WO2023078337A1 - Inhibiteurs doubles de cdk8/19 et leurs procédés d'utilisation - Google Patents

Inhibiteurs doubles de cdk8/19 et leurs procédés d'utilisation Download PDF

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WO2023078337A1
WO2023078337A1 PCT/CN2022/129486 CN2022129486W WO2023078337A1 WO 2023078337 A1 WO2023078337 A1 WO 2023078337A1 CN 2022129486 W CN2022129486 W CN 2022129486W WO 2023078337 A1 WO2023078337 A1 WO 2023078337A1
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substituted
unsubstituted
compound
pharmaceutically acceptable
acceptable salt
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Yingtao LIU
Jianping Wu
Xiaosong Liu
Feng Ren
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Insilico Medicine Ip Limited
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the disclosure relates to compounds that function as dual inhibitors of cyclic dependent kinase 8 and/or 19 (CDK8/19) and methods of use.
  • Cyclin-dependent kinase 8 ( “CDK8” ) and its paralog, CDK19, collectively termed ‘”Mediator Kinase, ’” are cyclin-dependent kinases that have been implicated as key rheostats in cellular homeostasis and developmental programming.
  • CDK8 and CDK19 are incorporated, in a mutually exclusive manner, as part of a 4-protein complex called the Mediator kinase module. This module reversibly associates with the Mediator, a 26 subunit protein complex that regulates RNA Polymerase II mediated gene expression.
  • the Mediator kinases have been implicated in diverse process such as developmental signaling, metabolic homeostasis and in innate immunity.
  • dysregulation of Mediator kinase module proteins including CDK8/19, has been implicated in the development of different human diseases, and in particular for oncological purposes.
  • the present disclosure provides a compound having the structure of Formula (II) , or a pharmaceutically acceptable salt thereof:
  • Ring C is a substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted 5 to 6-membered monocyclic heteroaryl, or substituted or unsubstituted 5 to 20-membered bicyclic or polycyclic heteroaryl;
  • X 1 , X 2 , and X 3 are each independently CR 5 or N;
  • X 4 is C or N
  • X 5 and X 7 are each independently CR 5 , NR 11 , N, O, or S, wherein at most one of X 5 and X 7 is O or S;
  • R 3 and R 4 together with the atoms to which they are attached form a substituted or unsubstituted 5 to 7-membered heterocycloalkyl ring;
  • each R 5 is independently selected from H, halogen, CN, -CF 3 , -OR 6 , -SR 6 , -NR 7 R 8 , substituted or unsubstituted C 1 -C 8 alkyl, or substituted or unsubstituted C 1 -C 8 heteroalkyl;
  • R 6 , R 7 , R 8 , and R 9 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, or C 2 -C 7 heterocycloalkyl;
  • each R 11 is independently selected from H, substituted or unsubstituted C 1 -C 8 alkyl, or substituted or unsubstituted C 1 -C 8 heteroalkyl;
  • n 1, 2, 3, 4 or 5.
  • the compound has the structure of Formula (II-I) , or a pharmaceutically acceptable salt thereof:
  • the compound has the structure of Formula (II-II) , or a pharmaceutically acceptable salt thereof:
  • X 7 is NR 11 , wherein R 11 is H or C 1 -C 8 alkyl; and X 4 is C. In some embodiments of Formula (II) , (II-I) , or (II-II) , X 7 is NH.
  • the compound has the structure of Formula (III) , or a pharmaceutically acceptable salt thereof:
  • each R 5 is independently selected from halogen, CN, -CF 3 , -OR 6 , -SR 6 , -NR 7 R 8 , C 2 -C 8 alkyl, and C 1 -C 8 heteroalkyl.
  • ach R 5 is independently selected from halogen, -OR 6 , -NR 7 R 8 , and C 1 -C 8 alkyl.
  • each R 5 is independently selected from -OCH 3 , -NHCH 3 , and CH 3 .
  • X 1 is N; and X 2 and X 3 are each CR 5 .
  • X 1 and X 3 are each CR 5 ; and X 2 is N.
  • X 1 and X 2 are CR 5 ; and X 3 is N.
  • X 1 , X 2 , and X 3 are each CR 5 .
  • X 1 , X 2 , and X 3 are each CH.
  • the compound has the structure of Formula (IV) , or a pharmaceutically acceptable salt thereof:
  • W is CH 2 , NR 10 , or O;
  • R 10 is H or C 1 -C 8 alkyl
  • p and q are each independently 0-3, wherein p + q is 1 to 4.
  • W is NR 10 or O. In some embodiments of Formula (IV) , W is NH or NCH 3 . In some embodiments of Formula (IV) , W is CH 2 . In some embodiments of Formula (IV) , p is 1 and q is 0. In some embodiments of Formula (IV) , p and q are each independently 1.
  • the present disclosure provides a compound having the structure of Formula (VI) , or a pharmaceutically acceptable salt thereof:
  • Ring C is substituted or unsubstituted phenyl, substituted or unsubstituted 6-membered monocyclic heteroaryl, substituted or unsubstituted bicyclic heteroaryl, substituted or unsubstituted 6-membered cycloalkyl, or substituted or unsubstituted 6-membered heteroalkyl;
  • X 4 is C or N
  • X 5 and X 7 are each independently CR 5 , NR 11 , N, O, or S, wherein at most one of X 5 and X 7 is O or S;
  • X 9 and X 10 are each independently CR 5 , NR 11 , N, O, or S.
  • R 3 and R 4 together with the atoms to which they are attached form a substituted or unsubstituted 5 to 7-membered cycloalkyl or heterocycloalkyl ring;
  • each R 5 is independently selected from H, halogen, CN, -CF 3 , -OR 6 , -SR 6 , -NR 7 R 8 , substituted or unsubstituted C 1 -C 8 alkyl, or substituted or unsubstituted C 1 -C 8 heteroalkyl;
  • R 6 , R 7 , R 8 , and R 9 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, or C 2 -C 7 heterocycloalkyl;
  • each R 11 is independently selected from H, substituted or unsubstituted C 1 -C 8 alkyl, or substituted or unsubstituted C 1 -C 8 heteroalkyl;
  • n 1, 2, 3, 4 or 5.
