WO2018106820A1 - Methods of promoting beta cell proliferation - Google Patents

Methods of promoting beta cell proliferation Download PDF

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Publication number
WO2018106820A1
WO2018106820A1 PCT/US2017/064937 US2017064937W WO2018106820A1 WO 2018106820 A1 WO2018106820 A1 WO 2018106820A1 US 2017064937 W US2017064937 W US 2017064937W WO 2018106820 A1 WO2018106820 A1 WO 2018106820A1
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Prior art keywords
alkyl
optionally substituted
carbocycle
membered heterocycle
halogen
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PCT/US2017/064937
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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 WO2018106820A1 publication Critical patent/WO2018106820A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine

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 Ktpl and pl8 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.
  • type 2 diabetes 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 administering a compound of Formula (I):
  • H is selected from C 5- i 2 carbocycle and 5- to 12-membered heterocycle, each of which is optionally substituted with one or more R 50 ;
  • A is selected from bond, C3-12 carbocycle and 3- to 12-membered heterocycle
  • B is selected from C 3- i 2 carbocycle and 3- to 12-membered heterocycle
  • C is 3- to 12-membered heterocycle
  • L 1 , L 2 and L 3 are each independently selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(0)N(R 51 )-, -C(0)N(R 51 )C(0)-, - C(0)N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0 , -N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)0-, -OC(0)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 )-, -S(0) 2 -, -OS(O
  • 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, p are each independently an integer from 0 to 6; independently selected at each occurrence from:
  • Ci-io alkyl C 2- io alkenyl, and C 2- io alkynyl, each of which is
  • 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 ;
  • R 57 is selected from:
  • Ci-io alkyl C 2- io alkenyl, and C 2- io alkynyl, each of which is
  • p is an integer from 1 to 6;
  • L is substituted with one or more R , wherein V is not -CH 2 CH(OH)-.
  • the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising :
  • H is selected from C 5- i 2 carbocycle and 5- to 12-membered heterocycle, each of which is optionally substituted with one or more R 50 ;
  • A, B and C are each independently selected from C 3- i 2 carbocycle and 3- to 12-membered heterocycle;
  • L 1 and L 2 are each independently selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, - C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(0)N(R 51 )-, -C(0)N(R 51 )C(0)-, - C(0)N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0 , -N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)0-, -OC(0)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 )-, -S(0) 2 _, -OS(O)-,
  • 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 and p are each independently an integer from 0 to 6;
  • R 50 is independently selected at each occurrence from:
  • Ci-io alkyl C 2 _io alkenyl, and C 2 _io alkynyl, each of which is
  • 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 ;
  • R 56 is independently selected at each occurrence from:
  • R 56 optionally forms a bond to ring C
  • C may be 5- to 12-membered heterocycle, wherein the heterocycle comprises at least one nitrogen atom.
  • the heterocycle is saturated.
  • the heterocycle is selected from piperidinyl and piperazinyl.
  • C is selected from and .
  • R c may be selected from Ci_ 3 alkyl and Ci_ 3 haloalkyl.
  • H is 5- to 12-membered heterocycle, optionally substituted with one or more R 50 ;
  • A is 3- to 12-membered heterocycle; and
  • B is 3- to 12-membered heterocycle.
  • H may be 6- to 12-membered bicyclic
  • H is
  • H is
  • X 3 and X 4 are each C.
  • X 1 is CR 2
  • R 2 is selected from hydrogen, halogen, -OH, -OR 52 , -NH2, - N(R 52 ) 2 , -CN, d_3 alkyl, -CH 2 OH, -CH 2 OR 52 , -CH 2 NH 2 , -CH 2 N(R 52 ) 2 , d_ 3 alkyl-N(R 52 ) 2 , d_ 3 haloalkyl, C 2 _3 alkenyl, and C 2 _3 alkynyl.
  • X 2 is N.
  • Y 2 is CR 3
  • R 3 is selected from hydrogen, halogen, -OH, -N(R 52 ) 2 , -CN, -C(0)OR 52 , C 1-3 alkyl, and C1-3 haloalkyl.
  • R 1 is C1-3 haloalkyl.
  • A may be 5- to 8-membered heterocycle, such as 6-membered monocyclic heterocycle.
  • the heterocycle comprises at least
  • A is selected from piperidinylene and piperazinylene
  • B may be 6- to 12-membered bicyclic heterocycle.
  • the heterocycle comprises at least one nitrogen atom.
  • B is indolylene, such optionally substituted with one or more R .
  • H is thienopyrimidinyl substituted with one or more R 50 ;
  • A is selected from piperidinylene and piperazinylene; and B is indolylene.
  • H may be substituted with -CH 2 CF 3 .
  • m is 0.
  • n is an integer from 1 to 3.
  • L 1 comprises less than 10 atoms.
  • L 1 is -N(R 51 )-.
  • L 2 comprises less than 10 atoms.
  • L 2 is C1-4 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(0 , and -N(R 51 )S(0) 2 -. In some embodiments, L comprises less than 20 atoms. In
  • L is C 1-6 alkylene, optionally substituted with one or more R JU .
  • L 3 is C 2 alkylene substituted with at least one C1-3 alkyl or C1-3 haloalkyl, and optionally further substituted with one or more R 50 .
  • L 3 is substituted with -C3 ⁇ 4.
  • a compound of Formula (I) or (II) is selected from Tabl
  • R 50 is methyl.
  • L 3 is selec and .
  • R is methyl.
  • the present disclosure provides a substantially pure stereoisomer of a compound of Formula (I) or (II).
  • stereoisomer is provided in at least 90% enantiomeric excess.
  • H is thienopyrimidinyl, optionally substituted with one or more R 50 ;
  • A is 3- to 12-membered heterocycle;
  • B is 6- to 12- membered bicyclic heterocycle;
  • m is an integer from 0 to 3 ; and
  • n is an integer from 1 to 3.
  • H is thienopyrimidinyl, optionally substituted with one or more R 50 ;
  • A is selected from piperidinylene and piperazinylene
  • L 1 and L 2 are each independently selected from -0-, -S-, -NH-, and -CH2-;
  • L 3 is selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, -C(0)0-, -OC(O)-, - OC(0)0-, -C(0)N(R 51 )-, -C(0)N(R 51 )C(0)-, -C(0)N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)-, - N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)0-, -OC(0)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 )-, -S(0) 2 -, -OS(O)-, -S(0)0-,
  • 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 1 to 3 ;
  • p is an integer from 0 to 6;
  • R 57 is selected from:
  • Ci-io alkyl C 2 _io alkenyl, and C 2 _io alkynyl, each of which is
  • H is thienopyrimidinyl, optionally substituted with one or more R 50 ;
  • A is selected from piperidinylene and piperazinylene
  • L 1 and L 2 are each independently selected from -0-, -S-, -NH-, and -CH 2 -;
  • L 3 is selected from Ci-6 alkylene, C 2 - 6 alkenylene, and C 2 - 6 alkynylene, each of which is substituted with one or more R 56 and optionally further 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 1 to 3 ;
  • p is an integer from 0 to 6;
  • R 56 is independently selected at each occurrence from:
  • R optionally forms a bond to ring C
  • H is
  • R 2 is selected from hydrogen, halogen, -OH, -OR 52 , -NH 2 , -N(R 52 ) 2 , -CN, Ci_ 3 alkyl, Ci_ 3 alkyl-N(R 52 ) 2 , Ci -3 haloalkyl, C 2 _ 3 alkenyl, and C 2 _ 3 alkynyl.
  • R 2 is selected from - -CH 3 , and -NHCH 3 .
  • H is and R 2 is selected from hydrogen, halogen, -OH, -OR 52 , -NH 2 , -N(R 52 ) 2 , -
  • R 2 is selected from -NH 2 , -CH 3 , -OCH 3 , -CH 2 OH, and -NHCH 3 .
  • L 3 may be selected from and
  • the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising:
  • H is selected from C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionall 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(0)-, 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(0)-;
  • B is selected from bond, C 3- i 2 carbocycle and 3- to 12-membered heterocycle
  • C is selected from bond, C 3- i 2 carbocycle and 3- to 12-membered heterocycle
  • L 1 , L 2 and L 3 are each independently selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(0)N(R 51 )-, -C(0)N(R 51 )C(0)-, - C(0)N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)-, -N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)0-, -OC(0)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 )-, -S(0) 2 -, -OS(O)
  • 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 is independently selected at each occurrence from hydrogen and R , or two R groups attached to the same atom or different atoms can together optionally form a bridge or ring;
  • R A1 and R ⁇ are each independently selected at each occurrence from hydrogen and R ; 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 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 administerin a compound of Formula (IV):
  • G a is selected from C3-12 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:
  • Ci-10 alkyl C 2 _io alkenyl, and C 2 _io alkynyl, each of which is
  • 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 selected from Table 1.
  • the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising administering a compound selected from Table 2 or 3.
  • 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 ldiabetes 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-4E depict confocal images of rat primary dispersed islet cells treated with Compound 132, Compound 135, Compound 9, Compound 10, and no compound, respectively.
  • FIG. 5A-5D depict the change in beta cell proliferation for rat primary dispersed islet cells treated with Compound 132, Compound 135, Compound 9, and Compound 10, 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.
  • the heterocycle is a heteroaryl.
  • the heterocycle is a heterocycloalkyl.
  • a heterocycle e.g., pyridyl
  • 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 Hiickel 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 1H (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.
  • 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.
  • 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 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 hydro xyl, 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 sulfonamide, a sulfonyl, a heterocyclyl, an aralkyl, a carbocycle, a hetero
  • 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.
  • 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 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.
  • antagonists 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, MLLl, 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.
  • agonist 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 la). Moreover, Type 1 diabetes also encompasses an idiopathic variant (Type lb). 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), (II), (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.
  • 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
  • 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.
  • 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.
  • “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 MLL.
  • a method of the disclosure provides a compound that interacts non-covalently with menin and inhibits the interaction of menin with 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 PI 3 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 I):
  • H is selected from C 5- i 2 carbocycle and 5- to 12-membered heterocycle, each of which is optionally substituted with one or more R 50 ;
  • A is selected from bond, C 3- i 2 carbocycle and 3- to 12-membered heterocycle;
  • B is selected from C 3- i 2 carbocycle and 3- to 12-membered heterocycle
  • C is 3- to 12-membered heterocycle
  • L 1 , L 2 and L 3 are each independently selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(0)N(R 51 )-, -C(0)N(R 51 )C(0)-, - C(0)N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0 , -N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)0-, -OC(0)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 )-,
  • 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 and p are each independently an integer from 0 to 6;
  • R 50 is independently selected at each occurrence from:
  • Ci-io alkyl C 2 _io alkenyl, and C 2 _io alkynyl, each of which is
  • R 51 is independently selected at each occurrence from:
  • R 57 is selected from:
  • Ci-10 alkyl C 2 _io alkenyl, and C 2 _io alkynyl, each of which is
  • p is an integer from 1 to 6;
  • L is substituted with one or more R 50 , wherein L 3 is not -CH 2 CH(OH)-.
  • the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising administering a compound of Formula (II):
  • H is selected from C5-12 carbocycle and 5- to 12-membered heterocycle, each of which is optionally substituted with one or more R 50 ;
  • A, B and C are each independently selected from C 3- i 2 carbocycle and 3- to 12-membered heterocycle;
  • L 1 and L 2 are each independently selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, - C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(0)N(R 51 )-, -C(0)N(R 51 )C(0)-, - C(0)N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)-, -N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)0-, -OC(0)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 )-, -S(0) 2 -, -OS(O)-, -
  • L 3 is selected from alkylene, alkenylene, and alkynylene, each of which is substituted with one or more R 56 and optionally further 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 and p are each independently an integer from 0 to 6;
  • 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 ;
  • R 56 is independently selected at each occurrence from:
  • R optionally forms a bond to ring C
  • H is 5- to 12-membered heterocycle, such as 6- to 12-membered bicyclic heterocycle, optionally substituted with one or more R 50 .
  • 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 50 .
  • H is substituted with C1-4 haloalkyl, such as -CH 2 CF 3 .
  • H is substituted with one or more R 50 (e.g., by replacing a hydrogen connected to a ring atom with a bond to R 50 ).
  • H may be substituted with 0, 1, 2, 3, 4, 5, 6 or more R 50 groups.
  • H may be substituted with 1, 2, 3, 4, 5 or 6 R 50 groups, such as H substituted with 1 or 2 R 50 groups.
  • H is substituted with at least 1, 2, 3, 4, 5 or 6 R 50 groups.
  • H is substituted with up to 6, 5, 4, 3, 2 or 1 R 50 groups.
  • H is
  • X 1 and X 2 are each independently selected from CR 2 and N; X 3 and X 4 are each independently selected from C and N; Y 1 and Y 2 are each independently selected from CR 3 , N, NR 4 , O, and S; R 1 , R 2 and R 3 are each 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 1 is CR 2
  • R 2 is selected from hydrogen, halogen, -OH, -NH 2 , -CN, C 1 - 3 alkyl, Ci-3 haloalkyl, C 2 -3 alkenyl, and C 2 -3 alkynyl.
  • X 2 is N.
  • Y 2 is CR 3
  • R 3 is selected from hydrogen, halogen, -OH, -N(R 52 ) 2 , -CN, - C(0)OR 52 , Ci_3 alkyl, and Ci_ 3 haloalkyl.
  • Y 1 is S.
  • At least one of Y 1 and Y 2 is selected from N, NR 4 , O and S.
  • R 1 is C 1 - 3 haloalkyl, such as -CH 2 CF 3 .
  • X 1 is CR 2
  • X 2 is N
  • X 3 and X 4 are each C
  • Y is S
  • Y 2 is CR 3
  • R 1 is selected from R 50 .
  • X 1 is CR 2 ; X 2 is N; X 3 and X 4 are each C; Y 1 is S; Y 2 is CH; R 1 is C 1 -3 haloalkyl; and R 2 is selected from hydrogen, halogen, -OH -NH 2 , -CN, Ci-3 alkyl, C 1 -3 haloalkyl, C 2 -3 alkenyl, and C 2 -3 alkynyl.
  • X 1 is CR 2 ; X 2 is N; X 3 and X 4 are each C; Y 1 is S; Y 2 is CH; R 1 is C 1 -3 haloalkyl; and R 2 is selected from hydrogen, halogen, -OH -NH 2 , -CN, Ci-3 alkyl, C 1 -3 haloalkyl, C 2 -3 alkenyl, and C 2 -3 alkynyl.
  • H such as or In some embodiments, H
  • R 2 is and R 2 is selected from hydrogen, halogen, -OH, -N3 ⁇ 4, -CN, C 1 -3 alkyl, 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 , -OCH 2 CH 3 ), aminoalkyl, alkylamino, -N(R 52 ) 2 (e.g., - NH 2 , -NHCH3, -NHCH2CH3), -N(CH 3 ) 2 , -CN, Ci_3 alkyl (e.g., -CH 3 ), cyclopropyl, Ci_ 3 alkyl- OR 52 (e.g., -CH2OH, -CH 2 OC(0)CH 3 ), Ci_3 alkyl-N(R 52 ) 2 , Ci_ 3 haloalkyl, C 2 - 3 alkenyl, and C 2 - 3 alkynyl.
  • alkoxy e.g., -OR 52 , -OCH 3 , -OCH 2 CH 3
  • aminoalkyl alkylamino
  • H is
  • 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
  • each of Y 1 and Y 2 is independently selected from S, CR 3 , N, NR 4 and O. In certain embodiments, up to one of Y 1 and Y 2 is O or S.
  • 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, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(0 , -C(0)0-, -OC(O)-, -C(0)N(R 51 )-, -N(R 51 )C(0)-, - N(R 51 )C(0)N(R 51 )-, -S(0) 2 -, -S(O)-, -N(R 51 )S(0) 2 -, -S(0) 2 N(R 51 )-, -N(R 51 )S(0) 2 N(R 51 )-, alkylene, alkenylene, heteroalkylene, and heteroalkenylene.
  • L 1 is selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, -C(0)0-, -OC(O)-, -C(0)N(R 51 )-, - N(R 51 )C(0)-, -N(R 51 )C(0)N(R 51 )-, -S(0) 2 _, -S(O)-, -N(R 51 )S(0) 2 -, -S(0) 2 N(R 51 )-, - N(R 51 )S(0) 2 N(R 51 )-, Ci-6 alkylene and C 2 - 6 alkenylene, wherein the Ci- 6 alkylene and C 2 - 6 alkenylene are each optionally substituted with one or more R 50 .
  • L is - N(R 51 )-, such as -NH-.
  • L 1 is selected from -0-, -N(R 51 )-, -N(R 51 )CH 2 -, - C(O)-, -C(0)N(R 51 )-, -N(R 51 )C(0)-, -N(R 51 )S(0) 2 -, -S(0) 2 N(R 51 )-, d_ 4 alkylene, C 2 _ 4 alkenylene, and Ci_ 4 heteroalkylene.
  • 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 is ome 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. N H , I— NH, NH ,
  • 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 , o 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 o R A groups.
  • A is unsubstituted.
  • A is substituted with m R A 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.
  • 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, hetero aryloxy, 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 Ci_io alkylene, such as Ci -4 alkylene, optionally substituted with one or more R 50 . In some embodiments, L 2 is substituted
  • L is unsubstituted.
  • L is selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, -C(0)0-, -OC(O)-, -C(0)N(R 51 )-, - N(R 51 )C(0)-, -N(R 51 )C(0)N(R 51 )-, -S(0) 2 _, -S(O)-, -N(R 51 )S(0) 2 -, -S(0) 2 N(R 51 )-, - N(R 51 )S(0) 2 N(R 51 )-, alkylene, alkenylene, heteroalkylene, and heteroalkenylene.
  • L 2 is selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, -C(0)0-, - OC(O)-, -C(0)N(R 51 )-, -N(R 51 )C(0)-, -N(R 51 )C(0)N(R 51 )-, -S(0) 2 _, -S(0 , -N(R 51 )S(0) 2 -, - S(0) 2 N(R 51 )-, -N(R 51 )S(0) 2 N(R 51 )-, Ci_ 6 alkylene and C 2 _ 6 alkenylene, wherein the Ci_ 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(0)N(R 51 )-, -N(R 51 )C(0)-, -N(R 51 )S(0) 2 -, - S(0) 2 N(R 51 )-, Ci-4 alkylene and C1-4 heteroalkylene.
  • L 2 is selected from - CH 2 -, -N(R 51 )-, -N(R 51 )CH 2 -, -N(R 51 )C(0)-, and -N(R 51 )S(0) 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 is indolylene, more R . In some embodiments, B is
  • B is selected from M 1 M , M 1 M 10 ,
  • 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 n 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 (e.g., by replacing a hydrogen connected to a ring atom with a bond to R B ).
  • B may 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 n R B 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 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, hetero aryloxy, 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 Ci-io alkylene, such as Ci -4 alkylene, optionally substituted with one or more R 50 . In some embodiments, L 3 is substituted with one or more R 50 . In some embodiments, L 3 is unsubstituted.
  • L 3 is selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, -C(0)0-, -OC(O)-, -C(0)N(R 51 )-, - N(R 51 )C(0 , -N(R 51 )C(0)N(R 51 )-, -S(0) 2 -, -S(O)-, -N(R 51 )S(0) 2 -, -S(0) 2 N(R 51 )-, - N(R 51 )S(0) 2 N(R 51 )-, alkylene, alkenylene, heteroalkylene, and heteroalkenylene.
  • L 3 is Ci_6 alkylene, optionally substituted with one or more R 50 , wherein R 50 is selected from deuterium, C1-4 alkyl, C1-4 haloalkyl, and -OR 52 .
  • R 50 is selected from deuterium, C1-4 alkyl, C1-4 haloalkyl, and -OR 52 .
  • L 3 is- CH 2 CH(R 50 )-, such as -CH 2 CH(CH 3 )-.
  • two R 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 substituted with one or more groups selected from deuterium, C1-4 alkyl, C1-4 haloalkyl, and -OR 52 . In some embodiments, L 3 is substituted with -Ct3 ⁇ 4. In some embodiments, L 3 is C 2 alkylene substituted with at least one C1- 3 alkyl or C 1- 3 haloalkyl, and optionally further
  • L is selected from and
  • R is methyl.
  • L may be selected from and .
  • L 3 is .
  • 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 5-isomer.
  • the 5-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 azetidinylene, piperidinylene or piperazinylene;
  • L 3 is substituted
  • 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 is Ci-io alkylene, such as Ci- 4 alkylene, substituted with one or more R 56 and optionally further substituted with one or more R 50 . In some embodiments, L 3 is substituted with one or more R 50 . In some embodiments, L 3 is substituted with R 56 .
  • L 3 is selected from alkylene and alkenylene.
  • L 3 is Ci-6 alkylene substituted with one or more R 56 , wherein R 56 is selected from deuterium, CM alkyl, Ci -4 haloalkyl, and -OR 59 .
  • L 3 is Ci- 4 alkylene substituted with R 56 , wherein R 56 forms a bond to ring C.
  • L 3 is- CH 2 CH(R 56 )-, such as -CH 2 CH(CH 3 )-.
  • two R 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 56 , wherein R 56 forms a bond to ring C.
  • L 3 is substituted with one or more groups selected from Ci- 4 alkyl, Ci- 4 haloalkyl, and -OR 59 .
  • L 3 is substituted with -Ct1 ⁇ 4.
  • L 3 is Ci- 4 alkylene substituted with -Ct3 ⁇ 4 and optionally further substituted with R 50 , wherein R 50 is not - OH, -NH 2 , or -CN.
  • L 3 may be selected from and . In some embodiments,
  • L 3 is . In some embodiments, L 3 is . In some embodiments, L 3 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 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 5-isomer. In some embodiments, the 5-isomer of L 3 is provided in at least 20%, 30%,
  • C is 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.
  • R c substituted with one or more R c
  • C is selected from
  • 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 p R c groups, wherein p is an integer from 0 to 6.
  • R c is selected from Ci -3 alkyl and Ci -3 haloalkyl, such as -CH 3 .
  • C is selected from C 3- i 2 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 inyl and piperazinyl, such as selected from hydrogen and
  • C is selected from 5 7 is selected from hydrogen and R 50 . In some embodiments, C is selected from and
  • R 57 is selected from hydrogen and R 50
  • C is
  • C is selected from
  • R c is selected from:
  • R c is selected from
  • NR 52 C(0)OR 52 -NR 52 C(0)N(R 52 ) 2 , -NR 52 C(0)NR 53 R 54 , -C(0)N(R 52 ) 2 , or -C(0)NR 53 R 54 .
  • C is selected from
  • H is 5- to 12-membered heterocycle, optionally substituted with one or more R 50 ; 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 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, 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 thienopyrimidinyl, optionally substituted with one or more R 50 ; A is 3- to 12-membered heterocycle; and B is 3- to 12-membered heterocycle.
  • H is 5- to 12-membered heterocycle, optionally substituted with one or more R 50 ; A is selected from piperidinylene and piperazinylene; and B is 3- to 12-membered heterocycle.
  • H is 5- to 12- membered heterocycle, optionally substituted with one or more R 50 ; A is 3- to 12-membered heterocycle; and B is indolylene.
  • H is thienopyrimidinyl substituted with one or more R 50 ; A is selected from piperidinylene and piperazinylene; and B is indolylene.
  • H is 5- to 12-membered heterocycle, optionally substituted with one or more R 50 ;
  • A is 3- to 12-membered heterocycle;
  • B is 3- to 12-membered heterocycle;
  • C is 3- to 12-membered heterocycle;
  • m is an integer from 0 to 3;
  • n is an integer from 1 to 3.
  • H is 6- to 12-membered bicyclic heterocycle, optionally substituted with one or more R 50 ;
  • A is 3- to 12-membered heterocycle; B is 6- to 12-membered bicyclic heterocycle; C is 3- to 12-membered heterocycle;
  • m is an integer from 0 to 3; and
  • n is an integer from 1 to 3.
  • H is 5- to 12-membered heterocycle, optionally substituted with one or more R 50 ;
  • 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, optionally substituted with one or more R 50 ;
  • 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, optionally substituted with one or more R 50 ;
  • 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, optionally substituted with one or more R 50 ;
  • A is selected from piperidinylene and piperazinylene;
  • B is 6- to 12-membered bicyclic heterocycle;
  • m is an integer from 0 to 3 ;
  • n is an integer from 1 to 3.
  • H is thienopyrimidinyl, 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 thienopyrimidinyl, optionally substituted with one or more R 50 ;
  • 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 1 to 3.
  • H is 9- to 10-membered bicyclic heterocycle, optionally substituted with one or more R 50 ;
  • 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, optionally substituted with one or more R 50 ;
  • A is 5- to 7-membered heterocycle;
  • B is 9-membered bicyclic heterocycle; and
  • n is an integer from 1 to 3, wherein each of said heterocycles comprises at least one nitrogen atom.
  • 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, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, - C(0)0-, -OC(O)-, -C(0)N(R 51 )-, -N(R 51 )C(0)-, -N(R 51 )C(0)N(R 51 )-, -S(0) 2 -, -S(O)-, - N(R 51 )S(0) 2 -, -S(0) 2 N(R 51 )-, -N(R 51 )S(0) 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(0)-, and -N(R 51 )S(0) 2 -.
  • L 1 is selected from -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, -C(0)0-, - OC(O)-, -C(0)N(R 51 )-, -N(R 51 )C(0)-, -N(R 51 )C(0)N(R 51 )-, -S(0) 2 _, -S(0 , -N(R 51 )S(0) 2 -, - S(0) 2 N(R 51 )-, -N(R 51 )S(0) 2 N(R 51 )-, alkylene, alkenylene, heteroalkylene, and heteroalkenylene; and L 2 and L 3 are independently selected from C1-4 alkylene, optionally substituted with one or more R 50 .
  • L 1 , L 2 and L 3 are each independently selected from -0-, -S-, - N(R 51 )-;
  • L is -NH-
  • L is -CH 2 -
  • L is C1-4 alkylene, optionally substituted with one or more R 50 .
  • 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 and L 2 are each independently selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(0 , -C(0)0-, -OC(O)-, -C(0)N(R 51 )-, -N(R 51 )C(0 , -N(R 51 )C(0)N(R 51 )-, -S(0) 2 _, -S(O)-, -N(R 51 )S(0) 2 -, - S(0) 2 N(R 51 )-, -N(R 51 )S(0) 2 N(R 51 )-, alkylene, alkenylene, heteroalkylene, and heteroalkenylene, and L 3 is selected from Ci-10 alkylene and C 2 -io alkenylene, substituted with one or more R 56 and optionally further substituted with one or more R 50 .
