removed. The residue was dissolved in ice- water (100 mL), and extracted with ethyl acetate (50 mL x 2). The combined organic layer was washed with brine (50 mL), dried over sodium sulphate and concentrated in vacuo. The residue was purified by flash column (eluted with 20% ethyl acetate in PE) to afford 2.3 g of ethyl 2-(6- (tritylamino)pyridin-3-yl)acrylate as a white solid (yield: 37%). ESI-MSm/z: 434.48 (M+H).
Figure imgf000225_0001
[00224] To a solution of trimethyl sulfoxide chloride (221 mg, 1.728 mmol) in THF (20 mL) was added potassium tert-butylate (194 mg, 1.728 mmol) at 0 oC. The reaction was stirred at room temperature for 1 hour. Then a solution of ethyl 2-(6-(tritylamino)pyridin-3-yl)acrylate in 5 mL of THF was added. The reaction mixture was stirred at room temperature for 0.5 hour. The reaction was concentrated and the residue was purified by silica gel column chromatography (eluted 20% ethyl acetate in PE) to give ethyl 1-(6-(tritylamino)pyridin-3-yl)cyclopropane-1- carboxylate as a solid (493mg, yield: 95%). ESI-MSm/z: 448.58 (M+H).
Figure imgf000225_0002
[00225] To a solution of ethyl 1-(6-(tritylamino)pyridin-3-yl)cyclopropane-1-carboxylate (493 mg, 1.1 mmol) in 20 mL of THF was added LiAlH4 (125 mg, 3.3 mmol) at 0 oC. The reaction was stirred at the same temperature for 1 hour before 0.12 ml of H2O, 0.12 mL of 15% NaOH, 0.36 mL H2O were added sequentially. The mixture was stirred at room temperature for 1 hour. The mixture was filtered and the organic solution was concentrated. The resulting residue was purified by silica gel column chromatography (eluted with 50% ethyl acetate in PE) to give (1- (6-(tritylamino) pyridin-3-yl)cyclopropyl)methanol as a solid (411mg, yield: 92%). ESI-MSm/z: 406.52 (M+H).
Figure imgf000225_0003
[00226] To a solution of (1-(6-(tritylamino)pyridin-3-yl)cyclopropyl)methanol (411 mg, 1.01 mmol) and Et3N (351 mg, 3.47 mmol) in 20 mL of DCM was added MsCl (297 mg, 2.605 mmol) at 0 oC. The reaction was stirred at room temperature for 1 hour. TLC test showed that the reaction was completed. The reaction mxiture was washed with H2O and brine, dried over sodium sulphate, and concentrated in vacuo to afford 332m g of (1-(6-(tritylamino)pyridin-3- yl)cyclopropyl)methyl methanesulfonate as a white solid (yield: 68%). ESI- MSm/z :484.63 (M+H).
Figure imgf000226_0001
[00227] A mixture of (1-(6-(tritylamino)pyridin-3-yl)cyclopropyl)methyl methanesulfonate (332 mg, 0.686 mmol), Cs2CO3 (279 mg, 0.857 mmol), 5-formyl-4-methyl-1H-indole-2- carbonitrile (63 mg, 0.343 mmol) in 30 mL of DMF was stirred at 60 °C for 3 hours. 200 mL of ethyl acetate was added into the resulting mixture after cooling to room temperature. The combined organic layer was washed with H2O and brine, dried over sodium sulphate, and concentrated. The residue was purified by flash column (eluted with 30% ethyl acetate in PE) to afford 103mg of 5-formyl-4-methyl-1-((1-(6-(tritylamino)pyridin-3-yl)cyclopropyl)methyl) -1H- indole-2-carbonitrile as a white solid (yield: 26%). ESI-MSm/z: 572.71 (M+H).
Figure imgf000226_0002
[00228] A mixture of 5-formyl-4-methyl-1-((1-(6-(tritylamino)pyridin-3-yl)cyclopropyl) methyl)-1H-indole-2-carbonitrile (103 mg, 0.18 mmol), N-(piperidin-4-yl)-6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidin-4-amine (85 mg, 0.27 mmol) and Et3N (109 mg, 1.08 mmol) in 20 mL of DCM was stirred at room temperature for 1 hour before NaBH(OAc)3 (229 mg, 1.08 mmol) was added under ice bath cooling. The mixture reaction was then stirred at room temperature overnight. Solvent was removed under vacuum and the residue was purified by silica gel column chromatography (eluted with 2.5% MeOH in dichloromethane) to give 4- methyl-5-((4-((6-(2,2,2-trifluoroethyl) thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1- yl)methyl)-1-((1-(6-(tritylamino)pyridin-3-yl)cyclopropyl)methyl)-1H-indole-2-carbonitrile as an oil (81 mg, yield: 52%). ESI-MSm/z :873.04 (M+H).
Figure imgf000227_0001
[00229] A solution of 4-methyl-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl) amino)piperidin-1-yl)methyl)-1-((1-(6-(tritylamino)pyridin-3-yl)cyclopropyl)methyl)-1H-indole- 2-carbonitrile (81 mg, 0.093 mmol) in TFA (15 mL) was stirred at room temperature for 2 hours. TFA was removed and 10 mL of 7N NH3 in MeOH was added. The resulting mixture was concentrated and residue was purified by silica gel column chromatography (eluted with 10% MeOH in dichloromethane) to give 1-((1-(6-aminopyridin-3-yl)cyclopropyl)methyl)-4-methyl-5- ((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H- indole-2-carbonitrile as an oil (57 mg, yield: 99%). ESI-MSm/z: 630.75 (M+H).
Figure imgf000227_0002
[00230] To a mixture of 1-((1-(6-aminopyridin-3-yl)cyclopropyl)methyl)-4-methyl -5-((4-((6- (2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2- carbonitrile (57 mg, 0.09 mmol) and Et3N (4 mg, 0.181 mmol) in 10 mL of DCM was add slowly acryloyl chloride (8 mg, 0.09 mmol) at -78oC under N2. The reaction mixture was stirred at room temperature for 2 hours before NH3.MeOH was added. Solvent was removed and the residue was purified by silica gel column chromatography (eluted with 10% MeOH in dichloromethane) to give Compound 216 as a solid (12 mg, yield: 21 %).1H NMR (400
MHz, DMSO) δ:10.78 (s, 1H) , 8.50 (s, 1H), 8.34 (s, 1H), 8.17 (d, J = 9.2 Hz, 1H), 7.98~7.91 (m, 2H), 7.72~7.70 (m, 2H), 7.47 (br, 1H), 6.62~6.55 (m, 1H), 6.29 (dd, J = 1.6, 17.2 Hz, 1H), 5.77 (dd, J = 2.0, 10.4 Hz,, 1H), 4.28~4.31 (m, 2H), 4.00~4.10 (m, 3H), 3.17~3.23 (m, 5H), 2.59 (s, 3H), 2.02~2.07 (m, 4H), 1.92 (m, 2H), 1.18~1.23 (m, 3H), 0.81~0.85 (m, 1H). ESI- MSm/z: 685.78 (M+H). Characterization of compounds 110 and 112
Compound 110:
Figure imgf000228_0001
[00231] 1H NMR (600 MHz, CD3OD): 8.38 (s, 1H), 7.54 (m, 2H), 7.42 (m, 2H), 7.36 (s, 1H), 7.21 (m, 2H), 6.38 (m, 1H), 6.30 (m, 1H), 5.66 (m, 1H), 5.05 (s, 1H), 4.5 (m, 4H), 3.88 (m, 2H), 3.59 (m, 2H), 2.67 (s, 3H), 2.35 (m, 2H), 1.95 (m, 2H).13C NMR (150 MHz, CD3OD): 166.0, 157.7, 139.6, 139.5, 138.9, 134.6, 132.4, 130.3, 130.1, 128.5, 127.9, 127.8, 126.5 (q, J = 277 Hz), 121.7, 121.1, 120.7, 118.2, 114.3, 113.5, 112.4, 111.1, 73.5, 59.0, 53.9, 52.9, 47.2, 35.7 (q, J = 32 Hz), 30.8, 30.0, 15.7. HRMS (ESI): M + H+ calculated 674.2520; found 674.2522.
Compound 112:
Figure imgf000228_0002
[00232] 1H NMR (600 MHz, CD3OD): 8.30 (s, 1H), 8.06 (m, 2H), 7.60 (m, 1H), 7.52 (s, 1H), 7.29 (m, 2H), 7.19 (d, J = 8.80 Hz.1H), 6.45 (m, 1H), 6.34 (d, J = 17.24 Hz, 1H), 5.69 (d, J = 11.7 Hz), 5.10 (t, J = 5.10 Hz, 2H), 4.55 (m, 1H), 4.45 (m, 1H), 4.15 (m, 1H), 3.84 (q, J = 10.5 Hz, 2H), 3.64 (s, 2H), 2.97 (m, 2H), 2.55 (s, 3H), 2.25 (m, 2H), 2.01 (m, 2H), 1.66 (m, 2H).13C NMR (150 MHz, CD3OD): 166.7, 166.1, 157.8, 155.0, 152.8, 147.2, 138.6, 137.4, 134.8, 132.2, 130.30, 129.5, 128.7, 128.5, 126.7 (q, J = 277 Hz), 121.9, 118.1, 115.3, 114.7, 113.1, 111.0, 109.4, 71.4, 60.8, 53.8, 53.4, 35.6, (q, J = 32 Hz), 32.4, 30.7, 15.3. HRMS (ESI): M + H+ calculated 674.2472; found 675.2478. [0233] Table 9
Figure imgf000229_0001
Figure imgf000230_0001
[0236] Table 10
Figure imgf000231_0001
[0237] General Synthesis Route: C
[0238] Compounds including, but not limited to, II-3, II-4, II-7, II-10, II-14, II-15, II-16, II-17, and II-18 can be synthesized using a procedure similar to general synthesis route: C.
Figure imgf000232_0001
[0239] A solution of II-14-1 (2.24 g) and triphosgene (1.80 g) in 50 ml dioxane was refluxed overnight. The reaction mixture was concentrated to give II-14-2 crude (3.0 g, 100%), which was used in the next step without further purification.
Figure imgf000233_0001
[0240] To a solution of II-14-2 crude (1.0 g) in POCl3 (25 ml) was added PCl5 (1.7 g). The reaction mixture was refluxed overnight. The reaction mixture was cool to room temperature and concentrated. The residue was diluted with DCM before ice-water was slowly added. The mixture was extracted with DCM for three times and the organic solution was washed with saturated NaHCO3, dried and concentrated. The obtained II-14-3 crude was used in the next step without further purifications.
Figure imgf000233_0002
[0241] A solution of II-14-3 (750 mg), tert-butyl 4-aminopiperidine-1-carboxylate (680 mg) and DIEA (680 mg) in 20 ml THF was refluxed overnight. The reaction mixture was poured into water and extracted with EtOAc. The combined organics solution was dried and concentrated. The residue was purified by chromatography (PE/EA = 5:1) to give II-14-4 (500 mg, 42%).
Figure imgf000233_0003
[0242] A solution of II-14-4 (450 mg), Zn(CN)2 (80 mg), DPPF (100 mg), Pd2(dba)3 (100 mg) and Zn (13 mg) in 20 mL of NMP was heated to 100 oC overnight. The reaction mixture was poured into water and extracted with EtOAc. The combined organics solution was dried and concentrated. The residue was purified by chromatography (PE/EA = 3:1) to give II-14-5 (200 mg, 45%).
Figure imgf000234_0001
5 6
[0243] A solution of II-14-5 (100 mg) in 6 ml of 1:1 TFA/DCM co-solvent was stirred at room temperature for 2 hours. Solvent was removed and the residue was diluted with NH3/MeOH. The obtained mixture was concentrated to give 120 mg of II-14-6 crude, which was used without further purifications.
Figure imgf000234_0002
6 II 14 7
[0244] A solution of II-14-6 crude (77 mg), 5-formyl-4-methyl-1- ((1-trityl-1H-pyrazol-4- yl)methyl)-1H-indole-2-carbonitrile (137 mg), NaBH(OAc)3 (290 mg) and TEA (140 mg) in 10 ml of DCM was stirred at room temperature overnight. The reaction mixture was diluted with DCM. The organic solution was washed with water and brine, dried and concentrated. The residue was purified by chromatography (DCM/MeOH = 50:1) to give II-14-7 (60 mg, 32%).
Figure imgf000234_0003
[0245] A solution of II-14-7 (60 mg) in 6 mL of 1:1 TFA/DCM was stirred at room temperature for 2 hours. Solvent was removed and the residue was diluted with NH3/MeOH. The obtained mixture was concentrated and the residue was purified by chromatography (DCM/MeOH = 20:1) to give II-14 (25mg, 59%). ESI-MS m/z: 590 (M+H).1H NMR (400 MHz, DMSO) 12.83 (s, 1H), 8.40 (d, J = 7.2 Hz, 1H) , 7.75 (m, 2H) 757 (m 2H) 7.45 (s, 1H), 7.30 (d, J = 8.8 Hz, 1H), 5.39 (s, 2H), 4.18 (m, 2H), 4.07 (m,1 H), 3.55 (s, 2H), 2.83 (m, 2H), 2.50 (s, 3H), 2.12 (m, 2H), 1.88 (m, 2H), 1.56 (m, 2H).
Figure imgf000235_0001
[0247] Table 11: IC50 values for Table 10 inhibitors of menin
Figure imgf000235_0002
[0248] Table 12
Figure imgf000236_0002
[0249] Table 13: IC50 values for Table 12 inhibitors of menin
Figure imgf000236_0003
[0250] General Synthesis Route: B
[0251] Compounds including, but not limited to, III-3, IV-2, IV-8, IV-9, V-13, and V-15 can be synthesized using a procedure similar to general synthesis route: B.