  • X 4 is C and X 5 is CR 5 . In some embodiments of Formula (VI) , X 5 is CR 5 . In some embodiments of Formula (VI) , R 5 is selected from halogen, -OR 6 , -NR 7 R 8 , or C 1 -C 8 alkyl.
  • the present disclosure provides a compound having the structure of Formula (A’) , or a pharmaceutically acceptable salt thereof:
  • Ring A is optionally substituted phenyl or a 5 or 6-membered optionally substituted heteroaromatic ring
  • Ring B is a 5 or 6-membered heteroaromatic ring comprising at least one N atom
  • Ring C is a substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted 5 to 6-membered monocyclic heteroaryl, or substituted or unsubstituted 5 to 20-membered bicyclic or polycyclic heteroaryl;
  • X 4 and X 8 are each independently C or N, wherein at most one of X 4 and X 8 is N;
  • X 5 and X 7 are each independently CR 5 , NR 11 , N, O, or S, wherein at most one of X 5 and X 7 is O or S;
  • R 2 and R 3 together with the carbon atom to which they are attached form a 3 to 6-membered cycloalkyl or heterocycloalkyl ring;
  • R 3 and R 4 together with the atoms to which they are attached form a substituted or unsubstituted 5 to 7-membered cycloalkyl or heterocycloalkyl ring;
  • each R 5 is independently selected from H, halogen, CN, -CF 3 , -OR 6 , -SR 6 , -NR 7 R 8 , substituted or unsubstituted C 1 -C 8 alkyl, or substituted or unsubstituted C 1 -C 8 heteroalkyl;
  • R 6 , R 7 , R 8 , and R 9 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, or C 2 -C 7 heterocycloalkyl;
  • each R 11 is independently selected from H, substituted or unsubstituted C 1 -C 8 alkyl, or substituted or unsubstituted C 1 -C 8 heteroalkyl;
  • n 0-5.
  • R 3 is halogen, -CN, -OR 6 , -SR 6 , C 1 -C 8 alkyl, or C 1 -C 8 heteroalkyl.
  • R 2 and R 3 are each independently H.
  • R 2 and R 3 together with the carbon atom to which they are attached form a 3 to 6-membered cycloalkyl or heterocycloalkyl ring.
  • R 4 is -CF 3 , -OR 6 , -SR 6 , -NR 8 R 9 , C 1 -C 8 alkyl, or C 1 -C 8 heteroalkyl.
  • R 4 is -CF 3 , -OCH 3 , -NCH 3 , or -CH 3 .
  • R 3 and R 4 together with the atoms to which they are attached form a substituted or unsubstituted 5 to 7-membered heterocycloalkyl ring.
  • Ring C is a substituted or unsubstituted phenyl, substituted or unsubstituted 6-membered monocyclic heteroaryl, or substituted or unsubstituted 6-membered monocyclic cycloalkyl.
  • Ring C is a phenyl, pyridyl, pyrimidyl or triazynyl.
  • Ring C is a phenyl or pyridyl.
  • Ring C is a substituted or unsubstituted C 3 -C 8 cycloalkyl.
  • Ring C is a cyclopentyl or cyclohexyl.
  • each R 1 is independently selected from halogen, -CN, -OR 6 , -SR 6 , -NR 8 R 9 , -NO 2 , or C 1 -C 8 alkyl.
  • each R 1 is independently selected from Br, Cl, F, -CN, -OCH 3 , -NCH 3 , -NO 2 , or -CH 3 .
  • n is 1.
  • the present disclosure provides a compound represented by Formula (A’) , or a pharmaceutically acceptable salt or solvate thereof:
  • Ring A is optionally substituted phenyl or a 5 or 6-membered optionally substituted heteroaromatic ring
  • Ring B is a 5 or 6-membered heteroaromatic ring comprising at least one N atom
  • Ring C is a substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted 5 to 6-membered monocyclic heteroaryl, or substituted or unsubstituted 5 to 20-membered bicyclic or polycyclic heteroaryl;
  • X 4 and X 8 are each independently C or N, wherein at most one of X 4 and X 8 is N;
  • X 5 and X 7 are each independently CR 5 , NR 11 , N, O, or S, wherein at most one of X 5 and X 7 is O or S;
  • R 2 and R 3 together with the carbon atom to which they are attached form a 3 to 6-membered cycloalkyl or heterocycloalkyl ring;
  • R 3 and R 4 together with the atoms to which they are attached form a substituted or unsubstituted 5 to 7-membered cycloalkyl or heterocycloalkyl ring;
  • each R 5 is independently selected from H, halogen, CN, -CF 3 , -OR 6 , -SR 6 , -NR 7 R 8 , substituted or unsubstituted C 1 -C 8 alkyl, or substituted or unsubstituted C 1 -C 8 heteroalkyl;
  • R 6 , R 7 , R 8 , and R 9 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, or C 2 -C 7 heterocycloalkyl;
  • each R 11 is independently selected from H, substituted or unsubstituted C 1 -C 8 alkyl, or substituted or unsubstituted C 1 -C 8 heteroalkyl;
  • n 0-5.
  • the compound has the structure of Formula (A) , or a pharmaceutically acceptable salt or solvate thereof:
  • X 1 , X 2 , and X 3 are each independently CR 5 or N.
  • the compound has a structure of Formula (A-I) , or a pharmaceutically acceptable salt or solvate thereof:
  • the compound has a structure of Formula (A-II) , or a pharmaceutically acceptable salt or solvate thereof:
  • ring A is pyridine, pyrimidine, pyridazine, pyrazine, thiazole, thiadiazole, pyrrole, imidazole, or oxazole.
  • ring A is phenyl.
  • ring B is a 6-membered heteroaromatic ring.
  • ring B is pyridyl, pyrimidyl, or triazinyl. In some embodiments of Formula (A’) , (A) , (A-I) , or (A-II) , ring B is a 5-membered heteroaromatic ring. In some embodiments of Formula (A’) , (A) , (A-I) , or (A-II) , ring B is a oxazolyl, triazolyl, imidazolyl, thiazolyl, oxadiazolyl, or thiadiazolyl.
  • the compounds has the structure of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof:
  • Y 1 and Y 2 are each independently CH, N, O, or S; wherein both Y 1 and Y 2 are not O or S at the same time;
  • Y 3 is CR 4 , NR 4 , or N;
  • Y 4 is C or N.