  • L 1 and L 2 are each independently selected from -CH 2 -, -N(R 51 )-, -N(R 51 )CH 2 -, -N(R 51 )C(0)-, and -N(R 51 )S(0) 2 -, and L 3 is selected from Ci_io alkylene and C 2 _io alkenylene, substituted with one or more R 56 and optionally further substituted with one or more R 50 .
  • L 1 is selected from - 0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, -C(0)0-, -OC(O)-, -C(0)N(R 51 )-, -N(R 51 )C(0)-, - N(R 51 )C(0)N(R 51 )-, -S(0) 2 -, -S(O)-, -N(R 51 )S(0) 2 -, -S(0) 2 N(R 51 )-, -N(R 51 )S(0) 2 N(R 51 )-, alkylene, alkenylene, heteroalkylene, and heteroalkenylene; and L 2 is C1-4 alkylene, optionally substituted with one or more R 50 , and L 3 is C1-4 alkylene substituted with one or more R 56 and optionally further substituted with one or more R 50 .
  • L 1 and L 2 are each
  • heteroalkylene each of which is optionally substituted with one or more R
  • V is C 1-4 alkylene substituted with one or more R 56 and optionally further substituted with one or more R 50 .
  • L 1 is -NH-
  • L 2 is -CH 2 -
  • L 3 is C1-4 alkylene substituted with one or more R and optionally further substituted with one or more R .
  • the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising administering a compound of Formula (I), wherein:
  • H is 5- to 12-membered heterocycle, optionally substituted with one or more R 50 ;
  • A, B, and C are each independently selected from 3- to 12-membered heterocycle
  • L 1 , L 2 and L 3 are each independently selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(0)N(R 51 )-, -C(0)N(R 51 )C(0)-, - C(0)N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0 , -N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)0-, -OC(0)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 )-, -S(0) 2 -, -OS(O
  • 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 1 to 3 ;
  • p is an integer from 0 to 6;
  • R 50 is independently selected at each occurrence from:
  • Ci-io alkyl C 2 _io alkenyl, and C 2 _io alkynyl, each of which is
  • 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 ;
  • R 57 is selected from:
  • Ci-io alkyl C 2- io alkenyl, and C 2- io alkynyl, each of which is
  • p is an integer from 1 to 6;
  • L is substituted with one or more R , wherein V is not -CH 2 CH(OH)-.
  • the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising administering a compound of Formula (II), wherein:
  • H is 5- to 12-membered heterocycle, optionally substituted with one or more R 50 ;
  • A, B and C are each independently selected from 3- to 12-membered heterocycle;
  • L 1 and L 2 are each independently selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, - C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(0)N(R 51 )-, -C(0)N(R 51 )C(0)-, - C(0)N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)-, -N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)0-, -OC(0)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 )-, -S(0) 2 -, -OS(O)-, -
  • L 3 is selected from Ci_6 alkylene, C 2 _ 6 alkenylene, and C 2 _ 6 alkynylene, each of which is substituted with one or more R 56 and optionally further 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 1 to 3 ;
  • p is an integer from 0 to 6;
  • R 50 is independently selected at each occurrence from:
  • Ci-io alkyl C 2 -io alkenyl, and C 2 -io alkynyl, each of which is
  • 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 ;
  • R 56 is independently selected at each occurrence from:
  • R 56 optionally forms a bond to ring C
  • H is thienopyrimidinyl, optionally substituted with one or more R 50 ;
  • A is selected from piperidinylene and piperazinylene
  • L 1 and L 2 are each independently selected from -0-, -S-, -NH-, and -CH 2 -;
  • L 3 is selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, -C(0)0-, -OC(O)-, - OC(0)0-, -C(0)N(R 51 )-, -C(0)N(R 51 )C(0)-, -C(0)N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)-, - N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)0-, -OC(0)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 )-, -S(0) 2 -, -OS(O)-, -S(0)0-,
  • 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 1 to 3 ;
  • p is an integer from 0 to 6;
  • R 57 is selected from:
  • Ci-10 alkyl C 2 _io alkenyl, and C 2 _io alkynyl, each of which is
  • p is an integer from 1 to 6;
  • L is substituted with one or more R , wherein V is not -CH 2 CH(OH)-.
  • H is thienopyrimidinyl, optionally substituted with one or more R 50 ;
  • A is selected from piperidinylene and piperazinylene
  • L 1 and L 2 are each independently selected from -0-, -S-, -NH-, and -CH2-;
  • L 3 is selected from Ci-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene, each of which is substituted with one or more R 56 and optionally further 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 1 to 3 ;
  • p is an integer from 0 to 6;
  • R 56 is independently selected at each occurrence from:
  • R 56 optionally forms a bond to ring C
  • C is selected from 5- to 7-membered monocyclic heterocycle, such as piperidinyl and piperazinyl.
  • R 50 is selected from deuterium, C1-4 alkyl, C1-4 haloalkyl, and -OR 52 , such as R 50 is methyl.
  • a compound of Formula (I) may be represented by: .
  • C is selected from 5- to 7-membered monocyclic heterocycle, such as piperidinyl and piperazinyl.
  • R 50 is selected from deuterium, C 1 -4 alkyl, C 1 -4 haloalkyl, and -OR 52 , such as R 50 is methyl.
  • a compound of Formula (II) may be represented by:
  • C is selected from 5- to 7-membered monocyclic heterocycle, such as piperidinyl and piperazinyl.
  • R 56 is selected from deuterium, C 1 -4 alkyl, C 1 -4 haloalkyl, and -OR 59 , such as R 56 is methyl.
  • p is an integer from 1 to 3, such as p is 1.
  • a compound of Formula (II) may be represented by:
  • C is selected from 5- to 7-membered monocyclic heterocycle, such as piperidinyl and piperazinyl.
  • R 56 is selected from deuterium, C 1 -4 alkyl, C 1 -4 haloalkyl, and -OR 59 , such as R 56 is methyl.
  • p is an integer from 1 to 3, such as p is 1.
  • the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising administering a stereoisomer of a compound of Formula (I) or (II).
  • 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) or (II).
  • 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) or (II) is preferably used in the subject methods as a non-racemic mixture, wherein one enantiomer is present in excess of its corresponding enantiomer.
  • such mixture will contain a mixture of the two isomers in a ratio of at least about 9:1 , preferably at least 19:1.
  • the compound is provided in at least 96% enantiomeric excess, meaning the compound has less than 2% of the corresponding enantiomer.
  • the compound is provided in at least 96% diastereomeric excess, meaning the compound has less than 2% of the corresponding diastereomer.
  • the compound of Formula (I) or (II) 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) or (II) 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 und of Formula (I):
  • H is selected from C 5- i 2 carbocycle and 5- to 12-membered heterocycle, each of which is optionally substituted with one or more R 50 ;
  • A is selected from bond, C3-12 carbocycle and 3- to 12-membered heterocycle
  • B is selected from C 3- i 2 carbocycle and 3- to 12-membered heterocycle
  • C is 3- to 12-membered heterocycle
  • L 1 , L 2 and L 3 are each independently selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(0)N(R 51 )-, -C(0)N(R 51 )C(0)-, - C(0)N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0 , -N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)0-, -OC(0)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 )-, -S(0) 2 -, -OS(O
  • 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 and p are each independently an integer from 0 to 6;
  • R 50 is independently selected at each occurrence from:
  • Ci-io alkyl C 2- io alkenyl, and C 2- io alkynyl, each of which is
  • 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 ;
  • R 57 is selected from:
  • Ci-io alkyl C2-10 alkenyl, and C2-10 alkynyl, each of which is
  • 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. In some embodiments, the stereoisomer is in greater than 95% enantiomeric excess, such as greater than 99% enantiomeric excess.
  • L 3 is selected from Optionally, R 50 is methyl. In some embodiments, L 3 is . In some
  • L 3 is
  • the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprisin und of Formula (II):
  • H is selected from C 5- i 2 carbocycle and 5- to 12-membered heterocycle, each of which is optionally substituted with one or more R 50 ;
  • A, B and C are each independently selected from C3-12 carbocycle and 3- to 12-membered heterocycle;
  • L 1 and L 2 are each independently selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, - C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(0)N(R 51 )-, -C(0)N(R 51 )C(0)-, - C(0)N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0 , -N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)0-, -OC(0)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 )-, -S(0) 2 -, -OS(O)-,
  • L 3 is selected from alkylene, alkenylene, and alkynylene, each of which is substituted with one or more R 56 and optionally further 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 and p are each independently an integer from 0 to 6;
  • R 50 is independently selected at each occurrence from:
  • Ci-io alkyl C2-10 alkenyl, and C2-10 alkynyl, each of which is
  • 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 ;
  • R 56 is independently selected at each occurrence from:
  • R 56 optionally forms a bond to ring C
  • the stereoisomer of a compound of Formula (II) 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.
  • L 3 is selected from .
  • R 56 is methyl.
  • L 3 is .
  • 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 application, while suitable 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. 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.
  • 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) or (II) 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
  • R c is selected from:
  • L 5 is selected from a bond; and Ci alkylene, Ci-6 heteroalkylene, C2 alkenylene, and C 2 alkynylene, each of which is independently optionally substituted with one or more R 32 ;
  • 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:
  • R 23 is selected from:
  • R is selected from:
  • R is selected from hydrogen, -CN; and Ci_6 alkyl optionally substituted with one or more substituents selected from halogen, 20 20 20 20
  • the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising:
  • H is selected from C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionall substituted with one or more R 50 ;
  • each of Z 1 , Z 2 , Z 3 , and Z 4 is independently selected from -QR ⁇ XR ⁇ )-, -C(R A1 )(R A2 )- C(R A1 )(R A2 )-, -C(O)-, and -C(R A1 )(R A2 )-C(0)-, 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(0)-;
  • 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
  • L 1 , L 2 and L 3 are each independently selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(0)N(R 51 )-, -C(0)N(R 51 )C(0)-, - C(0)N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0 , -N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)0-, -OC(0)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 )-, -S(0) 2 -, -OS(O
  • R is independently selected at each occurrence from R , or two R groups attached to the same atom or different atoms can together optionally form a bridge or ring;
  • R is independently selected at each occurrence from hydrogen and R , or two R groups attached to the same atom or different atoms can together optionally form a bridge or ring;
  • R A1 and R ⁇ are each independently selected at each occurrence from hydrogen and R ; 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:
  • Ci-io alkyl C 2 _io alkenyl, and C 2 _io alkynyl, each of which is
  • 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: (III- A), such as (III-B), wherein 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 Ci -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, Ci_ 3 alkyl, Ci_ 3 alkyl- OR 52 , Ci_ 3 alkyl-N(R 52 ) 2 , Ci_ 3 haloalkyl, C 2 - 3 alkenyl, and C 2 _ 3 alkynyl.
  • R is selected from halogen, -OH, -OR 52 , -NH 2 , -N(R 52 ) 2 , -CN, d_ 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(0)OR 52 , Ci_ 3 alkyl, and d_ 3 haloalkyl.
  • R 52 is selected from selected from hydrogen and alkyl, such as R 52 is hydrogen.
  • A is selected from * N/ N/ X ⁇ remind00+ 3 ⁇ 4 N C N 3 ⁇ 4 ⁇ + «O »+
  • 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- i 2 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:
  • Ci-io alkyl C 2 _io alkenyl, and C 2 _io alkynyl, each of which is
  • 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.
  • R a 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 Formula 1-7 may be prepared according to
  • methanesulfonyl chloride can be added to a solution of alcohol 1-1 and triethylamine to afford mesylate 1-2.
  • mesylate 1-2 can be added to a solution of CS2CO 3 and amine 1-3 to provide a compound of Formula 1-4.
  • Coupling of aldehyde 1-4 to amine 1-5 can proceed in the presence of a suitable reducing agent, such as NaBH(OAc) 3 , to give a compound of Formula 1-6.
  • Addition of TFA can reveal the free amine, which can optionally be reacted with R 57 -LG, wherein LG is a suitable leaving group, to afford a compound of Formula 1-7.
  • a compound of the present disclosure for use in the subject methods for example, a compound of a formula given in Table 1, Table 2, or Table 3, is synthesized according to one of the general routes outlined in Scheme 1, Examples 1-5, 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, Table 2 or Table 3. Table 1
  • 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), (II), (III) or (IV) and a pharmaceutically acceptable carrier.
  • 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.
  • 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), (II), (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), (II), (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.
  • 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), (II), (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), (II), (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), (II), (III) or (IV) is used for treatment of an acute condition.
  • a compound or salt of Formula (I), (II), (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), (II), (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), (II), (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), (II), (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), (II), (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), (II), (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), (II), (III) or (IV) may be found by routine experimentation in light of the instant disclosure.
  • a compound or salt of Formula (I), (II), (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), (II), (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), (II), (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), (II), (III) or (IV), or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition refers to a mixture of a compound or salt of Formula (I), (II), (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), (II), (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), (II), (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), (II), (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), (II), (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), (II), (III) or (IV) is formulated for oral administration.
  • a compound or salt of Formula (I), (II), (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), (II), (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), (II), (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), (II), (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), (II), (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), (II), (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), (II), (III) or (IV) is administered topically.
  • a compound or salt of Formula (I), (II), (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), (II), (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), (II), (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), (II), (III) or (IV).
  • the rate of absorption is slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel.
  • absorption enhancers are used to increase absorption.
  • transdermal devices include absorbable pharmaceutically acceptable solvents that assist passage through the skin.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing a compound or salt of Formula (I), (II), (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), (II), (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), (II), (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), (II), (III) or (IV) and a suitable powder base such as lactose or starch.
  • a compound or salt of Formula (I), (II), (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), (II), (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),
  • 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), (II),
  • 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), (II), (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), (II), (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), (II), (III) or (IV) takes the form of a liquid where the agents are present in solution, in suspension or both.
  • 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), (II), (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, (1) 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), (II), (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/
  • the concentration of a compound or salt of Formula (I), (II), (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%, 7.2
  • the concentration of a compound or salt of Formula (I), (II), (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), (II), (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), (II), (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
  • the amount of a compound or salt of Formula (I), (II), (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,
  • 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), (II), (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 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.
  • 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.
  • 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), (II), (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 ⁇ 27 ⁇ 1 and/or pl8 INK4C mRNA levels; (c) a decrease in p27 ⁇ and/or pl8 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. /. 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. /. 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. /. 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), (II), (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), (II), (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), (II), (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-pro liferative 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), (II), (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 (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, ⁇ -adrenergic agonists, i
  • 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, ⁇ - adrenergic receptor antagonists, agents for the treatment of hypercholesterolemia, and agents for the treatment of dyslipidemia.
  • 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.
  • therapeutic agents include antimicrobial agents, sulfonamides, trimethoprim-sulfamethoxazole quinolones, and agents for urinary tract infections, penicillins, cephalosporins, and other, ⁇ -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.
  • therapeutic agents used for immunomodulation such as immunomodulators, immunosuppressive agents, tolerogens, and immuno stimulants are contemplated by the methods herein.
  • therapeutic agents acting on the blood and the blood-forming organs such as hematopoietic agents, growth factors, minerals, and vitamins, anticoagulant, thrombolytic, and antiplatelet drugs.
  • 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.
  • the methods described herein may comprise use of a compound of Formula (I), (II), (III) or (IV) in combination with other suitable agents.
  • the one or more compounds of the disclosure will be co- administered with other agents as described above.
  • 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.
  • a compound of the present disclosure can be administered just followed by and any of the agents described above, or vice versa.
  • 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.
  • Step A Preparation of Compound 59-2: To a solution of ethyl-2-(diethoxylphosphoryl) acetate (1.91 g, 8.5 mmol) in THF (30 mL) was added NaH (421 mg, 10.5 mmol) at 0 °C. The reaction was stirred at 0 °C for 0.5 hour before 59-1 (2 g, 8 mmol) was added. The reaction mixture was stirred at room temperature for 5h. Ice-water (50 mL) was added, and the product extracted with ethyl acetate (50 mL x 2). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (eluted 20% EtOAc in pet. ether) to afford 2.15 g of 59-2 as a white solid (yield: 85%).
  • Step B Preparation of Compound 59-3: To a solution of 59-2 (905 mg, 2.85 mmol) in MeOH (20 mL) was added (Boc ⁇ O (1.24 g, 5.71 mmol) and Pd/C catalyst. The reaction mixture was stirred at room temperature for 8 hours under 3 ⁇ 4. TLC showed the reaction was complete. The reaction was filtered and concentrated. The residue was purified by silica gel column chromatography (eluted 20% EtOAc in pet. ether) to give 59-3 as a solid (740 mg, yield: 91%).
  • Step C Preparation of Compound 59-4: To a solution of 59-3 (670 mg, 2.35 mmol) in THF (20 mL) was added L1AIH 4 (179 mg, 4.7 mmol) at 0 °C. The reaction was stirred at 0 °C for 2h, then 0.2 mL H 2 0, 0.2 mL 15% NaOH, and 0.5 mL H 2 0 added. The mixture was stirred at room temperature for lh. The mixture was filtered and the organic solution was concentrated. The residue was purified by silica gel column chromatography (eluted 40% EtOAc in pet. ether) to give 59-4 as a solid (525 mg, yield: 92%).
  • Step D Preparation of Compound 59-5 : To a solution of 59-4 (486 mg, 2 mmol) and Et 3 N (404 mg, 4 mmol) in CH 2 C1 2 (20 mL) was added MsCl (344 mg, 3 mmol) at 0 °C. The reaction was stirred at room temperature for lh. TLC showed the reaction was complete. The combined organic layer was washed with 3 ⁇ 40 and brine, dried over sodium sulfate and concentrated in vacuo to afford 500 mg of 59-5 as a white solid (yield: 78%).
  • Step E Preparation of Compound 59-6: A mixture of 59-5 (500 mg, 1.56 mmol), CS2CO 3 (846 mg, 2.33 mmol), and 5-formyl-4-methyl-lH-indole-2-carbonitrile (143 mg, 0.78 mmol) was mixed in DMF (20 mL). The reaction mixture was heated at 85 °C for 3h. EtOAc (200 mL) was added into the resulting mixture. The combined organic layer was washed with 3 ⁇ 40 and brine, dried over sodium sulfate and concentrated. The residue was purified by flash column (eluted 30% EtOAc in pet. ether) to afford 278 mg of 59-6 as a white solid (yield: 43%).
  • Step F Preparation of Compound 59-7: A mixture of 59-6 (278 mg, 0.68 mmol), N- (piperidin-4-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-amine (280 mg, 0.88 mmol) and Et 3 N (412 mg, 4.08 mmol) in CH2CI2 (20 mL) was stirred at room temperature for 1 hour.
  • Step G Preparation of Compound 59-8: A solution of 59-7 (200 mg, 0.28 mmol) in TFA (15 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 resulting mixture was concentrated and the residue was purified by silica gel column chromatography (eluted 10% MeOH in dichloromethane) to give 59-8 as an oil (164 mg, yield: 96%).
  • Step H Preparation of Compound 59: To a solution of 59-8 (127 mg, 0.21 mmol) and Et 3 N (43mg, 0.42mmol) in CH 2 C1 2 (20 mL) was added MsCl (29 mg, 0.25 mmol) at 0 °C. The reaction was stirred at room temperature for lh. TLC showed the reaction was complete. The combined organic layer was washed with 3 ⁇ 40 and brine, dried over sodium sulfate, and concentrated in vacuo to afford 45 mg of 59 as a white solid (yield: 31%).
  • 1 H1S1MR 400
  • Step A Preparation of Compound 48-2: A mixture of 48-1 (300 mg, 1.40 mmol), 2- bromoethanol (347 mg, 2.80 mmol) and K 2 C0 3 (772 mg, 5.60 mmol) in CH 3 CN (30 mL) was stirred at 90 °C under N2 overnight. TLC showed the reaction was complete. Solid was removed by filtration and solvent was removed under vacuum. The residue was purified by silica gel column chromatography (eluted 2.5 % MeOH in dichloromethane) to give 48-2 as a yellow oil (296 mg, yield: 82%).
  • Step B Preparation of Compound 48-3 : To a mixture of 48-2 (296 mg, 1.15 mmol) and Et 3 N (232 mg, 2.30 mmol) in dichloromethane (20 mL) was added MsCl (197 mg, 1.73 mmol) at 0 °C. The reaction mixture was stirred at room temperature for lh. TLC showed the reaction was complete. Saturated aqueous NaHC0 3 was added to the reaction mixture. The organic layer was separated, washed with brine, dried over anhydrous Na 2 S0 4 , and concentrated. The residue was purified by silica gel column chromatography (eluted petroleum) to give 48-3 as an oil (270 mg, yield: 70%).
  • Step C Preparation of Compound 48-4: A mixture of 48-3 (270 mg, 0.8 mmol), 5- formyl-4-methyl-lH-indole-2-carbonitrile (123mg, 0.67 mmol) and CS 2 CO 3 (524 mg, 1.6 mmol) in DMF (10 mL) was stirred at 80 °C under N 2 overnight. Solid was removed by filtration before the reaction mixture was diluted with water and ethyl acetate.
  • Step D Preparation of Compound 48-5 : A mixture of 48-4 (169 mg, 0.4 mmol), N- (piperidin-4-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-amine (190 mg, 0.6 mmol) and Et 3 N (242 mg, 2.4 mmol) in CH 2 CI 2 (20 mL) was stirred at room temperature for 1 hour.
  • Step E Preparation of Compound 48-6: To a solution of 48-5 (174 mg, 0.24 mmol) in CH 2 CI 2 (15 mL) was added TFA (5 mL). The reaction was stirred at room temperature for 2 hours before solvent was removed. A solution of N]3 ⁇ 4/MeOH (7N, 10 mL) was added and the resulting mixture was concentrated. The residue and purified by silica gel column
  • Step F Preparation of Compound 48: To a mixture of 48-6 (120 mg, 0.192 mmol) and Et 3 N (39 mg, 0.384mmol) in CH 2 CI 2 (10 mL) was added slowly methanesulfonyl chloride (33 mg, 0.288 mmol) in CH 2 CI 2 (5mL) at -20 °C under N 2 . The reaction mixture was stirred at room temperature for 2 hours. TLC showed the reaction was complete. Saturated aqueous NaHC0 3 was added to the reaction mixture.
  • Step A Preparation of Compound 2-2: To a suspension of K 2 CO 3 (3.6 g, 26.5 mmol) and tert-butyl piperazine- 1 -carboxylate (1.0 g, 5.3 mmol) in CH 3 CN (15 mL) was added methyl 2- bromopropanoate (2.2 g, 13.4 mmol). The reaction was stirred at 80 °C for 10 hours. TLC showed that the reaction was complete. The reaction mixture was allowed to cool to room temperature, then the solid filtered off and solvent removed under vacuum.
  • Step B Preparation of Compound 2-3: To a solution of tert-butyl 4-(l-methoxy-l- oxopropan-2-yl)piperazine-l -carboxylate (540 mg, 2 mmol) in THF (10 mL) was added L1AIH 4
  • Step C Preparation of Compound 2-5: To a solution of tert-butyl 4-(l -hydro ypropan-2- yl)piperazine-l-carboxylate (200 mg, 0.82 mmol) and Et 3 N (171 mg, 1.64 mmol) in CH 2 C1 2 (10 mL) was added MsCl (112 mg, 0.98 mmol) at 0 °C. The reaction was stirred at room temperature for 30 min. The reaction was quenched with NaHC03, washed with brine and dried over Na 2 S0 4 . Solvent was removed under vacuum to give tert-butyl 4-(l-((methylsulfonyl)oxy)propan-2- yl)piperazine-l-carboxylate (2-4), used in the next step without further purification.
  • Step D Preparation of Compound 2-6: A mixture of tert-butyl 4-(l-(2-cyano-5-formyl-4- methyl-lH-indol-l-yl)propan-2-yl)piperazine-l-carboxylate (90 mg, 0.22 mmol), 6-(2,2,2- trifluoroethyl)-N-(piperidin-4-yl)thieno-[2,3-d]pyrimidin-4-amine (100 mg, 0.26 mmol) and Et 3 N (130 mg, 1.32 mmol) in CH 2 CI 2 (10 mL) was stirred at room temperature for 1 hour before NaBH(OAc)3 (280 mg, 1.32 mmol) was added.
  • Step E Preparation of Compound 2-7: 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-l-yl)methyl)- lH-indol-l-yl)-l-hydroxyethyl)piperidine-l-carboxylate (130 mg, 0.21 mmol) in CH 2 CI 2 (3 mL) was added TFA (2 mL). The reaction was stirred for 4 hours before solvent was removed under vacuum.
  • Step F Preparation of Compound 2: To a solution of 4-methyl-l-(2-(piperazin-l- yl)propyl)-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-l- yl)methyl)-lH-indole-2-carbonitrile (60 mg, 0.1 mmol) and Et 3 N (36 mg, 0.4 mmol) in CH 2 CI 2 (10 mL) was added MsCl (21 mg, 0.2 mmol) at 0 °C. The reaction was stirred at room temperature for 30 min.
  • Step A Preparation of Compound 61-2: A mixture of ethyl 1- aminocyclopropanecarboxylate hydrochloride (2.4 g, 14.5mmol), N-benzyl-2-chloro-N-(2- chloroethyl)ethanamine hydrochloride (4.26 g, 15.8 mmol), and N,N-Diisopropylethylamine (25 mL) in ethanol (32 mL) was stirred at reflux for 16 hours. The reaction mixture was concentrated to dryness. The residue was partitioned between dichloromethane and water. Two layers were separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were concentrated.
  • Step C Preparation of Compound 61-4: A mixture of (l-(4-benzylpiperazin-l- yl)cyclopropyl)methanol (600 mg, 2.4 mmol) and Pd/C (10%, 50 mg) in ethanol (10 mL) was stirred at 50 °C overnight under 3 ⁇ 4. The reaction mixture was filtered and the filtrate concentrated to give (l-(piperazin-l-yl)cyclopropyl)methanol (61-4) as an oil (400 mg, yield: 96%). The crude product was used in the next step without further purification.
  • Step D Preparation of Compound 61-5 : To a mixture of (l-(piperazin-l- yl)cyclopropyl)methanol (400 mg, 2.5 mmol) in dichloromethane (10 mL) was added Et 3 N (1.1 mL, 7.5 mmol), followed by a mixture of methanesulfonyl chloride (925 mg, 7.5 mmol) in dichloromethane (5 mL). The resulting mixture was stirred at room temperature for 4h. The reaction mixture was diluted with water and CH 2 CI 2 .