[0252] Synthesis of compound III-3
Figure imgf000236_0001
Figure imgf000237_0001
[0253] To a solution of III-3-1 (750 mg, 3.2 mmol) in DCM (20 mL) were added
phenylmethanamine (440 mg, 4.1mmol) and NaBH(OAc)3 (298 mg, 15.0 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was treated with saturated NaHCO3, extracted with DCM. The combined organic extracts were dried over Na2SO4 and concentrated. The residue was purified by silica gel column (PE/EA= 5:1) to give III-3-2 (500 mg, yield: 48%) as a colorless oil. ESI-MS m/z :327(M+H).
Figure imgf000237_0002
[0254] A mixture of III-3-2 (500 mg, 1.53 mmol) and wet Pd/C (10%) in MeOH (10 mL) was stirred under H2 atmosphere at room temperature overnight. The reaction mixture was filtered over celite and the cake was washed with MeOH and ethyl acetate. The filtrate was concentrated to give III-3-3 (334 mg, yield: 92%) as a colorless oil. ESI-MS m/z: 181 (M-56+H).
Figure imgf000238_0001
III-3-3 III-3-4
[0255] A mixture of III-3-3 (360 mg, 1.42 mmol), tert-butyl 4-amino-3,3-difluoropiperidine-1- carboxylate (334 mg, 1.42 mmol) in isopropanol (10 ml) was stirred at reflux overnight. The reaction mixture was concentrated and the residue was purified by silica gel column (PE/EA = 2:1) to give III-3-4 (110 mg, yield: 17%). ESI-MS m/z :453 (M+H).
Figure imgf000238_0002
III-3-4 III-3-5
[0256] The mixture of III-3-4 (110 mg, 0.24 mmol), in HCl/MeOH (4N) (10 mL) was stirred at room temperature for 2 hours. The mixture was concentrated to give 100 mg of III-3-5
hydrochloride crude as a white solid. ESI-MS m/z :353 (M+H).
Figure imgf000238_0003
III-3-5 III-3
[0257] A mixture of III-3-5 hydrochloride crude (100 mg, 0.24 mmol), 5-formyl-4-methyl-1H- indole-2-carbonitrile (87 mg, 0.48 mmol), TEA (0.20 ml, 1.44 mmol), NaBH(OAc)3 (300 mg, 1.44 mmol) in DCM (15 mL) was stirred at room temperature overnight. The reaction mixture was diluted with DCM and washed with brine. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column (PE/EA = 2:1) to give III-3 (17 mg, yield: 14%). ESI-MS m/z:521 (M+H).1H NMR (400 MHz, CDCl3) δ: 8.78 (br, 1H), 8.51 (s,1H), 7.33 (d, 1H), 7.25 (d, 1H), 7.14 (s, 1H), 5.31(d, 1H), 4.76-4.90 (m, 1H), 3.52-3.77 (m, 4H), 3.20-3.26 (m, 1H), 2.95-3.02 (m, 3H), 2.59 (s, 3H), 2.33-2.53 (m, 2H), 2.13-2.17 (m, 1H), 1.77-1.81 (m, 1H). [0258] Table 14
Figure imgf000239_0003
[0259] Table 15: IC50 values for Table 14 inhibitors of menin
Figure imgf000239_0002
[0260] Synthesis of compound IV-2
Figure imgf000239_0001
Figure imgf000240_0001
Figure imgf000240_0002
Figure imgf000240_0003
[
Figure imgf000241_0001
[0264] Table 17: IC50 values for Table 16 inhibitors of menin
Figure imgf000241_0002
[0265] General Synthesis Route: A
[0266] Compounds including, but not limited to V 1 can be synthesized using a procedure similar to general synthesis route: A.
[0267] Synthesis of compound V-1
Figure imgf000242_0001
[0268] A mixture of V-1-1 (250 mg, 1.0 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (250 mg, 1.2 mmol), KF (298 mg, 15.0 mmol) in DMSO (15 mL) was stirred at 100 oC overnight. Water was added, and the reaction mixture was extracted with ethyl acetate. The organic layer was concentrated and the residue was purified by silica gel column (PE/EA = 3:1) to give V-1-2 (130 mg, yield: 31%) as a colorless oil. ESI-MS m/z :418 (M+H).
Figure imgf000243_0001
V-1-2 V-1-3
[0269] A mixture of V-1-2 (130 mg, 0.31mmol) in HCl/MeOH (10 mL) was stirred at room temperature for 1 hour. The mixture was concentrated to give V-1-3 hydrochloride crude (98 mg, yield: 89%) as a white solid. ESI-MS m/z: 318 (M+H).
Figure imgf000243_0002
V-1-3 V-1
[0270] A mixture of V-1-3 hydrochloride crude (98 mg, 0.28 mmol), 5-formyl-4-methyl-1H- indole-2-carbonitrile (86 mg, 0.42 mmol), TEA (0.26 ml, 1.68 mmol), NaBH(OAc)3 (394 mg, 1.68 mmol) in DCM (150 mL) was stirred at room temperature overnight. The reaction mixture was diluted with DCM and washed with brine. The organic solution was dried over Na2SO4 and concentrated. The residue was purified by silica gel column (DCM/MeOH = 30:1) to give V-1 (10 mg, yield: 7.5%). ESI-MS m/z:486 (M+H).1H NMR (400 MHz, CDCl3) δ: 8.82 (br, 1H), 7.62 (s, 1H), 7.38 (d, 1H), 7.32 (s, 1H), 7.27 (s, 1H), 7.22 (d, 1H), 5.39-5.41 (m, 1H), 3.65-3.74 (m, 4H), 2.78-2.86 (m, 2H), 2.59 (s, 3H), 2.37-2.48 (m, 5H), 2.08-2.14 (m, 2H), 1.86-1.96 (m, 2H).
[0271] General Synthesis Route: D
[0272] Compounds including, but not limited to, V-3 can be synthesized using a procedure similar to general synthesis route: D.
[0273] Synthesis of compound V-3
Figure imgf000243_0003
Figure imgf000244_0001
[0274] A mixture of V-1-1 (125 mg, 0.5 mmol), Zn(CN)2 (60 mg, 0.5 mmol), Pd2(dba)3 (5 mg, 0.005 mmol), Zn (3 mg, 0.05 mmol) and Pd(dppf)Cl2 (4 mg, 0.005 mmol) in NMP (5 ml) was stirred at 130 oC under N2 for 10 hours. TLC showed that the reaction was complete. The reaction mixture was partitioned between EA and H2O, and the organic layer was washed by brine, dired over Na2SO4. Solvent was removed under vacuum and the residue was purified by silica gel column chromatography (PE/EA = 5:1~1:1) to give V-3-1 (60 mg, yield: 49%).
Figure imgf000244_0002
3
[0275] A suspension of V-3-1 (500 mg, 2 mmol) in 20 mL of about 10 N H2SO4 aqueous solution was stirred at 100 oC for 6 hours. TLC showed that the reaction was complete. The reaction mixture was extracted by EA, dired over Na2SO4. Solvent was removed under vacuum to V-3-2 crude as a brown solid (200 mg, 40%), which was used in next step without further purifications.
Figure imgf000244_0003
[0276] To a solution of V-3-2 crude (400 mg, 1.53 mmol) in DCM (20 mL) was added (COCl)2 (194 mg, 1.53 mmol) and one drop of DMF. The reaction was stirred at room temperature for 10 hours. Solvent was removed to give V-3-3 chloride crude, which was used in next step without further purifications.
[0277] To a solution of tert-butyl piperazine-1-carboxylate (854 mg, 4.6mmol) and TEA (929 mg, 9.2 mmol) in DCM (20ml) was added the solution of V-3-3 chloride crude in DCM (20 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction was diluted with DCM and washed with NaHCO3 and brine. The solution was dried over Na2SO4 and
concentrated. The residue was purified by silica gel column chromatography (PE/EA = 3:1~1:1) to give V-3-4 as a solid (300 mg, yield: 46%, 2 steps).
Figure imgf000245_0001
V-3-4 V-3-5
[0278] A solution of V-3-4 (120 mg, 0.3 mmol) in HCl/MeOH (8 ml) was stirred at room temperature for 2 hours. Solvent was removed under vacuum and the residue was diluted with DCM and washed with NaHCO3. The organic solution was washed with brine, dired over Na2SO4 and concentrated to give V-3-5 crude as a yellow oil (120 mg).
Figure imgf000245_0002
V-3-5 V-3
[0279] A mixture of V-3-5 crude (120 mg, 0.3 mmol), 5-formyl-4-methyl -1H-indole-2- carbonitrile (130 mg, 0.6 mmol), and TEA (300 mg, 3 mmol) in DCM (20 mL) was stirred at room temperature for 1 hour before NaBH(OAc)3 (0.5 g, 1.8 mmol) was added. The mixture reaction was stirred at room temperature overnight. The reaction mixture was partitioned between DCM and NaHCO3. The organic solution was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-TLC (DCM:MeOH = 20:1) to give V-3 as a yellow solid (20 mg, yield: 19%). ESI-MS H).1H NMR (400 MHz, CDCl3) 9.22 (br, 1H), 9.10 (s, 1H), 7.74 (s, 1H), 7.29 (s, 1H), 7.24 (s, 1H), 7.18 (m,1H), 3.88(m, 2H), 3.76 (m, 2H), 3.65 (s, 2H), 3.50 (m, 2H), 2.64 (m, 2H), 2.57 (s, 3H), 2.50 (m, 2H).
[0280] Table 18
Figure imgf000246_0001
Figure imgf000247_0001
Figure imgf000248_0002
[0281] Table 19: IC50 values for Table 18 inhibitors of menin
Figure imgf000248_0001
[0282] Synthesis of Compounds D-13 and D-3.
Figure imgf000249_0001
[0283] Step A: Preparation of Compound 3-2: To a solution of 3-1 (6 g, 25 mmol) in THF (100 mL) was added LiAlH4 (1.5 g, 37 mol) in small portions at 0 °C. The reaction was stirred until the TLC showed that the reaction was complete (about 2h). The reaction mixture was quenched by addition of EtOAc and partitioned between EtOAc and H2O. The organic layer was washed with brine and dried over Na2SO4. Solvent was removed under vacuum to give 3-2 as a yellow solid (5.2 g, yield: 97%).
[0284] Step B: Preparation of Compound 3-4: To a solution of 3-2 (800 mg, 3.7 mmol) and Et3N (740 mg, 7.4 mmol) in CH2Cl2 (10 mL) was added MsCl (428 mg, 4.4 mmol) at 0 °C. The reaction was stirred at room temperature for 30 min, then quenched by addition of NaHCO3, washed with brine and dried over Na2SO4. Solvent was removed under vacuum to give 3-3, which was used in the next step without further purification.
[0285] To a mixture of Cs2CO3 (3.0 g, 9.3 mmol) and 5-formyl-4-methyl-1H-indole-2- carbonitrile (800 mg, 4.4 mmol) in DMF (10 mL) was added 3-3 in DMF. The reaction mixture was stirred at 100 °C for 10h. The reaction mixture was then partitioned between EtOAc and H2O. The organic layer was washed with brine and dried over Na2SO4. Solvent was removed under vacuum and the residue purified by silica gel column chromatography (pet. ether/EtOAc = 5:1~3:1) to give 3-4 as a yellow solid (600 mg, yield: 42% according to alcohol).
[0286] Step C: Preparation of Compound 3-5: A mixture of 3-4 (2.2 g, 5.8 mmol), 6-(2,2,2- trifluoroethyl)-N-(piperidin-4-yl)thieno-[2, amine (2.3 g, 6.9 mmol) and Et3N (3.5 g, 34 mmol) in CH2Cl2 (50 mL) was stirred at room temperature for 1 hour before NaBH(OAc)3 (7.3 g, 34 mmol) was added to the reaction. The reaction mixture was stirred at room temperature overnight. The reaction mixture was then partitioned between CH2Cl2 and NaHCO3. The organic layer was washed with brine and dried over Na2SO4. Solvent was removed under vacuum and the residue was purified by silica gel column chromatography
(CH2Cl2:MeOH=50:1~20:1) to give 3-5 as a yellow solid (3.9 g, yield: 98%).
[0287] Step D: Preparation of Compound 13: To a solution 3-5 (3.9 g, 5.7 mmol) in CH2Cl2 (30 mL) was added TFA (20 mL). The reaction mixture was stirred for 4h at room temperature. Solvent was removed under vacuum to afford a residue, which was diluted with CH2Cl2 and washed with NaHCO3. The organic layer was washed with brine and dried over Na2SO4. Solvent was removed under vacuum and the residue was purified by silica gel column chromatography (CH2Cl2:MeOH=10:1) to give compound 13 as a white foam (2.6 g, yield: 79%).
[0288] Step E: Preparation of Compound 3: To a solution of propionic acid (450 mg, 6.0 mmol), BOP (3.0 g, 6.9 mmol) and iPr2NEt (3.0 g, 23 mmol) in CH2Cl2 (30 mL) was added compound 13 (2.7 g, 4.6 mmol). The reaction mixture was stirred at room temperature for 30 min before it was quenched by NaHCO3, washed with brine and dried over Na2SO4. Solvent was removed and the residue purified by silica gel column chromatography (CH2Cl2:MeOH=10:1) to afford compound 3 (1.8 g, yield: 61%).1H NMR (400 MHz, CDCl3): 8.49(s, 1H),7.34(d, 1H), 7.21 (s, 1H), 7.11 (d, 1H), 7.08 (s, 1H), 5.78 (s,1H),5.07 (d,1H), 4.45 (s,2H), 4.25 (m, 1H), 3.61-3.70 (m, 4H), 2.93(m, 2H), 2.57(s, 3H), 2.33-2.20(m, 2H), 2.00-2.13 (m, 2H), 2.02 (s, 6H), 1.90 (s, 3H), 1.50-1.70 (m,2H).