  • the compound has the structure of Formula (II) , or a pharmaceutically acceptable salt or solvate thereof:
  • X 7 is NR 11 , wherein R 11 is H or substituted or unsubstituted C 1 -C 8 alkyl.
  • X 4 is C.
  • X 5 is CR 5 , wherein R 5 is selected from halogen, CN, -CF 3 , -OR 6 , -SR 6 , -NR 7 R 8 , substituted or unsubstituted C 2 -C 8 alkyl, or substituted or unsubstituted C 1 -C 8 heteroalkyl.
  • R 5 is selected from -OR 6 , -NR 7 R 8 , or substituted or unsubstituted C 2 -C 8 alkyl. In some embodiments, R 5 is selected from -OCH 3 , -NCH 3 , or CH 3 .
  • the compound has the structure of Formula (III) , or a pharmaceutically acceptable salt or solvate thereof:
  • X 1 is N; and X 2 and X 3 are each CR 5 .
  • X 1 and X 3 are each CR 5 ; and X 2 is N.
  • X 1 and X 2 are CR 5 ; and X 3 is N.
  • R 3 is halogen, -CN, -OR 6 , -SR 6 , substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, or substituted or unsubstituted C 2 -C 5 heterocycloalkyl.
  • R 2 and R 3 are each independently H.
  • R 2 and R 3 together with the carbon atom to which they are attached form a 3 to 6-membered cycloalkyl or heterocycloalkyl ring.
  • R 4 is -CF 3 , -OR 6 , -SR 6 , -NR 8 R 9 , substituted or unsubstituted C 1 -C 8 alkyl, or substituted or unsubstituted C 1 -C 8 heteroalkyl.
  • R 3 and R 4 together with the atoms to which they are attached form a substituted or unsubstituted 5 to 7-membered cycloalkyl or heterocycloalkyl ring.
  • the compound has the structure of Formula (IV) , or a pharmaceutically acceptable salt or solvate thereof:
  • W is CH 2 , NR 10 , or O;
  • R 10 is H or C 1 -C 8 alkyl
  • p and q are each independently 0-3, wherein p + q is 1 to 4.
  • W is NR 10 or O. In some embodiments of Formula (IV) , W is NH or NCH 3 . In some embodiments of Formula (IV) , W is CH 2 . In some embodiments of Formula (IV) , p is 1 and q is 0. In some embodiments of Formula (IV) , p and q are each independently 1.
  • the compound has the structure of Formula B, or a pharmaceutically acceptable salt or solvate thereof:
  • X 9 and X 10 are each independently CR 5 , NR 11 , N, O, or S.
  • the compound has the structure of Formula (V) , or a pharmaceutically acceptable salt or solvate thereof:
  • Y 1 and Y 2 are each independently CH, N, O, or S; wherein both Y 1 and Y 2 are not O or S at the same time;
  • Y 3 is CR 4 , NR 4 , or N;
  • Y 4 is C or N.
  • the compound has the structure of Formula (VI) , or a pharmaceutically acceptable salt or solvate thereof:
  • Ring C is substituted or unsubstituted phenyl, substituted or unsubstituted 6-membered monocyclic heteroaryl, substituted or unsubstituted phenyl, substituted or unsubstituted 6-membered monocyclic heteroaryl, substituted or unsubstituted bicyclic heteroaryl, substituted or unsubstituted 6-membered cycloalkyl, or substituted or unsubstituted 6-membered heterocycloalkyl.
  • R 3 is halogen, -CN, -OR 6 , -SR 6 , substituted or unsubstituted C 1 -C 8 alkyl, or substituted or unsubstituted C 1 -C 8 heteroalkyl.
  • R 3 is cyclopropyl.
  • R 2 and R 3 are each independently H.
  • R 2 and R 3 together with the carbon atom to which they are attached form a 3 to 6-membered cycloalkyl or heterocycloalkyl ring.
  • R 4 is -CF 3 , -OR 6 , -SR 6 , -NR 8 R 9 , substituted or unsubstituted C 1 -C 8 alkyl, or substituted or unsubstituted C 1 -C 8 heteroalkyl.
  • R 4 is -CF 3 , -OCH 3 , -NCH 3 , or -CH 3 .
  • R 3 and R 4 together with the atoms to which they are attached form a substituted or unsubstituted 5 to 7-membered cycloalkyl or heterocycloalkyl ring.
  • Ring C is a substituted or unsubstituted aryl, substituted or unsubstituted 5 to 6-membered monocyclic heteroaryl.
  • Ring C is a substituted or unsubstituted phenyl, pyridyl, pyrimidyl or triazynyl.
  • Ring C is phenyl.
  • Ring C is a substituted or unsubstituted C 3 -C 8 cycloalkyl.
  • Ring C is a cyclopentyl or cyclohexyl.
  • R 1 is independently selected from halogen, -CN, -OR 6 , -SR 6 , -NR 8 R 9 , -NO 2 , or substituted or unsubstituted C 1 -C 8 alkyl.
  • R 1 is independently selected from Br, Cl, F, -CN, -OCH 3 , -NCH 3 , -NO 2 , or -CH 3 .
  • n is 2.
  • n is 1.
  • the compound is a compound described herein or a pharmaceutically acceptable salt or solvate thereof.
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound described herein and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition is formulated for administration to a mammal by oral administration, intravenous administration, or subcutaneous administration.
  • he pharmaceutical composition is in the form of a tablet, a pill, a capsule, a liquid, a suspension, a dispersion, a solution, or an emulsion.
  • the disclosure provides a method of inhibiting cyclic dependent kinase 8 and/or 19 (CDK8/19) activity in a subject, comprising administering to the subject a compound described herein or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of described herein.
  • the disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein.
  • the cancer is leukemia, acute myeloid leukemia (AML) , chronic myeloid leukemia, acute lymphoblastic leukemia (ALL) , non-Hodgkin lymphoma (NHL) , Hodgkin lymphoma (HL) , or multiple myeloma (MM) .
  • AML acute myeloid leukemia
  • ALL acute lymphoblastic leukemia
  • NHL non-Hodgkin lymphoma
  • NHL Hodgkin lymphoma
  • MM multiple myeloma
  • the cancer is AML.
  • the cancer is a solid cancer.