  • Step E Preparation of Compound 61-6: A mixture of crude (l-(4- (methylsulfonyl)piperazin-l-yl)cyclopropyl)methyl methanesulfonate (500 mg), 5-formyl-4- methyl-lH-indole-2-carbonitrile (200 mg, 1.1 mmol), and K 2 CO 3 (800 mg, 5.8 mmol) in acetonitrile was stirred at 80 °C overnight. The mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by silica gel column (pet.
  • Step F Preparation of Compound 61 : A mixture of 5-formyl-4-methyl-l-((l-(4- (methylsulfonyl)piperazin-l-yl)cyclopropyl)methyl)-lH-indole-2-carbonitrile (330 mg, crude), N-(piperidin-4-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-amine hydrochloride (391 mg, 1.1 mmol), and Et 3 N (0.5 mL) in dichloromethane (12 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water and CH 2 CI 2 .
  • Step A Preparation of Compound 35-2: A mixture of tert-butyl piperazine- 1 -carboxylate (1.9 g, 10 mmol) and Et 3 N (3 g, 30 mmol) in CH 2 C1 2 (40 mL) was stirred at 0 °C before 2- chloroacetyl chloride (2.2 g, 20 mmol) was added slowly. The reaction mixture was stirred at 0 °C under N 2 for 4 nr. TLC showed that the reaction was complete. The reaction mixture was partitioned between CH 2 CI 2 and J3 ⁇ 40, and the organic layer was washed with brine and dried over Na 2 S0 4 . Solvent was removed under vacuum and the residue (35-2) was used without further purifications as light yellow oil (2.5 g, yield: 95%).
  • Step B Preparation of Compound 35-3: To a mixture of N-(piperidin-4-yl)-6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidin-4-amine (1 g, 4 mmol), and 5-formyl-4-methyl-lH-indole- 2-carbonitrile (540 mg, 3 mmol) in THF (10 mL) was added NaH (180 mg, 4.5 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then partitioned between EtOAc and H 2 O, and the organic layer was washed with brine and dried over Na 2 S0 4 .
  • Step C Preparation of Compound 35-4: A mixture of methyl tert-butyl 4-(2-(2-cyano-5- formyl-4-methyl-lH-indol-l-yl)acetyl)piperazine-l-carboxylate (40 mg, 0.1 mmol), N- (piperidin-4-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-amine hydrochloride (60 mg, 0.2 mmol) and Et 3 N (60 mg, 0.6 mmol) in CH 2 CI 2 (5 mL) was stirred at room temperature for 2 hours.
  • NaBH(OAc)3 120 mg, 0.6 mmol was then added to the reaction with ice bath cooling. The reaction mixture was stirred at room temperature overnight. The reaction was partitioned between CH2CI2 and NaHCCh, and the organic layer was washed with brine and dried over Na2S0 4 .
  • Step D Preparation of Compound 35-5 : 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-l-yl)methyl)-lH- indol-l-yl)acetyl)piperazine-l-carboxylate (40 mg, 0.06 mmol) in HCl MeOH (10 mL) was stirred at room temperature for 16h. TLC showed that the reaction was complete. Solvent was removed under vacuum and the residue (35-5) was used without further purification in next step as a yellow solid (35 mg, yield: 85%).
  • Step E Preparation of Compound 35: To a mixture of 4-methyl-l-(2-oxo-2-(piperazin-l- yl)ethyl)-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-l- yl)methyl)-lH-indole-2-carbonitrile(35 mg, 0.05 mmol) and Et 3 N (15 mg, 0.15 mmol) in CH2CI2 (10 mL) was slowly added MsCl(12 mg, 0.1 mmol) at 0 °C.
  • Example 6 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 IC 50 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.
  • FP Fluorescence polarization
  • 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 IC 50 determination.
  • Table 4 shows biological activities of selected compounds in a fluorescence polarization assay.
  • Compound numbers correspond to the numbers and structures provided in Table 1 and Examples 1-5.
  • Example 7 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.
  • 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 (Eu 3+ -cryptate) donor to the
  • allophycocyanin (XL665) acceptor combined with time-resolved detection.
  • An Eu 3+ -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).
  • streptavidin which binds biotinylated MLL peptide.
  • Example 8 Menin engagement assay. Sample Preparation: 2.5 of 100 ⁇ compound is added to 47.5 ⁇ . of 526 nM menin in PBS (5 ⁇ 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 ⁇ 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 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
  • MaxEntl 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.
  • Example 9 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 ⁇ ) 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 ⁇ ; 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).
  • Example 10 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.
  • RPMI medium Invitrogen
  • FBS Thermo Scientific
  • 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.
  • Example 11 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
  • FIG. 4A-4E depict confocal images of rat primary dispersed islet cells treated with Compound 132, Compound 135, Compound 9, Compound 10, and no compound, respectively.
  • the rat primary dispersed islet cells were treated with Compound 132 (FIG. 4A), Compound 135 (FIG. 4B), Compound 9 (FIG. 4C), Compound 10 (FIG. 4D), and no compound (FIG. 4E).
  • 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
  • the portions in blue represent the cells that were stained with Hoechst.
  • FIG. 5A-5D depict the change in beta cell proliferation for rat primary dispersed islet cells treated with Compound 132 (FIG. 5A), Compound 135 (FIG. 5B), Compound 9 (FIG. 5C), and Compound 10 (FIG. 5D).
  • the x-axis represents the concentration of compound in ⁇ .
  • the % Edu + Insulin gradually increases in the presence of increased concentrations of Compound 132, and at a Compound 132 concentration of 0.8 ⁇ , the % Edu + Insulin is approximately 39%.
  • FIG. 5B the % Edu + Insulin gradually increases in the presence of increased concentrations of Compound 135, and at a Compound 135
  • the % Edu + Insulin is approximately 32%.
  • the % Edu + Insulin reaches a maximum of approximately 15% at a Compound 9 concentration of 0.05 ⁇ . Thereafter, the % Edu + Insulin gradually decreases at increased concentrations and at a
  • Example 12 Human islet proliferation assay. Freshly-isolated explants of non-diabetic, human pancreatic islets were cultured in the presence of DMSO or a compound disclosed herein for 120 hours in growth medium containing 10 ⁇ EdU (1000 islet equivalents per sample). Islets were fixed and stained by immunofluorescence for insulin and EdU. Beta cell proliferation, islet area, and average beta cell number per islet were assessed in accordance with methods described herein. As reported in Table 5, treatment with a menin inhibitor disclosed herein in Table 1 induced beta cell proliferation, increased the size of human islets, and increased the average beta cell number per islet.
  • Example 13 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 NBl 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.
  • islets are cultured in Connaught Medical Research Laboratories 1066 medium (pH 7.4) with 0.5% human serum albumin and 0.1 ⁇ g/mL insulin-like growth factor-1 at 37 °C under 5% C0 2 for up to 72 hours.

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. 62/431,405, 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 p27Ktpl and pl8INK4C 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 administering a compound of Formula (I):
Figure imgf000004_0001
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
H is selected from C5-i2 carbocycle and 5- to 12-membered heterocycle, each of which is optionally substituted with one or more R50;
A is selected from bond, C3-12 carbocycle and 3- to 12-membered heterocycle;
B is selected from C3-i2 carbocycle and 3- to 12-membered heterocycle;
C is 3- to 12-membered heterocycle;
L1, L2 and L3 are each independently selected from bond, -0-, -S-, -N(R51)-, -N(R51)CH2-, -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(0)N(R51)-, -C(0)N(R51)C(0)-, - C(0)N(R51)C(0)N(R51)-, -N(R51)C(0 , -N(R51)C(0)N(R51)-, -N(R51)C(0)0-, -OC(0)N(R51)-, - C(NR51)-, -N(R51)C(NR51)-, -C(NR51)N(R51)-, -N(R51)C(NR51)N(R51)-, -S(0)2-, -OS(O)-, - S(0)0-, -S(0 , -OS(0)2-, -S(0)20-, -N(R51)S(0)2-, -S(0)2N(R51)-, -N(R51)S(0 , -S(0)N(R51)-, -N(R51)S(0)2N(R51)-, -N(R51)S(0)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;
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, n and p are each independently an integer from 0 to 6; independently selected at each occurrence from:
halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52);
Ci-io alkyl, C2-io alkenyl, and C2-io alkynyl, each of which is
independently optionally substituted at each occurrence with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54 -S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; and
C3-i2 carbocycle and 3- to 12-membered heterocycle,
wherein each C3-i2 carbocycle and 3- to 12-membered heterocycle in R50 is independently optionally substituted with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), Ci_6 alkyl, Ci_6 haloalkyl, C2_ alkenyl, and C2_6 alkynyl;
independently selected at each occurrence from:
hydrogen, -C(0)R52, -C(0)OR52, -C(0)N(R52)2, -C(0)NR53R54;
Ci-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, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R , -S(=0)2N(R3Z)2, -S(=0)2NR3JR , -NR3ZS(=0)2R , - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C3-12 carbocycle and 3- to 12- membered heterocycle; and
C3-i2 carbocycle and 3- to 12-membered heterocycle, wherein each C3-i2 carbocycle and 3- to 12-membered heterocycle in R51 is independently optionally substituted with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), d_6 alkyl, d_6 haloalkyl, C2_6 alkenyl, and C2_6 alkynyl;
R52 is independently selected at each occurrence from hydrogen; and Ci-20 alkyl, C2_2o alkenyl, C2-20 alkynyl, 1- to 6-membered heteroalkyl, C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -N02, -NH2, -NHCH3, - NHCH2CH3, =0, -OH, -OCH3, -OCH2CH3, C3_i2 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;
R57 is selected from:
halogen, -N02, -CN, -SR52, -NR53R54, -S(=0)R52, -S(=0)2R58, - S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, -NR52S(=0)2N(R52)2, - NR52S(=0)2NR53R54, -C(0)OR52, -OC(0)R52, -OC(0)OR52, -OC(0)N(R52)2, - OC(0)NR53R54, -NR52C(0)OR52, -NR52C(0)N(R52)2, - NR52C(0)NR53R54, -C(0)NH(Ci_6 alkyl), -C(0)NR53R54, -P(0)(OR52)2, - P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =S, =N(R52); and
Ci-io alkyl, C2-io alkenyl, and C2-io alkynyl, each of which is
independently substituted at each occurrence with one or more substituents selected from -N02, -CN, -SR , -N(R3Z)2, -NR R , -S(=0)R , -S(=0)2R , - S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, -NR52S(=0)2N(R52)2, - NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, -OC(0)OR52, - OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -P(0)(OR52)2, -P(0)(R52)2, - P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), -P(0)(NR52)(OR52), - P(0)(NR52)2, =S, and =N(R52); and
58
R is selected from hydrogen; and Ci-20 alkyl, C3-20 alkenyl, C2-20 alkynyl, 1- to 6- membered heteroalkyl, C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -N02, -NH2, -NHCH3, -NHCH2CH3, =0, -OH, -OCH3, - OCH2CH3, C3-i2 carbocycle, or 3- to 6-membered heterocycle,
wherein for a compound or salt of Formula (I), when C is azetidinylene, piperidinylene or piperazinylene and R57 is -S(=0)2R58, -S(=0)2N(R52)2, or -NR52S(=0)2R52:
p is an integer from 1 to 6; and/or
3 50 3
L is substituted with one or more R , wherein V is not -CH2CH(OH)-.
[0010] In one aspect, the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising :
Figure imgf000007_0001
or a pharmaceutically acceptable salt thereof, wherein:
H is selected from C5-i2 carbocycle and 5- to 12-membered heterocycle, each of which is optionally substituted with one or more R50;
A, B and C are each independently selected from C3-i2 carbocycle and 3- to 12-membered heterocycle;
L1 and L2 are each independently selected from bond, -0-, -S-, -N(R51)-, -N(R51)CH2-, - C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(0)N(R51)-, -C(0)N(R51)C(0)-, - C(0)N(R51)C(0)N(R51)-, -N(R51)C(0 , -N(R51)C(0)N(R51)-, -N(R51)C(0)0-, -OC(0)N(R51)-, - C(NR51)-, -N(R51)C(NR51)-, -C(NR51)N(R51)-, -N(R51)C(NR51)N(R51)-, -S(0)2_, -OS(O)-, - S(0)0-, -S(O)-, -OS(0)2-, -S(0)20-, -N(R51)S(0)2-, -S(0)2N(R51)-, -N(R51)S(0)-, -S(0)N(R51)-, -N(R51)S(0)2N(R51)-, -N(R51)S(0)N(R51)-; alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is optionally substituted with one or more L3 is selected from alkylene, alkenylene, and alkynylene, each of which is substituted with one or more R56 and optionally further 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, n and p are each independently an integer from 0 to 6;
R50 is independently selected at each occurrence from:
halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52);
Ci-io alkyl, C2_io alkenyl, and C2_io alkynyl, each of which is
independently optionally substituted at each occurrence with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; and
C3-i2 carbocycle and 3- to 12-membered heterocycle, wherein each C3-i2 carbocycle and 3- to 12-membered heterocycle in R50 is independently optionally substituted with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR3Z)(OR3Z), -P(0)(NR3Z)2, =0, =S, =N(R3Z), Ci_6 alkyl, Ci_6 haloalkyl, C2_ alkenyl, and C2-6 alkynyl;
R51 is independently selected at each occurrence from:
hydrogen, -C(0)R52, -C(0)OR52, -C(0)N(R52)2, -C(0)NR53R54;
Ci-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, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C3-12 carbocycle and 3- to 12- membered heterocycle; and
C3-i2 carbocycle and 3- to 12-membered heterocycle, wherein each C3-i2 carbocycle and 3- to 12-membered heterocycle in R51 is independently optionally substituted with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), Ci_6 alkyl, Ci_6 haloalkyl, C2_ alkenyl, and C2-6 alkynyl;
R52 is independently selected at each occurrence from hydrogen; and Ci-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, 1- to 6-membered heteroalkyl, C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -N02, -NH2, -NHCH3, - NHCH2CH3, =0, -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;
R56 is independently selected at each occurrence from:
-N02, -OR59, -SR52, -NR53R54, -S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, - S(=0)2NR53R54, -NR52S(=0)2R52, -NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, - C(0)R , -C(0)OR , -OC(0)R , -OC(0)OR , -OC(0)N(R3Z)2, -OC(0)NR3JR , -NR52C(0)R52, -NR52C(0)OR52, -NR52C(0)N(R52)2, -
NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, -P(0)(OR52)2, -P(0)(R52)2, - P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), -P(0)(NR52)(OR52), - P(0)(NR52)2, =0, =S, =N(R52), CLIO alkyl, C2_10 alkenyl, C2_10 alkynyl, C3- 12 carbocycle and 3- to 12-membered heterocycle,
wherein each Ci_io alkyl, C2-io alkenyl, and C2-io alkynyl in R56 is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -N02, -CN, -OR59, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle;
wherein each C3-i2 carbocycle and 3- to 12-membered heterocycle in R56 is independently optionally substituted with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C1-6 alkyl, C1-6 haloalkyl, C2.6 alkenyl, and C2-6 alkynyl; and
further wherein R56 optionally forms a bond to ring C; and
R59 is independently selected at each occurrence from Ci-20 alkyl, C2_2o alkenyl, C2_2o alkynyl, 1- to 6-membered heteroalkyl, C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -N02, -NH2, -NHCH3, -NHCH2CH3, =0, -OH, -OCH3, -OCH2CH3, C3-i2 carbocycle, or 3- to 6-membered heterocycle,
wherein for a compound or salt of Formula (II), when R56 is -CH3, L3 is not further substituted with -OH, -NH2, or -CN.
[0011] In some embodiments, for a compound of Formula (II), Rc is selected from -C(0)R52, - S(=0)R , -S(=0)2R , -S(=0)2N(R3Z)2, -S(=0)2NR3JR , -NR3ZS(=0)2R , =0, Ci_3 alkyl, and Ci-3 haloalkyl, or two Rc groups attached to different atoms can together form a C1-3 bridge.
[0012] For a compound of Formula (I) or (II), C may be 5- to 12-membered heterocycle, wherein the heterocycle comprises at least one nitrogen atom. In some embodiments, the heterocycle is saturated. In some embodiments, the heterocycle is selected from piperidinyl and piperazinyl.
[0013] In some embodiments, for a compound of Formula (I), C is selected from
Figure imgf000011_0001
Figure imgf000011_0002
and . In some embodiments, R is selected from 32, -S(=0)2R3S, -S(=0)2N(R32)2, and -NR32S(=0)2R32.
Figure imgf000011_0003
S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52; and C1-10 alkyl substituted with one or more substituents selected from -S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, and -NR52S(=0)2R52. In some embodiments, R57 is selected from -S(=0)R52, -S(=0)2R52, - S(=0)2N(R52)2, and -NR52S(=0)2R52. In some embodiments, R57 is selected from -S(=0)CH3, - S(=0)2CH3, -S(=0)2NH2, -NHS(=0)2CH3, and -S(=0)2NHCH3.
[0015] For a compound of Formula (I) or (II), Rc may be selected from Ci_3 alkyl and Ci_3 haloalkyl.
[0016] In some embodiments, for a compound of Formula (I) or (II), H is 5- to 12-membered heterocycle, optionally substituted with one or more R50; A is 3- to 12-membered heterocycle; and B is 3- to 12-membered heterocycle.
[0017] For a compound of Formula (I) or (II), H may be 6- to 12-membered bicyclic
heterocycle, optionally substituted with one or more R50. In some embodiments, H is
thienopyrimidinyl, optionally substituted with one or more R50. In some embodiments, H is
Figure imgf000012_0001
each independently selected from C and N; Y1 and Y2 are each independently selected from CR3, N, NR4, O, and S; R1, R2 and R3 are each 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, X1 is CR2, and R2 is selected from hydrogen, halogen, -OH, -OR52, -NH2, - N(R52)2, -CN, d_3 alkyl, -CH2OH, -CH2OR52, -CH2NH2, -CH2N(R52)2, d_3 alkyl-N(R52)2, d_3 haloalkyl, C2_3 alkenyl, and C2_3 alkynyl. In some embodiments, X2 is N. In some embodiments, Y2 is CR3, and R3 is selected from hydrogen, halogen, -OH, -N(R52)2, -CN, -C(0)OR52, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R1 is C1-3 haloalkyl.
[0018] For a compound of Formula (I) or (II), A may be 5- to 8-membered heterocycle, such as 6-membered monocyclic heterocycle. In some embodiments, the heterocycle comprises at least
In some embodiments, A is selected from piperidinylene and piperazinylene,
Figure imgf000012_0002
such as 'm
[0019] For a compound of Formula (I) or (II), B may be 6- to 12-membered bicyclic heterocycle. In some embodiments, the heterocycle comprises at least one nitrogen atom. In some
Figure imgf000012_0003
embodiments, B is indolylene, such optionally substituted with one or more R .
[0020] In some embodiments, for a compound of Formula (I) or (II), H is thienopyrimidinyl substituted with one or more R50; A is selected from piperidinylene and piperazinylene; and B is indolylene.
[0021] For a compound of Formula (I) or (II), H may be substituted with -CH2CF3. In some embodiments, m is 0. In some embodiments, n is an integer from 1 to 3. In some embodiments, L1 comprises less than 10 atoms. In some embodiments, L1 is -N(R51)-. In some embodiments, L2 comprises less than 10 atoms. In some embodiments, L2 is C1-4 alkylene, optionally substituted with one or more R50. In some embodiments, L2 is selected from -CH2-, -N(R51)-, -N(R51)CH2-, - N(R51)C(0 , and -N(R51)S(0)2-. In some embodiments, L comprises less than 20 atoms. In
3 50
some embodiments, L is C 1-6 alkylene, optionally substituted with one or more RJU. In some embodiments, L3 is C2 alkylene substituted with at least one C1-3 alkyl or C1-3 haloalkyl, and optionally further substituted with one or more R50. In some embodiments, L3 is substituted with =0, Ci_6 alkyl, Ci_6 haloalkyl, Ci_3 alkyl(cyclopropyl), Ci_3 alkyl(NR3ZC(0)R3Z) or -0(Ci_6 In some embodiments, L3 is substituted with -C¾. In some embodiments, a compound of Formula (I) or (II) is selected from Tabl
[0022] For a compound of Formula (I),
R50 is methyl. In some embodiments, for
Figure imgf000013_0001
a compound of Formula (II), L3 is selec and
Figure imgf000013_0002
. Optionally, R is methyl. In certain aspects, the present disclosure provides a substantially pure stereoisomer of a compound of Formula (I) or (II). Optionally, the
stereoisomer is provided in at least 90% enantiomeric excess.
[0023] In some embodiments, for a compound of Formula (I) or (II), H is thienopyrimidinyl, optionally substituted with one or more R50; A is 3- to 12-membered heterocycle; B is 6- to 12- membered bicyclic heterocycle; m is an integer from 0 to 3 ; and n is an integer from 1 to 3.
[0024] In some embodiments, for a compound of Formula (I):
H is thienopyrimidinyl, optionally substituted with one or more R50;
A is selected from piperidinylene and piperazinylene;
B is indolylene;
L1 and L2 are each independently selected from -0-, -S-, -NH-, and -CH2-;
L3 is selected from bond, -0-, -S-, -N(R51)-, -N(R51)CH2-, -C(O)-, -C(0)0-, -OC(O)-, - OC(0)0-, -C(0)N(R51)-, -C(0)N(R51)C(0)-, -C(0)N(R51)C(0)N(R51)-, -N(R51)C(0)-, - N(R51)C(0)N(R51)-, -N(R51)C(0)0-, -OC(0)N(R51)-, -C(NR51)-, -N(R51)C(NR51)-, - C(NR51)N(R51)-, -N(R51)C(NR51)N(R51)-, -S(0)2-, -OS(O)-, -S(0)0-, -S(0 , -OS(0)2-, -S(0)20-, -N(R51)S(0)2-, -S(0)2N(R51)-, -N(R51)S(0)-, -S(0)N(R51)-, -N(R51)S(0)2N(R51)-, - N(R51)S(0)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 1 to 3 ;
p is an integer from 0 to 6;
R57 is selected from:
-S(=0)R , -S(=0)2R , -S(=0)2N(R3Z)2, -S(=0)2NR3JR , - NR3ZS(=0)2R , -NR3ZS(=0)2N(R3Z)2, -NR3ZS(=0)2NR3JR , -NR3ZC(0)N(R3Z)2, - NR52C(0)NR53R54, -C(0)NH(Ci_6 alkyl), -C(0)NR53R54, -P(0)(OR52)2, - P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2; and
Ci-io alkyl, C2_io alkenyl, and C2_io alkynyl, each of which is
independently substituted at each occurrence with one or more substituents selected from -S(=0)R52, -S(=0)2R58, -S(=0)2N(R52)2, -S(=0)2NR53R54, - NR52S(=0)2R52, -NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -NR52C(0)N(R52)2, - NR52C(0)NR53R54, -C(0)NH(Ci-6 alkyl), -C(0)NR53R54, -P(0)(OR52)2, and - P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2; and
58
R is selected from hydrogen; and Ci_2o alkyl, C3_2o alkenyl, C2_2o alkynyl, 1- to 6- membered heteroalkyl, C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -N02, -NH2, -NHCH3, -NHCH2CH3, =0, -OH, -OCH3, - OCH2CH3, C3-i2 carbocycle, or 3- to 6-membered heterocycle.
[0025] In some embodiments, for a compound of Formula (II):
H is thienopyrimidinyl, optionally substituted with one or more R50;
A is selected from piperidinylene and piperazinylene;
B is indolylene;
L1 and L2 are each independently selected from -0-, -S-, -NH-, and -CH2-;
L3 is selected from Ci-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene, each of which is substituted with one or more R56 and optionally further 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 1 to 3 ;
p is an integer from 0 to 6;
R56 is independently selected at each occurrence from:
-OR59, =0, Ci-io alkyl, C2-io alkenyl, and C2-io alkynyl, wherein each Ci-io alkyl, C2-io alkenyl, and C2-io alkynyl in R56 is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -N02, -CN, -OR59, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR3ZS(=0)2N(R3Z)2, -NR3ZS(=0)2NR3JR , -C(0)R , -C(0)OR , -OC(0)R , - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C3-12 carbocycle, and 3- to
12-membered heterocycle;
wherein each C3-i2 carbocycle and 3- to 12-membered heterocycle is independently optionally substituted with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C1-6 alkyl, C1-6 haloalkyl, C2.6 alkenyl, and C2_6 alkynyl; and
further wherein R optionally forms a bond to ring C; and
R59 is independently selected at each occurrence from Ci-20 alkyl, C2_2o alkenyl, C2_2o alkynyl, 1- to 6-membered heteroalkyl, C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -N02, -NH2, -NHCH3, -NHCH2CH3, =0, -OH, -OCH3, -OCH2CH3, C3-i2 carbocycle, or 3- to 6-membered heterocycle.