-
Figure imgf000250_0001
[0290] Step A: Preparation of Compound 29-2: To a solution of 29-1 (200 mg, 1.0 mmol) and Et3N (202 mg, 2.0 mmol) in CH2Cl2 (10 mL) was added MsCl (172 mg, 1.5 mmol) at 0 °C. The reaction mixture was stirred at room temperature overnight before water was added to the reaction. The solution mixture was extracted with CH2Cl23 times. The organic layer was washed with brine and dried over Na2SO4. The solution was filtered and concentrated to give 29-2 as a white solid (250 mg, yield: 90%).
[0291] Step B: Preparation of Compound 29-3: A mixture of 29-2 (250 mg, 0.9 mmol), 5- formyl-4-methyl-1H-indole-2-carbonitrile (82 mg, 0.45 mmol) and Cs2CO3 (438 mg, 1.35mmol) in DMF (6 mL) was stirred at 60 °C for 6 hours before water (15 mL) was added. The reaction mixture was extracted with ethyl acetate (20 mL x 3). The combined organic solution was washed with brine and dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (33% EtOAc in pet. ether to 50% EtOAc in pet. ether) to give 29-3 as a yellow solid (110 mg, yield: 33%).
[0292] Step C: Preparation of Compound 29-4: A mixture of 29-3 (110 mg, 0.3 mmol), 6-(2,2,2- trifluoroethyl)-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine hydrochloride (116 mg, 0.3 mmol) and Et3N (185 mg, 1.8 mmol) in CH2Cl2 (20 mL) was stirred at room temperature for 1 hour before NaBH(OAc)3 (381 mg, 1.8 mmol) was added to the reaction under ice bath. The reaction mixture was stirred at room temperature overnight. Solvent was removed by vacuum and the residue was purified by silica gel column chromatography (2.5% MeOH in CH2Cl2) to give 29-4 as a solid (180 mg, yield: 90%).
[0293] Step D: Preparation of Compound 29-5: A solution of tert-butyl carbamate 29-4 (180 mg, 0.27 mmol) in HCl/MeOH (10 mL) was stirred at room temperature for 2 hours. Solvent was removed and a solution of NH3 (7N) in MeOH (10 mL) was added. The reaction mixture was stirred for 10 minutes before solvent was removed and the residue purified by silica gel column chromatography (10% MeOH in CH2Cl2) to give 29-5 as an oil (100 mg, yield:65%).
[0294] Step E: Preparation of Compound 29: To a mixture of 29-5 (100 mg, 0.17 mmol) and Et3N (27 mg, 0.26 mmol) in CH2Cl2/THF (10 mL, 1:1) was add slowly acryloyl chloride (19 mg, 0.21 mmol) at -78 °C under N2. The mixture was stirred at room temperature for 15 min, then NH3·MeOH was added. Solvent was removed and the residue was purified by silica gel column chromatography (10% MeOH in CH2Cl2) to give final product 29 as a solid (78 mg, yield: 71 %).1H NMR (400 MHz, DMSO): δ:8.32 (s, 1H) , 7.81~7.80(d, 1H),7.64 (s, 1H), 7.55(s, 1H), 7.39 (s, 1H), 7.34~7.32 (m, 2H), 6.16~6.01 (m, 2H), 5.57~6.54 (m, 1H), 4.33~4.31 (d,
2H),4.09~4.00 (m, 4H), 3.68 (s, 3H), 2.86~2.85 (m, 2H), 2.45~2.41 (m, 1H), 2.26~2.24 (m, 2H), 2.10 (brs, 2H), 1.99 (s, 1H), 1.89 (brs, 2H), 1.75~1.67 (m, 2H), 1.57(brs, 2H); ESI-MS m/z: 622.40 (M+H). [0295] Synthesis of Compound D-10.
Figure imgf000252_0001
[0296] Step A: Preparation of Compound 10-1: To a solution of 3-1 (300 mg, 1.24 mmol) in DMF (15mL) was added NaH (210 mg, 2.5 mmol) at 0 °C. The reaction mixture was stirred at the same temperature for 20 min before iodomethane (50 mg, 2.5 mmol) was added. The resulting mixture was stirred at room temperature for 3h before water was added. The reaction mixture was extracted with ethyl acetate. The combined organic layer was concentrated to dryness. The residue was purified by silica gel column (pet. ether/EtOAc=5:1) to give 10-1 (310 mg, yield: 97%) as a colorless oil.
[0297] Step B: Preparation of Compound 10-2: To a mixture of methyl ester 10-1 (310 mg, 1.21 mmol) in THF (10 mL) was slowly added LiAlH4 at 0 °C. The reaction mixture was stirred at room temperature for 1h before water (0.2 mL) was added, followed by EtOAc. The reaction mixture was filtered and concentrated to dryness. The residue was purified by silica gel column (pet. ether/EtOAc=3:1) to give 10-2 (237 mg, yield: 86%).
[0298] Step C: Preparation of Compound 10-3: To a solution of 10-2 (230 mg, 1.01 mmol) in CH2Cl2 was added Et3N (0.42 mL, 3.03 mmol) at 0 °C, followed by methanesulfonyl chloride (231 mg, 2.02 mmol). The resulting mixture was stirred at room temperature for 1h. CH2Cl2 was added, the mixture was washed with NaHCO3, and the organic layer was washed with brine and dried over Na2SO4. Solvent was removed to give 10-3 (330 mg) as a brown oil.
[0299] Step D: Preparation of Compound 10-4: A mixture of crude 10-3 (330 mg), 5-formyl-4- methyl-1H-indole-2-carbonitrile (200 mg, 1.08 mmol), and Cs2CO3 (1 g, 3.24 mmol) in DMF (10 mL) was stirred at 100 °C overnight. Water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated to dryness. The residue was purified by silica gel column (pet. ether/EtOAc=4:1) to give 10-4 (177 mg, yield: 41%). ESI-MS m/z: 394 (M+H).
[0300] Step E: Preparation of Compound 10-5: A mixture of 10-4 (177 mg, 0.45 mmol), N- (piperidin-4-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-amine hydrochloride (238 mg, 0.68 mmol), Et3N (0.2 mL, 1.3 mmol), and CH2Cl2 was stirred at room temperature overnight. The reaction mixture was diluted with CH2Cl2, washed with brine, and concentrated. The residue was purified by silica gel column (CH2Cl2/MeOH = 30:1) to give 10-5 (210 mg, yield: 67%). ESI-MS m/z: 694 (M+H).
[0301] Step F: Preparation of Compound 10: A solution of 10-5 (100 mg, 0.14 mmol), TFA (1 mL) in CH2Cl2 (5 mL) was stirred at room temperature for 3h. The mixture was concentrated and the residue dissolved in CH2Cl2, washed with NaHCO3, dried over Na2SO4, and concentrated. The residue was purified by silica gel column (CH2Cl2/MeOH = 30:1) to give 10 (50 mg, yield: 58%). ESI-MS m/z: 594 (M+H).1H NMR (400 MHz, CDCl3) δ: 8.48(s, 1H), 7.38(d,1H), 7.22(s, 1H), 71.5 (s, 1H), 7.13(s,1H), 5.23(brs,1H),4.46 (s,2H), 4.26-4.28(m, 1H), 3.62-3.69(m, 4H), 2.97(d, 2H), 2.63(s,3H),2.31-2.37(m,5H), 2.08-2.14(m, 2H),1.65-1.73(m,8H).
Figure imgf000253_0001
[0303] Step A: Preparation of Compound 12-1: A mixture of 3-3 and Bu4CN (3.5 g, 13 mmol) in CH3CN (30 mL) was stirred under reflux for 10 h until TLC showed that the reaction was complete. Solvent was removed and the residue was purified by silica gel column
chromatography (pet. ether/EtOAc = 3:1) to give 12-1 as a white solid (1.0 g, yield: 86% according to alcohol).
[0304] Step B: Preparation of Compound 12-2: To a solution of 12-1 (460 mg, 2 mmol) in CH2Cl2 was added DIBAL-H (6 mmol) dropwise at -78 °C and the reaction mixture stirred at the same temperature for 2 h. The reaction was quenched with NH4Cl and dried over Na2SO4.
Solvent was removed under vacuum and the residue was purified by silica gel column
chromatography (pet. ether/EtOAc = 5:1~3:1) to give 12-2 as a white solid (200 mg, yield: 44%).
[0305] Step C: Preparation of Compound 12-3: To a solution of 12-2 (200 mg, 1 mmol) in THF was added BH3/THF (4 mmol) dropwise at -78 °C. The reaction was stirred for 10 h before it was quenched by MeOH. Solvent was removed under vacuum to give 12-3 as a white solid (200 mg, yield: 99%), used in the next step without further purifications.
[0306] Step D: Preparation of Compound 12-5: To a solution of 12-3 (120 mg, 0.54 mmol) and Et3N (109 mg, 1.0 mmol) in CH2Cl2 (10 mL) was added MsCl (73 mg, 0.63 mmol) at 0 °C. The reaction was stirred at room temperature for 30 min. The reaction was quenched by NaHCO3, washed with brine and dried over Na2SO4. Solvent was removed under vacuum to give crude 12- 4, used in the next step without further purification.
[0307] To a mixture of Cs2CO3 (400 mg, 1.2 mmol) and 5-formyl-4-methyl-1H-indole-2- carbonitrile (70 mg, 0.3 mmol) in DMF (10 mL) was added 12-4 in DMF. The reaction was stirred at 100 °C for 10h. The reaction mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine and dried over Na2SO4. Solvent was removed under vacuum to get a residue, which was purified by silica gel column chromatography (pet.
ether/EtOAc=5:1~3:1) to give 12-5 as a white solid (100 mg, yield: 52% 2 steps).
[0308] Step E: Preparation of Compound 12-6: A mixture of 12-5 (30 mg, 0.1 mmol), 6-(2,2,2- trifluoroethyl)-N-(piperidin-4-yl)thieno-[2,3-d]pyrimidin-4-amine (50 mg, 0.12 mmol) and Et3N (60 mg, 0.6 mmol) in CH2Cl2 (10 mL) was stirred at room temperature for 1 hour before
NaBH(OAc)3 (130 mg, 0.6 mmol) was added. The mixture reaction was stirred at room temperature overnight. The reaction was partitioned between CH2Cl2 and NaHCO3, and the organic layer was washed with brine and dried over Na2SO4. Solvent was removed under vacuum to give a residue, which was purified by silica gel column chromatography
(CH2Cl2:MeOH = 50:1~20:1) to give 12-6 as a yellow solid (40 mg, yield: 60%).
[0309] Step F: Preparation of Compound 11: To a solution of 12-6 (130 mg, 0.19 mmol) in CH2Cl2 (3 mL) was added TFA (2 mL). The reaction was stirred for 4h at room temperature. Solvent was removed under vacuum to give a residue, which was diluted with CH2Cl2 and washed with NaHCO3. The organic layer was washed with brine and dried over Na2SO4. Solvent was removed under vacuum to give compound 11 as a yellow foam (100 mg, crude).
[0310] Step G: Preparation of Compound 12: To a solution of propionic acid (6 mg, 0.07 mmol), BOP (40 g, 0.09 mmol), and iPr2NEt (40 mg, 0.3 mmol) in CH2Cl2 (10 mL) was added compound 11 (35 mg, 0.06 mmol), then the reaction was stirred at room temperature for 30 min. The reaction was quenched by addition of NaHCO3, washed with brine and dried over Na2SO4. Solvent was removed give a residue, which was purified by Prep-TLC (CH2Cl2:MeOH = 10:1) to give 12 (10 mg, yield: 30%).1H NMR (400 MHz, CDCl3) 8.46(s, 1H),7.51(d, 1H), 7.17~7.22 (m, 3H),5.85 (s, 1H), 5.79 (br, 1H), 4.23~4.32(m,3H), 3.86(s,2H), 3.66(q,2H), 3.12(m, 2H), 2.58 (s, 3H), 2.53~2.40 (m, 2H), 2.20~2.14(m, 6H),1.99(s, 6H), 1.86~1.90 (m, 2H), 1.12(t,3H). ESI- MS m/z: 650.25 (M+H). [0311] Synthesis of Compounds D-20 and D-18.
Figure imgf000255_0001
[0312] Step A: Preparation of Compound 18-2: A mixture of 18-1 and Et3N (600 mg, 6 mmol) in CH2Cl2 was stirred at 0 °C before MsCl (460 mg, 4 mmol) was added slowly. The reaction mixture was stirred at 0 °C under N2 for 2 hr. TLC showed that the reaction was complete. The reaction mixture was partitioned between CH2Cl2 and H2O, and the organic layer was washed with brine and dried over Na2SO4. Solvent was removed under vacuum and the resulting compound (18-2) was used without further purification as a light yellow oil (460 mg, yield: 99%).
[0313] Step B: Preparation of Compound 18-3: A mixture of crude 18-2 (460 mg, 2 mmol), 5- formyl-4-methyl-1H-indole-2-carbonitrile (440 mg, 2.4 mmol) and Cs2CO3 (1.3 g, 4 mmol) in DMF (10 mL) was stirred at 60 °C for 4 hours. The reaction was cooled and the solid was removed by filtration. The reaction mixture was partitioned between EtOAc and H2O, and the organic layer was washed by brine and dried over Na2SO4. Solvent was removed under vacuum to give a residue, which was purified by silica gel column chromatography (pet. ether:EtOAc = 10:1~4:1) to give 18-3 as a light yellow solid (280 mg, yield: 43%). ESI-MS m/z: 323 (M+H).