  • the cancer is a skin cancer, ocular cancer, gastrointestinal cancer, thyroid cancer, breast cancer, ovarian cancer, central nervous system cancer, laryngeal cancer, cervical cancer, lymphatic system cancer, genitourinary tract cancer, bone cancer, biliary tract cancer, pancreatic cancer, endometrial cancer, liver cancer, lung cancer, prostate cancer, or colon cancer.
  • the method further comprising administering a second therapeutic agent.
  • the second therapeutic agent is chemotherapy, target therapy or an immune checkpoint inhibitor.
  • the second therapeutic agent is a CDK4/6 inhibitor, BCL-2 inhibitor, EGFR inhibitor, JAK1/2 inhibitor, anti-PD-L1 inhibitor or anti-PD1 inhibitor.
  • the disclosure provides a method of treating an auto-immune (AI) disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein.
  • AI auto-immune
  • Carboxyl refers to -COOH.
  • Cyano refers to -CN.
  • Alkyl refers to a straight-chain, or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2, 2-dimethyl-1-butyl, 3, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopent
  • a numerical range such as “C 1 -C 6 alkyl” or “C 1-6 alkyl” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • the alkyl is a C 1-10 alkyl.
  • the alkyl is a C 1-6 alkyl.
  • the alkyl is a C 1-5 alkyl.
  • the alkyl is a C 1-4 alkyl.
  • the alkyl is a C 1-3 alkyl.
  • an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkyl is optionally substituted with halogen.
  • Alkenyl refers to a straight-chain, or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms.
  • a numerical range such as “C 2 -C 6 alkenyl” or “C 2-6 alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated.
  • an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkenyl is optionally substituted with halogen.
  • Alkynyl refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1, 3-butadiynyl and the like.
  • a numerical range such as “C 2 -C 6 alkynyl” or “C 2-6 alkynyl” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated.
  • an alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkynyl is optionally substituted with halogen.
  • Alkylene refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.
  • Alkoxy refers to a radical of the formula -OR a where R a is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.
  • Aryl refers to a radical derived from an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom.
  • the aromatic monocyclic or aromatic multicyclic hydrocarbon ring system can contain only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ⁇ –electron system in accordance with the Hückel theory.
  • the ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.
  • the aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems.
  • the aryl is a 6-to 10-membered aryl.
  • the aryl is a 6-membered aryl (phenyl) .
  • Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
  • Carbocycle refers to a saturated, unsaturated or aromatic rings in which each atom of the ring is carbon.
  • 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.
  • 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 may be optionally substituted.
  • Cycloalkyl refers to a partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated.
  • Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C 3 -C 15 fully saturated cycloalkyl or C 3 -C 15 cycloalkenyl) , from three to ten carbon atoms (C 3 -C 10 fully saturated cycloalkyl or C 3 -C 10 cycloalkenyl) , from three to eight carbon atoms (C 3 -C 8 fully saturated cycloalkyl or C 3 -C 8 cycloalkenyl) , from three to six carbon atoms (C 3 -C 6 fully saturated cycloalkyl or C 3 -C 6 cycloalkenyl) , from three to five carbon atoms (C 3 -C 5 fully saturated cycloalkyl or C 3 -C 5 cycloalkenyl) , or three to four carbon atoms (C 3 -C 4 fully saturated cycloalkyl or C 3 -C
  • the cycloalkyl is a 3-to 10-membered fully saturated cycloalkyl or a 3-to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3-to 6-membered fully saturated cycloalkyl or a 3-to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5-to 6-membered fully saturated cycloalkyl or a 5-to 6-membered cycloalkenyl.
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo [3.3.0] octane, bicyclo [4.3.0] nonane, cis-decalin, trans-decalin, bicyclo [2.1.1] hexane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane, and bicyclo [3.3.2] decane, and 7, 7-dimethyl-bicyclo [2.2.1] heptanyl.
  • Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • the cycloalkyl is optionally substituted with halogen.
  • Cycloalkenyl refers to an unsaturated non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, preferably having from three to twelve carbon atoms and comprising at least one double bond.
  • a cycloalkenyl comprises three to ten carbon atoms.
  • a cycloalkenyl comprises five to seven carbon atoms.
  • the cycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls includes, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
  • haloalkyl or “haloalkane” refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2, 2, 2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • the alkyl part of the fluoroalkyl radical is optionally further substituted.
  • halogen substituted alkanes examples include halomethane (e.g., chloromethane, bromomethane, fluoromethane, iodomethane) , di-and trihalomethane (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane) , 1-haloethane, 2-haloethane, 1, 2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1, 2-dihalopropane, 1, 3-dihalopropane, 2, 3-dihalopropane, 1, 2, 3-trihalopropane, and any other suitable combinations of alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, I, etc. ) .
  • halogen substituted alkanes e.g., Cl, Br, F, I, etc.
  • Fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2, 2, 2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.
  • Aminoalkyl refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.
  • Heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N (alkyl) -) , sulfur, phosphorus, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C 1 -C 6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g.
  • heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • heteroalkyl are, for example, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH 3 , -CH (CH 3 ) OCH 3 , -CH 2 NHCH 3 , -CH 2 N (CH 3 ) 2 , -CH 2 CH 2 NHCH 3 , or -CH 2 CH 2 N (CH 3 ) 2 .
  • a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
  • Heterocycloalkyl refers to a 3-to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens.
  • the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen.
  • the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (C 2 -C 15 fully saturated heterocycloalkyl or C 2 -C 15 heterocycloalkenyl) , from two to ten carbon atoms (C 2 -C 10 fully saturated heterocycloalkyl or C 2 -C 10 heterocycloalkenyl) , from two to eight carbon atoms (C 2 -C 8 fully saturated heterocycloalkyl or C 2 -C 8 heterocycloalkenyl) , from two to seven carbon atoms (C 2 -C 7 fully saturated heterocycloalkyl or C 2 -C 7 heterocycloalkenyl) , from two to six carbon atoms (C 2 -C 6 fully saturated heterocycloalkyl or C 2 -C 7 heterocycloalkenyl) , from two to five carbon atoms (C 2 -C 5 fully saturated heterocycloalkyl or C 2 -C 5
  • heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl [1, 3] dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides.
  • heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring) .