[0026] For a compound of Formula (I), R57 may be selected from -S(=0)2R58, -S(=0)2N(R52)2, and -S(=0)2NR53R54, such as -S(=0)2CH3 and -S(=0)2NHCH3. For a compound of Formula (II), C may be substituted with -S(=0)2R58, -S(=0)2N(R52)2, or -S(=0)2NR53R54
[0027] In some embodiments, for a compound of Formula (I) or (II), H is
Figure imgf000015_0001
and R2 is selected from hydrogen, halogen, -OH, -OR52, -NH2, -N(R52)2, -CN, Ci_3 alkyl, Ci_3 alkyl-N(R52)2, Ci-3 haloalkyl, C2_3 alkenyl, and C2_3 alkynyl. Optionally, R2 is selected from - -CH3, and -NHCH3. In some embodiments, for a compound of Formula (I) or (II), H is
Figure imgf000015_0002
and R2 is selected from hydrogen, halogen, -OH, -OR52, -NH2, -N(R52)2, -
CN, Ci_3 alkyl, Ci_3 alkyl-OR52, Ci_3 alkyl-N(R52)2, Ci_3 haloalkyl, C2_3 alkenyl, and C2_3 alkynyl. Optionally, R2 is selected from -NH2, -CH3, -OCH3, -CH2OH, and -NHCH3. For a compound of Formula (I) or (II), L3 may be selected from and
Figure imgf000016_0001
[0028] In certain aspects, the present disclosure provides a method of promoting proliferation of a pancreatic cell, compris :
Figure imgf000016_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 optionall substituted with one or more R50;
Figure imgf000016_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(0)-, wherein no more than one of Z1, Z2, Z3, and Z4 is -C(O)- or -C(RA1)(RA2)-C(0)-;
B is selected from bond, C3-i2 carbocycle and 3- to 12-membered heterocycle;
C is selected from bond, C3-i2 carbocycle and 3- to 12-membered heterocycle;
L1, L2 and L3 are each independently selected from bond, -0-, -S-, -N(R51)-, -N(R51)CH2-, -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(0)N(R51)-, -C(0)N(R51)C(0)-, - C(0)N(R51)C(0)N(R51)-, -N(R51)C(0)-, -N(R51)C(0)N(R51)-, -N(R51)C(0)0-, -OC(0)N(R51)-, - C(NR51)-, -N(R51)C(NR51)-, -C(NR51)N(R51)-, -N(R51)C(NR51)N(R51)-, -S(0)2-, -OS(O)-, - S(0)0-, -S(O)-, -OS(0)2-, -S(0)20-, -N(R51)S(0)2-, -S(0)2N(R51)-, -N(R51)S(0)-, -S(0)N(R51)-, -N(R51)S(0)2N(R51)-, -N(R51)S(0)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;
C 50 C
R is independently selected at each occurrence from hydrogen and R , or two R groups attached to the same atom or different atoms can together optionally form a bridge or ring;
RA1 and R^ are each independently selected at each occurrence from hydrogen and R ; 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, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52);
Ci-io alkyl, C2_io alkenyl, and C2_io alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; and
C3-i2 carbocycle and 3- to 12-membered heterocycle,
wherein each C3-i2 carbocycle and 3- to 12-membered heterocycle in R50 is independently optionally substituted with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), d_6 alkyl, d_6 haloalkyl, C2_6 alkenyl, and C2-6 alkynyl;
independently selected at each occurrence from:
hhyyddrrooggeenn,, --CC((00))RR5322,, --CC((00))OORR5322,, --CC((00))IN(R32)2, -C(0)NR3JR34;
Ci-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, -N02, -CN, -OR , -SR , -N(R3Z)2, -NR R , -S(=0)R , - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C3-12 carbocycle and 3- to 12- membered heterocycle; and
C3-i2 carbocycle and 3- to 12-membered heterocycle, wherein each C3-i2 carbocycle and 3- to 12-membered heterocycle in R51 is independently optionally substituted with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), d_6 alkyl, d_6 haloalkyl, C2_6 alkenyl, and C2-6 alkynyl;
R is independently selected at each occurrence from hydrogen; and Ci-20 alkyl, C2-20 alkenyl, C2_2o alkynyl, 1- to 6-membered heteroalkyl, C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -N02, -NH2, -NHCH3, - NHCH2CH3, =0, -OH, -OCH3, -OCH2CH3, C3_i2 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.
[0029] In certain aspects, the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising administerin a compound of Formula (IV):
Figure imgf000018_0001
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
Figure imgf000019_0001
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(=0)-, -C(=0)-0-, -C(=0)-N(R52)-, -CH2N(R52)-CH2-, -
C(=0)N(R52)-CH2-, -CH2CH2-N(R52)-, -CH2N(R52)-C(=0)-, and -CH20-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(=0)-, -C(=0)N(R52)-, -[C(R14a)2]i-50-, -[C(R14a)2]i-5NR52-,
-[C(R14a)2]!_5-, -CH2(=0)-, and -S(=0)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, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, -
S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, -
NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, -
OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, -
NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, -
P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), -
P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52);
Ci-10 alkyl, C2_io alkenyl, and C2_io alkynyl, each of which is
independently optionally substituted at each occurrence with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54,
-S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, -
NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, -
OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, -
NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR3Z)2, -P(0)(R3Z)2, -P(0)(OR3Z)(R3Z), -P(0)(NR3Z)(R3Z), -NR3ZP(0)(R3Z), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =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-i2 carbocycle and 3- to 12-membered heterocycle in R50 is independently optionally substituted with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), d_6 alkyl, d_6 haloalkyl, C2_6 alkenyl, and C2-6 alkynyl;
R52 is independently selected at each occurrence from hydrogen; and Ci-20 alkyl, C2-20 alkenyl, C2_2o alkynyl, 1- to 6-membered heteroalkyl, C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -N02, -NH2, -NHCH3, - NHCH2CH3, =0, -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.
[0030] In certain aspects, the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising administering a compound selected from Table 1. In certain aspects, the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising administering a compound selected from Table 2 or 3. 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 ldiabetes 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
[0031] 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
[0032] 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:
[0033] FIG. 1 is an amino acid sequence of human menin, isoform 1 (SEQ ID NO: 1).
[0034] FIG. 2 is an amino acid sequence of human menin, isoform 2 (SEQ ID NO: 2).
[0035] FIG. 3 is an amino acid sequence of human menin, isoform 3 (SEQ ID NO: 3).
[0036] FIG. 4A-4E depict confocal images of rat primary dispersed islet cells treated with Compound 132, Compound 135, Compound 9, Compound 10, and no compound, respectively.
[0037] FIG. 5A-5D depict the change in beta cell proliferation for rat primary dispersed islet cells treated with Compound 132, Compound 135, Compound 9, and Compound 10, respectively.
DETAILED DESCRIPTION OF THE INVENTION
[0038] 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.
[0039] 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.
[0040] "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.
[0041] "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.
[0042] "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 Hiickel 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[£>][l,4]dioxepinyl, benzo[b][l,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[l,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[l,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- lH-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- cjpyridazinyl, 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.
[0043] 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.
[0044] 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.
[0045] "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.
[0046] 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.
[0047] 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 hydro xyl, 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 sulfonamide, 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 (=0), thioxo (=S), cyano (-CN), nitro (-N02), imino (=N-H), oximo (=N-OH), hydrazino (=N- NH2), -Rb-ORa, -Rb-OC(0)-Ra, -Rb-OC(0)-ORa, -Rb-OC(0)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(0)Ra, - Rb-C(0)ORa, -Rb-C(0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)ORa, - Rb-N(Ra)C(0)Ra, -Rb-N(Ra)S(0),Ra (where t is 1 or 2), -Rb-S(0),Ra (where t is 1 or
2), -Rb-S(0),ORa (where t is 1 or 2), and -Rb-S(0),N(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 (=0), thioxo (=S), cyano (-CN), nitro (-N02), imino (=N-H), oximo (=N-OH), hydrazine (=N-NH2), - Rb-ORa, -Rb-OC(0)-Ra, -Rb-OC(0)-ORa, -Rb-OC(0)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(0)Ra, - Rb-C(0)ORa, -Rb-C(0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)ORa, -Rb-N(Ra)C(0)Ra, - Rb-N(Ra)S(0),Ra (where t is 1 or 2), -Rb-S(0),Ra (where t is 1 or 2), -Rb-S(0),ORa (where t is 1 or 2) and -Rb-S(0)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 (=0), thioxo (=S), cyano (-CN), nitro (-N02), imino (=N-H), oximo (=N-OH), hydrazine (=N-NH2), -Rb-ORa, -Rb-OC(0)-Ra, -Rb-OC(0)-ORa, -Rb-OC(0)-N(Ra)2, -Rb-N(Ra)2, - Rb-C(0)Ra, -Rb-C(0)ORa, -Rb-C(0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)ORa, -Rb-N(Ra )C(0)Ra, -Rb-N(Ra)S(0),Ra (where t is 1 or 2), -Rb-S(0),Ra (where t is 1 or 2), -Rb-S(0),ORa (where t is 1 or 2) and -Rb-S(0)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.
[0048] 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. [0049] 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-.
[0050] 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.
[0051] 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.
[0052] 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.
[0053] 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.
[0054] 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.
[0055] 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, MLLl, 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.
[0056] 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. [0057] "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.
[0058] 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 la). Moreover, Type 1 diabetes also encompasses an idiopathic variant (Type lb). 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.
[0059] 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.
[0060] "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.
[0061] "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), (II), (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.
[0062] The term "in vivo" refers to an event that takes place in a subject' s body.
[0063] 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.
[0064] "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. [0065] "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.
[0066] 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 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 MLL.
[0067] 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 PI 3 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.
[0068] In certain aspects, the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising I):
Figure imgf000030_0001
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
H is selected from C5-i2 carbocycle and 5- to 12-membered heterocycle, each of which is optionally substituted with one or more R50;
A is selected from bond, C3-i2 carbocycle and 3- to 12-membered heterocycle;
B is selected from C3-i2 carbocycle and 3- to 12-membered heterocycle;
C is 3- to 12-membered heterocycle; L1, L2 and L3 are each independently selected from bond, -0-, -S-, -N(R51)-, -N(R51)CH2-, -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(0)N(R51)-, -C(0)N(R51)C(0)-, - C(0)N(R51)C(0)N(R51)-, -N(R51)C(0 , -N(R51)C(0)N(R51)-, -N(R51)C(0)0-, -OC(0)N(R51)-, - C(NR51)-, -N(R51)C(NR51)-, -C(NR51)N(R51)-, -N(R51)C(NR51)N(R51)-, -S(0)2-, -OS(O)-, - S(0)0-, -S(O)-, -OS(0)2-, -S(0)20-, -N(R51)S(0)2-, -S(0)2N(R51)-, -N(R51)S(0)-, -S(0)N(R51)-, -N(R51)S(0)2N(R51)-, -N(R51)S(0)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;
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, n and p are each independently an integer from 0 to 6;
R50 is independently selected at each occurrence from:
halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52);
Ci-io alkyl, C2_io alkenyl, and C2_io alkynyl, each of which is
independently optionally substituted at each occurrence with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; and
C3-i2 carbocycle and 3- to 12-membered heterocycle, wherein each C3-i2 carbocycle and 3- to 12-membered heterocycle in R50 is independently optionally substituted with one or more substituents selected from halogen, -N02, -CN, -OR , -SR , -N(R3Z)2, -NR R , -S(=0)R , - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), d_6 alkyl, d_6 haloalkyl, C2_6 alkenyl, and C2-6 alkynyl;
R51 is independently selected at each occurrence from:
hydrogen, -C(0)R52, -C(0)OR52, -C(0)N(R52)2, -C(0)NR53R54;
Ci-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, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C3-12 carbocycle and 3- to 12- membered heterocycle; and
C3-i2 carbocycle and 3- to 12-membered heterocycle, wherein each C3-i2 carbocycle and 3- to 12-membered heterocycle in R51 is independently optionally substituted with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), d_6 alkyl, d_6 haloalkyl, C2_6 alkenyl, and C2-6 alkynyl;
R52 is independently selected at each occurrence from hydrogen; and Ci-2o alkyl, C2-20 alkenyl, C2_2o alkynyl, 1- to 6-membered heteroalkyl, C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -N02, -NH2, -NHCH3, - NHCH2CH3, =0, -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;
R57 is selected from:
halogen, -N02, -CN, -SR52, -NR53R54, -S(=0)R52, -S(=0)2R58, - S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, -NR52S(=0)2N(R52)2, - NR52S(=0)2NR53R54, -C(0)OR52, -OC(0)R52, -OC(0)OR52, -OC(0)N(R52)2, - OC(0)NR53R54, -NR52C(0)OR52, -NR52C(0)N(R52)2, - NR52C(0)NR53R54, -C(0)NH(Ci-6 alkyl), -C(0)NR53R54, -P(0)(OR52)2, - P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =S, =N(R52); and
Ci-10 alkyl, C2_io alkenyl, and C2_io alkynyl, each of which is
independently substituted at each occurrence with one or more substituents selected from -N02, -CN, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, -S(=0)2R52, - S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, -NR52S(=0)2N(R52)2, - NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, -OC(0)OR52, - OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -P(0)(OR52)2, -P(0)(R52)2, - P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), -P(0)(NR52)(OR52), - P(0)(NR52)2, =S, and =N(R52); and
58
R is selected from hydrogen; and Ci-20 alkyl, C3-20 alkenyl, C2-20 alkynyl, 1- to 6- membered heteroalkyl, C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -N02, -NH2, -NHCH3, -NHCH2CH3, =0, -OH, -OCH3, - OCH2CH3, C3-i2 carbocycle, or 3- to 6-membered heterocycle,
wherein for a compound or salt of Formula (I), when C is azetidinylene, piperidinylene or piperazinylene and R57 is -S(=0)2R58, -S(=0)2N(R52)2, or -NR52S(=0)2R52:
p is an integer from 1 to 6; and/or
L is substituted with one or more R50, wherein L3 is not -CH2CH(OH)-.
[0069] In certain aspects, the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising administering a compound of Formula (II):
Figure imgf000034_0001
or a pharmaceutically acceptable salt thereof, wherein:
H is selected from C5-12 carbocycle and 5- to 12-membered heterocycle, each of which is optionally substituted with one or more R50;
A, B and C are each independently selected from C3-i2 carbocycle and 3- to 12-membered heterocycle;
L1 and L2 are each independently selected from bond, -0-, -S-, -N(R51)-, -N(R51)CH2-, - C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(0)N(R51)-, -C(0)N(R51)C(0)-, - C(0)N(R51)C(0)N(R51)-, -N(R51)C(0)-, -N(R51)C(0)N(R51)-, -N(R51)C(0)0-, -OC(0)N(R51)-, - C(NR51)-, -N(R51)C(NR51)-, -C(NR51)N(R51)-, -N(R51)C(NR51)N(R51)-, -S(0)2-, -OS(O)-, - S(0)0-, -S(O)-, -OS(0)2-, -S(0)20-, -N(R51)S(0)2-, -S(0)2N(R51)-, -N(R51)S(0)-, -S(0)N(R51)-, -N(R51)S(0)2N(R51)-, -N(R51)S(0)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 L1 or L2 can together optionally form a ring;
L3 is selected from alkylene, alkenylene, and alkynylene, each of which is substituted with one or more R56 and optionally further 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, n and p are each independently an integer from 0 to 6;
R50 is independently selected at each occurrence from:
halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52);
Ci-10 alkyl, C2_io alkenyl, and C2_io alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54 -S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; and
C3-i2 carbocycle and 3- to 12-membered heterocycle,
wherein each C3-i2 carbocycle and 3- to 12-membered heterocycle in R50 is independently optionally substituted with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), Ci_6 alkyl, Ci_6 haloalkyl, C2_ alkenyl, and C2-6 alkynyl;
independently selected at each occurrence from:
hydrogen, -C(0)R52, -C(0)OR52, -C(0)N(R52)2, -C(0)NR53R54;
Ci-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, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C3-12 carbocycle and 3- to 12 membered heterocycle; and
C3-i2 carbocycle and 3- to 12-membered heterocycle,
wherein each C3-i2 carbocycle and 3- to 12-membered heterocycle in R51 is independently optionally substituted with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =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 Ci-20 alkyl, C2_2o alkenyl, C2_2o alkynyl, 1- to 6-membered heteroalkyl, C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -N02, -NH2, -NHCH3, - NHCH2CH3, =0, -OH, -OCH3, -OCH2CH3, C3_i2 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;
R56 is independently selected at each occurrence from:
-N02, -OR59, -SR52, -NR53R54, -S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, - S(=0)2NR53R54, -NR52S(=0)2R52, -NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, - C(0)R52, -C(0)OR52, -OC(0)R52, -OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, -NR52C(0)N(R52)2, -
NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, -P(0)(OR52)2, -P(0)(R52)2, - P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), -P(0)(NR52)(OR52), - P(0)(NR52)2, =0, =S, =N(R52), CLIO alkyl, C2_10 alkenyl, C2_10 alkynyl, C3_12 carbocycle and 3- to 12-membered heterocycle,
wherein each Ci-io alkyl, C2-io alkenyl, and C2-io alkynyl in R56 is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -N02, -CN, -OR59, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C3_i2 carbocycle, and 3- to 12-membered heterocycle; 56 wherein each C3-i2 carbocycle and 3- to 12-membered heterocycle in R" is independently optionally substituted with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C1-6 alkyl, C1-6 haloalkyl, C2.6 alkenyl, and C2_6 alkynyl; and
further wherein R optionally forms a bond to ring C; and
R59 is independently selected at each occurrence from Ci-20 alkyl, C2_2o alkenyl, C2_2o alkynyl, 1- to 6-membered heteroalkyl, C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -N02, -NH2, -NHCH3, -NHCH2CH3, =0, -OH, -OCH3, -OCH2CH3, C3-i2 carbocycle, or 3- to 6-membered heterocycle,
wherein for a compound or salt of Formula (II), when R56 is -CH3, L3 is not further substituted with -OH, -NH2, or -CN.
[0070] In some embodiments, for a compound of Formula (I) or (II), H is 5- to 12-membered heterocycle, such as 6- to 12-membered bicyclic heterocycle, optionally substituted with one or more R50. 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 R50. In some embodiments, H is substituted with C1-4 haloalkyl, such as -CH2CF3. In some embodiments, H is substituted with one or more R50 (e.g., by replacing a hydrogen connected to a ring atom with a bond to R50). H may be substituted with 0, 1, 2, 3, 4, 5, 6 or more R50 groups. H may be substituted with 1, 2, 3, 4, 5 or 6 R50 groups, such as H substituted with 1 or 2 R50 groups. In some embodiments, H is substituted with at least 1, 2, 3, 4, 5 or 6 R50 groups. In some embodiments, H is substituted with up to 6, 5, 4, 3, 2 or 1 R50 groups.
[0071] In some embodiments, for a compound of Formula (I) or (II), H is
Figure imgf000037_0001
wherein X1 and X2 are each independently selected from CR2 and N; X3 and X4 are each independently selected from C and N; Y1 and Y2 are each independently selected from CR3, N, NR4, O, and S; R1, R2 and R3 are each 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, X1 is CR2, and R2 is selected from hydrogen, halogen, -OH, -NH2, -CN, C1-3 alkyl, Ci-3 haloalkyl, C2-3 alkenyl, and C2-3 alkynyl. In some embodiments, X2 is N. In some embodiments, Y2 is CR3, and R3 is selected from hydrogen, halogen, -OH, -N(R52)2, -CN, - C(0)OR52, Ci_3 alkyl, and Ci_3 haloalkyl. In some embodiments, Y1 is S. In some embodiments, at least one of Y1 and Y2 is selected from N, NR4, O and S. In some embodiments, R1 is C1-3 haloalkyl, such as -CH2CF3. In some embodiments, X1 is CR2, X2 is N, X3 and X4 are each C, Y is S, Y2 is CR3, and R1 is selected from R50. In some embodiments, X1 is CR2; X2 is N; X3 and X4 are each C; Y1 is S; Y2 is CH; R1 is C1-3 haloalkyl; and R2 is selected from hydrogen, halogen, -OH -NH2, -CN, Ci-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, and C2-3 alkynyl. In some embodiments,
H
Figure imgf000038_0001
, such as or In some embodiments, H
is
Figure imgf000038_0002
and R2 is selected from hydrogen, halogen, -OH, -N¾, -CN, C1-3 alkyl, C1-3 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, Ci_3 alkyl (e.g., -CH3), cyclopropyl, Ci_3 alkyl- OR52 (e.g., -CH2OH, -CH2OC(0)CH3), Ci_3 alkyl-N(R52)2, Ci_3 haloalkyl, C2-3 alkenyl, and C2-3 alkynyl.
[0072] In some embodiments, for a compound of Formula (I) or (II), H is
Figure imgf000038_0003
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 Y1 and Y2 is independently selected from S, CR3, N, NR4 and O. In certain embodiments, up to one of Y1 and Y2 is O or S.
[0073] In some embodiments, for a compound of Formula (I) or (II), 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, -0-, -S-, -N(R51)-, -N(R51)CH2-, -C(0 , -C(0)0-, -OC(O)-, -C(0)N(R51)-, -N(R51)C(0)-, - N(R51)C(0)N(R51)-, -S(0)2-, -S(O)-, -N(R51)S(0)2-, -S(0)2N(R51)-, -N(R51)S(0)2N(R51)-, alkylene, alkenylene, heteroalkylene, and heteroalkenylene. In some embodiments, L1 is selected from bond, -0-, -S-, -N(R51)-, -N(R51)CH2-, -C(O)-, -C(0)0-, -OC(O)-, -C(0)N(R51)-, - N(R51)C(0)-, -N(R51)C(0)N(R51)-, -S(0)2_, -S(O)-, -N(R51)S(0)2-, -S(0)2N(R51)-, - N(R51)S(0)2N(R51)-, Ci-6 alkylene and C2-6 alkenylene, wherein the Ci-6 alkylene and C2-6 alkenylene are each optionally substituted with one or more R50. In some embodiments, L is - N(R51)-, such as -NH-. In some embodiments, L1 is selected from -0-, -N(R51)-, -N(R51)CH2-, - C(O)-, -C(0)N(R51)-, -N(R51)C(0)-, -N(R51)S(0)2-, -S(0)2N(R51)-, d_4 alkylene, C2_4 alkenylene, and Ci_4 heteroalkylene. In some embodiments, L1 is -N(R51)-, wherein R51 is selected from hydrogen and alkyl.
[0074] In some embodiments, for a compound of Formula (I) or (II), 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
piperidinylene and piperazinylene, such as 'RA'm . In some embodiments, A is
Figure imgf000039_0001
ome 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. NH, I— NH, NH ,
Figure imgf000039_0002
0 0 0 0 ON00 ?NH 0 O- c? ΓΪ r ~r O
Figure imgf000040_0001
[0076] 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 , o 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 o RA groups. In some embodiments, A is unsubstituted. In some embodiments, A is substituted with m RA 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.
[0077] 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, hetero aryloxy, heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino. In some embodiments, two RA groups attached to the same atom or different atoms can together form a ring.
[0078] In some embodiments, for a compound of Formula (I) or (II), 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 Ci_io alkylene, such as Ci-4 alkylene, optionally substituted with one or more R50. In some embodiments, L2 is substituted
50 2 2 with one or more RJU. In some embodiments, L is unsubstituted. In some embodiments, L is selected from bond, -0-, -S-, -N(R51)-, -N(R51)CH2-, -C(O)-, -C(0)0-, -OC(O)-, -C(0)N(R51)-, - N(R51)C(0)-, -N(R51)C(0)N(R51)-, -S(0)2_, -S(O)-, -N(R51)S(0)2-, -S(0)2N(R51)-, - N(R51)S(0)2N(R51)-, alkylene, alkenylene, heteroalkylene, and heteroalkenylene. In some embodiments, L2 is selected from bond, -0-, -S-, -N(R51)-, -N(R51)CH2-, -C(O)-, -C(0)0-, - OC(O)-, -C(0)N(R51)-, -N(R51)C(0)-, -N(R51)C(0)N(R51)-, -S(0)2_, -S(0 , -N(R51)S(0)2-, - S(0)2N(R51)-, -N(R51)S(0)2N(R51)-, Ci_6 alkylene and C2_6 alkenylene, wherein the Ci_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(0)N(R51)-, -N(R51)C(0)-, -N(R51)S(0)2-, - S(0)2N(R51)-, Ci-4 alkylene and C1-4 heteroalkylene. In some embodiments, L2 is selected from - CH2-, -N(R51)-, -N(R51)CH2-, -N(R51)C(0)-, and -N(R51)S(0)2-. In some embodiments, L2 is - CH2-.
[0079] In some embodiments, for a compound of Formula (I) or (II), 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
In some embodiments, B is indolylene, more R . In some embodiments, B is
Figure imgf000041_0001
, suc as 3
[0080] In some embodiments, B is selected from
Figure imgf000041_0002
M1 M , M1 M10 ,
and
Figure imgf000041_0003
, 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, CRnR12, 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 imgf000042_0001
-40-
Figure imgf000043_0001
[0082] In some embodiments, B is substituted with one or more R (e.g., by replacing a hydrogen connected to a ring atom with a bond to RB). B may 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 n RB 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 an integer from 1 to 3.
[0083] 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, hetero aryloxy, 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.
[0084] 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 Ci-io alkylene, such as Ci-4 alkylene, optionally substituted with one or more R50. In some embodiments, L3 is substituted with one or more R50. In some embodiments, L3 is unsubstituted. In some embodiments, L3 is selected from bond, -0-, -S-, -N(R51)-, -N(R51)CH2-, -C(O)-, -C(0)0-, -OC(O)-, -C(0)N(R51)-, - N(R51)C(0 , -N(R51)C(0)N(R51)-, -S(0)2-, -S(O)-, -N(R51)S(0)2-, -S(0)2N(R51)-, - N(R51)S(0)2N(R51)-, alkylene, alkenylene, heteroalkylene, and heteroalkenylene. In some embodiments, L3 is Ci_6 alkylene, optionally substituted with one or more R50, wherein R50 is selected from deuterium, C1-4 alkyl, C1-4 haloalkyl, and -OR52. In some embodiments, L3 is- CH2CH(R50)-, such as -CH2CH(CH3)-. In some embodiments, two R 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 substituted with one or more groups selected from deuterium, C1-4 alkyl, C1-4 haloalkyl, and -OR52. In some embodiments, L3 is substituted with -Ct¾. In some embodiments, L3 is C2 alkylene substituted with at least one C1-3 alkyl or C 1-3 haloalkyl, and optionally further
50 3
substituted with one or more RJU. In some embodiments, L is substituted with =0, Ci_6 alkyl, Ci_ 6 haloalkyl, Ci_3 alkyl(cyclopropyl), Ci_3 alkyl(NR52C(0)R52) or -0(Ci_6 alkyl).
.V.
3 )(R)
[0085] In some embodiments, for a compound of Formula (I), L is selected from and
Figure imgf000044_0001
. Optionally, R is methyl. L may be selected from and . In some embodiments, L3 is
Figure imgf000044_0002
. 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 5-isomer. In some embodiments, the 5-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.
[0086] In some embodiments, for a compound of Formula (I), C is azetidinylene, piperidinylene or piperazinylene; R57 is -S(=0)2R58, -S(=0)2N(R52)2, or -NR52S(=0)2R52; and L3 is substituted
50 3
with one or more R , wherein V is not -CH2CH(OH)-. In some embodiments, C is azetidinylene, piperidinylene or piperazinylene; R is
Figure imgf000045_0001
-S(=0)2N(R )2, or - 52S(=0)2R52; and L3 is substituted with Ci_4 alkyl or Ci_4 haloalkyl.
Figure imgf000045_0002
[0088] In some embodiments, for a compound of Formula (II), 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 is Ci-io alkylene, such as Ci-4 alkylene, substituted with one or more R56 and optionally further substituted with one or more R50. In some embodiments, L3 is substituted with one or more R50. In some embodiments, L3 is substituted with R56. In some embodiments, L3 is selected from alkylene and alkenylene. In some embodiments, L3 is Ci-6 alkylene substituted with one or more R56, wherein R56 is selected from deuterium, CM alkyl, Ci-4 haloalkyl, and -OR59. In some embodiments, L3 is Ci-4 alkylene substituted with R56, wherein R56 forms a bond to ring C. In some embodiments, L3 is- CH2CH(R56)-, such as -CH2CH(CH3)-. In some embodiments, two R 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 R56, wherein R56 forms a bond to ring C. In some embodiments, L3 is substituted with one or more groups selected from Ci-4 alkyl, Ci-4 haloalkyl, and -OR59. In some embodiments, L3 is substituted with -Ct¼. In some embodiments, L3 is Ci-4 alkylene substituted with -Ct¾ and optionally further substituted with R50, wherein R50 is not - OH, -NH2, or -CN. In some embodiments, L3 is C2 alkylene substituted with at least one C1-3 alkyl or C1-3 haloalkyl, and optionally further substituted with one or more R50. In some embodiments, L3 is substituted with =0, Ci_6 alkyl, Ci_6 haloalkyl, C1-3 alkyl(cyclopropyl), C1-3 alkyl(NR52C(0)R52) or -0(C1-6 alkyl).