[0314] Step C: Preparation of Compound 18-4: A mixture of 18-3 (280 mg, 0.87 mmol), N- (piperidin-4-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-amine hydrochloride (435 mg, 1.35 mmol) and Et3N (400 mg, 4 mmol) in CH2Cl2 (30 mL) was stirred at room temperature for 2 hours before NaBH(OAc)3 (570 mg, 2.7 mmol) was added with ice bath cooling. The reaction mixture was stirred at room temperature overnight. The reaction was partitioned between CH2Cl2 and NaHCO3, and the organic layer was washed by brine and dried over Na2SO4. Solvent was removed under vacuum to give a residue, which was purified by silica gel column
chromatography (pet. ether:EtOAc = 10:1 ~ 1:1) to give 18-4 as a yellow solid (300 mg, yield: 56%). ESI-MS m/z: 623 (M+H).
[0315] Step D: Preparation of Compound 20: To a solution of 18-4 (180 mg, 0.3 mmol) in water (4 mL) and THF (10 mL) was added LiOH (24 mg, 0.6 mmol). The reaction was stirred at room temperature for 16 h. TLC showed that the reaction was complete. The pH of the mixture was adjusted to pH 4 with HCl (a.q., 1N). The reaction mixture was diluted with EtOAc and the organic layer was dried over Na2SO4. Solvent was removed under vacuum to give compound 20, which was used without further purification as a yellow solid (130 mg, yield: 75%)
[0316] Step E: Preparation of Compound 18: A mixture of crude compound 20 (40 mg, 0.07 mmol), methylamine hydrochloride (30 mg, 0.44 mmol), EDCI (40 mg, 0.28 mmol), HOBT (15 mg, 0.11 mmol) and Et3N (50 mg, 0.5 mmol) in CH2Cl2 (10 mL) was stirred at room temperature for 40 hours. The reaction mixture was partitioned between CH2Cl2 and NaHCO3, and the organic layer was washed by brine and dried over Na2SO4. The solvent was removed under vacuum to give a residue, which was purified by prep-TLC (CH2Cl2:MeOH = 10:1) to provide compound 18 as a white solid (15 mg, yield: 35%).1H NMR (400 MHz, MeOD) 8.31(s, 1H), 7.54(s, 1H), 7.41~7.32(m, 3H), 4.45(s, 2H), 4.24~4.17(m, 1H), 3.89~3.81(m, 2H), 3.74(s, 2H), 3.08~3.05(m, 2H), 2.66(s, 3H), 2.60(s, 3H), 2.40~2.34 (m, 2H), 2.07~2.03 (m, 2H), 1.88(s, 6H), 1.76~1.70 (m, 2H). ESI-MS m/z: 622 (M+H).
[0317] Synthesis of Compounds D-17 and D-33:
Figure imgf000256_0001
[0318] Step A: Preparation of Compound 33-1: A mixture of compound 13 (190 mg, 0.33 mmol), 2-(tert-butoxycarbonyl)acetic acid (79 mg, 0.43 mmol), benzotriazol-1- yloxytris(dimethylamino)-phosphonium hexafluorophosphate (229 mg, 0.5 mmol), and iPr2NEt (0.3 mL,1.65 mmol) in CH2Cl2 (10 mL) was stirred at room temperature for 30 min. Water was added and the resulting mixture was extracted with CH2Cl2. The organic layer was concentrated and the residue was purified by silica gel column (CH2Cl2/MeOH = 20:1) to give 33-1 (210 mg, yield: 87%) as a solid. ESI-MS m/z: 737 (M+H). [0319] Step B: Preparation of Compound 17: A mixture of 33-1 (230 mg, 0.34 mmol) in CH2Cl2 (5 mL) and trifluoroacetic acid (5 mL) was stirred at room temperature for 2h. The reaction mixture was concentrated to dryness and the residue was dissolved in NH3/MeOH (7N). The mixture was concentrated to dryness. The residue was purified by silica gel column to give compound 17 as a yellow solid (210 mg, yield: 83%). ESI-MS m/z: 637 (M+H).
[0320] Step C: Preparation of Compound 33: A mixture of compound 17 (50 mg, 0.08 mmol), formic acid (8 mg, 0.16 mmol), benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (52 mg, 0.12 mmol), and iPr2NEt (0.07 mL, 0.4 mmol) in CH2Cl2 (5 mL) was stirred at room temperature for 30 min. Water was added and the resulting reaction mixture was extracted with CH2Cl2. The organic layer was concentrated and the residue was purified by silica gel column (CH2Cl2/MeOH = 15:1) to give compound 33 as a solid (40 mg, yield: 77%). 1H NMR (400 MHz, CD3OD) δ: 8.30 (s, 1H), 8.09(s,1H), 7.52(s, 1H), 7.30-7.34 (m, 3H), 4.51(s,2H), 4.20(m,1H), 3.67-3.85 (m,6H), 3.07-3.10 (m, 2H), 2.59(s, 3H), 2.34-2.44(m, 2H), 2.05-2.08(m, 2H),1.96(s,6H), 1.62-1.76(m, 2H). ESI-MS m/z: 664 (M+H).
Figure imgf000257_0001
Figure imgf000258_0001
[0322] Table 21: IC50 values for Table 20 inhibitors of menin
Figure imgf000259_0001
[0323] Table 22
Figure imgf000259_0002
Figure imgf000260_0001
Figure imgf000261_0001
Figure imgf000262_0001
Figure imgf000263_0001
Figure imgf000264_0001
Figure imgf000265_0001
Figure imgf000266_0001
Figure imgf000267_0001
Figure imgf000268_0001
Figure imgf000269_0001
Figure imgf000270_0001
Figure imgf000271_0001
Figure imgf000272_0001
Figure imgf000273_0001
Figure imgf000274_0001
Figure imgf000275_0001
Figure imgf000276_0001
Figure imgf000277_0001
Figure imgf000278_0001
Figure imgf000279_0001
Figure imgf000280_0001
Figure imgf000281_0001
Figure imgf000282_0001
Figure imgf000283_0001
Figure imgf000284_0001
Figure imgf000285_0001
Figure imgf000286_0001
[0324] Table 23
Figure imgf000287_0001
Figure imgf000288_0001
Figure imgf000289_0001
Figure imgf000290_0001
Figure imgf000291_0001
Figure imgf000292_0001
Figure imgf000293_0001
Figure imgf000294_0001
Figure imgf000295_0001
Figure imgf000296_0001
[0325] Pharmaceutical Compositions
[0326] The methods of the present disclosure may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or the compound of the subject methods is preferably administered as a pharmaceutical composition comprising, for example, a compound or salt of Formula (I), (III) or (IV) and a pharmaceutically acceptable carrier.
[0327] In some embodiments, the pharmaceutical composition is formulated for oral
administration. In other embodiments, the pharmaceutical composition is formulated for injection. In still more embodiments, the pharmaceutical compositions comprise a compound as disclosed herein and an additional therapeutic agent (e.g., anticancer agent). Non-limiting examples of such therapeutic agents are described herein below.
[0328] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
[0329] In certain embodiments, the present disclosure provides a method comprising
administering a composition of a compound or salt of Formula (I), (III) or (IV) in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, a compound or salt of Formula (I), (III) or (IV) is delivered in a targeted drug delivery system, for example, in a liposome coated with organ-specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ. In yet other embodiments, the composition is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation. In yet other embodiments, the composition is administered topically.
[0330] The compound of Formula (I), (III) or (IV) for use in the subject methods may be effective over a wide dosage range. For example, in the treatment of adult humans, dosages from 0.01 to 1000 mg per day, from 0.5 to 100 mg per day, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.
[0331] In some embodiments, a compound or salt of Formula (I), (III) or (IV) for use in the subject methods is administered in a single dose. In some embodiments, a single dose of a compound or salt of Formula (I), (III) or (IV) is used for treatment of an acute condition.
[0332] In some embodiments, a compound or salt of Formula (I), (III) or (IV) for use in the subject methods is administered in multiple doses. In some embodiments, dosing is about once, twice, three times, four times, five times, six times, or more than six times per day. In other embodiments, dosing is about once a month, once every two weeks, once a week, or once every other day. In another embodiment, a compound or salt of Formula (I), (III) or (IV) and another agent are administered together about once per day to about 6 times per day. In another embodiment, the administration of a compound or salt of Formula (I), (III) or (IV) and an agent continues for less than about 7 days. In yet another embodiment, the administration continues for more than about 6 days, more than about 10 days, more than about 14 days, more than about 28 days, more than about two months, more than about six months, or one year or more. In some cases, continuous dosing is achieved and maintained as long as necessary.
[0333] Administration of a compound or salt of Formula (I), (III) or (IV) may continue as long as necessary. In some embodiments, a compound of the disclosure is administered for more than 1, more than 2, more than 3, more than 4, more than 5, more than 6, more than 7, more than 14, or more than 28 days. In some embodiments, a compound of the disclosure is administered 28 days or less, 14 days or less, 7 days or less, 6 days or less, 5 days or less, 4 days or less, 3 days or less, 2 days or less, or 1 day or a part thereof. In some embodiments, a compound or salt of Formula (I), (III) or (IV) is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects.
[0334] In some embodiments, a compound or salt of Formula (I), (III) or (IV) is administered in dosages. It is known in the art that due to intersubject variability in compound pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. Dosing for a compound or salt of Formula (I), (III) or (IV) may be found by routine experimentation in light of the instant disclosure.
[0335] In some embodiments, a compound or salt of Formula (I), (III) or (IV) is formulated into pharmaceutical compositions for use in the subject methods. In specific embodiments, pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are used as suitable to formulate the
pharmaceutical compositions described herein: Remington: The Science and Practice of
Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975;
Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999).
[0336] Provided herein are methods of promoting proliferation of a pancreatic cell, comprising administering pharmaceutical compositions comprising a compound or salt of Formula (I), (III) or (IV) and a pharmaceutically acceptable diluent(s), excipient(s), or carrier(s). In certain embodiments, the compounds or salts described are administered as pharmaceutical
compositions in which a compound or salt of Formula (I), (III) or (IV) is mixed with other active ingredients, as in combination therapy. Encompassed herein are all combinations of active ingredients set forth in the combination therapies section below and throughout this disclosure. In specific embodiments, the pharmaceutical compositions include one or more compounds of Formula (I), (III) or (IV), or a pharmaceutically acceptable salt thereof.
[0337] A pharmaceutical composition, as used herein, refers to a mixture of a compound or salt of Formula (I), (III) or (IV) with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. In certain embodiments, the pharmaceutical composition facilitates administration of the compound to an organism. In some embodiments, practicing the methods of treatment or use provided herein, therapeutically effective amounts of a compound or salt of Formula (I), (III) or (IV) are administered in a pharmaceutical composition to a mammal having a disease, disorder or medical condition to be treated. In specific embodiments, the mammal is a human. In certain
embodiments, therapeutically effective amounts vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. A compound or salt of Formula (I), (III) or (IV) may be used singly or in combination with one or more therapeutic agents as components of mixtures.
[0338] In one embodiment, a compound or salt of Formula (I), (III) or (IV) is formulated in an aqueous solution. In specific embodiments, the aqueous solution is selected from, by way of example only, a physiologically compatible buffer, such as Hank’s solution, Ringer’s solution, or physiological saline buffer. In other embodiments, a compound or salt of Formula (I), (III) or (IV) is formulated for transmucosal administration. In specific embodiments, transmucosal formulations include penetrants that are appropriate to the barrier to be permeated. In still other embodiments wherein a compound or salt of Formula (I), (III) or (IV) is formulated for other parenteral injections, appropriate formulations include aqueous or nonaqueous solutions. In specific embodiments, such solutions include physiologically compatible buffers and/or excipients.
[0339] In another embodiment, a compound or salt of Formula (I), (III) or (IV) is formulated for oral administration. A compound or salt of Formula (I), (III) or (IV) may be formulated by combining the active compounds with, e.g., pharmaceutically acceptable carriers or excipients. In various embodiments, a compound or salt of Formula (I), (III) or (IV) is formulated in oral dosage forms that include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like.
[0340] In certain embodiments, pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with a compound or salt of Formula (I), (III) or (IV), optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In specific embodiments, disintegrating agents are optionally added. Disintegrating agents include, by way of example only, cross-linked croscarmellose sodium,
polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
[0341] In one embodiment, dosage forms, such as dragee cores and tablets, are provided with one or more suitable coating. In specific embodiments, concentrated sugar solutions are used for coating the dosage form. The sugar solutions, optionally contain additional components, such as by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs and/or pigments are also optionally added to the coatings for identification purposes. Additionally, the dyestuffs and/or pigments are optionally utilized to characterize different combinations of active compound doses.
[0342] In certain embodiments, practicing the methods of treatment or use provided herein, a therapeutically effective amount of a compound or salt of Formula (I), (III) or (IV) is formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In specific embodiments, push-fit capsules contain the active ingredients in admixture with one or more filler. Fillers include, by way of example only, lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In other embodiments, soft capsules, contain one or more active compound that is dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers are optionally added.