  • the heterocycloalkyl is a 3-to 8-membered fully saturated heterocycloalkyl.
  • the heterocycloalkyl is a 3-to 7-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-to 7-membered heterocycloalkenyl.
  • the heterocycloalkyl is a 3-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkenyl.
  • a heterocycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.
  • Heteroaryl refers to a 5-to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen.
  • the heteroaryl comprises one to three nitrogens.
  • the heteroaryl comprises one or two nitrogens.
  • the heteroaryl comprises one nitrogen.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • the heteroaryl is a 5-to 10-membered heteroaryl.
  • the heteroaryl is a 5-to 6-membered heteroaryl.
  • the heteroaryl is a 6-membered heteroaryl.
  • the heteroaryl is a 5-membered heteroaryl.
  • examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [b] [1, 4] dioxepinyl, 1, 4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl) , benzotriazolyl, benzo [4, 6] imidazo [1, 2-a] pyridinyl, carbazolyl, cinnolinyl,
  • a heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., NH, 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, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group.
  • 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.
  • one or more when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.
  • 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.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • phrases “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;
  • an “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
  • treat, ” “treating” or “treatment, ” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition.
  • the disclosure provides a compound represented by Formula (A’) , or a pharmaceutically acceptable salt or solvate thereof:
  • Ring A is optionally substituted phenyl or a 5 or 6-membered optionally substituted heteroaromatic ring
  • Ring B is a 5 or 6-membered heteroaromatic ring comprising at least one N atom
  • Ring C is a substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted 5 to 6-membered monocyclic heteroaryl, or substituted or unsubstituted 5 to 20-membered bicyclic or polycyclic heteroaryl;
  • X 4 and X 8 are each independently C or N, wherein at most one of X 4 and X 8 is N;
  • X 5 and X 7 are each independently CR 5 , NR 11 , N, O, or S, wherein at most one of X 5 and X 7 is O or S;
  • R 2 and R 3 together with the carbon atom to which they are attached form a 3 to 6-membered cycloalkyl or heterocycloalkyl ring;
  • R 3 and R 4 together with the atoms to which they are attached form a substituted or unsubstituted 5 to 7-membered cycloalkyl or heterocycloalkyl ring;
  • each R 5 is independently selected from H, halogen, CN, -CF 3 , -OR 6 , -SR 6 , -NR 7 R 8 , substituted or unsubstituted C 1 -C 8 alkyl, or substituted or unsubstituted C 1 -C 8 heteroalkyl;
  • R 6 , R 7 , R 8 , and R 9 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, or C 2 -C 7 heterocycloalkyl;
  • each R 11 is independently selected from H, substituted or unsubstituted C 1 -C 8 alkyl, or substituted or unsubstituted C 1 -C 8 heteroalkyl;
  • n 0, 1, 2, 3, 4, or 5.
  • the disclosure provides a compound represented by Formula (A’) , or a pharmaceutically acceptable salt or solvate thereof:
  • Ring A is optionally substituted phenyl or a 5 or 6-membered optionally substituted heteroaromatic ring
  • Ring B is a 5 or 6-membered heteroaromatic ring comprising at least one N atom
  • Ring C is a substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted 5 to 6-membered monocyclic heteroaryl, or substituted or unsubstituted 5 to 20-membered bicyclic or polycyclic heteroaryl;
  • X 4 and X 8 are each independently C or N, wherein at most one of X 4 and X 8 is N;
  • X 5 and X 7 are each independently CR 5 , NR 11 , N, O, or S, wherein at most one of X 5 and X 7 is O or S;
  • alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents selected from halogen, oxo, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; or
  • R 2 and R 3 together with the carbon atom to which they are attached form a 3 to 6-membered cycloalkyl or heterocycloalkyl ring;
  • alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents selected from halogen, oxo, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; or
  • R 3 and R 4 together with the intervening atoms to which they are attached form a substituted or unsubstituted 5 to 7-membered cycloalkyl or heterocycloalkyl ring,
  • each R 5 is independently selected from H, halogen, CN, -CF 3 , -OR 6 , -SR 6 , -NR 7 R 8 , substituted or unsubstituted C 1 -C 8 alkyl, or substituted or unsubstituted C 1 -C 8 heteroalkyl,
  • R 6 , R 7 , R 8 , and R 9 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, or C 2 -C 7 heterocycloalkyl;
  • each R 11 is independently selected from H, substituted or unsubstituted C 1 -C 8 alkyl, or substituted or unsubstituted C 1 -C 8 heteroalkyl,
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl (cycloalkyl) , C 1 -C 6 alkyl (heterocycloalkyl) , C 1 -C 6 alkyl (aryl) , or C 1 -C 6 alkyl (heteroaryl) , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R a are taken together with the atom to which they are attached to form a
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl (cycloalkyl) , C 1 -C 6 alkyl (heterocycloalkyl) , C 1 -C 6 alkyl (aryl) , or C 1 -C 6 alkyl (heteroaryl) , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R b are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl (cycloalkyl) , C 1 -C 6 alkyl (heterocycloalkyl) , C 1 -C 6 alkyl (aryl) , or C 1 -C 6 alkyl (heteroaryl) , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;
  • n 0, 1, 2, 3, 4, or 5.
  • ring A is a 5 or 6-heteroaromatic ring joined to X 4 and X 8 . In some embodiments of Formula (A’) , ring A is a 6-membered heteoaromatic ring. In some embodiments of Formula (A’) , ring A is a 5-membered heteroaromatic ring.
  • ring A is pyridine, pyrimidine, pyridazine, pyrazine, thiazole, thiadiazole, pyrrole, imidazole, oxazole, or oxadiazole, each of which is optionally substituted.
  • ring A is phenyl.
  • ring A is pyridine, pyrimidine, or pyridazine.
  • ring A is pyrimidine.
  • ring A is pyridine.
  • ring A is pyridazine. In some embodiments of Formula (A’) , ring A is thiazole, thiadiazole, pyrrole, imidazole, or oxazole. In some embodiments of Formula (A’) , ring A is thiazole. In some embodiments of Formula (A’) , ring A is thiadiazole. In some embodiments of Formula (A’) , ring A is pyrrole. In some embodiments of Formula (A’) , ring A is imidazole. In some embodiments of Formula (A’) , ring A is oxazole. In some embodiments of Formula (A’) , ring A is oxadiazole.