[0089] In some embodiments, for a compound of Formula (II), L
Figure imgf000045_0003
and
Figure imgf000045_0004
. Optionally, R56 is methyl. L3 may be selected from and . In some
A (R) us)
embodiments, L3 is . In some embodiments, L3 is . 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 5-isomer. In some embodiments, the 5-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%,
-isomer.
Figure imgf000046_0001
[0091] In some embodiments, for a compound of Formula (I), C is 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
Figure imgf000046_0002
Figure imgf000047_0001
, , 5 XN 5 XN an(j 5 optionally
substituted with one or more Rc In some embodiments is selected from
Figure imgf000047_0002
Figure imgf000047_0003
S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52; and C1-10 alkyl substituted with one or more substituents selected from -S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, and - NR52S(=0)2R52. In some embodiments, R57 is selected from -S(=0)R52, -S(=0)2R58, - S(=0)2N(R52)2, and -NR52S(=0)2R52, such as R57 is selected from -S(=0)CH3, -S(=0)2CH3, - S(=0)2NH2, -NHS(=0)2CH3, and -S(=0)2NHCH3.
[0092] In some embodiments, for a compound of Formula (I), C is selected from
Figure imgf000047_0004
of Formula (I), 57 58
[0093] In some embodiments, for a compound R is selected from -S(=0)2R , - S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, -NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, - C(0)NH(Ci_6 alkyl), -C(0)NR53R54; and Ci_6 alkyl and C2_6 alkenyl, each of which is independently substituted at each occurrence with one or more substituents selected from - S(=0)2R58, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, -NR52S(=0)2N(R52)2, - NR52S(=0)2NR53R54, -C(0)NH(Ci-6 alkyl), -C(0)NR53R54. In some embodiments, R57 is selected from -S(=0)2R58, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, -NR52S(=0)2N(R52)2, - NR52S(=0)2NR53R54, and Ci_6 alkyl substituted with one or more substituents selected from - S(=0)2R58, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, -NR52S(=0)2N(R52)2, and - NR52S(=0)2NR53R54. In some embodiments, R57 is selected from -S(=0)R52, -S(=0)2R58, - S(=0)2N(R52)2, and -NR52S(=0)2R52. In some embodiments, R57 is selected from -S(=0)CH3, - S(=0)2CH3, -S(=0)2NH2, -NHS(=0)2CH3, and -S(=0)2NHCH3.
[0094] In some embodiments, for a compound of Formula (I) or (II), 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 p Rc 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 0. In some embodiments, p is 1 or 2. In some embodiments, for a compound of Formula (I), C is azetidinylene, piperidinylene or piperazinylene; R57 is -S(=0)2R58,
Figure imgf000048_0001
or - NR52S(=0)2R52; and p is an integer from 1 to 6.
[0095] In some embodiments, Rc is selected from -C(0)R52, -S(=0)R52, -S(=0)2R52, - S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, =0, C1-3 alkyl, and C1-3 haloalkyl, or two Rc groups attached to different atoms can together form a Ci-3 bridge. In some embodiments, Rc is selected from Ci-3 alkyl and Ci-3 haloalkyl, such as -CH3.
[0096] In some embodiments, for a compound of Formula (II), C is selected from C3-i2 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 inyl and piperazinyl, such as
Figure imgf000048_0002
selected from hydrogen and
R . In some embodiments, C is selected from 57 is selected from hydrogen and R50. In some
Figure imgf000048_0003
embodiments, C is selected from and
Figure imgf000048_0004
Figure imgf000049_0001
, optionally substituted with one or more Rc, wherein R57 is selected from hydrogen and R50 In some embodiments, C is
selected from
Figure imgf000049_0002
ryf rV' rr R"C" , wherein R57 is selected from -
S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52; and C1-10 alkyl substituted with one or more substituents selected from -S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, and -NR52S(=0)2R52. In some embodiments, R57 is selected from -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, and -NR52S(=0)2R52, such as R57 is selected from -S(=0)CH3, - S(=0)2CH3, -S(=0)2NH2, -NHS(=0)2CH3, and -S(=0)2NHCH3.
[0097] In some embodiments, for a compound of Formula (II), C is selected from
Figure imgf000049_0003
[0098] In some embodiments, for a compound of Formula (I) or (II), Rc is selected from:
halogen, -OR52, -N(R52)2, -NR53R54, -S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, - S(=0)2NR53R54, -NR52S(=0)2R52, -NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, - C(0)OR52, -OC(0)R52, -OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, - NR52C(0)OR52, -NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2; and
Ci-io alkyl, C2-io alkenyl, and C2-io alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -N02, -CN, - OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, - NR52S(=0)2R52, -NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, -OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, -P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), -P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C3-i2 carbocycle, and 3- to 12-membered heterocycle;
wherein each C3-i2 carbocycle and 3- to 12-membered heterocycle in Rc is independently optionally substituted with one or more substituents selected from halogen, -N02, -CN, -OR52, - SR52, -N(R52)2, -NR53R54, -S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, - NR52S(=0)2R52, -NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, -OC(0)OR , -OC(0)N(R3Z)2, -OC(0)NR3JR , -NR3ZC(0)R , -NR3ZC(0)OR , -
NR5 C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, -P(0)(OR52)2, -P(0)(R52)2,
-P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), -P(0)(NR52)(OR52), -P(0)(NR52)2, =0,
=S, =N(R52), Ci-6 alkyl, Ci-6 haloalkyl, C2.6 alkenyl, and C2.6 alkynyl.
[0099] In some embodiments, Rc is selected from -N(R52)2, -NR53R54, -NR52S(=0)2R52, -
C(0)R52, -C(0)OR52, -NR52C(0)R52, -NR52C(0)OR52, -NR52C(0)N(R52)2, -
NR52C(0)NR53R54, -C(0)N(R52)2, and -C(0)NR53R54. In some embodiments, Rc is selected from
-N(R52)2, -NR53R54, -NR52S(=0)2R52, -C(0)R52, -C(0)OR52, -NR52C(0)R52, -NR52C(0)OR52, -
NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, C 6 alkyl, and C 6 alkyl substituted with -N(R52)2, -NR53R54, -NR52S(=0)2R52, -C(0)R52, -C(0)OR52, -NR52C(0)R52, -
NR52C(0)OR52, -NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, or -C(0)NR53R54.
[0100] In some embodiments, C is selected from
Figure imgf000050_0001
Figure imgf000050_0002
[0101] In some embodiments, for a compound of Formula (I) or (II), H is 5- to 12-membered heterocycle, optionally substituted with one or more R50; 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 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, 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 thienopyrimidinyl, optionally substituted with one or more R50; 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, optionally substituted with one or more R50; 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, optionally substituted with one or more R50; A is 3- to 12-membered heterocycle; and B is indolylene. In some embodiments, H is thienopyrimidinyl substituted with one or more R50; A is selected from piperidinylene and piperazinylene; and B is indolylene.
[0102] In some embodiments, for a compound of Formula (I) or (II), H is 5- to 12-membered heterocycle, optionally substituted with one or more R50; A is 3- to 12-membered heterocycle; B is 3- to 12-membered heterocycle; C is 3- to 12-membered heterocycle; m is an integer from 0 to 3; and n is an integer from 1 to 3. 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; B is 6- to 12-membered bicyclic heterocycle; C is 3- to 12-membered heterocycle; m is an integer from 0 to 3; and n is an integer from 1 to 3. In some embodiments, H is 5- to 12-membered heterocycle, optionally substituted with one or more R50; 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, optionally substituted with one or more R50; 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, optionally substituted with one or more R50; 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, optionally substituted with one or more R50; A is selected from piperidinylene and piperazinylene; B is 6- to 12-membered bicyclic heterocycle; m is an integer from 0 to 3 ; and n is an integer from 1 to 3. In some embodiments, H is thienopyrimidinyl, 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 thienopyrimidinyl, optionally substituted with one or more R50; A is 3- to 12- membered heterocycle; B is 6- to 12-membered bicyclic heterocycle; m is an integer from 0 to 3; and n is an integer from 1 to 3. In some embodiments, H is 9- to 10-membered bicyclic heterocycle, optionally substituted with one or more R50; 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, optionally substituted with one or more R50; A is 5- to 7-membered heterocycle; B is 9-membered bicyclic heterocycle; and n is an integer from 1 to 3, wherein each of said heterocycles comprises at least one nitrogen atom.
[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, -0-, -S-, -N(R51)-, -N(R51)CH2-, -C(O)-, - C(0)0-, -OC(O)-, -C(0)N(R51)-, -N(R51)C(0)-, -N(R51)C(0)N(R51)-, -S(0)2-, -S(O)-, - N(R51)S(0)2-, -S(0)2N(R51)-, -N(R51)S(0)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(0)-, and -N(R51)S(0)2-. In some embodiments, L1 is selected from -0-, -S-, -N(R51)-, -N(R51)CH2-, -C(O)-, -C(0)0-, - OC(O)-, -C(0)N(R51)-, -N(R51)C(0)-, -N(R51)C(0)N(R51)-, -S(0)2_, -S(0 , -N(R51)S(0)2-, - S(0)2N(R51)-, -N(R51)S(0)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 -0-, -S-, - N(R51)-; Ci-4 alkylene and 1- to 4-membered heteroalkylene, each of which is optionally
50 1 3 substituted with one or more RJU. In some embodiments, L is -NH-, L is -CH2-, and L is C1-4 alkylene, optionally substituted with one or more R50.
[0104] In some embodiments, for a compound of Formula (II), 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 and L2 are each independently selected from bond, -0-, -S-, -N(R51)-, -N(R51)CH2-, -C(0 , -C(0)0-, -OC(O)-, -C(0)N(R51)-, -N(R51)C(0 , -N(R51)C(0)N(R51)-, -S(0)2_, -S(O)-, -N(R51)S(0)2-, - S(0)2N(R51)-, -N(R51)S(0)2N(R51)-, alkylene, alkenylene, heteroalkylene, and heteroalkenylene, and L3 is selected from Ci-10 alkylene and C2-io alkenylene, substituted with one or more R56 and optionally further substituted with one or more R50. In some embodiments, L1 and L2 are each independently selected from -CH2-, -N(R51)-, -N(R51)CH2-, -N(R51)C(0)-, and -N(R51)S(0)2-, and L3 is selected from Ci_io alkylene and C2_io alkenylene, substituted with one or more R56 and optionally further substituted with one or more R50. In some embodiments, L1 is selected from - 0-, -S-, -N(R51)-, -N(R51)CH2-, -C(O)-, -C(0)0-, -OC(O)-, -C(0)N(R51)-, -N(R51)C(0)-, - N(R51)C(0)N(R51)-, -S(0)2-, -S(O)-, -N(R51)S(0)2-, -S(0)2N(R51)-, -N(R51)S(0)2N(R51)-, alkylene, alkenylene, heteroalkylene, and heteroalkenylene; and L2 is C1-4 alkylene, optionally substituted with one or more R50, and L3 is C1-4 alkylene substituted with one or more R56 and optionally further substituted with one or more R50. In some embodiments, L1 and L2 are each independently selected from -0-, -S-, -N(R51)-; C1-4 alkylene and 1- to 4-membered
50 3
heteroalkylene, each of which is optionally substituted with one or more R , and V is C1-4 alkylene substituted with one or more R56 and optionally further substituted with one or more R50. In some embodiments, L1 is -NH-, L2 is -CH2-, and L3 is C1-4 alkylene substituted with one or more R and optionally further substituted with one or more R .
[0105] In certain aspects, the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising administering a compound of Formula (I), wherein:
H is 5- to 12-membered heterocycle, optionally substituted with one or more R50;
A, B, and C are each independently selected from 3- to 12-membered heterocycle;
L1, L2 and L3 are each independently selected from bond, -0-, -S-, -N(R51)-, -N(R51)CH2-, -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(0)N(R51)-, -C(0)N(R51)C(0)-, - C(0)N(R51)C(0)N(R51)-, -N(R51)C(0 , -N(R51)C(0)N(R51)-, -N(R51)C(0)0-, -OC(0)N(R51)-, - C(NR51)-, -N(R51)C(NR51)-, -C(NR51)N(R51)-, -N(R51)C(NR51)N(R51)-, -S(0)2-, -OS(O)-, - S(0)0-, -S(O)-, -OS(0)2-, -S(0)20-, -N(R51)S(0)2-, -S(0)2N(R51)-, -N(R51)S(0)-, -S(0)N(R51)-, -N(R51)S(0)2N(R51)-, -N(R51)S(0)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 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 1 to 3 ;
p is an integer from 0 to 6;
R50 is independently selected at each occurrence from:
halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52);
Ci-io alkyl, C2_io alkenyl, and C2_io alkynyl, each of which is
independently optionally substituted at each occurrence with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR3ZC(0)N(R3Z)2, -NR3ZC(0)NR3JR , -C(0)N(R3Z)2, -C(0)NR3JR , - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; and
C3-i2 carbocycle and 3- to 12-membered heterocycle,
wherein each C3-i2 carbocycle and 3- to 12-membered heterocycle in R50 is independently optionally substituted with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C 6 alkyl, C1-6 haloalkyl, C2. alkenyl, and C2-6 alkynyl;
independently selected at each occurrence from:
hydrogen, -C(0)R52, -C(0)OR52, -C(0)N(R52)2, -C(0)NR53R54;
Ci-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, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C3-12 carbocycle and 3- to 12 membered heterocycle; and
C3-i2 carbocycle and 3- to 12-membered heterocycle,
wherein each C3-i2 carbocycle and 3- to 12-membered heterocycle in R51 is independently optionally substituted with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, NR3ZC(0)N(R3Z)2, -NR3ZC(0)NR3JR , -C(0)N(R3Z)2, -C(0)NR3JR , - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =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 Ci-20 alkyl, C2_2o alkenyl, C2_2o alkynyl, 1- to 6-membered heteroalkyl, C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -N02, -NH2, -NHCH3, - NHCH2CH3, =0, -OH, -OCH3, -OCH2CH3, C3-i2 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;
R57 is selected from:
-S(=0)R52, -S(=0)2R58, -S(=0)2N(R52)2, -S(=0)2NR53R54, - NR52S(=0)2R52, -NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -NR52C(0)N(R52)2, - NR52C(0)NR53R54, -C(0)NH(Ci-6 alkyl), -C(0)NR53R54, -P(0)(OR52)2, - P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2; and
Ci-io alkyl, C2-io alkenyl, and C2-io alkynyl, each of which is
independently substituted at each occurrence with one or more substituents selected from -S(=0)R52, -S(=0)2R58, -S(=0)2N(R52)2, -S(=0)2NR53R54, - NR52S(=0)2R52, -NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -NR52C(0)N(R52)2, - NR52C(0)NR53R54, -C(0)NH(Ci-6 alkyl), -C(0)NR53R54, -P(0)(OR52)2, and - P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2; and
58
R is selected from hydrogen; and Ci-20 alkyl, C3_2o alkenyl, C2_2o alkynyl, 1- to 6- membered heteroalkyl, C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -N02, -NH2, -NHCH3, -NHCH2CH3, =0, -OH, -OCH3, - OCH2CH3, C3-i2 carbocycle, or 3- to 6-membered heterocycle,
wherein for a compound or salt of Formula (I), when C is azetidinylene, piperidinylene or piperazinylene and R57 is -S(=0)2R58, -S(=0)2N(R52)2, or -NR52S(=0)2R52:
p is an integer from 1 to 6; and/or
3 50 3
L is substituted with one or more R , wherein V is not -CH2CH(OH)-.
[0106] In certain aspects, the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising administering a compound of Formula (II), wherein:
H is 5- to 12-membered heterocycle, optionally substituted with one or more R50; A, B and C are each independently selected from 3- to 12-membered heterocycle;
L1 and L2 are each independently selected from bond, -0-, -S-, -N(R51)-, -N(R51)CH2-, - C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(0)N(R51)-, -C(0)N(R51)C(0)-, - C(0)N(R51)C(0)N(R51)-, -N(R51)C(0)-, -N(R51)C(0)N(R51)-, -N(R51)C(0)0-, -OC(0)N(R51)-, - C(NR51)-, -N(R51)C(NR51)-, -C(NR51)N(R51)-, -N(R51)C(NR51)N(R51)-, -S(0)2-, -OS(O)-, - S(0)0-, -S(0 , -OS(0)2-, -S(0)20-, -N(R51)S(0)2-, -S(0)2N(R51)-, -N(R51)S(0 , -S(0)N(R51)-, -N(R51)S(0)2N(R51)-, -N(R51)S(0)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 L1 or L2 can together optionally form a ring;
L3 is selected from Ci_6 alkylene, C2_6 alkenylene, and C2_6 alkynylene, each of which is substituted with one or more R56 and optionally further 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 1 to 3 ;
p is an integer from 0 to 6;
R50 is independently selected at each occurrence from:
halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52);
Ci-io alkyl, C2-io alkenyl, and C2-io alkynyl, each of which is
independently optionally substituted at each occurrence with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR3Z)(OR3Z), -P(0)(NR3Z)2, =0, =S, =N(R3Z), 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, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), Ci_6 alkyl, Ci_6 haloalkyl, C2_ alkenyl, and C2_6 alkynyl;
independently selected at each occurrence from:
hydrogen, -C(0)R52, -C(0)OR52, -C(0)N(R52)2, -C(0)NR53R54;
Ci-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, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =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, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), P(0)(NR3Z)(OR3Z), -P(0)(NR3Z)2, =0, =S, =N(R3Z), d_6 alkyl, d_6 haloalkyl, C2_6 alkenyl, and C2-6 alkynyl;
R52 is independently selected at each occurrence from hydrogen; and Ci-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, =0, -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;
R56 is independently selected at each occurrence from:
-OR59, =0, Ci_io alkyl, C2-10 alkenyl, C2-10 alkynyl, wherein each Ci_io alkyl, C2-10 alkenyl, and C2-10 alkynyl in R56 is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -N02, -CN, -OR59, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle;
wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R56 is independently optionally substituted with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), d_6 alkyl, d_6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; and
further wherein R56 optionally forms a bond to ring C; and
R59 is independently selected at each occurrence from Ci-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, -N02, -NH2, -NHCH3, -NHCH2CH3, =0, -OH, -OCH3, -OCH2CH3, C3-12 carbocycle, or 3- to 6-membered heterocycle, wherein for a compound or salt of Formula (II), when R56 is -Ct¾, L3 is not further substituted with -OH, -NH2, or -CN.
[0107] In certain aspects, for a compound of Formula (I):
H is thienopyrimidinyl, optionally substituted with one or more R50;
A is selected from piperidinylene and piperazinylene;
B is indolylene;
L1 and L2 are each independently selected from -0-, -S-, -NH-, and -CH2-;
L3 is selected from bond, -0-, -S-, -N(R51)-, -N(R51)CH2-, -C(O)-, -C(0)0-, -OC(O)-, - OC(0)0-, -C(0)N(R51)-, -C(0)N(R51)C(0)-, -C(0)N(R51)C(0)N(R51)-, -N(R51)C(0)-, - N(R51)C(0)N(R51)-, -N(R51)C(0)0-, -OC(0)N(R51)-, -C(NR51)-, -N(R51)C(NR51)-, - C(NR51)N(R51)-, -N(R51)C(NR51)N(R51)-, -S(0)2-, -OS(O)-, -S(0)0-, -S(O)-, -OS(0)2-, -S(0)20-, -N(R51)S(0)2-, -S(0)2N(R51)-, -N(R51)S(0)-, -S(0)N(R51)-, -N(R51)S(0)2N(R51)-, - N(R51)S(0)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 1 to 3 ;
p is an integer from 0 to 6;
R57 is selected from:
-S(=0)R52, -S(=0)2R58, -S(=0)2N(R52)2, -S(=0)2NR53R54, - NR52S(=0)2R52, -NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -NR52C(0)N(R52)2, - NR52C(0)NR53R54, -C(0)NH(Ci-6 alkyl), -C(0)NR53R54, -P(0)(OR52)2, - P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2; and
Ci-10 alkyl, C2_io alkenyl, and C2_io alkynyl, each of which is
independently substituted at each occurrence with one or more substituents selected from -S(=0)R52, -S(=0)2R58, -S(=0)2N(R52)2, -S(=0)2NR53R54, - NR52S(=0)2R52, -NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -NR52C(0)N(R52)2, - NR52C(0)NR53R54, -C(0)NH(Ci_6 alkyl), -C(0)NR53R54, -P(0)(OR52)2, and - P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR3Z)(OR3Z), -P(0)(NR3Z)2; and
58
R is selected from hydrogen; and Ci-20 alkyl, C3-20 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, -N02, -NH2, -NHCH3, -NHCH2CH3, =0, -OH, -OCH3, - OCH2CH3, C3-12 carbocycle, or 3- to 6-membered heterocycle,
wherein for a compound or salt of Formula (I), when C is azetidinylene, piperidinylene or piperazinylene and R57 is -S(=0)2R58, -S(=0)2N(R52)2, or -NR52S(=0)2R52:
p is an integer from 1 to 6; and/or
3 50 3
L is substituted with one or more R , wherein V is not -CH2CH(OH)-.
[0108] In certain aspects, for a compound of Formula (II) :
H is thienopyrimidinyl, optionally substituted with one or more R50;
A is selected from piperidinylene and piperazinylene;
B is indolylene;
L1 and L2 are each independently selected from -0-, -S-, -NH-, and -CH2-;
L3 is selected from Ci-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene, each of which is substituted with one or more R56 and optionally further 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 1 to 3 ;
p is an integer from 0 to 6;
R56 is independently selected at each occurrence from:
-OR59, =0, Ci-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl,
wherein each Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl in R56 is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -N02, -CN, -OR59, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; wherein each C3-i2 carbocycle and 3- to 12-membered heterocycle in R is independently optionally substituted with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C1-6 alkyl, C1-6 haloalkyl, C2.6 alkenyl, and C2_6 alkynyl; and
further wherein R56 optionally forms a bond to ring C; and
R59 is independently selected at each occurrence from Ci-20 alkyl, C2_2o alkenyl, C2_2o alkynyl, 1- to 6-membered heteroalkyl, C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -N02, -NH2, -NHCH3, -NHCH2CH3, =0, -OH, -OCH3, -OCH2CH3, C3-i2 carbocycle, or 3- to 6-membered heterocycle,
wherein for a compound or salt of Formula (II), when R56 is -CH3, L3 is not further substituted with -OH, -NH2, or -CN.
e represented by:
Figure imgf000061_0001
. In some embodiments, C is selected from 5- to 7-membered monocyclic heterocycle, such as piperidinyl and piperazinyl. In some embodiments, R50 is selected from deuterium, C1-4 alkyl, C1-4 haloalkyl, and -OR52, such as R50 is methyl. In some embodiments, R57 is selected from -S(=0)R52, -S(=0)2R58, - S(=0)2N(R52)2, and -NR52S(=0)2R52, such as R57 is selected from -S(=0)CH3, -S(=0)2CH3, - S(=0)2NH2, -NHS(=0)2CH3, and -S(=0)2NHCH3. In some embodiments, R57 is -S(=0)2CH3. In some embodiments, R50 is methyl and R57 is -S(=0)2CH3.
[0110] In certain aspects, a compound of Formula (I) may be represented by:
Figure imgf000062_0001
. In some embodiments, C is selected from 5- to 7-membered monocyclic heterocycle, such as piperidinyl and piperazinyl. In some embodiments, R50 is selected from deuterium, C1-4 alkyl, C1-4 haloalkyl, and -OR52, such as R50 is methyl. In some embodiments, R57 is selected from -S(=0)R52, -S(=0)2R58, - S(=0)2N(R52)2, and -NR52S(=0)2R52, such as R57 is selected from -S(=0)CH3, -S(=0)2CH3, - S(=0)2NH2, -NHS(=0)2CH3, and -S(=0)2NHCH3. In some embodiments, R57 is -S(=0)2CH3. In some embodiments, R50 is methyl and R57 is -S(=0)2CH3.
[0111] In certain aspects, a compound of Formula (II) may be represented by:
Figure imgf000062_0002
. In some embodiments, C is selected from 5- to 7-membered monocyclic heterocycle, such as piperidinyl and piperazinyl. In some embodiments, R56 is selected from deuterium, C1-4 alkyl, C1-4 haloalkyl, and -OR59, such as R56 is methyl. In some embodiments, Rc is selected from -S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, and -NR52S(=0)2R52, such as Rc is selected from -S(=0)CH3, -S(=0)2CH3, -S(=0)2NH2, - NHS(=0)2CH3, and -S(=0)2NHCH3. In some embodiments, p is an integer from 1 to 3, such as p is 1. In some embodiments, Rc is -S(=0)2CH3. In some embodiments, R56 is methyl and Rc is - S(=0)2CH3.
[0112] In certain aspects, a compound of Formula (II) may be represented by:
Figure imgf000062_0003
. In some embodiments, C is selected from 5- to 7-membered monocyclic heterocycle, such as piperidinyl and piperazinyl. In some embodiments, R56 is selected from deuterium, C1-4 alkyl, C1-4 haloalkyl, and -OR59, such as R56 is methyl. In some embodiments, Rc is selected from -S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, and -NR52S(=0)2R52, such as Rc is selected from -S(=0)CH3, -S(=0)2CH3, -S(=0)2NH2, - NHS(=0)2CH3, and -S(=0)2NHCH3. In some embodiments, p is an integer from 1 to 3, such as p is 1. In some embodiments, Rc is -S(=0)2CH3. In some embodiments, R56 is methyl and Rc is - S(=0)2CH3.
[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) or (II). 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.
[0114] 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) or (II). 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.
[0115] In certain embodiments, the compound of Formula (I) or (II) 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.
[0116] In certain embodiments, the compound of Formula (I) or (II) 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%.
[0117] In certain embodiments, the compound of Formula (I) or (II) 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%.