[0343] In other embodiments, a therapeutically effective amount of a compound or salt of Formula (I), (III) or (IV) is formulated for buccal or sublingual administration. Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, lozenges, or gels. In still other embodiments, a compound or salt of Formula (I), (III) or (IV) is formulated for parental injection, including formulations suitable for bolus injection or continuous infusion. In specific embodiments, formulations for injection are presented in unit dosage form (e.g., in ampoules) or in multi-dose containers. Preservatives are, optionally, added to the injection formulations. In still other embodiments, the pharmaceutical compositions are formulated in a form suitable for parenteral injection as sterile suspensions, solutions or emulsions in oily or aqueous vehicles. Parenteral injection formulations optionally contain formulatory agents such as suspending, stabilizing and/or dispersing agents. In specific embodiments, pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In additional embodiments, a suspension of a compound or salt of Formula (I), (III) or (IV) is prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. In certain specific embodiments, aqueous injection suspensions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension contains suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. In certain embodiments, the active agent is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
[0344] In still other embodiments, a compound or salt of Formula (I), (III) or (IV) is
administered topically. A compound or salt of Formula (I), (III) or (IV) may be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments. Such pharmaceutical compositions optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
[0345] In yet other embodiments, a compound or salt of Formula (I), (III) or (IV) is formulated for transdermal administration. Transdermal formulations may employ transdermal delivery devices and transdermal delivery patches and can be lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive. In various embodiments, such patches are constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. In additional embodiments, the transdermal delivery of a compound or salt of Formula (I), (III) or (IV) is accomplished by means of iontophoretic patches and the like. In certain embodiments, transdermal patches provide controlled delivery of a compound or salt of Formula (I), (III) or (IV). In specific embodiments, the rate of absorption is slowed by using rate- controlling membranes or by trapping the compound within a polymer matrix or gel. In alternative embodiments, absorption enhancers are used to increase absorption. Absorption enhancers or carriers include absorbable pharmaceutically acceptable solvents that assist passage through the skin. For example, in one embodiment, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing a compound or salt of Formula (I), (III) or (IV), optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
[0346] In other embodiments, a compound or salt of Formula (I), (III) or (IV) is formulated for administration by inhalation. Various forms suitable for administration by inhalation include, but are not limited to, aerosols, mists or powders. Pharmaceutical compositions of a compound or salt of Formula (I), (III) or (IV) are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In specific embodiments, the dosage unit of a pressurized aerosol is determined by providing a valve to deliver a metered amount. In certain embodiments, capsules and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufflator are formulated containing a powder mix of a compound or salt of Formula (I), (III) or (IV) and a suitable powder base such as lactose or starch.
[0347] In still other embodiments, a compound or salt of Formula (I), (III) or (IV) is formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. In suppository forms of the compositions, a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted.
[0348] In certain embodiments, pharmaceutical compositions are formulated in any conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients may be optionally used as suitable. Pharmaceutical compositions comprising a compound or salt of Formula (I), (III) or (IV) are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
[0349] Pharmaceutical compositions for use in the subject methods include at least one pharmaceutically acceptable carrier, diluent or excipient and a compound or salt of Formula (I), (III) or (IV), sometimes referred to herein as an active agent or ingredient. The active ingredient may be in free-acid or free-base form, or in a pharmaceutically acceptable salt form.
Additionally, a compound or salt of Formula (I), (III) or (IV) may be in unsolvated or solvated forms with pharmaceutically acceptable solvents such as water and ethanol. In addition, the pharmaceutical compositions optionally include other medicinal or pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, buffers, and/or other therapeutically valuable substances.
[0350] Methods of the present disclosure may include a compound or salt of Formula (I), (III) or (IV) formulated with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound or salt of Formula (I), (III) or (IV). Semi-solid compositions include, but are not limited to, gels, suspensions and creams. The form of the pharmaceutical compositions of a compound or salt of Formula (I), (III) or (IV) include liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions also optionally contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so forth.
[0351] In some embodiments, a pharmaceutical composition comprising a compound or salt of Formula (I), (III) or (IV) takes the form of a liquid where the agents are present in solution, in suspension or both. Typically when the composition is administered as a solution or suspension a first portion of the agent is present in solution and a second portion of the agent is present in particulate form, in suspension in a liquid matrix. In some embodiments, a liquid composition includes a gel formulation. In other embodiments, the liquid composition is aqueous.
[0352] In certain embodiments, aqueous suspensions contain one or more polymers as suspending agents. Polymers include water-soluble polymers such as cellulosic polymers, e.g., hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl- containing polymers. Certain pharmaceutical compositions described herein comprise a mucoadhesive polymer, selected for example from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.
[0353] Pharmaceutical compositions also, optionally, include solubilizing agents to aid in the solubility of a compound described herein. The term“solubilizing agent” generally includes agents that result in formation of a micellar solution or a true solution of the agent. Certain acceptable nonionic surfactants, for example polysorbate 80, are useful as solubilizing agents, as can ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers.
[0354] Pharmaceutical compositions optionally include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.
[0355] Additionally, useful compositions also, optionally, include one or more salts in an amount required to bring osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.
[0356] Pharmaceutical compositions optionally include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.
[0357] Pharmaceutical compositions may include one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40.
[0358] Pharmaceutical compositions may include one or more antioxidants to enhance chemical stability where required. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.
[0359] In certain embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.
[0360] In certain embodiments, delivery systems for hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also employed. In additional embodiments, a compound or salt of Formula (I), (III) or (IV) is delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials may be used herein. In some embodiments, sustained-release capsules release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization are employed.
[0361] In certain embodiments, the formulations described herein comprise one or more antioxidants, metal chelating agents, thiol containing compounds and/or other general stabilizing agents. Examples of such stabilizing agents, include, but are not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.
[0362] In some embodiments, the concentration of a compound or salt of Formula (I), (III) or (IV) provided in a pharmaceutical composition for use in the subject methods is less than about:100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v or v/v.
[0363] In some embodiments, the concentration of a compound or salt of Formula (I), (III) or (IV) provided in a pharmaceutical composition for use in the subject methods is greater than about: 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25%, 15%, 14.75%, 14.50%, 14.25%, 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25%, 11%, 10.75%, 10.50%, 10.25%, 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25%, 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 1.25%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v, or v/v.
[0364] In some embodiments, the concentration of a compound or salt of Formula (I), (III) or (IV) in a pharmaceutical composition for use in the subject methods is in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40 %, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately 1% to approximately 10% w/w, w/v or v/v.
[0365] In some embodiments, the concentration of a compound or salt of Formula (I), (III) or (IV) in a pharmaceutical composition for use in the subject methods is in the range from approximately 0.001% to approximately 10%, approximately 0.01% to approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1%, approximately 0.1% to approximately 0.9% w/w, w/v or v/v.
[0366] In some embodiments, the amount of a compound or salt of Formula (I), (III) or (IV) in a pharmaceutical composition for use in the subject methods is equal to or less than about: 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g.
[0367] In some embodiments, the amount of a compound or salt of Formula (I), (III) or (IV) in a pharmaceutical composition for use in the subject methods is more than about: 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5 g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5g, 7 g, 7.5g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g.
[0368] In some embodiments, the amount of one or more compounds of the disclosure in a pharmaceutical composition for use in the subject methods is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.
[0369] For use in the therapeutic applications described herein, kits and articles of manufacture are also provided. In some embodiments, such kits comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers are formed from a variety of materials such as glass or plastic.
[0370] The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products include those found in, e.g., U.S. Pat. Nos.5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. For example, the container(s) includes a compound or salt of Formula (I), (III) or (IV), optionally in a composition or in combination with another agent as disclosed herein. The container(s) optionally have a sterile access port (for example the container is an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). Such kits optionally comprising a compound with an identifying description or label or instructions relating to its use in the methods described herein.
[0371] For example, a kit typically includes one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and/or devices) desirable from a commercial and user standpoint for use of a compound described herein. Non- limiting examples of such materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and/or tube labels listing contents and/or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included. A label is optionally on or associated with the container. For example, a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself, a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. In addition, a label is used to indicate that the contents are to be used for a specific therapeutic application. In addition, the label indicates directions for use of the contents, such as in the methods described herein. In certain embodiments, the pharmaceutical composition is presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein. The pack, for example, contains metal or plastic foil, such as a blister pack. Or, the pack or dispenser device is accompanied by instructions for administration. Or, the pack or dispenser is
accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. In some embodiments, compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
[0372] Methods
[0373] The present disclosure provides a method of promoting beta cell proliferation. In some embodiments, the method comprises contacting menin with an effective amount of a compound of Formula (I), (III) or (IV). Optionally, the compound inhibits the interaction of menin and MLL. Inhibition of the menin/MLL interaction can be assessed by a wide variety of techniques known in the art. Non-limiting examples include a showing of (a) a decrease in menin binding to MLL, or a peptide fragment thereof; (b) a decrease in p27Kip1 and/or p18INK4C mRNA levels; (c) a decrease in p27Kip1 and/or p18INK4C protein levels; (d) a decrease in the levels of downstream targets of MLL; (e) an increase in beta cells; and/or (f) an increase in pancreatic islet cell proliferation. Kits and commercially available assays can be utilized for determining one or more of the above. In some embodiments, the promoted beta cell proliferation is evidenced by an increase in insulin production. Optionally, contacting menin comprises contacting a cell that expresses menin. The contacting step may take place in vivo or in vitro. The promoted beta cell proliferation may be evidenced by an increase in beta cell production. In some embodiments, the number of beta cells in a treated islet increases by at least 1.1-fold, at least 1.2-fold, at least 1.3- fold, at least 1.4-fold, at least 1.5-fold, at least 1.6-fold, at least 1.7-fold, at least 1.8-fold, at least 1.9-fold, at least 2-fold, at least 2.5-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 7.5-fold, or at least 10-fold relative to the number of beta cells in an islet treated with vehicle only. In some embodiments, the increase in the number of beta cells in a treated islet is compared to a number of beta cells in an islet prior to treatment. Beta cell proliferation may be assessed using methods known in the art. For example, beta cell proliferation can be assessed using quantitative-stereological methods or by immunohistochemistry imaging methods, either using manual or automated image processing. Non-limiting examples of suitable methods are described in Noorafshan, A.; et al. J. Pancreas 2012, 13, 427-432; Chen, H.; et al. Frontiers in Physiology 2013, 3, 1-9; and Kilimnik, G.; et al. Islets 2012, 4, 167-172.
[0374] In certain embodiments, the present disclosure provides a method of increasing the size of a pancreatic islet, comprising administering an effective amount of a compound described herein to a subject in need thereof. In some embodiments, the average size of treated pancreatic islets increases by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, or at least 60% relative to the average size of pancreatic islets treated with vehicle only. The size of pancreatic islets may be expressed in any unit commonly used in the art, such as area (e.g., mm2) or volume (e.g., mm3), and can be assessed using methods known in the art. For example, pancreatic islet size can be assessed using quantitative-stereological methods or by immunohistochemistry imaging methods, either using manual or automated image processing. Non-limiting examples of suitable methods are described in Noorafshan, A.; et al. J. Pancreas 2012, 13, 427-432; Chen, H.; et al. Frontiers in Physiology 2013, 3, 1-9; and Kilimnik, G.; et al. Islets 2012, 4, 167-172.
[0375] In certain embodiments, the present disclosure provides a method of increasing the average beta cell number per islet, comprising administering an effective amount of a compound described herein to a subject in need thereof. In some embodiments, the average beta cell number per islet of treated islets increases by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, or at least 40% relative to the average beta cell number per islet of islets treated with vehicle only. The average beta cell number per islet can be assessed using methods known in the art. For example, average beta cell number per islet can be assessed using quantitative-stereological methods or by immunohistochemistry imaging methods, either using manual or automated image processing. Non-limiting examples of suitable methods are described in Noorafshan, A.; et al. J. Pancreas 2012, 13, 427-432; Chen, H.; et al. Frontiers in Physiology 2013, 3, 1-9; and Kilimnik, G.; et al. Islets 2012, 4, 167-172.
[0376] In certain embodiments, the present disclosure provides a method of improving islet transplantation, comprising contacting an islet cell with an effective amount of a compound described herein. In some embodiments, the contacting takes place prior to transplantation of the islet into a recipient. In some embodiments, the contacting takes place after transplantation of the islet into a recipient. The contacting may take place in vivo, ex vivo or in vitro.
[0377] In certain embodiments, the present disclosure provides a method of treating a disease or condition in a subject having impaired beta cell production, comprising administering to the subject an effective amount of a compound of Formula (I), (III) or (IV). The disease or condition may comprise diabetes, such as type 1 diabetes or type 2 diabetes. In some embodiments, the disease or condition is characterized by impaired glucose metabolism and/or hyperglycemia. The treated subject may exhibit decreased plasma glucose levels. For example, plasma glucose levels may be reduced by at least 10 mg/dL, 20 mg/dL, 30 mg/dL, 40 mg/dL, 50 mg/dL, 60 mg/dL, 70 mg/dL, 80 mg/dL, 90 mg/dL, or at least 100 mg/dL relative to plasma glucose levels measured before the administering the effective amount of the compound of Formula (I), (III) or (IV). A fasting plasma glucose level of the treated subject may be less than 150 mg/dL, such as less than 140 mg/dL, 130 mg/dL, 120 mg/dL, 110 mg/dL, 100 mg/dL, 90 mg/dL, or less than 80 mg/dL. [0378] In certain embodiments, the present disclosure provides a method of treating impaired glucose metabolism, comprising administering an effective amount of a compound or salt of Formula (I), (III) or (IV) to a subject in need thereof.
[0379] Subjects that can be treated according the subject methods include, for example, subjects that have been diagnosed as having impaired glucose tolerance, hyperglycemia, impaired glucose metabolism, diabetes, type 1 diabetes, or type 2 diabetes, or subjects suffering from a disease associated with reduced beta cell number and/or impaired beta-cell function, for example but not limited to one of the diseases for which a pro-proliferative effect on pancreatic beta cells and/or an anti-apoptotic/pro-survival effect on pancreatic beta cells and/or a beta cell neogenesis- promoting effect would be beneficial: Type I diabetes: new onset, established, prevention in high-risk patients (identified e.g. via screening for multiple autoantibodies); LADA: new onset and established; Type II diabetes: when loss of beta cell mass occurs; MODY (Maturity Onset Diabetes of the Young, all forms); Gestational diabetes; Islet+duct cell transplantation-treatment of recipients before or after transplantation; Treatment of islets before transplantation/during pre- transplantation culture; and Pancreatitis-associated beta cell loss.