  • the compound of Formula (A’) has the structure of Formula (A) , or a pharmaceutically acceptable salt or solvate thereof:
  • X 1 , X 2 , and X 3 are each independently CR 5 or N.
  • the compound of the structure of Formula (A) has a structure of Formula (A-I) , or a pharmaceutically acceptable salt or solvate thereof:
  • the compound of the structure of Formula (A) has a structure of Formula (A-II) , or a pharmaceutically acceptable salt or solvate thereof:
  • At least one of X 1 , X 2 , X 3 and X 4 is N.
  • ring B is a 6-membered heteroaromatic ring. In some embodiments of Formula (A’) , (A) , (A-I) , or (A-II) , ring B is a 6- membered heteroaromatic ring comprising 1, 2, or 3 nitrogen atoms. In some embodiments of Formula (A’) , (A) , (A-I) , or (A-II) , ring B is pyridyl, pyrimidyl, or triazinyl.
  • ring B is a 5-membered heteroaromatic ring. In some embodiments of Formula (A’) , (A) , (A-I) , or (A-II) , ring B is a 5-membered heteroaromatic ring comprising at least 1nitrogen atom. In some embodiments of Formula (A’) , (A) , (A-I) , or (A-II) , ring B is a oxazolyl, triazolyl, imidazolyl, thiazolyl, oxadiazolyl, or thiadiazolyl.
  • ring B is a triazolyl or imidazolyl. In some embodiments of Formula (A’) , (A) , (A-I) , or (A-II) , ring B is a oxazolyl. In some embodiments of Formula (A’) , (A) , (A-I) , or (A-II) , ring B is a triazolyl. In some embodiments of Formula (A’) , (A) , (A-I) , or (A-II) , ring B is a imidazolyl.
  • ring B is a thiazolyl. In some embodiments of Formula (A’) , (A) , (A-I) , or (A-II) , ring B is a oxadiazolyl. In some embodiments of Formula (A’) , (A) , (A-I) , or (A-II) , ring B is a thiadiazolyl.
  • the compounds of Formula (A’) has the structure of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof:
  • Y 1 and Y 2 are each independently CH, N, O, or S; wherein both Y 1 and Y 2 are not O or S at the same time;
  • Y 3 is CR 4 , NR 4 , or N;
  • Y 4 is C or N.
  • Y 1 and Y 2 are each N. In some embodiments of Formula (I) , Y 1 and Y 2 are each independently CH, N, O, or S. In some embodiments of Formula (I) , Y 1 is O. In some embodiments of Formula (I) , Y 1 is N. In some embodiments, Y 1 is S. In some embodiments of Formula (I) , Y 1 is CH. In some embodiments of Formula (I) , Y 2 is O. In some embodiments of Formula (I) , Y 2 is N. In some embodiments of Formula (I) , Y 2 is S. In some embodiments of Formula (I) , Y 2 is CH.
  • Y 4 is C. In some embodiments of Formula (I) , Y 4 is N.
  • the compound of Formula (I) has the structure of Formula (II) , or a pharmaceutically acceptable salt or solvate thereof:
  • the compound has the structure of Formula (II) , or a pharmaceutically acceptable salt or solvate thereof:
  • Ring C is a substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted 5 to 6-membered monocyclic heteroaryl, or substituted or unsubstituted 5 to 20-membered bicyclic or polycyclic heteroaryl;
  • X 1 , X 2 , and X 3 are each independently CR 5 or N
  • X 4 is C or N
  • X 7 is NR 11 , O, or S
  • X 5 are each independently CR 5 ;
  • R 3 and R 4 together with the atoms to which they are attached form a substituted or unsubstituted 5 to 7-membered cycloalkyl or heterocycloalkyl ring;
  • each R 5 is independently selected from H, halogen, CN, -CF 3 , -OR 6 , -SR 6 , -NR 7 R 8 , substituted or unsubstituted C 1 -C 8 alkyl, or substituted or unsubstituted C 1 -C 8 heteroalkyl;
  • R 6 , R 7 , R 8 , and R 9 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, or C 2 -C 7 heterocycloalkyl;
  • each R 11 is independently selected from H, substituted or unsubstituted C 1 -C 8 alkyl, or substituted or unsubstituted C 1 -C 8 heteroalkyl;
  • n 1, 2, 3, 4 or 5.
  • X 7 is NR 11 , O, or S; X 5 are each independently CR 5 .
  • the compound has the structure of Formula (II) , or a pharmaceutically acceptable salt or solvate thereof:
  • Ring C is a substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted 5 to 6-membered monocyclic heteroaryl, or substituted or unsubstituted 5 to 20-membered bicyclic or polycyclic heteroaryl;
  • X 1 , X 2 , and X 3 are each independently CR 5 or N;
  • X 4 is C or N
  • X 5 and X 7 are each independently CR 5 , NR 11 , N, O, or S, wherein at most one of X 5 and X 7 is O or S;
  • R 3 and R 4 together with the atoms to which they are attached form a substituted or unsubstituted 5 to 7-membered heterocycloalkyl ring;
  • each R 5 is independently selected from H, halogen, CN, -CF 3 , -OR 6 , -SR 6 , -NR 7 R 8 , substituted or unsubstituted C 1 -C 8 alkyl, or substituted or unsubstituted C 1 -C 8 heteroalkyl;
  • R 6 , R 7 , R 8 , and R 9 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, or C 2 -C 7 heterocycloalkyl;
  • each R 11 is independently selected from H, substituted or unsubstituted C 1 -C 8 alkyl, or substituted or unsubstituted C 1 -C 8 heteroalkyl;
  • n 1, 2, 3, 4 or 5.