[0118] In certain aspects, the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising und of Formula (I):
Figure imgf000064_0001
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
H is selected from C5-i2 carbocycle and 5- to 12-membered heterocycle, each of which is optionally substituted with one or more R50;
A is selected from bond, C3-12 carbocycle and 3- to 12-membered heterocycle;
B is selected from C3-i2 carbocycle and 3- to 12-membered heterocycle;
C is 3- to 12-membered heterocycle;
L1, L2 and L3 are each independently selected from bond, -0-, -S-, -N(R51)-, -N(R51)CH2-, -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(0)N(R51)-, -C(0)N(R51)C(0)-, - C(0)N(R51)C(0)N(R51)-, -N(R51)C(0 , -N(R51)C(0)N(R51)-, -N(R51)C(0)0-, -OC(0)N(R51)-, - C(NR51)-, -N(R51)C(NR51)-, -C(NR51)N(R51)-, -N(R51)C(NR51)N(R51)-, -S(0)2-, -OS(O)-, - S(0)0-, -S(0 , -OS(0)2-, -S(0)20-, -N(R51)S(0)2-, -S(0)2N(R51)-, -N(R51)S(0 , -S(0)N(R51)-, -N(R51)S(0)2N(R51)-, -N(R51)S(0)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;
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, n and p are each independently an integer from 0 to 6;
R50 is independently selected at each occurrence from:
halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52);
Ci-io alkyl, C2-io alkenyl, and C2-io alkynyl, each of which is
independently optionally substituted at each occurrence with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; and
C3-i2 carbocycle and 3- to 12-membered heterocycle, wherein each C3-i2 carbocycle and 3- to 12-membered heterocycle in R50 is independently optionally substituted with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), d_6 alkyl, d_6 haloalkyl, C2_6 alkenyl, and C2_6 alkynyl; R51 is independently selected at each occurrence from:
hydrogen, -C(0)R52, -C(0)OR52, -C(0)N(R52)2, -C(0)NR53R54;
Ci-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, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C3-12 carbocycle and 3- to 12- membered heterocycle; and
C3-i2 carbocycle and 3- to 12-membered heterocycle, wherein each C3-i2 carbocycle and 3- to 12-membered heterocycle in R51 is independently optionally substituted with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), d_6 alkyl, d_6 haloalkyl, C2_6 alkenyl, and C2_6 alkynyl;
R52 is independently selected at each occurrence from hydrogen; and Ci-20 alkyl, C2_2o alkenyl, C2-20 alkynyl, 1- to 6-membered heteroalkyl, C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -N02, -NH2, -NHCH3, - NHCH2CH3, =0, -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;
R57 is selected from:
halogen, -N02, -CN, -SR52, -NR53R54, -S(=0)R52, -S(=0)2R58, - S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, -NR52S(=0)2N(R52)2, - NR52S(=0)2NR53R54, -C(0)OR52, -OC(0)R52, -OC(0)OR52, -OC(0)N(R52)2, - OC(0)NR53R54, -NR52C(0)OR52, -NR52C(0)N(R52)2, - NR52C(0)NR53R54, -C(0)NH(Ci alkyl), -C(0)NR53R54, -P(0)(OR52)2, - P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =S, =N(R52); and
Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl, each of which is
independently substituted at each occurrence with one or more substituents selected from -N02, -CN, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, -S(=0)2R52, - S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, -NR52S(=0)2N(R52)2, - NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, -OC(0)OR52, - OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -P(0)(OR52)2, -P(0)(R52)2, - P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), -P(0)(NR52)(OR52), - P(0)(NR52)2, =S, and =N(R52); and
R is selected from hydrogen; and Ci-20 alkyl, C3_2o alkenyl, C2_2o alkynyl, 1- to 6- membered heteroalkyl, C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -N02, -NH2, -NHCH3, -NHCH2CH3, =0, -OH, -OCH3, - OCH2CH3, C3-i2 carbocycle, or 3- to 6-membered heterocycle.
[0119] 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.
[0120] In some embodiments, for a stereoisomer of a compound of Formula (I), L3 is selected from
Figure imgf000067_0001
Optionally, R50 is methyl. In some embodiments, L3 is . In some
embodiments, L3 is
Figure imgf000067_0002
Figure imgf000067_0003
[0121] 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).
[0122] In certain aspects, the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprisin und of Formula (II):
Figure imgf000068_0001
or a pharmaceutically acceptable salt thereof, wherein:
H is selected from C5-i2 carbocycle and 5- to 12-membered heterocycle, each of which is optionally substituted with one or more R50;
A, B and C are each independently selected from C3-12 carbocycle and 3- to 12-membered heterocycle;
L1 and L2 are each independently selected from bond, -0-, -S-, -N(R51)-, -N(R51)CH2-, - C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(0)N(R51)-, -C(0)N(R51)C(0)-, - C(0)N(R51)C(0)N(R51)-, -N(R51)C(0 , -N(R51)C(0)N(R51)-, -N(R51)C(0)0-, -OC(0)N(R51)-, - C(NR51)-, -N(R51)C(NR51)-, -C(NR51)N(R51)-, -N(R51)C(NR51)N(R51)-, -S(0)2-, -OS(O)-, - S(0)0-, -S(O)-, -OS(0)2-, -S(0)20-, -N(R51)S(0)2-, -S(0)2N(R51)-, -N(R51)S(0)-, -S(0)N(R51)-, -N(R51)S(0)2N(R51)-, -N(R51)S(0)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 L1 or L2 can together optionally form a ring;
L3 is selected from alkylene, alkenylene, and alkynylene, each of which is substituted with one or more R56 and optionally further 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, n and p are each independently an integer from 0 to 6;
R50 is independently selected at each occurrence from:
halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR3Z)2, -P(0)(R3Z)2, -P(0)(OR3Z)(R3Z), -P(0)(NR3Z)(R3Z), -NR3ZP(0)(R3Z), P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52);
Ci-io 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, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54 -S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; and
C3-i2 carbocycle and 3- to 12-membered heterocycle,
wherein each C3-i2 carbocycle and 3- to 12-membered heterocycle in R50 is independently optionally substituted with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), Ci_6 alkyl, Ci_6 haloalkyl, C2_ alkenyl, and C2_6 alkynyl;
independently selected at each occurrence from:
hydrogen, -C(0)R52, -C(0)OR52, -C(0)N(R52)2, -C(0)NR53R54;
Ci-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, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C3_i2 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, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), d_6 alkyl, d_6 haloalkyl, C2_6 alkenyl, and C2_6 alkynyl;
R52 is independently selected at each occurrence from hydrogen; and Ci_2o alkyl, C2_2o alkenyl, C2-20 alkynyl, 1- to 6-membered heteroalkyl, C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -N02, -NH2, -NHCH3, - NHCH2CH3, =0, -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;
R56 is independently selected at each occurrence from:
-N02, -OR59, -SR52, -NR53R54, -S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, - S(=0)2NR53R54, -NR52S(=0)2R52, -NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, - C(0)R52, -C(0)OR52, -OC(0)R52, -OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, -NR52C(0)N(R52)2, -
NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, -P(0)(OR52)2, -P(0)(R52)2, - P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), -P(0)(NR52)(OR52), - P(0)(NR52)2, =0, =S, =N(R52), Ci-10 alkyl, C2-io alkenyl, C2-io alkynyl, C3-12 carbocycle and 3- to 12-membered heterocycle,
wherein each Ci_io alkyl, C2_io alkenyl, and C2_io alkynyl in R56 is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -N02, -CN, -OR59, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle;
wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R56 is independently optionally substituted with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), d_6 alkyl, d_6 haloalkyl, C2_6 alkenyl, and C2_6 alkynyl; and
further wherein R56 optionally forms a bond to ring C; and
R59 is independently selected at each occurrence from Ci-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, 1- to 6-membered heteroalkyl, C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -N02, -NH2, -NHCH3, -NHCH2CH3, =0, -OH, -OCH3, -OCH2CH3, C3-i2 carbocycle, or 3- to 6-membered heterocycle.
[0123] In some embodiments, the stereoisomer of a compound of Formula (II) 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.
[0124] In some embodiments, for a stereoisomer of a compound of Formula (II), L3 is selected from
Figure imgf000071_0001
. Optionally, R56 is methyl. In some embodiments, L3 is . In some
,
Figure imgf000071_0002
X , and C is selected from
Figure imgf000072_0001
[0125] Any combination of the groups described above for the various variables of a compound of Formula (II) is contemplated herein for the stereoisomer of a compound of Formula (II).
[0126] 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).
[0127] In some embodiments, for a compound of Formula (I) or (II), 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.
[0128] In some embodiments, for a compound of Formula (I) or (II), 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).
[0129] In some embodiments, for a compound of Formula (I) or (II), 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) or (II) is capable of (a) binding covalently to menin and (b) inhibiting the interaction of menin and MLL.
[0130] In some embodiments, for a compound of Formula (I) or (II), 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.
[0131] In some embodiments, for a compound of Formula (I) or (II), 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.
[0132] In some embodiments, for a compound of Formula (I) or (II), Rc is selected from:
Figure imgf000073_0001
O O
I LSACF, , 9
L5 CHF, R _ ^L5 CF3. L AH 9
R _ ari(j
wherein:
L5 is selected from a bond; and Ci alkylene, Ci-6 heteroalkylene, C2 alkenylene, and C2 alkynylene, each of which is independently optionally substituted with one or more R32;
22 23
and are each independently selected from: hydrogen, halogen, -OR , -SR , -N(RZU)2, -N(Rzu)C(0)Rzu - C(0)R20, -C(0)OR20, -C(O)N(R20)2, -OC(0)R20, -S(0)2R2°, - S(O)2N(R20)2, -N(R20)S(O)2R20, -N02, =0, =S, =N(R20), -P(O)(OR20)2, - P(O)(R20)2, -OP(O)(OR20)2, and -CN;
Ci-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(0)R20, -C(0)OR20, -C(O)N(R20)2, -OC(0)R20, - S(0)2R20, -S(O)2N(R20)2, -N(R20)S(O)2R20, -N02, =0, =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 R 22 and R 23 is independently optionally substituted with one or more substituents selected from halogen, -OR20, -SR20, -N(R20)2, - N(R20)C(O)R20 -C(0)R20, -C(0)OR20, -C(O)N(R20)2, -OC(0)R20, - S(0)2R20, -S(O)2N(R20)2, -N(R20)S(O)2R20, -N02, =0, =S,
=N(R20), -P(O)(OR20)2, -P(O)(R20)2, -OP(O)(OR20)2, -CN, d_6 alkyl, C2_6 alkenyl, and C2_6 alkynyl; or R 22 and R 23 , together with the carbon atoms to which they are attached, form a carbocyclic ring;
selected from:
hydrogen, -C(0)R20, -C(0)OR20, -C(O)N(R20)2, -OC(0)R20, - S(0)2R20, and -S(O)2N(R20)2;
Ci-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(0)R20, -C(0)OR20, -C(O)N(R20)2, -OC(0)R20, - S(0)2R20, -S(O)2N(R20)2, -N(R20)S(O)2R20, -N02, =0, =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(Rzu)C(0)Rzu -C(0)R , -C(0)OR , -C(0)N(Rzu)2, -OC(0)R , - S(0)2R20, -S(O)2N(R20)2, -N(R20)S(O)2R20, -N02, =0, =S,
=N(R20), -P(O)(OR20)2, -P(O)(R20)2, -OP(O)(OR20)2, -CN, Ci-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.
[0133] In some embodiments, L5 is a bond. In some embodiments, L5 is optionally substituted Ci-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, -N02, =0, =S, -OR20, -SR20, and -N(R20)2.
[0134] In some embodiments, R23 is selected from:
hydrogen;
Ci-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(0)R20, -C(0)OR20, -C(O)N(R20)2, - OC(0)R20, -S(0)2R20, -S(O)2N(R20)2, -N(R20)S(O)2R20, -N02, =0, =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(0)R20, -C(0)OR20, -C(O)N(R20)2, - OC(0)R20, -S(0)2R20, -S(O)2N(R20)2, -N(R20)S(O)2R20, -N02, =0, =S,
=N(R20), -P(O)(OR20)2, -P(O)(R20)2, -OP(O)(OR20)2, -CN, d_6 alkyl, C2_6 alkenyl, and C2_ 6 alkynyl.
[0135] In some embodiments, R23 is selected from:
hydrogen;
Ci-6 alkyl optionally substituted with one or more substituents selected from halogen, -OR20, -SR20, -N(R20)2, =0, =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(0)R20, -C(0)OR20, -C(O)N(R20)2, -OC(0)R20, -S(0)2R20, -S(O)2N(R20)2, - N(R20)S(O)2R20, -N02, =0, =S, =N(R20), -P(O)(OR20)2, -P(O)(R20)2, -OP(O)(OR20)2, - CN, Ci-6 alkyl, C2_6 alkenyl, and C2_6 alkynyl. [0136] In some embodiments, R is selected from hydrogen and Ci_6 alkyl optionally substituted with one or more substituents selected from halogen, -OR20, -SR20, -N(R20)2, =0, =S, =N(R20), and -CN.
embodiments, 22
[0137] In some R is selected from:
hydrogen and -CN;
Ci-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(0)R20, -C(0)OR20, -C(O)N(R20)2, - OC(0)R20, -S(0)2R20, -S(O)2N(R20)2, -N(R20)S(O)2R20, -N02, =0, =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(0)R20, -C(0)OR20, -C(O)N(R20)2, - OC(0)R20, -S(0)2R20, -S(O)2N(R20)2, -N(R20)S(O)2R20, -N02, =0, =S, =N(R20), - P(O)(OR20)2, -P(O)(R20)2, -OP(O)(OR20)2, -CN, d_6 alkyl, C2_6 alkenyl, and C2_6 alkynyl. In some embodiments, 22
[0138] R is selected from hydrogen, -CN; and Ci_6 alkyl optionally substituted with one or more substituents selected from halogen, 20 20 20
-OR , -SR , and -N(R )2. ome embodiments, 22 23
[0139] In s R and R , together with the carbon atoms to which they are attached, form a 5-, 6-, or 7-membered carbocyclic ring.
[0140] In some embodiments, R24 is selected from hydrogen and Ci_6 alkyl optionally substituted with one or more substituents selected from halogen, -OR20, -SR20, -N(R20)2, -N02, =0, and - CN.
Figure imgf000076_0001
Figure imgf000077_0001
[0142] In certain aspects, the present disclosure provides a method of promoting proliferation of a pancreatic cell, compris :
Figure imgf000077_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 optionall substituted with one or more R50;
Figure imgf000077_0003
each of Z1, Z2, Z3, and Z4 is independently selected from -QR^XR^)-, -C(RA1)(RA2)- C(RA1)(RA2)-, -C(O)-, and -C(RA1)(RA2)-C(0)-, wherein no more than one of Z1, Z2, Z3, and Z4 is -C(O)- or -C(RA1)(RA2)-C(0)-;
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, -0-, -S-, -N(R51)-, -N(R51)CH2-, -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(0)N(R51)-, -C(0)N(R51)C(0)-, - C(0)N(R51)C(0)N(R51)-, -N(R51)C(0 , -N(R51)C(0)N(R51)-, -N(R51)C(0)0-, -OC(0)N(R51)-, - C(NR51)-, -N(R51)C(NR51)-, -C(NR51)N(R51)-, -N(R51)C(NR51)N(R51)-, -S(0)2-, -OS(O)-, - S(0)0-, -S(O)-, -OS(0)2-, -S(0)20-, -N(R51)S(0)2-, -S(0)2N(R51)-, -N(R51)S(0)-, -S(0)N(R51)-, -N(R51)S(0)2N(R51)-, -N(R51)S(0)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;
B 50 B
R is independently selected at each occurrence from R , or two R groups attached to the same atom or different atoms can together optionally form a bridge or ring;
C 50 C
R is independently selected at each occurrence from hydrogen and R , or two R groups attached to the same atom or different atoms can together optionally form a bridge or ring;
RA1 and R^ are each independently selected at each occurrence from hydrogen and R ; 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, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52);
Ci-io alkyl, C2_io alkenyl, and C2_io alkynyl, each of which is
independently optionally substituted at each occurrence with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; and
C3-i2 carbocycle and 3- to 12-membered heterocycle, wherein each C3-i2 carbocycle and 3- to 12-membered heterocycle in R50 is independently optionally substituted with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR3Z)2, -P(0)(R3Z)2, -P(0)(OR3Z)(R3Z), -P(0)(NR3Z)(R3Z), -NR3ZP(0)(R3Z), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), d_6 alkyl, d_6 haloalkyl, C2_6 alkenyl, and C2-6 alkynyl;
R51 is independently selected at each occurrence from:
hydrogen, -C(0)R52, -C(0)OR52, -C(0)N(R52)2, -C(0)NR53R54;
Ci-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, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C3-12 carbocycle and 3- to 12- membered heterocycle; and
C3-i2 carbocycle and 3- to 12-membered heterocycle, wherein each C3-i2 carbocycle and 3- to 12-membered heterocycle in R51 is independently optionally substituted with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =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 Ci-20 alkyl, C2-20 alkenyl, C2_2o alkynyl, 1- to 6-membered heteroalkyl, C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -N02, -NH2, -NHCH3, - NHCH2CH3, =0, -OH, -OCH3, -OCH2CH3, C3_i2 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.
[0143] In certain aspects, a compound of Formula (III) may be represented by:
Figure imgf000080_0001
(III- A), such as (III-B), wherein R1, R2 and R 3 are each independently selected at each occurrence from hydrogen and R 50. In some embodiments, R1 is selected from R50. In some embodiments, R1 is Ci-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, Ci_3 alkyl, Ci_3 alkyl- OR52, Ci_3 alkyl-N(R52)2, Ci_3 haloalkyl, C2-3 alkenyl, and C2_3 alkynyl. In some embodiments, R is selected from halogen, -OH, -OR52, -NH2, -N(R52)2, -CN, d_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(0)OR52, Ci_3 alkyl, and d_3 haloalkyl. In some embodiments, R52 is selected from selected from hydrogen and alkyl, such as R52 is hydrogen.
[0144] In some embodiments, for a compound of Formula (III), A is selected from * N/ N/ X < „00+ ¾N CN ¾ΝΟΟ+ «O »+
Figure imgf000080_0002
[0145] In certain aspects, the present disclosure provides a method of promoting proliferation of a pancreatic cell, comprising administering a compound of Formula (IV):
Figure imgf000080_0003
or a p acceptable salt or prodrug thereof, wherein:
Figure imgf000080_0004
thienyl or fused phenyl group;
Ga is selected from C3-i2 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(=0)-, -C(=0)-0-, -C(=0)-N(R52)-, -CH2N(R52)-CH2-, - C(=0)N(R52)-CH2-, -CH2CH2-N(R52)-, -CH2N(R52)-C(=0)-, and -CH20-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(=0)-, -C(=0)N(R52)-, -[C(R14a)2]i-50-, -[C(R14a)2]i_5NR52-, -[C(R14a)2]!_5-, -CH2(=0)-, and -S(=0)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, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52);
Ci-io alkyl, C2_io alkenyl, and C2_io alkynyl, each of which is
independently optionally substituted at each occurrence with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; and
C3-i2 carbocycle and 3- to 12-membered heterocycle, wherein each C3-i2 carbocycle and 3- to 12-membered heterocycle in R is independently optionally substituted with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =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 Ci-20 alkyl, C2_2o alkenyl, C2_2o alkynyl, 1- to 6-membered heteroalkyl, C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -N02, -NH2, -NHCH3, - NHCH2CH3, =0, -OH, -OCH3, -OCH2CH3, C3-i2 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.
[0146] In some embodiments, for a compound of Formula (IV), Ga is piperidinyl. In some
Figure imgf000082_0001
R a is selected from hydrogen and fluoro.
[0147] 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.
[0148] 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.
[0149] 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 in Scheme 1 and Examples 1-5, the steps in some cases may be performed in a different order than the order shown in Scheme 1 and
Examples 1-5. 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.
[0150] 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.
[0151] In general, compounds of the disclosure for use in the subject methods may be prepared by the following reaction scheme: Scheme 1
Figure imgf000084_0001
1-6 1-7
[0152] In some embodiments, a compound of Formula 1-7 may be prepared according to
Scheme 1. For example, methanesulfonyl chloride can be added to a solution of alcohol 1-1 and triethylamine to afford mesylate 1-2. Addition of mesylate 1-2 to a solution of CS2CO3 and amine 1-3 can provide a compound of Formula 1-4. Coupling of aldehyde 1-4 to amine 1-5 can proceed in the presence of a suitable reducing agent, such as NaBH(OAc)3, to give a compound of Formula 1-6. Addition of TFA can reveal the free amine, which can optionally be reacted with R57-LG, wherein LG is a suitable leaving group, to afford a compound of Formula 1-7.
[0153] 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, Table 2, or Table 3, is synthesized according to one of the general routes outlined in Scheme 1, Examples 1-5, 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, Table 2 or Table 3. Table 1
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
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
No. Structure MW (calc'd) m/z (found)
211 743.30 744.40 [M+H]+
212 707.33 708.45 [M+H]+
Figure imgf000111_0001
213 709.35 710.50 [M+H]+
214 732.29 733.40 [M+H]+
215 711.33 712.45 [M+H]+
216 683.30 684.45 [M+H]+
Figure imgf000112_0001
Figure imgf000113_0001
- Ill - No. Structure MW (calc'd) m/z (found)
251 745.32 746.3 [M+H]+
252 731.30 732.3 [M+H]+
253 716.29 717.3 [M+H]+
[0154] Table 2
Figure imgf000114_0001
Figure imgf000114_0002
Figure imgf000114_0003
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 imgf000124_0002
Figure imgf000124_0003
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
[0155] Table 3
Figure imgf000142_0003
Figure imgf000142_0002
Figure imgf000142_0001
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
[0156] Pharmaceutical Compositions
[0157] 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), (II), (III) or (IV) and a pharmaceutically acceptable carrier.
[0158] 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.
[0159] 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.
[0160] In certain embodiments, the present disclosure provides a method comprising
administering a composition of a compound or salt of Formula (I), (II), (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), (II), (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.
[0161] The compound of Formula (I), (II), (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.
[0162] In some embodiments, a compound or salt of Formula (I), (II), (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), (II), (III) or (IV) is used for treatment of an acute condition.
[0163] In some embodiments, a compound or salt of Formula (I), (II), (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), (II), (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), (II), (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.
[0164] Administration of a compound or salt of Formula (I), (II), (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), (II), (III) or (IV) is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects.
[0165] In some embodiments, a compound or salt of Formula (I), (II), (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), (II), (III) or (IV) may be found by routine experimentation in light of the instant disclosure.
[0166] In some embodiments, a compound or salt of Formula (I), (II), (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 & Wi nsl999).
[0167] Provided herein are methods of promoting proliferation of a pancreatic cell, comprising administering pharmaceutical compositions comprising a compound or salt of Formula (I), (II), (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), (II), (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), (II), (III) or (IV), or a pharmaceutically acceptable salt thereof.
[0168] A pharmaceutical composition, as used herein, refers to a mixture of a compound or salt of Formula (I), (II), (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), (II), (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), (II), (III) or (IV) may be used singly or in combination with one or more therapeutic agents as components of mixtures.
[0169] In one embodiment, a compound or salt of Formula (I), (II), (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), (II), (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), (II), (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.
[0170] In another embodiment, a compound or salt of Formula (I), (II), (III) or (IV) is formulated for oral administration. A compound or salt of Formula (I), (II), (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), (II), (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.
[0171] 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), (II), (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.
[0172] 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.
[0173] In certain embodiments, practicing the methods of treatment or use provided herein, a therapeutically effective amount of a compound or salt of Formula (I), (II), (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.
[0174] In other embodiments, a therapeutically effective amount of a compound or salt of Formula (I), (II), (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), (II), (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), (II), (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.
[0175] In still other embodiments, a compound or salt of Formula (I), (II), (III) or (IV) is administered topically. A compound or salt of Formula (I), (II), (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.
[0176] In yet other embodiments, a compound or salt of Formula (I), (II), (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), (II), (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), (II), (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), (II), (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.
[0177] In other embodiments, a compound or salt of Formula (I), (II), (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), (II), (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), (II), (III) or (IV) and a suitable powder base such as lactose or starch.
[0178] In still other embodiments, a compound or salt of Formula (I), (II), (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.
[0179] 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), (II), (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.
[0180] 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),
(II) , (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), (Π), (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.
[0181] Methods of the present disclosure may include a compound or salt of Formula (I), (II),
(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), (II), (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), (II), (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. [0182] In some embodiments, a pharmaceutical composition comprising a compound or salt of Formula (I), (II), (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.
[0183] 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.
[0184] 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.
[0185] 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.
[0186] 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.
[0187] 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.
[0188] 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.
[0189] 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.
[0190] 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.
[0191] 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), (II), (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.
[0192] 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, (1) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.
[0193] In some embodiments, the concentration of a compound or salt of Formula (I), (II), (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.
[0194] In some embodiments, the concentration of a compound or salt of Formula (I), (II), (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.
[0195] In some embodiments, the concentration of a compound or salt of Formula (I), (II), (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.
[0196] In some embodiments, the concentration of a compound or salt of Formula (I), (II), (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.
[0197] In some embodiments, the amount of a compound or salt of Formula (I), (II), (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.
[0198] In some embodiments, the amount of a compound or salt of Formula (I), (II), (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.
[0199] 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.
[0200] 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.
[0201] 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), (II), (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.
[0202] 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.
[0203] Methods
[0204] 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), (II), (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 ρ27Κψ1 and/or pl8INK4C mRNA levels; (c) a decrease in p27 ψ and/or pl8 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. /. 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.
[0205] 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. /. 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.
[0206] 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. /. 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.
[0207] 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.
[0208] 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), (II), (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), (II), (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.
[0209] 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), (II), (III) or (IV) to a subject in need thereof.
[0210] 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-pro liferative 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.
[0211] 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.
[0212] 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), (II), (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.
[0213] 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.
[0214] 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-a-[[[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.
[0215] 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.
[0216] 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.
[0217] 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. [0218] 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.
[0219] Moreover, therapeutic agents used for immunomodulation, such as immunomodulators, immunosuppressive agents, tolerogens, and immuno stimulants 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.
[0220] 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.
[0221] 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.
[0222] The methods described herein may comprise use of a compound of Formula (I), (II), (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.
[0223] 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
[0224] Example 1: Synthesis of Compound 59.
Figure imgf000171_0001
[0225] Step A: Preparation of Compound 59-2: To a solution of ethyl-2-(diethoxylphosphoryl) acetate (1.91 g, 8.5 mmol) in THF (30 mL) was added NaH (421 mg, 10.5 mmol) at 0 °C. The reaction was stirred at 0 °C for 0.5 hour before 59-1 (2 g, 8 mmol) was added. The reaction mixture was stirred at room temperature for 5h. Ice-water (50 mL) was added, and the product extracted with ethyl acetate (50 mL x 2). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (eluted 20% EtOAc in pet. ether) to afford 2.15 g of 59-2 as a white solid (yield: 85%).