[0380] The methods described herein may be used to treat diabetes type I, LADA or prognosed diabetes type II, but also used preventively on subjects at risk to develop complete beta-cell degeneration, like for example but not limited to patients suffering from diabetes type II or LADA and type I diabetes in early stages, or other types of diseases as indicated above. The methods may also be used to prevent or ameliorate diabetes in patients at risk for type I diabetes or LADA (identified e.g. by screening for autoantibodies, genetic predisposition, impaired glucose tolerance or combinations thereof.
[0381] The present disclosure also provides methods for combination therapies in which an agent known to modulate other pathways, or other components of the same pathway, or even overlapping sets of target enzymes are used in combination with a compound or salt of Formula (I), (III) or (IV). In one aspect, such therapy includes but is not limited to the combination of one or more compounds of the disclosure with anti-diabetic agents to provide a synergistic or additive therapeutic effect.
[0382] In some embodiments, the compounds described herein are formulated or administered in conjunction with liquid or solid tissue barriers also known as lubricants. Examples of tissue barriers include, but are not limited to, polysaccharides, polyglycans, seprafilm, interceed and hyaluronic acid.
[0383] In some embodiments, medicaments which are administered in conjunction with the compounds described herein include any suitable drugs usefully delivered by inhalation for example, analgesics, e.g., codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations, e.g., diltiazem; antiallergics, e.g., cromoglycate, ketotifen or nedocromil; anti- infectives, e.g., cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines or pentamidine; antihistamines, e.g., methapyrilene; anti-inflammatories, e.g., beclomethasone, flunisolide, budesonide, tipredane, triamcinolone acetonide or fluticasone; antitussives, e.g., noscapine; bronchodilators, e.g., ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, salbutamol, salmeterol, terbutalin, isoetharine, tulobuterol, orciprenaline or (-)-4-amino-3,5- dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]-amino]methyl]benzenemethanol; diuretics, e.g., amiloride; anticholinergics e.g., ipratropium, atropine or oxitropium; hormones, e.g., cortisone, hydrocortisone or prednisolone; xanthines e.g., aminophylline, choline theophyllinate, lysine theophyllinate or theophylline; and therapeutic proteins and peptides, e.g., insulin or glucagon. It will be clear to a person skilled in the art that, where appropriate, the medicaments are used in the form of salts (e.g., as alkali metal or amine salts or as acid addition salts) or as esters (e.g., lower alkyl esters) or as solvates (e.g., hydrates) to optimize the activity and/or stability of the medicament.
[0384] Other exemplary therapeutic agents useful for a combination therapy include but are not limited to agents as described above, hormone antagonists, hormones and their releasing factors, thyroid and antithyroid drugs, estrogens and progestins, androgens, adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogs; inhibitors of the synthesis and actions of adrenocortical hormones, insulin, oral hypoglycemic agents, and the pharmacology of the endocrine pancreas, agents affecting calcification and bone turnover: calcium, phosphate, parathyroid hormone, vitamin D, calcitonin, vitamins such as water-soluble vitamins, vitamin B complex, ascorbic acid, fat-soluble vitamins, vitamins A, K, and E, growth factors, cytokines, chemokines, muscarinic receptor agonists and antagonists; anticholinesterase agents; agents acting at the neuromuscular junction and/or autonomic ganglia; catecholamines,
sympathomimetic drugs, and adrenergic receptor agonists or antagonists; and 5- hydroxytryptamine (5-HT, serotonin) receptor agonists and antagonists.
[0385] Therapeutic agents can also include agents for pain and inflammation such as histamine and histamine antagonists, bradykinin and bradykinin antagonists, 5-hydroxytryptamine
(serotonin), lipid substances that are generated by biotransformation of the products of the selective hydrolysis of membrane phospholipids, eicosanoids, prostaglandins, thromboxanes, leukotrienes, aspirin, nonsteroidal anti-inflammatory agents, analgesic-antipyretic agents, agents that inhibit the synthesis of prostaglandins and thromboxanes, selective inhibitors of the inducible cyclooxygenase, selective inhibitors of the inducible cyclooxygenase-2, autacoids, paracrine hormones, somatostatin, gastrin, cytokines that mediate interactions involved in humoral and cellular immune responses, lipid-derived autacoids, eicosanoids, β-adrenergic agonists, ipratropium, glucocorticoids, methylxanthines, sodium channel blockers, opioid receptor agonists, calcium channel blockers, membrane stabilizers and leukotriene inhibitors.
[0386] Additional therapeutic agents contemplated herein include diuretics, vasopressin, agents affecting the renal conservation of water, rennin, angiotensin, agents useful in the treatment of myocardial ischemia, anti-hypertensive agents, angiotensin converting enzyme inhibitors, β- adrenergic receptor antagonists, agents for the treatment of hypercholesterolemia, and agents for the treatment of dyslipidemia.
[0387] Other therapeutic agents contemplated include drugs used for control of gastric acidity, agents for the treatment of peptic ulcers, agents for the treatment of gastroesophageal reflux disease, prokinetic agents, antiemetics, agents used in irritable bowel syndrome, agents used for diarrhea, agents used for constipation, agents used for inflammatory bowel disease, agents used for biliary disease, agents used for pancreatic disease. Therapeutic agents used to treat protozoan infections, drugs used to treat Malaria, Amebiasis, Giardiasis, Trichomoniasis, Trypanosomiasis, and/or Leishmaniasis, and/or drugs used in the chemotherapy of helminthiasis. Other therapeutic agents include antimicrobial agents, sulfonamides, trimethoprim-sulfamethoxazole quinolones, and agents for urinary tract infections, penicillins, cephalosporins, and other, β-lactam
antibiotics, an agent comprising an aminoglycoside, protein synthesis inhibitors, drugs used in the chemotherapy of tuberculosis, mycobacterium avium complex disease, and leprosy, antifungal agents, antiviral agents including nonretroviral agents and antiretroviral agents.
[0388] Moreover, therapeutic agents used for immunomodulation, such as immunomodulators, immunosuppressive agents, tolerogens, and immunostimulants are contemplated by the methods herein. In addition, therapeutic agents acting on the blood and the blood-forming organs, hematopoietic agents, growth factors, minerals, and vitamins, anticoagulant, thrombolytic, and antiplatelet drugs.
[0389] The compounds of the subject methods may be administered alone or in combination with another medicament useful to prevent or treat pancreatic disorders or metabolic syndrome, particularly beta-cell degeneration, for example known beta cell mitogens, beta cell protective agents, hormones, growth factors or antioxidants such as GLP-1 and stabilized forms of GLP-1, GLP-1 analogues, DPP-IV inhibitors, nicotinamide, vitamin C, INGAP peptide, TGF-alpha, gastrin, prolactin, NGF, members of the EGF-family, or immune modulating agents such as anti- CD3 antibodies, DiaPep277 or anti-inflammatory agents such as Cox2 inhibitors, acetyl-salicylic acid, or acetaminophen. The compositions may be administered in combination with the beta cell regenerating proteins, nucleic acids and effectors/modulators thereof.
[0390] Further therapeutic agents that can be combined with a compound of the disclosure are found in Goodman and Gilman’s“The Pharmacological Basis of Therapeutics” Tenth Edition edited by Hardman, Limbird and Gilman or the Physician’s Desk Reference, both of which are incorporated herein by reference in their entirety.
[0391] The methods described herein may comprise use of a compound of Formula (I), (III) or (IV) in combination with other suitable agents. Hence, in some embodiments, the one or more compounds of the disclosure will be co-administered with other agents as described above. When used in combination therapy, the compounds described herein are administered with the second agent simultaneously or separately. This administration in combination can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, a compound described herein and any of the agents described above can be formulated together in the same dosage form and administered simultaneously. Alternatively, a compound of the disclosure and any of the agents described above can be simultaneously administered, wherein both the agents are present in separate formulations. In another alternative, a compound of the present disclosure can be administered just followed by and any of the agents described above, or vice versa. In some embodiments of the separate administration protocol, a compound of the disclosure and any of the agents described above are administered a few minutes apart, or a few hours apart, or a few days apart.
[0392] The following examples are given for the purpose of illustrating various embodiments of the disclosure and are not meant to limit the present disclosure in any fashion. The present examples, along with the methods and compositions described herein, are presently
representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the disclosure. Changes therein and other uses which are encompassed within the spirit of the disclosure as defined by the scope of the claims will occur to those skilled in the art. EXAMPLES
[0393] Example 1: Fluorescence polarization assay. This example illustrates an assay effective in monitoring the binding of MLL to menin. Fluorescence polarization (FP) competition experiments were performed to determine the effectiveness with which a compound inhibits the menin-MLL interaction, reported as an IC50 value. A fluorescein-labeled peptide containing the high affinity menin binding motif found in MLL was produced according to Yokoyama et al. (Cell, 2005, 123(2): 207-218), herein incorporated by reference in its entirety. Binding of the labeled peptide (1.7 kDa) to the much larger menin (~67 kDa) is accompanied by a significant change in the rotational correlation time of the fluorophore, resulting in a substantial increase in the fluorescence polarization and fluorescence anisotropy (excitation at 500 nm, emission at 525 nm). The effectiveness with which a compound inhibits the menin-MLL interaction was measured in an FP competition experiment, wherein a decrease in fluorescence anisotropy correlates with inhibition of the interaction and was used as a read-out for IC50 determination.
[0394] Example 2: Homogenous time-resolve fluorescence (HTRF) assay. A homogeneous time-resolve fluorescence (HTRF) assay is utilized as a secondary assay to confirm the results of the FP assay. In some embodiments, the HTRF assay is the primary assay and the FP assay is used as a secondary assay to confirm results. HTRF is based on the non-radiative energy transfer of the long-lived emission from the Europium cryptate (Eu3+-cryptate) donor to the
allophycocyanin (XL665) acceptor, combined with time-resolved detection. An Eu3+-cryptate donor is conjugated with mouse anti-6His monoclonal antibody (which binds His-tagged menin) and XL665-acceptor is conjugate to streptavidin (which binds biotinylated MLL peptide). When these two fluorophores are brought together by the interaction of menin with the MLL peptide, energy transfer to the acceptor results in an increase in fluorescence emission at 665 nm and increased HTRF ratio (emission intensity at 665 nm/emission intensity at 620 nm). Inhibition of the menin-MLL interaction separates the donor from the acceptor, resulting in a decrease in emission at 665 nm and decreased HTRF ratio.
[0395] Example 3: Menin engagement assay. Sample Preparation: 2.5 µL of 100 µM compound is added to 47.5 µL of 526 nM menin in PBS (5µM compound 500nM menin in 5% DMSO final concentration). The reaction is incubated at room temperature for variable lengths of time and quenched with 2.5 µL of 4% formic acid (FA, 0.2% final concentration). Method: A Thermo Finnigan Surveyor Autosampler, PDA Plus UV detector and MS Pump along with an LTQ linear ion trap mass spectrometer were used to collect sample data under XCalibur software control. A 5µL sample in“no waste” mode was injected onto a Phenomenex Jupiter 5u 300A C5 (guard column) 2 x 4.00 mm at 45○C. Mobile phase composition: Buffer A (95:5 water:acetonitrile, 0.1% FA) and Buffer B (acetonitrile, 0.1% FA). Gradient elution was used with an initial mobile phase of 85:15 (Buffer A:B) and a flow rate of 250 µL/min. Upon injection, 85:15 A:B was held for 1.3 min, Buffer B was increased to 90% over 3.2 min, held for 1 min, and then returned to initial conditions in 0.1 min and held for 2.4 min. The total run time is 8 min. A post-column divert valve employed to direct void volume salts to waste was used for the first 2 min of the sample method. Blank injection of Buffer A is used in between each of the sample injections. A needle wash of 1:1 acetonitrile:water with 0.1% FA was used. The electrospray ionization (ESI) source used a 300○C capillary temperature, 40 units sheath gas flow, 20 units aux gas flow, 3 units sweep gas flow, 3.5 kV spray voltage, 120 V tube lens. Data Collection: Data collection was performed in the positive ion full scan mode 550-1500 Da, 10 microscans, 200 ms max ion time. Data analysis: Protein mass spectra were acquired as XCalibur datafiles. The best scans were added together using XCalibur Qual Browser. The spectra were displayed using
“View/Spectrum List with a Display option to display all peaks. The Edit/Copy cell menu was used to copy the mass spectrum into the PC clipboard. The spectrum in the PC clipboard was pasted into Excel. The first two columns (m/z and Intensity were kept and the third column (Relative) was deleted. The remaining two columns were then saved as a tab delimited file (m/z and intensity) as filename.txt from Excel. The Masslynx Databridge program was then used to convert the filename.txt tab delimited file to Masslynx format. In some cases, an external calibration using a (similarly converted) myoglobin spectrum was applied in Masslynx to correct the m/z values of the menin protein m/z data. MaxEnt1 software from the MassLynx software suite was used for deconvolution of the mass spectrum to yield the average MW of the protein(s). The percentage of covalent adduct formation was determined from the deconvoluted spectrum and used to calculate the reaction rate (k) of the covalent reaction.