  • the compound has the structure of Formula (II) , or a pharmaceutically acceptable salt or solvate thereof:
  • Ring C is a substituted or unsubstituted phenyl, substituted or unsubstituted 6-membered monocyclic heteroaryl, or substituted or unsubstituted 6-membered monocyclic cycloalkyl;
  • X 1 , X 2 , and X 3 are each independently CR 5 or N;
  • X 4 is C
  • X 7 is NR 11 ;
  • X 5 are each independently CR 5 ;
  • R 4 is selected from H, halogen, -CN, -CF 3 , -OR 6 , -SR 6 , -NR 8 R 9 , -NO 2 , and C 1 -C 8 alkyl, C 1 -C 8 heteroalkyl, and C 3 -C 6 cycloalkyl; or
  • R 3 and R 4 together with the atoms to which they are attached form a 5 to 7-membered cycloalkyl or heterocycloalkyl ring;
  • each R 5 is independently selected from H, halogen, CN, -CF 3 , -OR 6 , -SR 6 , -NR 7 R 8 , C 1 -C 8 alkyl, or C 1 -C 8 heteroalkyl;
  • R 6 , R 7 , R 8 , and R 9 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, or C 2 -C 7 heterocycloalkyl;
  • each R 11 is independently selected from H, or C 1 -C 8 alkyl
  • n 1, 2, 3, 4 or 5.
  • the compound of Formula (II) has the structure of Formula (II-I) , or a pharmaceutically acceptable salt or solvate thereof:
  • the compound of Formula (II) has the structure of Formula (II-II) , or a pharmaceutically acceptable salt or solvate thereof:
  • X 4 is C.In some embodiments of Formula (A’) , (A) , (A-I) , (A-II) , (I) , (II) , (II-I) , or (II-II) , X 4 is N.
  • X 5 is CR 5 , wherein R 5 is selected from halogen, CN, -CF 3 , -OR 6 , -SR 6 , -NR 7 R 8 , substituted or unsubstituted C 2 -C 8 alkyl, or substituted or unsubstituted C 1 -C 8 heteroalkyl.
  • R 5 is selected from halogen, CN, -CF 3 , -OR 6 , -SR 6 , -NR 7 R 8 , substituted or unsubstituted C 2 -C 8 alkyl, or substituted or unsubstituted C 1 -C 8 heteroalkyl.
  • X 5 is CR 5 .
  • X 5 is NR 11 .
  • X 5 is N.
  • X 5 is O. In some embodiments, X 5 is S. In some embodiments of Formula (A’) , (A) , (A-I) , (A-II) , (I) , (II) , (II-I) , or (II-II) , R 5 is selected from -OR 6 , -NR 7 R 8 , or substituted or unsubstituted C 2 -C 8 alkyl.
  • R 5 is selected from -OCH 3 , -NHCH 3 , or CH 3 .
  • R 5 is H.
  • R 5 is halogen.
  • R 5 is CN.
  • R 5 is -CF 3 .
  • R 5 is -OR 6 .
  • R 5 is -SR 6 .
  • R 5 is -NR 7 R 8 .
  • R 5 is substituted or unsubstituted C 1 -C 8 alkyl. In some embodiments, R 5 is substituted or unsubstituted C 1 -C 6 alkyl. In some embodiments, R 5 is substituted or unsubstituted C 1 -C 3 alkyl. In some embodiments, R 5 is methyl. In some embodiments, R 5 is ethyl. In some embodiments, R 5 is propyl. In some embodiments, R 5 is substituted or unsubstituted C 1 -C 8 heteroalkyl. In some embodiments, R 5 is substituted or unsubstituted C 1 -C 6 heteroalkyl.
  • X 7 is NR 11 , wherein R 11 is H or substituted or unsubstituted C 1 -C 8 alkyl.
  • R 11 is H.
  • R 11 is substituted or unsubstituted C 1 -C 8 alkyl.
  • R 11 is -CH 3 , CH 2 CH 3 , CH (CH 3 ) 2 , or C (CH 3 ) 3 .
  • X 7 is NH. In some embodiments, X 7 is CR 5 . In some embodiments, X 7 is NR 11 . In some embodiments, X 7 is N. In some embodiments, X 7 is O. In some embodiments, X 7 is S.
  • the compound of Formula (II) has the structure of Formula (III) , or a pharmaceutically acceptable salt or solvate thereof:
  • X 1 is N; and X 2 and X 3 are each CR 5 .
  • X 1 and X 3 are each CR 5 ; and X 2 is N.
  • X 1 and X 2 are CR 5 ; and X 3 is N.
  • X 1 , X 2 , and X 3 are CR 5 .
  • X 1 , X 2 , and X 3 are CH.
  • X 1 is N.
  • X 1 is CR 5 .
  • X 2 is N.
  • X 2 is CR 5 .
  • X 3 is N.
  • X 3 is CR 5 .
  • X 1 is N;and X 2 and X 3 are each CR 5a .
  • X 1 and X 3 are each CR 5a ; and X 2 is N.
  • X 1 and X 2 are CR 5a ; and X 3 is N.
  • X 1 , X 2 , and X 3 are CR 5a .
  • X 1 , X 2 , and X 3 are CH.
  • R 3 and R 4 together with the atoms to which they are attached form a substituted or unsubstituted 5 to 7-membered cycloalkyl or heterocycloalkyl ring. In some embodiments, R 3 and R 4 together with the atoms to which they are attached form a substituted or unsubstituted 5 to 7-membered heterocycloalkyl ring.
  • R 3 and R 4 together with the atoms to which they are attached form a substituted or unsubstituted 5 to 7-membered heterocycloalkyl ring, wherein the heterocycloalkyl ring comprises 1 to 3 heteroatoms selected from N and O. In some embodiments, R 3 and R 4 together with the atoms to which they are attached form a substituted or unsubstituted 6 membered heterocycloalkyl ring, wherein the heterocycloalkyl ring comprises 1 to 2 heteroatoms selected from N and O.
  • the compound of Formula (III) has the structure of Formula (IV) , or a pharmaceutically acceptable salt or solvate thereof:
  • W is CH 2 , NR 10 , or O;
  • R 10 is H or C 1 -C 8 alkyl
  • p and q are each independently 0-3, wherein p + q is 1 to 4.
  • the compound of Formula (A’) has the structure of Formula (B) , or a pharmaceutically acceptable salt or solvate thereof:
  • X 9 and X 10 are each independently CR 5 , NR 11 , N, O, or S.
  • X 9 is CR 5 , NR 11 , N, O, or S. In some embodiments of Formula (B) , X 9 is CR 5 . In some embodiments of Formula (B) , X 9 is NR 11 . In some embodiments of Formula (B) , X 9 is N. In some embodiments of Formula (B) , X 9 is O. In some embodiments of Formula (B) , X 9 is S.