[0226] Step B: Preparation of Compound 59-3: To a solution of 59-2 (905 mg, 2.85 mmol) in MeOH (20 mL) was added (Boc^O (1.24 g, 5.71 mmol) and Pd/C catalyst. The reaction mixture was stirred at room temperature for 8 hours under ¾. TLC showed the reaction was complete. The reaction was filtered and concentrated. The residue was purified by silica gel column chromatography (eluted 20% EtOAc in pet. ether) to give 59-3 as a solid (740 mg, yield: 91%).
[0227] Step C: Preparation of Compound 59-4: To a solution of 59-3 (670 mg, 2.35 mmol) in THF (20 mL) was added L1AIH4 (179 mg, 4.7 mmol) at 0 °C. The reaction was stirred at 0 °C for 2h, then 0.2 mL H20, 0.2 mL 15% NaOH, and 0.5 mL H20 added. The mixture was stirred at room temperature for lh. The mixture was filtered and the organic solution was concentrated. The residue was purified by silica gel column chromatography (eluted 40% EtOAc in pet. ether) to give 59-4 as a solid (525 mg, yield: 92%).
[0228] Step D: Preparation of Compound 59-5 : To a solution of 59-4 (486 mg, 2 mmol) and Et3N (404 mg, 4 mmol) in CH2C12 (20 mL) was added MsCl (344 mg, 3 mmol) at 0 °C. The reaction was stirred at room temperature for lh. TLC showed the reaction was complete. The combined organic layer was washed with ¾0 and brine, dried over sodium sulfate and concentrated in vacuo to afford 500 mg of 59-5 as a white solid (yield: 78%).
[0229] Step E: Preparation of Compound 59-6: A mixture of 59-5 (500 mg, 1.56 mmol), CS2CO3 (846 mg, 2.33 mmol), and 5-formyl-4-methyl-lH-indole-2-carbonitrile (143 mg, 0.78 mmol) was mixed in DMF (20 mL). The reaction mixture was heated at 85 °C for 3h. EtOAc (200 mL) was added into the resulting mixture. The combined organic layer was washed with ¾0 and brine, dried over sodium sulfate and concentrated. The residue was purified by flash column (eluted 30% EtOAc in pet. ether) to afford 278 mg of 59-6 as a white solid (yield: 43%).
[0230] Step F: Preparation of Compound 59-7: A mixture of 59-6 (278 mg, 0.68 mmol), N- (piperidin-4-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-amine (280 mg, 0.88 mmol) and Et3N (412 mg, 4.08 mmol) in CH2CI2 (20 mL) was stirred at room temperature for 1 hour.
NaBH(OAc)3 (865 mg, 4.08 mmol) was added to the reaction under ice bath and the reaction mixture stirred at room temperature overnight. The solvent was removed by vacuum and the residue was purified by silica gel column chromatography (eluted 2.5% MeOH in
dichloromethane) to give 59-7 as a white solid (400 mg, yield: 82%).
[0231] Step G: Preparation of Compound 59-8: A solution of 59-7 (200 mg, 0.28 mmol) in TFA (15 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 resulting mixture was concentrated and the residue was purified by silica gel column chromatography (eluted 10% MeOH in dichloromethane) to give 59-8 as an oil (164 mg, yield: 96%).
[0232] Step H: Preparation of Compound 59: To a solution of 59-8 (127 mg, 0.21 mmol) and Et3N (43mg, 0.42mmol) in CH2C12 (20 mL) was added MsCl (29 mg, 0.25 mmol) at 0 °C. The reaction was stirred at room temperature for lh. TLC showed the reaction was complete. The combined organic layer was washed with ¾0 and brine, dried over sodium sulfate, and concentrated in vacuo to afford 45 mg of 59 as a white solid (yield: 31%). 1H1S1MR (400
MHz, DMSO) δ: 8.33(s, 1H), 7.87(s, lH),7.67(s, 1H) 7.45-7.56 (m, 3H), 4.35-4.32 (m, 2H), 4.08-4.02 (m, 4H), 3.57-3.54 (m, 3H), 3.17(m,lH, 2.88-2.83(m, 6H), 2.54 (s, 3H), 2,20-1.47 (m, 12H), 1.25 (d, 3H). ESI-MS m/z: 688.84 (M+H). [0233] Example 2: Synthesis of Compound 48.
Figure imgf000173_0001
48-6 48
[0234] Step A: Preparation of Compound 48-2: A mixture of 48-1 (300 mg, 1.40 mmol), 2- bromoethanol (347 mg, 2.80 mmol) and K2C03 (772 mg, 5.60 mmol) in CH3CN (30 mL) was stirred at 90 °C under N2 overnight. TLC showed the reaction was complete. Solid was removed by filtration and solvent was removed under vacuum. The residue was purified by silica gel column chromatography (eluted 2.5 % MeOH in dichloromethane) to give 48-2 as a yellow oil (296 mg, yield: 82%).
[0235] Step B: Preparation of Compound 48-3 : To a mixture of 48-2 (296 mg, 1.15 mmol) and Et3N (232 mg, 2.30 mmol) in dichloromethane (20 mL) was added MsCl (197 mg, 1.73 mmol) at 0 °C. The reaction mixture was stirred at room temperature for lh. TLC showed the reaction was complete. Saturated aqueous NaHC03 was added to the reaction mixture. The organic layer was separated, washed with brine, dried over anhydrous Na2S04, and concentrated. The residue was purified by silica gel column chromatography (eluted petroleum) to give 48-3 as an oil (270 mg, yield: 70%). [0236] Step C: Preparation of Compound 48-4: A mixture of 48-3 (270 mg, 0.8 mmol), 5- formyl-4-methyl-lH-indole-2-carbonitrile (123mg, 0.67 mmol) and CS2CO3 (524 mg, 1.6 mmol) in DMF (10 mL) was stirred at 80 °C under N2 overnight. Solid was removed by filtration before the reaction mixture was diluted with water and ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous Na2S04, concentrated and purified by silica gel column chromatography (eluted 20% ethyl acetate in petroleum) to give 48-4 as an oil (169 mg, yield: 50%). ESI-MS m/z: 424.54 (M+H).
[0237] Step D: Preparation of Compound 48-5 : A mixture of 48-4 (169 mg, 0.4 mmol), N- (piperidin-4-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-amine (190 mg, 0.6 mmol) and Et3N (242 mg, 2.4 mmol) in CH2CI2 (20 mL) was stirred at room temperature for 1 hour.
NaBH(OAc)3 (508 mg, 2.4 mmol) was added to the reaction under ice bath cooling and the mixture reaction was stirred at room temperature overnight. Solvent was removed by vacuum and the residue was purified by silica gel column chromatography (eluted 2.5% MeOH in dichloromethane) to give 48-5 as an oil (174 mg, yield: 60%). ESI-MS m/z: 724.88 (M+H).
[0238] Step E: Preparation of Compound 48-6: To a solution of 48-5 (174 mg, 0.24 mmol) in CH2CI2 (15 mL) was added TFA (5 mL). The reaction was stirred at room temperature for 2 hours before solvent was removed. A solution of N]¾/MeOH (7N, 10 mL) was added and the resulting mixture was concentrated. The residue and purified by silica gel column
chromatography (eluted 10% MeOH in dichloromethane) to give 48-6 as an oil (120 mg, yield: 80%). ESI-MS m/z: 624.30(M+H).
[0239] Step F: Preparation of Compound 48: To a mixture of 48-6 (120 mg, 0.192 mmol) and Et3N (39 mg, 0.384mmol) in CH2CI2 (10 mL) was added slowly methanesulfonyl chloride (33 mg, 0.288 mmol) in CH2CI2 (5mL) at -20 °C under N2. The reaction mixture was stirred at room temperature for 2 hours. TLC showed the reaction was complete. Saturated aqueous NaHC03 was added to the reaction mixture. The organic layer was separated, washed with brine, dried over anhydrous Na2S04, concentrated and purified by silica gel column chromatography (eluted 10% MeOH in dichloromethane) to give final product 48 as a solid (54 mg, yield: 40%). H MR (400 MHz, CDC13) δ: 8.48(s, 1H), 7.38(d, 1H), 7.21(s,lH), 7.15(d,lH), 7.08(s,lH), 5.10(d,lH), 4.34(m,2H), 4.24(m,lH),3.87(m, 2H), 3.65(m, 4H), 2.93(m, 5H),2.71(m, 2H), 2.63(m, 2H), 2.57(s,3H),2.29(m, 2H) , 2.21(m, 2H) ,2.10(d, 2H), 1.61(m, 2H), 1.31(d, 6H); ESI- MS m/z: 702.27 (M+H). [
Figure imgf000175_0001
2-7
[0241] Step A: Preparation of Compound 2-2: To a suspension of K2CO3 (3.6 g, 26.5 mmol) and tert-butyl piperazine- 1 -carboxylate (1.0 g, 5.3 mmol) in CH3CN (15 mL) was added methyl 2- bromopropanoate (2.2 g, 13.4 mmol). The reaction was stirred at 80 °C for 10 hours. TLC showed that the reaction was complete. The reaction mixture was allowed to cool to room temperature, then the solid filtered off and solvent removed under vacuum. The residue was purified by silica gel column chromatography (Cl kCk/MeOH = 50:1) to give tert-butyl 4-(l- methoxy-l-oxopropan-2-yl)piperazine-l -carboxylate (2-2) as a brown oil (1.4 g, yield: 99%).
[0242] Step B: Preparation of Compound 2-3: To a solution of tert-butyl 4-(l-methoxy-l- oxopropan-2-yl)piperazine-l -carboxylate (540 mg, 2 mmol) in THF (10 mL) was added L1AIH4
(1.0 mL, 2.5 mol in THF) at 0 °C drop wise. The reaction mixture was stirred at the same temperature for 2 hours. TLC showed that the reaction was complete. The reaction was quenched with EtOAc. The reaction was partitioned between EtOAc and ¾0, and the organic layer was washed with brine and dried over Na2S04. Solvent was removed under vacuum and the residue was purified by silica gel column chromatography (CH2Ci2/MeOH = 20:1) to give tert-butyl 4-
(l-hydroxypropan-2-yl)piperazine-l-carboxylate (2-3) as a brown oil (300 mg, yield: 65%). [0243] Step C: Preparation of Compound 2-5: To a solution of tert-butyl 4-(l -hydro ypropan-2- yl)piperazine-l-carboxylate (200 mg, 0.82 mmol) and Et3N (171 mg, 1.64 mmol) in CH2C12 (10 mL) was added MsCl (112 mg, 0.98 mmol) at 0 °C. The reaction was stirred at room temperature for 30 min. The reaction was quenched with NaHC03, washed with brine and dried over Na2S04. Solvent was removed under vacuum to give tert-butyl 4-(l-((methylsulfonyl)oxy)propan-2- yl)piperazine-l-carboxylate (2-4), used in the next step without further purification.
[0244] To a mixture of Cs2C03 (682 mg, 2.1 mmol) and 5-formyl-4-methyl-lH-indole-2- carbonitrile (77 mg, 0.42 mmol) in DMF was added tert-butyl 4-(l-
((methylsulfonyl)oxy)propan-2-yl)piperazine-l-carboxylate in DMF. The reaction was stirred at 100 °C for 10 hours. The reaction mixture was partitioned between EtOAc and ¾0, and the organic layer was washed with brine and dried over Na2S04. Solvent was removed under vacuum and the residue was purified by silica gel column chromatography (pet. ether/EtOAc = 5:1-3 :1) to give tert-butyl 4-(l-(2-cyano-5-formyl-4-methyl-lH-indol-l-yl)propan-2- yl)piperazine-l-carboxylate (2-5) as a yellow solid (90 mg, yield: 53%).
[0245] Step D: Preparation of Compound 2-6: A mixture of tert-butyl 4-(l-(2-cyano-5-formyl-4- methyl-lH-indol-l-yl)propan-2-yl)piperazine-l-carboxylate (90 mg, 0.22 mmol), 6-(2,2,2- trifluoroethyl)-N-(piperidin-4-yl)thieno-[2,3-d]pyrimidin-4-amine (100 mg, 0.26 mmol) and Et3N (130 mg, 1.32 mmol) in CH2CI2 (10 mL) was stirred at room temperature for 1 hour before NaBH(OAc)3 (280 mg, 1.32 mmol) was added. The reaction mixture was stirred at room temperature overnight, then partitioned between CH2CI2 and NaHC03. The organic layer was washed with brine and dried over Na2S04. Solvent was removed under vacuum and the residue was purified by silica gel column chromatography (CfkCkMeOH = 50:1-20:1) to give tert- butyl 4-(l-(2-cyano-4-methyl-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4- yl)amino)piperidin-l-yl)methyl)-lH-indol-l-yl)propan-2-yl)piperazine-l-carboxylate (2-6) as a yellow solid (130 mg, yield: 81%).
[0246] Step E: Preparation of Compound 2-7: 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-l-yl)methyl)- lH-indol-l-yl)-l-hydroxyethyl)piperidine-l-carboxylate (130 mg, 0.21 mmol) in CH2CI2 (3 mL) was added TFA (2 mL). The reaction was stirred for 4 hours before solvent was removed under vacuum. The residue was diluted with CH2CI2 and washed with NaHC03. The organic layer was washed with brine and dried over Na2S04. Solvent was removed under vacuum and the residue (2-7) was used without further purification as a yellow foam (100 mg, yield: 98%).
[0247] Step F: Preparation of Compound 2: To a solution of 4-methyl-l-(2-(piperazin-l- yl)propyl)-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-l- yl)methyl)-lH-indole-2-carbonitrile (60 mg, 0.1 mmol) and Et3N (36 mg, 0.4 mmol) in CH2CI2 (10 mL) was added MsCl (21 mg, 0.2 mmol) at 0 °C. The reaction was stirred at room temperature for 30 min. The reaction was quenched by NaHC03, washed with brine and dried over Na2S04. Solvent was removed and the residue was purified by Prep-TLC (CH2Cl2:MeOH = 15 :1) to give 4-methyl-l-(2-(4-(methylsulfonyl)piperazin-l-yl)propyl)-5-((4-((6-(2,2,2- trifluoroethyl)thieno[23-d]pyrimidin-4-yl)amino)piperidin-l-yl)methyl)-lH-indole-2- carbonitrile (compound 2) as a white solid (10 mg, yield: 20%). H NMR (400 MHz, CDC13) 8.48(s, 1H), 7.36(d, 1H), 7.20(s, 1H), 7.00-7.15(m, 2H), 5.16 (d, 1H), 4.20-4.40(m, 2H), 4.00- 4.10(m, 1H), 3.60-3.70 (m,4H), 3.10-3.30(m, 5H), 2.80-2.90 (m, 4H), 2.77 (s, 3H), 2.57 (s, 3H), 1.56-2.53(m, 8H), 1.08 (d,3H). ESI-MS m/z: 689.25 (M+H).
[0248] Example 4: Synthesis of Compound 61 :
Figure imgf000177_0001
61 -5 61-6 61
[0249] Step A: Preparation of Compound 61-2: A mixture of ethyl 1- aminocyclopropanecarboxylate hydrochloride (2.4 g, 14.5mmol), N-benzyl-2-chloro-N-(2- chloroethyl)ethanamine hydrochloride (4.26 g, 15.8 mmol), and N,N-Diisopropylethylamine (25 mL) in ethanol (32 mL) was stirred at reflux for 16 hours. The reaction mixture was concentrated to dryness. The residue was partitioned between dichloromethane and water. Two layers were separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were concentrated. The residue was purified by silica gel column (pet. ether/EtOAc = 1 :0-10:1 ) to give ethyl l-(4-benzylpiperazin-l-yl)cyclopropanecarboxylate (61-2, 1.8 g, yield:
43%) as a yellow oil. H NMR (400 MHz, CDC13) δ: 7.37-7.27 (m, 5H), 4.19-4.13 (m, 2H), 3.54 (s, 2H), 3.00(brs, 2H), 2.39 (brs, 2H), 1.31-1.26 (m, 5H), 7.52 (m 1H), 0.93-0.91 (m, 2H).
[0250] Step B: Preparation of Compound 61-3 : To a mixture of ethyl l-(4-benzylpiperazin-l- yl)cyclopropanecarboxylate (880 mg, 3 mmol) in THF (12 mL) was added LiAlH* (290 mg, 6 mmol) slowly at 0 °C. The resulting mixture was stirred at 0 °C for lh. Water (0.5 mL) was added, followed by ethyl acetate (20 mL). Solid was filtered off and solvent was removed. The residue was purified by silica gel column (pet. ether/EtOAc = 3 :1 ) to give (l-(4- benzylpiperazin-l-yl)cyclopropyl)methanol (61-3, 660 mg, yield: 88%) as a white solid.
[0251] Step C: Preparation of Compound 61-4: A mixture of (l-(4-benzylpiperazin-l- yl)cyclopropyl)methanol (600 mg, 2.4 mmol) and Pd/C (10%, 50 mg) in ethanol (10 mL) was stirred at 50 °C overnight under ¾. The reaction mixture was filtered and the filtrate concentrated to give (l-(piperazin-l-yl)cyclopropyl)methanol (61-4) as an oil (400 mg, yield: 96%). The crude product was used in the next step without further purification.
[0252] Step D: Preparation of Compound 61-5 : To a mixture of (l-(piperazin-l- yl)cyclopropyl)methanol (400 mg, 2.5 mmol) in dichloromethane (10 mL) was added Et3N (1.1 mL, 7.5 mmol), followed by a mixture of methanesulfonyl chloride (925 mg, 7.5 mmol) in dichloromethane (5 mL). The resulting mixture was stirred at room temperature for 4h. The reaction mixture was diluted with water and CH2CI2. The organic layer was dried over Na2S04, and concentrated to give a crude product (l-(4-(methylsulfonyl)piperazin-l- yl)cyclopropyl)methyl methanesulfonate (61-5) as a brown oil (500 mg).
[0253] Step E: Preparation of Compound 61-6: A mixture of crude (l-(4- (methylsulfonyl)piperazin-l-yl)cyclopropyl)methyl methanesulfonate (500 mg), 5-formyl-4- methyl-lH-indole-2-carbonitrile (200 mg, 1.1 mmol), and K2CO3 (800 mg, 5.8 mmol) in acetonitrile was stirred at 80 °C overnight. The mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by silica gel column (pet. ether/EtOAc = 3: 1 ) to give 5-formyl-4-methyl- 1 -((1 -(4-(methylsulfonyl)piperazin- 1 -yl)cyclopropyl)methyl)- 1 H- indole-2-carbonitrile (61-6, 330 mg) as a brown solid. ESI-MS m/z: 401 (M+H).
[0254] Step F: Preparation of Compound 61 : A mixture of 5-formyl-4-methyl-l-((l-(4- (methylsulfonyl)piperazin-l-yl)cyclopropyl)methyl)-lH-indole-2-carbonitrile (330 mg, crude), N-(piperidin-4-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-amine hydrochloride (391 mg, 1.1 mmol), and Et3N (0.5 mL) in dichloromethane (12 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water and CH2CI2. The organic layer was separated, dried over Na2S04, and concentrated. The residue was purified by silica gel column (dichloromethane/methanol = 50: 1-30:1) to give a crude product. The crude product was purified by Prep-TLC with dichloromethane/methanol (7N NH3/MeOH) = 50:1 to give the product (compound 61) as a colorless solid (12 mg). ESI-MS m/z: 701 (M+H).^ NMR (400 MHz, CDCI3) δ: 8.46 (s, 1H), 7.20-7.28 (m, 3H), 4.30-4.36 (m, 3H), 3.84 (brs, 2H), 3.61- 3.68 (m, 2H), 3.09-3.13 (m, 6H), 2.76 (s, 3H), 2.64-2.66 (m, 4H), 2.59 (s, 3H), 2.40-2.48 (m, 2H), 2.14-2.18 (m, 2H), 1.87-1.90 (m, 2H), 0.79-0.82 (t, 2H), 0.61-0.64 (t, 2H).
Figure imgf000179_0001
35
[0256] Step A: Preparation of Compound 35-2: A mixture of tert-butyl piperazine- 1 -carboxylate (1.9 g, 10 mmol) and Et3N (3 g, 30 mmol) in CH2C12 (40 mL) was stirred at 0 °C before 2- chloroacetyl chloride (2.2 g, 20 mmol) was added slowly. The reaction mixture was stirred at 0 °C under N2 for 4 nr. TLC showed that the reaction was complete. The reaction mixture was partitioned between CH2CI2 and J¾0, and the organic layer was washed with brine and dried over Na2S04. Solvent was removed under vacuum and the residue (35-2) was used without further purifications as light yellow oil (2.5 g, yield: 95%).
[0257] Step B: Preparation of Compound 35-3: To a mixture of N-(piperidin-4-yl)-6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidin-4-amine (1 g, 4 mmol), and 5-formyl-4-methyl-lH-indole- 2-carbonitrile (540 mg, 3 mmol) in THF (10 mL) was added NaH (180 mg, 4.5 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then partitioned between EtOAc and H2O, and the organic layer was washed with brine and dried over Na2S04. Solvent was removed under vacuum and the residue purified by silica gel column chromatography (pet. ether:EtOAc = 10:1-1:1) to give tert-butyl 4-(2-(2-cyano-5-formyl-4- methyl-lH-indol-l-yl)acetyl)piperazine-l-carboxylate (35-3) as a light yellow solid (60 mg, yield: 4%).
[0258] Step C: Preparation of Compound 35-4: A mixture of methyl tert-butyl 4-(2-(2-cyano-5- formyl-4-methyl-lH-indol-l-yl)acetyl)piperazine-l-carboxylate (40 mg, 0.1 mmol), N- (piperidin-4-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-amine hydrochloride (60 mg, 0.2 mmol) and Et3N (60 mg, 0.6 mmol) in CH2CI2 (5 mL) was stirred at room temperature for 2 hours. NaBH(OAc)3 (120 mg, 0.6 mmol) was then added to the reaction with ice bath cooling. The reaction mixture was stirred at room temperature overnight. The reaction was partitioned between CH2CI2 and NaHCCh, and the organic layer was washed with brine and dried over Na2S04. Solvent was removed under vacuum and the residue was purified by silica gel column chromatography (CH2Cl2:MeOH = 100: 1-20:1) 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)- 1 H-indol-1- yl)acetyl)piperazine-l-carboxylate (35-4) as a yellow solid (40 mg, yield: 55%).
[0259] Step D: Preparation of Compound 35-5 : 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-l-yl)methyl)-lH- indol-l-yl)acetyl)piperazine-l-carboxylate (40 mg, 0.06 mmol) in HCl MeOH (10 mL) was stirred at room temperature for 16h. TLC showed that the reaction was complete. Solvent was removed under vacuum and the residue (35-5) was used without further purification in next step as a yellow solid (35 mg, yield: 85%).
[0260] Step E: Preparation of Compound 35: To a mixture of 4-methyl-l-(2-oxo-2-(piperazin-l- yl)ethyl)-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-l- yl)methyl)-lH-indole-2-carbonitrile(35 mg, 0.05 mmol) and Et3N (15 mg, 0.15 mmol) in CH2CI2 (10 mL) was slowly added MsCl(12 mg, 0.1 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 4 hours and then partitioned between CH2CI2 and NaHC03. The organic layer was washed with brine and dried over Na2S04. Solvent was removed under vacuum and the residue was purified by Prep-TLC (CH2Cl2:MeOH = 20:1) to give 4-methyl-l-(2-(4- (methylsulfonyl)piperazin-l-yl)-2-oxoethyl)-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3- d]pyrimidin-4-yl)amino)piperidin-l-yl)methyl)-lH-indole-2-carbonitrile (compound 35) as a white solid (16 mg, yield: 56%). 1H MR (400 MHz, CDC13) 8.42 (s, 1H), 7.84-7.76
(m,lH), 7.33-7.22 (m,3H), 5.15 (s, 2H), 4.37~4.08(m, 2H), 3.78(s, 3H), 3.69~3.61(m, 2H), 3.44~3.30(m, 5H), 2.86(s, 3H), 2.70-2.54 (m, 4H), 2.15-2.06 (m, 3H), 1.35-1.23 (m, 4H), 0.91-0.85 (m, 2H).
[0261] Example 6: 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.
[0262] Table 4 shows biological activities of selected compounds in a fluorescence polarization assay. Compound numbers correspond to the numbers and structures provided in Table 1 and Examples 1-5.
Table 4
Figure imgf000181_0001
[0263] Example 7: 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.
[0264] Example 8: Menin engagement assay. Sample Preparation: 2.5 of 100 μΜ compound is added to 47.5 μΐ. of 526 nM menin in PBS (5μΜ 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 μί 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 5μΙ, 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 μί/ηιίη. 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. MaxEntl 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.
[0265] Example 9: 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 μί) 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 μιη; 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).
[0266] Example 10: 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.
[0267] Example 11: 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 μΜ 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.
[0268] FIG. 4A-4E depict confocal images of rat primary dispersed islet cells treated with Compound 132, Compound 135, Compound 9, Compound 10, and no compound, respectively. In particular, the rat primary dispersed islet cells were treated with Compound 132 (FIG. 4A), Compound 135 (FIG. 4B), Compound 9 (FIG. 4C), Compound 10 (FIG. 4D), and no compound (FIG. 4E). In FIG. 4A-4E, 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.
[0269] FIG. 5A-5D depict the change in beta cell proliferation for rat primary dispersed islet cells treated with Compound 132 (FIG. 5A), Compound 135 (FIG. 5B), Compound 9 (FIG. 5C), and Compound 10 (FIG. 5D). In FIG. 5A-5D, the x-axis represents the concentration of compound in μΜ. In FIG. 5A, the % Edu + Insulin gradually increases in the presence of increased concentrations of Compound 132, and at a Compound 132 concentration of 0.8 μΜ, the % Edu + Insulin is approximately 39%. In FIG. 5B, the % Edu + Insulin gradually increases in the presence of increased concentrations of Compound 135, and at a Compound 135
concentration of 0.8 μΜ, the % Edu + Insulin is approximately 32%. In FIG. 5C, the % Edu + Insulin reaches a maximum of approximately 15% at a Compound 9 concentration of 0.05 μΜ. Thereafter, the % Edu + Insulin gradually decreases at increased concentrations and at a
Compound 9 concentration of 0.8 μΜ, the % Edu + Insulin is approximately 8%. In FIG. 5D, the % Edu + Insulin gradually increases in the presence of increased concentrations of
Compound 10, with a maximum % Edu + Insulin of approximately 17% at a Compound 10 concentration of 0.05 μΜ. Thereafter, the % Edu + Insulin gradually decreases at increased concentrations and at a Compound 10 concentration of 0.8 μΜ, the % Edu + Insulin is approximately 11 %.