[0396] Example 4: Pharmacokinetic studies in mice. The pharmacokinetics of menin-MLL inhibitors are determined in female C57BL/6 mice following intravenous (iv) dosing at 15 mg/kg and oral dosing (po) at 30 mg/kg. Compounds are dissolved in the vehicle containing 25% (v/v) DMSO, 25% (v/v) PEG-400 and 50% (v/v) PBS. Serial blood samples (50 µL) are collected over 24 h, centrifuged at 15,000 rpm for 10 min and saved for analysis. Plasma concentrations of the compounds are determined by the LC-MS/MS method developed and validated for this study. The LC-MS/MS method consists of an Agilent 1200 HPLC system and chromatographic separation of tested compound is achieved using an Agilent Zorbax Extend-C18 column (5 cm x 2.1 mm, 3.5 µm; Waters). An AB Sciex QTrap 3200 mass spectrometer equipped with an electrospray ionization source (ABI-Sciex, Toronto, Canada) in the positive-ion multiple reaction monitoring (MRM) mode is used for detection. All pharmacokinetic parameters are calculated by noncompartmental methods using WinNonlin® version 3.2 (Pharsight Corporation, Mountain View, CA, USA).
[0397] Example 5: Cell culture and islet isolation. Islet cells can be isolated from a variety of species according to methods known in the art. For example, rat islets were isolated by the standard collagenase digestion method from the pancreata of adult Sprague–Dawley rats (200– 250 g) and cultured in RPMI medium (Invitrogen) with 10% FBS (Thermo Scientific). In brief, approximately 9 mL of ice-cold Collagenase V (Sigma) solution was injected into the pancreas via the common bile duct. After dissection, the pancreas was incubated for approximately 35 min at about 37°C and then further dissociated by repeated pipetting by using a 10-mL pipette. Islets were purified by Histopaque 1.077 (Sigma) density gradient centrifugation and manually picked by using a stereomicroscope. Islets were allowed to recover from the isolation procedure for an approximate duration of 1-2 days in RPMI medium containing approximately 10% fetal bovine serum in non-tissue culture-treated petri dishes to prevent attachment.
[0398] Example 6: Rat primary dispersed islet cell proliferation assay. Rested islets, such as rat islets, were trypsinized to single-cell suspensions and plated in 384-well clear bottom plates and cultured in the presence or absence of a subject compound disclosed herein for approximately 4 days in growth medium containing approximately 2 μM EdU (Invitrogen). Cells were fixed in 4% paraformaldehyde solution (Electron Microscopy Sciences) and stained by standard immunofluorescence techniques for insulin (polyclonal guinea pig antiinsulin, DAKO) and nuclear DNA was stained with Hoechst. EdU incorporation was measured by click reaction with AlexaFluor-647-azide (Invitrogen). Plates were imaged on ImageXpress Ultra (Molecular Devices). Imaging data were analyzed by MetaXpress (Molecular Devices). Total insulin positive cells and EdU/insulin-double positive cells were counted and reported as percentage of insulin positive cells containing EdU. Fold change can be calculated by normalizing percent EdU-positive β cells to DMSO-treated wells.
[0399] FIG.4A-4D depict confocal images of rat primary dispersed islet cells treated with Compound B-403, Compound C-35, Compound C-36, and no compound, respectively. In particular, the rat primary dispersed islet cells were treated with Compound B-403 (FIG.4A), Compound C-35 (FIG.4B), Compound C-36 (FIG.4C), and no compound (FIG.4D). In FIG. 4A-4D, the portions in red represent the cells that were stained with EdU, the portions in green represent insulin tagged with polyclonal guinea pig anti-insulin, and the portions in blue represent the cells that were stained with Hoechst.
[0400] FIG.5A-5C depict the change in beta cell proliferation for rat primary dispersed islet cells treated with Compound B-403 (FIG.5A), Compound C-35 (FIG.5B), and Compound C- 36 (FIG.5C). In FIG.5A-5C, the x-axis represents the concentration of compound in µM. In FIG.5A, the % Edu + Insulin gradually increases in the presence of increased concentrations of Compound B-403, with a maximum % Edu + Insulin of approximately 17% at a Compound B- 403 concentration of 0.05 µM. Thereafter, the % Edu + Insulin gradually decreases at increased concentrations and at 0.8 µM of Compound B-403, the % Edu + Insulin is approximately 6%. In FIG.5B, the % Edu + Insulin gradually increases in the presence of increased concentrations of Compound C-35, with a maximum % Edu + Insulin of approximately 21% at a Compound C-35 concentration of 0.3 µM. Thereafter, the % Edu + Insulin decreases at 0.8 µM of Compound C- 35 with a % Edu + Insulin of approximately 16%. In FIG.5C, the % Edu + Insulin reaches a maximum of approximately 15% at a Compound C-36 Concentration of 0.05 µM. Thereafter, the % Edu + Insulin gradually decreases at increased concentrations and at a Compound C-36 concentration of 0.8 µM, the % Edu + Insulin is approximately 7%.
[0401] Example 7: Human islet proliferation assay. Freshly-isolated explants of non-diabetic, human pancreatic islets are cultured in the presence of DMSO or a compound disclosed herein for 120 hours in growth medium containing 10 µM EdU (1000 islet equivalents per sample). Islets are fixed and stained by immunofluorescence for insulin and EdU. Beta cell proliferation, islet area, and average beta cell number per islet are assessed in accordance with methods described herein. Treatment with a compound disclosed herein induces beta cell proliferation, as evidenced by an increase in the size of human islets and/or an increase in the average beta cell number per islet.
[0402] Example 8: Human islet isolation. Human islet isolations are conducted using standard procedures in the art, for example, as described in Qi, M. et al. Transplantation Direct 2015, 1-9 (doi: 10.1097/TXD.0000000000000522). In short, a donor pancreas is cleaned and cannulated, then subjected to automated perfusion using a perfusion apparatus. Liberase HI, collagenase NB1 with NP, or liberase MTF C/T is infused, then the distended pancreas is cut into pieces and loaded into a digestion chamber for digestion at 37 °C. Once 50% or more of the islets are free from acinar tissues, the enzyme digestion is terminated by adding surplus media for enzyme dilution. Tissue is collected, centrifuged and combined with human serum albumin. The combined tissue is purified using a cell processor and continuous density gradients. After isolations, islets are cultured in Connaught Medical Research Laboratories 1066 medium (pH 7.4) with 0.5% human serum albumin and 0.1 µg/mL insulin-like growth factor-1 at 37 °C under 5% CO2 for up to 72 hours.
[0403] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. It should be understood that various alternatives to the embodiments of the disclosure described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

CLAIMS What is claimed is:
1. A method of promoting proliferation of a pancreatic cell, comprising
administering a compound of Formula (I):
Figure imgf000320_0001
or a pharmaceutically acceptable salt thereof, wherein:
H is selected from C3-12 carbocycle and 3- to 12-membered heterocycle;
A is selected from bond, C3-12 carbocycle, and 3- to 12-membered heterocycle;
B is selected from C3-12 carbocycle and 3- to 12-membered heterocycle;
C is selected from bond, C3-12 carbocycle, and 3- to 12-membered heterocycle;
each of L1, L2, and L3 is independently selected from bond, -O-, -S-, -N(R51)-, - N(R51)CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R51)-, - C(O)N(R51)C(O)-, -C(O)N(R51)C(O)N(R51)-, -N(R51)C(O)-, -N(R51)C(O)N(R51)-, -N(R51)C(O)O-, -OC(O)N(R51)-, -C(NR51)-, -N(R51)C(NR51)-, -C(NR51)N(R51)-, - N(R51)C(NR51)N(R51)-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, - N(R51)S(O)2-, -S(O)2N(R51)-, -N(R51)S(O)-, -S(O)N(R51)-, -N(R51)S(O)2N(R51)-, and -N(R51)S(O)N(R51)- or from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is optionally substituted with one or more R50, wherein two R50 groups attached to the same atom or different atoms of any one of L1, L2, or L3 can together optionally form a bridge or ring;
R50 is, at each occurrence, independently selected from:
halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, - S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, - NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, - OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, - NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, - P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52);
C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, - S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, - NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, - OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), - P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; and
C3-12 carbocycle and 3- to 12-membered heterocycle,
wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R50 is independently optionally substituted with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, - S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, - NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, - P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), - P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;
R51 is independently selected at each occurrence from:
hydrogen, -C(O)R52, -C(O)OR52, -C(O)N(R52)2, -C(O)NR53R54;
C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, - S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, - NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, - OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, - NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, - P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C3-12 carbocycle and 3- to 12-membered heterocycle; and
C3-12 carbocycle and 3- to 12-membered heterocycle,
wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R51 is independently optionally substituted with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, - S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, - NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, - P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), - P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;
R52 is independently selected at each occurrence from hydrogen; and C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, 1- to 6-membered heteroalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -NO2, -NH2, -NHCH3, - NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C3-12 carbocycle, or 3- to 6-membered heterocycle;
R53 and R54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R50;
each of RH, RA, and RB is, at each occurrence, independently selected from R50, or two RH groups, two RA groups, or two RB groups attached to the same atom or different atoms can together optionally form a bridge or ring;
RC is, at each occurrence, independently selected from hydrogen or R50, or two RC groups attached to the same atom or different atoms can together optionally form a bridge or ring; and each of m, n, p, and q is independently an integer from 0 to 12.
2. The method of claim 1, wherein:
H is 5- to 12-membered heterocycle;
A is 3- to 12-membered heterocycle; and
B is 5- to 12-membered heterocycle or C4-8 carbocycle.
3. The method of claim 1 or 2, wherein H is 6-membered to 12-membered bicyclic heterocycle.
4. The method of claim 3, wherein:
Figure imgf000322_0001
each of X1 and X2 is independently selected from CR2 and N;
each of X3 and X4 is independently selected from C and N;
each of X5 and X6 is independently selected from CR3, N, NR4, O, and S;
each of R1, R2 and R3 is independently selected at each occurrence from hydrogen and R50; and R4 is selected from R51.
5. The method of claim 4, wherein X3 and X4 are each C.
6. The method of claim 4 or 5, wherein X6 is CR3, and R3 is selected from hydrogen, halogen, -OR52, -N(R52)2, -CN, -C(O)OR52, C1-3 alkyl, and C1-3 haloalkyl.
7. The method of claim 4, wherein H is
Figure imgf000323_0001
.
8. The method of claim 7, wherein R2 is selected from hydrogen, halogen, -OR52, - NH2, -N(R52)2, -CN, C1-3 alkyl, C1-3 alkyl-OR52, C1-3 alkyl-N(R52)2, C1-3 haloalkyl, C2-3 alkenyl, and C2-3 alkynyl.
9. The method of claim 7 or 8, wherein R3 is selected from hydrogen, halogen, - OR52, -N(R52)2, -CN, -C(O)OR52, C1-3 alkyl, and C1-3 haloalkyl.
10. The method of any one of claims 4-9, wherein R1 is C1-3 haloalkyl.
11. The method of claim 10, wherein R1 is
Figure imgf000323_0002
.
12. The method of claim 3, wherein H is thienopyrimidinyl or thienopyridinyl.
13. The method of claim 3, wherein:
Figure imgf000323_0003
;
each of X1 and X2 is independently CR2 or N;
each of X7, X8, X9, and X10 is independently CR16, CR17R18, N, NR19, O, or S; each of R16, R17, and R18 is independently selected at each occurrence from hydrogen and R50; and
R19 is selected from R51.
14. The method of any one of claims 3-6 or 13, wherein X1 is CR2, and R2 is selected from hydrogen, halogen, -OH, -OR52, -NH2, -N(R52)2, -CN, C1-3 alkyl, C1-3 alkyl-OR52, C1-3 alkyl-N(R52)2, C1-3 haloalkyl, C2-3 alkenyl, and C2-3 alkynyl.
15. The method of any one of claims 3-11 or 13-14, wherein X2 is N.
16. The method of any one of claims 1-2, wherein H is 5- or 6-membered monocyclic heterocycle.
17. The method of claim 16, wherein:
Figure imgf000324_0001
each of Y1, Y2, and Y4 is independently CR2, N, NR21, O, or S;
Y5 is CR20, N, NR21, O, or S;
Y6 is C or N;
Y3 is a bond, CR22, or N, wherein when Y3 is CR22 or N, then each of Y1, Y2, and Y4 is independently CR2, N, or NR21 and Y5 is CR20, N, or NR21;
each of R2 and R20 is independently selected at each occurrence from hydrogen and R50; and
R21 is selected from R51.
18. The method of any one of the preceding claims, wherein L1 is a bond or -N(R51)-.
19. The method of any one of claims 1-17, wherein L1 is not a bond.
20. The method of any one of the preceding claims, wherein L1 is -NH-.
21. The method of any one of the preceding claims, wherein L2 is not a bond.
22. The method of any one of the preceding claims, wherein L2 is alkylene or heteroalkylene, each of which is optionally substituted with one or more R50.
23. The method of any one of the preceding claims, wherein L2 is C1-4 alkylene, optionally substituted with one or more R50.
24. The method of claim 23, wherein L2 is substituted with =O.
25. The method of any one of claims 1 to 21, wherein L2 is selected from -CH2-, - N(R51)-, -N(R51)CH2-, -N(R51)C(O)-, and -N(R51)S(O)2-.
26. The method of claim 25, wherein L2 is -CH2-.
27. The method of any one of the preceding claims, wherein L3 comprises less than 20 atoms.
28. The method of any one of the preceding claims, wherein L3 is not a bond.
29. The method of any one of the preceding claims, wherein L3 is C1-6 alkylene, optionally substituted with one or more R50.
30. The method of an one of claims 1 to 29 wherein L3 is selected from
Figure imgf000325_0007
Figure imgf000325_0001
, , , , , , O , wherein any one of which is optionally substituted with one or more R50.
31. The method of any one of claims 1 to 28, wherein L3 is selected from
Figure imgf000325_0005
Figure imgf000325_0004
, wherein any one of which is optionally substituted with one or more R50.
Figure imgf000325_0006
32. The method of any one of the preceding claims, wherein A is 5- to 10-membered heterocycle.
33. The method of claim 32, wherein A is 6-membered monocyclic heterocycle.
34. The method of claim 32 or 33, wherein A comprises at least one nitrogen atom.
35. The method of claim 34, wherein A is selected from piperidinylene and piperazinylene.
36. The method of claim 35, wherein A is
Figure imgf000325_0002
.
37. The method of any one of the preceding claims, wherein n is 0.
38. The method of any one of the preceding claims, wherein B is 6- to 12-membered bicyclic heterocycle.
39. The method of claim 38, wherein B comprises at least one nitrogen atom.
40. The method of claim 39, wherein B is
Figure imgf000325_0003
optionally substituted with one or more RB, wherein each of E and G is independently N or C.
41. The method of claim 39, wherein B is indolylene.
42. The method of claim 41, wherein B is
Figure imgf000326_0002
optionally substituted with one or more RB.
43. The method of any one of claims 1-37, wherein B is phenylene.
44. The method of any one of the preceding claims, wherein RB is selected from halogen, methyl, -CN, -OR52, and -N(R52)2.
45. The method of any one of the preceding claims, wherein C is 5- to 12-membered heterocycle, wherein the heterocycle comprises at least one nitrogen atom.
46. The method of claim 45, wherein C is aromatic.
47. The method of claim 45, wherein C is saturated.
48. The method of claim 47, wherein C is selected from piperidinyl, piperazinyl, and morpholinyl.
49. The method of any one of the preceding claims, wherein RC is selected from C1-3 alkyl and C1-3 haloalkyl.
50. The method of any one of claims 1-44, wherein:
Figure imgf000326_0001
W1 is C1-4 alkylene, optionally substituted with one or more R50;
W2 is selected from a bond; and C1-4 alkylene, optionally substituted with one or more R50;
W3 is selected from absent; and C1-4 alkylene, optionally substituted with one or more R50;
wherein when W3 is absent:
W1 is C1 alkylene, W2 is a bond, and L3 is not a bond;
W1 is C2-4 alkylene and W2 is a bond; or
W1 and W2 are each C1 alkylene and L3 is not a bond, wherein each C1 alkylene is independently optionally substituted with one or more R50.
51. The method of claim 50, wherein W1, W2 and W3 are each independently selected from C1-4 alkylene, wherein each C1-4 alkylene is optionally substituted with one or more R50.
52. The method of claim 51, wherein W1, W2 and W3 are each C1 alkylene.
53. The method of claim 50, wherein W1 and W2 are each C1 alkylene and W3 is absent.
54. The method of any one of claims 50-53, wherein RC is selected from -N(R52)2, - NR53R54, -NR52S(=O)2R52, -C(O)R52, -C(O)OR52, -NR52C(O)R52, -NR52C(O)OR52, - NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, and -C(O)NR53R54.
55. The method of claim 1, wherein the compound is selected from Table 1-6, 9-10, 12, 14, 16, 18, or 20.
56. The method of claim 1, wherein:
H is 5- to 12-membered heterocycle;
A is piperidinylene or piperazinylene;
B is indolylene; and
C is 5- to 6-membered heterocycle.
57. The method of claim 1, wherein:
H is thienopyrimidinyl or thienopyridinyl;
A is piperidinylene or piperazinylene;
B is indolylene; and
C is piperidinyl, piperazinyl, or morpholinyl.
58. The method of claim 1, wherein:
H is thienopyrimidinyl or thienopyridinyl;
A is piperidinylene or piperazinylene;
B is indolylene; and
L1, L2, and L3 are not bonds.
59. The method of claim 1 wherein the com ound has a structure of
Figure imgf000327_0001
60. The method of claim 1, wherein:
H is thienopyrimidinyl;
A is 3- to 12-membered heterocycle;
B is 6- to 12-membered bicyclic heterocycle; m is an integer from 0 to 3;
n is an integer from 0 to 3; and
p is an integer from 0 to 3.
61. The method of claim 1, wherein:
H is thienopyrimidinyl;
A is selected from piperidinylene and piperazinylene;
B is indolylene;
L1 and L2 are each independently selected from -O-, -S-, -NH-, and -CH2-;
L3 is selected from bond, -O-, -S-, -N(R51)-, -N(R51)CH2-, -C(O)-, -C(O)O-, - OC(O)-, -OC(O)O-, -C(O)N(R51)-, -C(O)N(R51)C(O)-, -C(O)N(R51)C(O)N(R51)-, - N(R51)C(O)-, -N(R51)C(O)N(R51)-, -N(R51)C(O)O-, -OC(O)N(R51)-, -C(NR51)-, - N(R51)C(NR51)-, -C(NR51)N(R51)-, -N(R51)C(NR51)N(R51)-, -S(O)2-, -OS(O)-, -S(O)O-, - S(O)-, -OS(O)2-, -S(O)2O-, -N(R51)S(O)2-, -S(O)2N(R51)-, -N(R51)S(O)-, -S(O)N(R51)-, - N(R51)S(O)2N(R51)-, -N(R51)S(O)N(R51)-; alkylene, alkenylene, alkynylene,
heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is optionally substituted with one or more R50, wherein two R50 groups attached to the same atom or different atoms of L3 can together optionally form a ring;
RA, RB and RC are each independently selected at each occurrence from R50, or two RA groups, two RB groups or two RC groups attached to the same atom or different atoms can together optionally form a ring;
m is an integer from 0 to 3;
n is an integer from 0 to 3;
p is an integer from 0 to 6; and
q is an integer from 0 to 6.
62. The method of claim 1, wherein:
H is thienopyrimidinyl;
A is selected from piperidinylene and piperazinylene;
B is indolylene;
L1 and L2 are each independently selected from -O-, -S-, -NH-, and -CH2-;
L3 is selected from C1-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene, each of which is optionally substituted with one or more R50;
RA, RB and RC are each independently selected at each occurrence from R50, or two RA groups, two RB groups or two RC groups attached to the same atom or different atoms can together optionally form a bridge or ring;
m is an integer from 0 to 3;
n is an integer from 0 to 3;
p is an integer from 0 to 3; and
q is an integer from 0 to 6.
63. The method of any one of claims 60 to 62, wherein H is
Figure imgf000329_0001
and R2 is selected from hydrogen, halogen, -OH, -OR52, -NH2, -N(R52)2, -CN, C1-3 alkyl, C1-3 alkyl- OR52, C1-3 alkyl-N(R52)2, C1-3 haloalkyl, C2-3 alkenyl, and C2-3 alkynyl.
64. The method of claim 63, wherein R2 is selected from -NH2, -CH3, and -NHCH3.
65. A method of promoting proliferation of a pancreatic cell, comprising
administering a compound of Formula III :
Figure imgf000329_0002
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
H is selected from C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more R50;
Figure imgf000329_0003
each of Z1, Z2, Z3, and Z4 is independently selected from -C(RA1)(RA2)-, -C(RA1)(RA2)- C(RA1)(RA2)-, -C(O)-, and -C(RA1)(RA2)-C(O)-, wherein no more than one of Z1, Z2, Z3, and Z4 is -C(O)- or -C(RA1)(RA2)-C(O)-;
B is selected from bond, C3-12 carbocycle and 3- to 12-membered heterocycle;
C is selected from bond, C3-12 carbocycle and 3- to 12-membered heterocycle;
L1, L2 and L3 are each independently selected from bond, -O-, -S-, -N(R51)-, -N(R51)CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R51)-, -C(O)N(R51)C(O)-, - C(O)N(R51)C(O)N(R51)-, -N(R51)C(O)-, -N(R51)C(O)N(R51)-, -N(R51)C(O)O-, -OC(O)N(R51)-, - C(NR51)-, -N(R51)C(NR51)-, -C(NR51)N(R51)-, -N(R51)C(NR51)N(R51)-, -S(O)2-, -OS(O)-, - S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R51)S(O)2-, -S(O)2N(R51)-, -N(R51)S(O)-, -S(O)N(R51)-, -N(R51)S(O)2N(R51)-, -N(R51)S(O)N(R51)-; alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is optionally substituted with one or more R50, wherein two R50 groups attached to the same atom or different atoms of any one of L1, L2 or L3 can together optionally form a bridge or ring;
RB is independently selected at each occurrence from R50, or two RB groups attached to the same atom or different atoms can together optionally form a bridge or ring;
RC is independently selected at each occurrence from hydrogen and R50, or two RC groups attached to the same atom or different atoms can together optionally form a bridge or ring;
RA1 and RA2 are each independently selected at each occurrence from hydrogen and R50; n is an integer from 0 to 6;
p is an integer from 1 to 6;
R50 is independently selected at each occurrence from:
halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, - S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, - NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, - OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, - NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, - P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), - P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52);
C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl, each of which is
independently optionally substituted at each occurrence with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, - NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, - OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, - NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, - P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), - P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; and
C3-12 carbocycle and 3- to 12-membered heterocycle, wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R50 is independently optionally substituted with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, - S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, - NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, - OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, - NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, - P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), - P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;
R51 is independently selected at each occurrence from:
hydrogen, -C(O)R52, -C(O)OR52, -C(O)N(R52)2, -C(O)NR53R54;
C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, - S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, - NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, - OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, - NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, - P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), - P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C3-12 carbocycle and 3- to 12- membered heterocycle; and
C3-12 carbocycle and 3- to 12-membered heterocycle, wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R51 is independently optionally substituted with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, - S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, - NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, - OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, - NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, - P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), - P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;
R52 is independently selected at each occurrence from hydrogen; and C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, 1- to 6-membered heteroalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -NO2, -NH2, -NHCH3, - NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C3-12 carbocycle, or 3- to 6-membered heterocycle; and
R53 and R54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R50.
66. A method of promoting proliferation of a pancreatic cell, comprising
administering a compound of Formula (IV):
Figure imgf000332_0001
or a ph cally acceptable salt or prodrug thereof, wherein:
Figure imgf000332_0002
fused thienyl or fused phenyl group;
Ga is selected from C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is substituted with -E1-R4a and optionally further substituted with one or more R50;
R2a is selected from hydrogen, alkyl, alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, optionally substituted heteroaryl, and aralkyl;
R3a and R3b are each independently selected from hydrogen, alkyl, halo, hydroxy, cyano, amino, alkylamino, dialkylamino, haloalkyl, alkoxy, and haloalkoxy;
Xa-Ya is selected from -N(R52)-C(=O)-, -C(=O)-O-, -C(=O)-N(R52)-, -CH2N(R52)-CH2-, - C(=O)N(R52)-CH2-, -CH2CH2-N(R52)-, -CH2N(R52)-C(=O)-, and–CH2O-CH2-; or
Xa and Ya do not form a chemical bond, wherein:
Xa is selected from hydrogen, alkyl, halo, hydroxy, cyano, amino, alkylamino, dialkylamino, haloalkyl, alkoxy, and haloalkoxy; and
Ya is selected from cyano, hydroxy, and -CH2R50;
E1 is selected from absent, -C(=O)-, -C(=O)N(R52)-, -[C(R14a)2]1-5O-, -[C(R14a)2]1-5NR52-, -[C(R14a)2]1-5-, -CH2(=O)-, and -S(=O)2-;
R4a is selected from hydrogen, alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, optionally substituted heteroaryl, aralkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl;
R14a is selected from hydrogen and alkyl;
R50 is independently selected at each occurrence from:
halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, - S(=O)2R52, -S(=O)2N(R52)2, -S(=O) 2
2NR53R54, -NR5 S(=O)2R52, - NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, - OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, - NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, - P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), - P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52);
C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl, each of which is
independently optionally substituted at each occurrence with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, - NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, - OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, - NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, - P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), - P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; and
C3-12 carbocycle and 3- to 12-membered heterocycle, wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R50 is independently optionally substituted with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, - S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, - NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, - OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, - NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, - P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), - P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;
R52 is independently selected at each occurrence from hydrogen; and C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, 1- to 6-membered heteroalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -NO2, -NH2, -NHCH3, - NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C3-12 carbocycle, or 3- to 6-membered heterocycle; and
R53 and R54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R50.
67. The method of any one of the preceding claims, wherein the compound is provided as a substantially pure stereoisomer.
68. The method of claim 67, wherein the stereoisomer is provided in at least 90% enantiomeric excess.
69. The method of any one of the preceding claims, wherein the compound is isotopically enriched.
70. A method of promoting proliferation of a pancreatic cell, comprising
administering a compound selected from Table 1-6, 9-10, 12, 14, 16, 18, or 20.
71. A method of promoting proliferation of a pancreatic cell, comprising
administering a compound selected from Table 22 or 23.
72. The method of any one of the preceding claims, wherein the pancreatic cell is an islet cell.
73. The method of any one of the preceding claims, wherein the pancreatic cell is a beta cell.
74. The method of claim 73, wherein the beta cell proliferation is evidenced by an increase in beta cell production.
75. The method of claim 73, wherein the beta cell proliferation is evidenced by an increase in insulin production.
76. The method of any one of the preceding claims, further comprising administering a second therapeutic agent.
77. The method of any one of the preceding claims, further comprising administering the compound to a subject.
78. The method of claim 77, wherein the subject suffers from diabetes.
79. The method of claim 78, wherein the diabetes is type 1 diabetes.
80. The method of claim 78, wherein the diabetes is type 2 diabetes.
81. The method of claim 77, wherein the subject suffers from prediabetes.
82. The method of claim 77, wherein the subject suffers from impaired beta cell production.
83. The method of claim 77, wherein the subject is human.
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