[0270] Example 12: Human islet proliferation assay. Freshly-isolated explants of non-diabetic, human pancreatic islets were cultured in the presence of DMSO or a compound disclosed herein for 120 hours in growth medium containing 10 μΜ EdU (1000 islet equivalents per sample). Islets were fixed and stained by immunofluorescence for insulin and EdU. Beta cell proliferation, islet area, and average beta cell number per islet were assessed in accordance with methods described herein. As reported in Table 5, treatment with a menin inhibitor disclosed herein in Table 1 induced beta cell proliferation, increased the size of human islets, and increased the average beta cell number per islet.
Table 5
Figure imgf000185_0001
[0271] Example 13: 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 NBl 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% C02 for up to 72 hours.
[0272] 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

What is claimed is:
1. A method of promoting proliferation of a pancreatic cell, comprising
administering a compound of Formula (I):
Figure imgf000186_0001
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
H is selected from C5-i2 carbocycle and 5- to 12-membered heterocycle, each of which is optionally substituted with one or more R50;
A is selected from bond, C3-12 carbocycle and 3- to 12-membered heterocycle;
B is selected from C3-i2 carbocycle and 3- to 12-membered heterocycle;
C is 3- to 12-membered heterocycle;
L1, L2 and L3 are each independently selected from bond, -0-, -S-, -N(R51)-, -N(R51)CH2-, -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(0)N(R51)-, -C(0)N(R51)C(0)-, - C(0)N(R51)C(0)N(R51)-, -N(R51)C(0 , -N(R51)C(0)N(R51)-, -N(R51)C(0)0-, -OC(0)N(R51)-, - C(NR51)-, -N(R51)C(NR51)-, -C(NR51)N(R51)-, -N(R51)C(NR51)N(R51)-, -S(0)2-, -OS(O)-, - S(0)0-, -S(O)-, -OS(0)2-, -S(0)20-, -N(R51)S(0)2-, -S(0)2N(R51)-, -N(R51)S(0)-, -S(0)N(R51)-, -N(R51)S(0)2N(R51)-, -N(R51)S(0)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;
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, n and p are each independently an integer from 0 to 6;
R50 is independently selected at each occurrence from:
halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR3Z)2, -P(0)(R3Z)2, -P(0)(OR3Z)(R3Z), -P(0)(NR3Z)(R3Z), -NR3ZP(0)(R3Z), P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52);
Ci-io 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, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54 -S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; and
C3-i2 carbocycle and 3- to 12-membered heterocycle,
wherein each C3-i2 carbocycle and 3- to 12-membered heterocycle in R50 is independently optionally substituted with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), Ci_6 alkyl, Ci_6 haloalkyl, C2_ alkenyl, and C2_6 alkynyl;
independently selected at each occurrence from:
hydrogen, -C(0)R52, -C(0)OR52, -C(0)N(R52)2, -C(0)NR53R54;
Ci-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, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C3_i2 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, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), d_6 alkyl, d_6 haloalkyl, C2_6 alkenyl, and C2_6 alkynyl;
R52 is independently selected at each occurrence from hydrogen; and Ci_2o alkyl, C2_2o alkenyl, C2-20 alkynyl, 1- to 6-membered heteroalkyl, C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -N02, -NH2, -NHCH3, - NHCH2CH3, =0, -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;
R57 is selected from:
halogen, -N02, -CN, -SR52, -NR53R54, -S(=0)R52, -S(=0)2R58, - S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, -NR52S(=0)2N(R52)2, - NR52S(=0)2NR53R54, -C(0)OR52, -OC(0)R52, -OC(0)OR52, -OC(0)N(R52)2, - OC(0)NR53R54, -NR52C(0)OR52, -NR52C(0)N(R52)2, - NR52C(0)NR53R54, -C(0)NH(Ci_6 alkyl), -C(0)NR53R54, -P(0)(OR52)2, - P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =S, =N(R52); and
Ci-10 alkyl, C2-io alkenyl, and C2-io alkynyl, each of which is
independently substituted at each occurrence with one or more substituents selected from -N02, -CN, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, -S(=0)2R52, - S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, -NR52S(=0)2N(R52)2, - NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, -OC(0)OR52, - OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -P(0)(OR52)2, -P(0)(R52)2, - P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), -P(0)(NR52)(OR52), - P(0)(NR3Z)2, =S, and =N(R3Z); and
R 58 is selected from hydrogen; and Ci-20 alkyl, C3-20 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, -N02, -NH2, -NHCH3, -NHCH2CH3, =0, -OH, -OCH3, - OCH2CH3, C3-12 carbocycle, or 3- to 6-membered heterocycle,
wherein for a compound or salt of Formula (I), when C is azetidinylene, piperidinylene or piperazinylene and R57 is -S(=0)2R58, -S(=0)2N(R52)2, or -NR52S(=0)2R52:
p is an integer from 1 to 6; and/or
L 3 is substituted with one or more R 50 , wherein V 3 is not -CH2CH(OH)-.
2. A method of promoting proliferation of a pancreatic cell, comprising
administering a compound of Formula (II):
Figure imgf000189_0001
or a pharmaceutically acceptable salt thereof, wherein:
H is selected from C5-12 carbocycle and 5- to 12-membered heterocycle, each of which is optionally substituted with one or more R50;
A, B and C are each independently selected from C3-12 carbocycle and 3- to 12-membered heterocycle;
L1 and L2 are each independently selected from bond, -0-, -S-, -N(R51)-, -N(R51)CH2-, - C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(0)N(R51)-, -C(0)N(R51)C(0)-, - C(0)N(R51)C(0)N(R51)-, -N(R51)C(0 , -N(R51)C(0)N(R51)-, -N(R51)C(0)0-, -OC(0)N(R51)-, - C(NR51)-, -N(R51)C(NR51)-, -C(NR51)N(R51)-, -N(R51)C(NR51)N(R51)-, -S(0)2-, -OS(O)-, - S(0)0-, -S(O)-, -OS(0)2-, -S(0)20-, -N(R51)S(0)2-, -S(0)2N(R51)-, -N(R51)S(0)-, -S(0)N(R51)-, -N(R51)S(0)2N(R51)-, -N(R51)S(0)N(R51)-; alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is optionally substituted with one or more R50;
L3 is selected from alkylene, alkenylene, and alkynylene, each of which is substituted with one or more R56 and optionally further 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, n and p are each independently an integer from 0 to 6;
R50 is independently selected at each occurrence from:
halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52);
Ci-io alkyl, C2_io alkenyl, and C2_io alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; and
C3-i2 carbocycle and 3- to 12-membered heterocycle,
wherein each C3-i2 carbocycle and 3- to 12-membered heterocycle in R50 is independently optionally substituted with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), d_6 alkyl, d_6 haloalkyl, C2_6 alkenyl, and C2_6 alkynyl;
R51 is independently selected at each occurrence from:
hydrogen, -C(0)R52, -C(0)OR52, -C(0)N(R52)2, -C(0)NR53R54;
Ci-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, -N02, -CN, -OR , -SR , -N(R3Z)2, -NR R , -S(=0)R , - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C3-12 carbocycle and 3- to 12- membered heterocycle; and
C3-i2 carbocycle and 3- to 12-membered heterocycle, wherein each C3-i2 carbocycle and 3- to 12-membered heterocycle in R51 is independently optionally substituted with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), d_6 alkyl, d_6 haloalkyl, C2_6 alkenyl, and C2_6 alkynyl;
R52 is independently selected at each occurrence from hydrogen; and Ci-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, 1- to 6-membered heteroalkyl, C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -N02, -NH2, -NHCH3, - NHCH2CH3, =0, -OH, -OCH3, -OCH2CH3, C3_i2 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;
R56 is independently selected at each occurrence from:
-N02, -OR59, -SR52, -NR53R54, -S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, - S(=0)2NR53R54, -NR52S(=0)2R52, -NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, - C(0)R52, -C(0)OR52, -OC(0)R52, -OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, -NR52C(0)N(R52)2, -
NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, -P(0)(OR52)2, -P(0)(R52)2, - P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), -P(0)(NR52)(OR52), - P(0)(NR52)2, =0, =S, =N(R52), CLIO alkyl, C2_10 alkenyl, C2_10 alkynyl, C3_12 carbocycle and 3- to 12-membered heterocycle, wherein each Ci_io alkyl, C2-io alkenyl, and C2-io alkynyl in R is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -N02, -CN, -OR59, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle;
wherein each C3-i2 carbocycle and 3- to 12-membered heterocycle in R56 is independently optionally substituted with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), d_6 alkyl, d_6 haloalkyl, C2_6 alkenyl, and C2-6 alkynyl; and
further wherein R56 optionally forms a bond to ring C; and
R59 is independently selected at each occurrence from Ci-20 alkyl, C2_2o alkenyl, C2_2o alkynyl, 1- to 6-membered heteroalkyl, C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -N02, -NH2, -NHCH3, -NHCH2CH3, =0, -OH, -OCH3, -OCH2CH3, C3-i2 carbocycle, or 3- to 6-membered heterocycle,
wherein for a compound or salt of Formula (II), when R56 is -CH3, L3 is not further substituted with -OH, -NH2, or -CN.
3. The method of claim 2, wherein Rc is selected from -C(0)R52, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, =0, Ci_3 alkyl, and Ci_3 haloalkyl, or two Rc groups attached to different atoms can together form a Ci-3 bridge.
4. 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.
5. The method of claim 4, wherein the heterocycle is saturated.
6. The method of claim 5, wherein the heterocycle is selected from piperidinyl and piperazinyl.
7. The method of claim 1, wherein C is selected from:
Figure imgf000193_0001
8. The method of claim 1 or 7, wherein R57 is selected from -S(=0)R52, -S(=0)2R58, -S(=0)2N(R52)2, and -NR52S(=0)2R52.
9. The method of claim 2, wherein C is selected from:
Figure imgf000193_0002
wherein R57 is selected from -S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, - NR52S(=0)2R52; and Ci_io alkyl substituted with one or more substituents selected from - S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, and -NR52S(=0)2R52.
10. The method of claim 9, wherein R57 is selected from -S(=0)R52, -S(=0)2R52, - S(=0)2N(R52)2, and -NR52S(=0)2R52.
11. The method of any one of claims 1 or 7 to 10, wherein R57 is selected from - S(=0)CH3, -S(=0)2CH3, -S(=0)2NH2, -NHS(=0)2CH3, and -S(=0)2NHCH3.
12. The method of any one of the preceding claims, wherein Rc is selected from Ci_3 alkyl and Ci_3 haloalkyl.
13. The method of any one of the preceding claims, wherein:
H is 5- to 12-membered heterocycle, optionally substituted with one or more R50;
A is 3- to 12-membered heterocycle; and
B is 3- to 12-membered heterocycle.
14. The method of any one of the preceding claims, wherein H is 6- to 12-membered bicyclic heterocycle, optionally substituted with one or more R50.
15. The method of claim 14, wherein H is thienopyrimidinyl, optionally substituted with one or more R50.
16. The method of claim 14, wherein:
Figure imgf000193_0003
X1 and X2 are each independently selected from CR2 and N;
X3 and X4 are each independently selected from C and N; Y1 and Y2 are each independently selected from CR3, N, NR4, O, and S;
R 2" and R 3J are each independently selected at each occurrence from hydrogen and R 50 ; and
R4 is selected from R51.
17. The method of claim 16, wherein X3 and X4 are each C.
18. The method of claim 16 or 17, wherein X1 is CR2, and R2 is selected from hydrogen, halogen, -OH, -OR52, -NH2, -N(R52)2, -CN, Ci_3 alkyl, -CH2OH, -CH2OR52, -CH2NH2, -CH2N(R52)2, Ci-3 alkyl-N(R52)2, C1-3 haloalkyl, C2.3 alkenyl, and C2.3 alkynyl
19. The method of any one of claims 16 to 18, wherein X2 is N.
20. The method of any one of claims 16 to 19, wherein Y2 is CR3, and R3 is selected from hydrogen, halogen, -OH, -N(R52)2, -CN, -C(0)OR52, Ci_3 alkyl, and d_3 haloalkyl.
21. The method of any one of claims 16 to 20, wherein R1 is Ci_3 haloalkyl.
22. The method of any one of the preceding claims, wherein A is 5- to 8-membered heterocycle.
23. The method of claim 22, wherein A is 6-membered monocyclic heterocycle.
24. The method of claim 22 or 23, wherein the heterocycle comprises at least one nitrogen atom.
25. The method of claim 24, wherein A is selected from piperidinylene and piperazinylene.
Figure imgf000194_0001
27. The method of any one of the preceding claims, wherein B is 6- to 12-membered bicyclic heterocycle.
28. The method of claim 27, wherein the heterocycle comprises at least one nitrogen atom.
29. The method of claim 28, wherein B is indolylene.
The method of claim 29, wherein B is
Figure imgf000194_0002
, optionally substituted with one or more R .
31. The method of claim 13 , wherein:
H is thienopyrimidinyl substituted with one or more R3U;
A is selected from piperidinylene and piperazinylene; and
B is indolylene.
32. The method of any one of the preceding claims, wherein H is substituted with -
33. The method of any one of the preceding claims, wherein m is 0.
34. The method of any one of the preceding claims, wherein n is an integer from 1 to
3.
35. The method of any one of the preceding claims, wherein L1 comprises less than 10 atoms.
36. The method of any one of the preceding claims, wherein L1 is -N(R51)-.
37. The method of any one of the preceding claims, wherein L2 comprises less than 10 atoms.
38. The method of any one of the preceding claims, wherein L2 is C1-4 alkylene, optionally substituted with one or more R50.
39. The method of any one of claims 1 to 37, wherein L2 is selected from -C¾-, - N(R51)-, -N(R51)CH2-, -N(R51)C(0 , and -N(R51)S(0)2-.
40. The method of any one of the preceding claims, wherein L3 comprises less than 20 atoms.
41. The method of any one of the preceding claims, wherein L3 is Ci_6 alkylene, optionally substituted with one or more R50.
42. The method of claim 41 , wherein L3 is C2 alkylene substituted with at least one Ci-3 alkyl or C1-3 haloalkyl, and optionally further substituted with one or more R50.
43. The method of any one of the preceding claims, wherein L3 is substituted with =0, Ci_6 alkyl, Ci_6 haloalkyl, Ci_3 alkyl(cyclopropyl), Ci_3 alkyl(NR52C(0)R52) or -0(C 6 alkyl).
44. The method of claim 43, wherein L3 is substituted with -CH3.
45. The method of any one of claims 1 to 41 , wherein L3 is selected from
V. ,
\ (R) \ (S)
and .
46. The method of claim 45, wherein R50 is methyl.
47. The method of any one of claims 1 to 41 , wherein L3 is selected from
Figure imgf000195_0001
48. The method of claim 47, wherein R56 is methyl.
49. The method of claim 1 or 2, wherein:
H is thienopyrimidinyl, optionally substituted with one or more R50;
A is 3- to 12-membered heterocycle;
B is 6- to 12-membered bicyclic heterocycle; m is an integer from 0 to 3 ; and
n is an integer from 1 to 3
50. The method of claim 1, wherein:
H is thienopyrimidinyl, optionally substituted with one or more R50;
A is selected from piperidinylene and piperazinylene;
B is indolylene;
L1 and L2 are each independently selected from -0-, -S-, -NH-, and -CH2-;
L3 is selected from bond, -0-, -S-, -N(R51)-, -N(R51)CH2-, -C(O)-, -C(0)0-, -OC(O)-, - OC(0)0-, -C(0)N(R51)-, -C(0)N(R51)C(0)-, -C(0)N(R51)C(0)N(R51)-, -N(R51)C(0)-, - N(R51)C(0)N(R51)-, -N(R51)C(0)0-, -OC(0)N(R51)-, -C(NR51)-, -N(R51)C(NR51)-, - C(NR51)N(R51)-, -N(R51)C(NR51)N(R51)-, -S(0)2-, -OS(O)-, -S(0)0-, -S(0 , -OS(0)2-, -S(0)20-, -N(R51)S(0)2-, -S(0)2N(R51)-, -N(R51)S(0)-, -S(0)N(R51)-, -N(R51)S(0)2N(R51)-, - N(R51)S(0)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 1 to 3 ;
p is an integer from 0 to 6;
R57 is selected from:
-S(=0)R52, -S(=0)2R58, -S(=0)2N(R52)2, -S(=0)2NR53R54, - NR52S(=0)2R52, -NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -NR52C(0)N(R52)2, - NR52C(0)NR53R54, -C(0)NH(Ci-6 alkyl), -C(0)NR53R54, -P(0)(OR52)2, - P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2; and
Ci-io alkyl, C2_io alkenyl, and C2_io alkynyl, each of which is
independently substituted at each occurrence with one or more substituents selected from -S(=0)R52, -S(=0)2R58, -S(=0)2N(R52)2, -S(=0)2NR53R54, - NR52S(=0)2R52, -NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -NR52C(0)N(R52)2, - NR52C(0)NR53R54, -C(0)NH(Ci-6 alkyl), -C(0)NR53R54, -P(0)(OR52)2, and - P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2; and R is selected from hydrogen; and Ci-20 alkyl, C3-20 alkenyl, C2-20 alkynyl, 1- to 6- membered heteroalkyl, C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -N02, -NH2, -NHCH3, -NHCH2CH3, =0, -OH, -OCH3, - OCH2CH3, C3-12 carbocycle, or 3- to 6-membered heterocycle.
51. The method of claim 2, wherein:
H is thienopyrimidinyl, optionally substituted with one or more R50;
A is selected from piperidinylene and piperazinylene;
B is indolylene;
L1 and L2 are each independently selected from -0-, -S-, -NH-, and -CH2-;
L3 is selected from Ci_6 alkylene, C2-6 alkenylene, and C2-6 alkynylene, each of which is substituted with one or more R56 and optionally further 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 1 to 3 ;
p is an integer from 0 to 6;
R56 is independently selected at each occurrence from:
-OR59, =0, Ci-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl,
wherein each Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl in R56 is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -N02, -CN, -OR59, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C3_i2 carbocycle, and 3- to 12-membered heterocycle;
wherein each C3-i2 carbocycle and 3- to 12-membered heterocycle in R56 is independently optionally substituted with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR , -OC(0)N(R3Z)2, -OC(0)NR3JR , -NR3ZC(0)R , -NR3ZC(0)OR , - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C1-6 alkyl, C1-6 haloalkyl, C2.6 alkenyl, and C2_6 alkynyl; and
further wherein R56 optionally forms a bond to ring C; and
R59 is independently selected at each occurrence from Ci-20 alkyl, C2_2o alkenyl, C2_2o alkynyl, 1- to 6-membered heteroalkyl, C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -N02, -NH2, -NHCH3, -NHCH2CH3, =0, -OH, -OCH3, -OCH2CH3, C3-i2 carbocycle, or 3- to 6-membered heterocycle.
52. The method of claim 50, wherein R57 is selected from -S(=0)2R58, -S(=0)2N(R52)2, and -S(=0)2NR53R54.
53. The method of claim 52, wherein R57 is selected from -S(=0)2CH3 and - S(=0)2NHCH3.
54. The method of claim 51, wherein C is substituted with -S(=0)2R 58 , - S(=0)2N(R52)2, or -S(=0)2NR53R54.
55. The method of any one of claims 49 to 54, wherein H is
Figure imgf000198_0001
and R2 is selected from hydrogen, halogen, -OH, -OR52, -NH2, -N(R52)2, -CN, C1-3 alkyl, C1-3 alkyl- OR52, Ci-3 alkyl-N(R52)2, C1-3 haloalkyl, C2.3 alkenyl, and C2.3 alkynyl.
56. The method of claim 55, wherein R2 is selected from -NH2, -CH3, and -NHCH3.
method of any one of claims 49 to 56, wherein L3 is selected from
Figure imgf000198_0002
58. A method of promoting proliferation of a pancreatic cell, comprising
administering a compound
Figure imgf000198_0003
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
H is selected from C3-i2 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more R50;
Figure imgf000199_0001
each of Z1, Z2, Z3, and Z4 is independently selected from -QR^XR^)-, -C(RA1)(RA2)- C(RA1)(RA2)-, -C(O)-, and -C(RA1)(RA2)-C(0)-, wherein no more than one of Z1, Z2, Z3, and Z4 is -C(O)- or -C(RA1)(RA2)-C(0)-;
B is selected from bond, C3-12 carbocycle and 3- to 12-membered heterocycle;
C is selected from bond, C3-i2 carbocycle and 3- to 12-membered heterocycle;
L1, L2 and L3 are each independently selected from bond, -0-, -S-, -N(R51)-, -N(R51)CH2-, -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(0)N(R51)-, -C(0)N(R51)C(0)-, - C(0)N(R51)C(0)N(R51)-, -N(R51)C(0)-, -N(R51)C(0)N(R51)-, -N(R51)C(0)0-, -OC(0)N(R51)-, - C(NR51)-, -N(R51)C(NR51)-, -C(NR51)N(R51)-, -N(R51)C(NR51)N(R51)-, -S(0)2-, -OS(O)-, - S(0)0-, -S(0 , -OS(0)2-, -S(0)20-, -N(R51)S(0)2-, -S(0)2N(R51)-, -N(R51)S(0 , -S(0)N(R51)-, -N(R51)S(0)2N(R51)-, -N(R51)S(0)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;
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;
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 R^ are each independently selected at each occurrence from hydrogen and R ; 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, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52);
Ci-10 alkyl, C2_io alkenyl, and C2_io alkynyl, each of which is
independently optionally substituted at each occurrence with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R , -S(=0)2R , -S(=0)2N(R3Z)2, -S(=0)2NR3JR , -NR3ZS(=0)2R , - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; and
C3-i2 carbocycle and 3- to 12-membered heterocycle,
wherein each C3-i2 carbocycle and 3- to 12-membered heterocycle in R50 is independently optionally substituted with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), Ci_6 alkyl, Ci_6 haloalkyl, C2_ alkenyl, and C2_6 alkynyl;
independently selected at each occurrence from:
hydrogen, -C(0)R52, -C(0)OR52, -C(0)N(R52)2, -C(0)NR53R54;
Ci-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, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C3_i2 carbocycle and 3- to 12 membered heterocycle; and
C3-i2 carbocycle and 3- to 12-membered heterocycle,
wherein each C3-i2 carbocycle and 3- to 12-membered heterocycle in R51 is independently optionally substituted with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R , -S(=0)2N(R3Z)2, -S(=0)2NR3JR , -NR3ZS(=0)2R , - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), d_6 alkyl, d_6 haloalkyl, C2_6 alkenyl, and C2_6 alkynyl;
R is independently selected at each occurrence from hydrogen; and Ci-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, 1- to 6-membered heteroalkyl, C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -N02, -NH2, -NHCH3, - NHCH2CH3, =0, -OH, -OCH3, -OCH2CH3, C3_i2 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.
59. A method of promoting proliferation of a pancreatic cell, comprising
administering a compound of Formula (IV :
Figure imgf000201_0001
or a p cally acceptable salt or prodrug thereof, wherein:
Figure imgf000201_0002
fused thienyl or fused phenyl group;
Ga is selected from C3-i2 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(=0)-, -C(=0)-0-, -C(=0)-N(R52)-, -CH2N(R52)-CH2-, - C(=0)N(R52)-CH2-, -CH2CH2-N(R52)-, -CH2N(R52)-C(=0)-, and -CH20-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(=0)-, -C(=0)N(R52)-, -[C(R14a)2]i-50-, -[C(R14a)2]i-5NR52-, -[C(R14a)2h_5-, -CH2(=0)-, and -S(=0)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, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52);
Ci-io alkyl, C2-io alkenyl, and C2-io alkynyl, each of which is
independently optionally substituted at each occurrence with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, -S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; and
C3-i2 carbocycle and 3- to 12-membered heterocycle, wherein each C3-i2 carbocycle and 3- to 12-membered heterocycle in R50 is independently optionally substituted with one or more substituents selected from halogen, -N02, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=0)R52, - S(=0)2R52, -S(=0)2N(R52)2, -S(=0)2NR53R54, -NR52S(=0)2R52, - NR52S(=0)2N(R52)2, -NR52S(=0)2NR53R54, -C(0)R52, -C(0)OR52, -OC(0)R52, - OC(0)OR52, -OC(0)N(R52)2, -OC(0)NR53R54, -NR52C(0)R52, -NR52C(0)OR52, - NR52C(0)N(R52)2, -NR52C(0)NR53R54, -C(0)N(R52)2, -C(0)NR53R54, - P(0)(OR52)2, -P(0)(R52)2, -P(0)(OR52)(R52), -P(0)(NR52)(R52), -NR52P(0)(R52), - P(0)(NR52)(OR52), -P(0)(NR52)2, =0, =S, =N(R52), d_6 alkyl, d_6 haloalkyl, C2_6 alkenyl, and C2-6 alkynyl;
R52 is independently selected at each occurrence from hydrogen; and Ci-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, -N02, -NH2, -NHCH3, - NHCH2CH3, =0, -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.
60. The method of any one of claims 1 to 59, wherein the compound is provided as a substantially pure stereoisomer.
61. The method of claim 60, wherein the stereoisomer is provided in at least 90% enantiomeric excess.
62. The method of any one of the preceding claims, wherein the compound is isotopically enriched.
63. A method of promoting proliferation of a pancreatic cell, comprising administering a compound selected from Table 1.
64. A method of promoting proliferation of a pancreatic cell, comprising administering a compound selected from Table 2 or Table 3.
65. The method of any one of the preceding claims, wherein the pancreatic cell is an islet cell.
66. The method of any one of the preceding claims, wherein the pancreatic cell is a beta cell.
67. The method of claim 66, wherein the beta cell proliferation is evidenced by an increase in beta cell production.
68. The method of claim 66, wherein the beta cell proliferation is evidenced by an increase in insulin production.
69. The method of any one of the preceding claims, further comprising administering a second therapeutic agent.
70. The method of any one of the preceding claims, further comprising administering the compound to a subject.
71. The method of claim 70, wherein the subject suffers from diabetes.
72. The method of claim 71, wherein the diabetes is type 1 diabetes.
73. The method of claim 71, wherein the diabetes is type 2 diabetes.
74. The method of claim 70, wherein the subject suffers from prediabetes.
75. The method of claim 70, wherein the subject suffers from impaired beta cell production.
76. The method of claim 70, wherein the subject is human.
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