  • X 10 is CR 5 , NR 11 , N, O, or S. In some embodiments of Formula (B) , X 10 is CR 5 . In some embodiments of Formula (B) , X 10 is NR 11 . In some embodiments of Formula (B) , X 10 is N. In some embodiments, X 10 is O. In some embodiments of Formula (B) , X 10 is S.
  • ring B is ring B is a 6-membered heteroaromatic ring. In some embodiments of Formula (B) , ring B is pyridyl, pyrimidyl, or triazinyl. In some embodiments of Formula (B) , B is a 5-membered heteroaromatic ring. In some embodiments of Formula (B) , ring B is a oxazolyl, triazolyl, imidazolyl, thiazolyl, oxadiazolyl, or thiadiazolyl.
  • the compound of Formula (B) has the structure of Formula (V) , or a pharmaceutically acceptable salt or solvate thereof:
  • Y 1 and Y 2 are each independently CH, N, O, or S; wherein both Y 1 and Y 2 are not O or S at the same time;
  • Y 3 is CR 4 , NR 4 , or NH
  • Y 4 is C or N.
  • Y 1 and Y 2 are each N. In some embodiments of Formula (V) , Y 1 and Y 2 are each independently CH, N, O, or S. In some embodiments of Formula (V) , Y 1 is O. In some embodiments of Formula (V) , Y 1 is N. In some embodiments of Formula (V) , Y 1 is S. In some embodiments of Formula (V) , Y 1 is CH. In some embodiments of Formula (V) , Y 2 is O. In some embodiments of Formula (V) , Y 2 is N. In some embodiments , of Formula (V) Y 2 is S. In some embodiments of Formula (V) , Y 2 is CH.
  • Y 4 is C. In some embodiments of Formula (V) , Y 4 is N.
  • the compound of Formula (V) has the structure of Formula (VI) , or a pharmaceutically acceptable salt or solvate thereof:
  • Ring C is substituted or unsubstituted phenyl, substituted or unsubstituted 6-membered monocyclic heteroaryl, substituted or unsubstituted bicyclic heteroaryl, substituted or unsubstituted 6-membered cycloalkyl, or substituted or unsubstituted 6-membered heterocycloalkyl.
  • R 3 and R 4 together with the atoms to which they are attached form a substituted or unsubstituted 5 to 7-membered cycloalkyl or heterocycloalkyl ring. In some embodiments of Formula (VI) , R 3 and R 4 together with the atoms to which they are attached form a substituted or unsubstituted 5 to 7-membered heterocycloalkyl ring.
  • R 3 and R 4 together with the atoms to which they are attached form a substituted or unsubstituted 5 to 7-membered heterocycloalkyl ring, wherein the heterocycloalkyl ring comprises 1 to 3 heteroatoms selected from N and O.
  • R 3 and R 4 together with the atoms to which they are attached form a substituted or unsubstituted 6 membered heterocycloalkyl ring, wherein the heterocycloalkyl ring comprises 1 to 2 heteroatoms selected from N and O.
  • the compound of Formula (VI) has the structure of Formula (VII) , or a pharmaceutically acceptable salt or solvate thereof:
  • W is CH 2 , NR 10 , or O;
  • R 10 is H or C 1 -C 8 alkyl
  • p and q are each independently 0-3, wherein p + q is 1 to 4.
  • W is NR 10 or O. In some embodiments of Formula (VII) , W is NH or NCH 3 . In some embodiments of Formula (IV) or (VII) , W is NH. In some embodiments of Formula (VII) , W is NCH 3 . In some embodiments of Formula (VI) or (VII) , W is O. In some embodiments of Formula (IV) or (VII) , W is CH 2 .
  • p is 3 and q is 0. In some embodiments of Formula (IV) or (VII) , p is 2 and q is 0. In some embodiments of Formula (IV) or (VII) , p is 1 and q is 0. In some embodiments of Formula (IV) or (VII) , q is 3 and p is 0. In some embodiments of Formula (IV) or (VII) , q is 2 and p is 0. In some embodiments of Formula (IV) or (VII) , q is 1 and p is 0. In some embodiments of Formula (IV) or (VII) , p is 3 and q is 1.
  • p is 2 and q is 1. In some embodiments of Formula (IV) or (VII) , q is 3 and p is 1. In some embodiments of Formula (IV) or (VII) , q is 2 and p is 1.
  • p and q are each independently 1. In some embodiments of Formula (IV) or (VII) , p and q are each independently 2.
  • R 2 is substituted or unsubstituted C 3 -C 6 cycloalkyl or substituted or unsubstituted C 2 -C 5 heterocycloalkyl.
  • R 2 is halogen, -CN, -OR 6 , -SR 6 , substituted or unsubstituted C 1 -C 8 alkyl, or substituted or unsubstituted C 1 -C 8 heteroalkyl.
  • R 2 is substituted or unsubstituted C 1 -C 8 alkyl.
  • R 2 is halogen.
  • R 2 is H.
  • R 3 is substituted or unsubstituted C 3 -C 6 cycloalkyl or substituted or unsubstituted C 2 -C 5 heterocycloalkyl.
  • R 3 is halogen, -CN, -OR 6 , -SR 6 , substituted or unsubstituted C 1 -C 8 alkyl, or substituted or unsubstituted C 1 -C 8 heteroalkyl.
  • R 3 is substituted or unsubstituted C 1 -C 8 alkyl. In some embodiments of Formula (A’) , (A) , (A-I) , (A-II) , (II) , (II-I) , (II-II) , (III) , (B) , (V) , or (VI) , R 3 is methyl.
  • R 3 is cyclopropyl. In some embodiments of Formula (A’) , (A) , (A-I) , (A-II) , (II) , (II-I) , (II-II) , (III) , (B) , (V) , or (VI) , R 3 is halogen.
  • R 3 is Cl, F, Br, -CN, -OH, -OCH 3 , -SCH 3 , or CH 3 .
  • R 3 is H.
  • R 2 and R 3 are each independently H.
  • R 2 and R 3 together with the carbon atom to which they are attached form a 3 to 6-membered cycloalkyl or heterocycloalkyl ring.
  • R 2 and R 3 together with the carbon atom to which they are attached form a 4-membered cycloalkyl or heterocycloalkyl ring.
  • R 2 and R 3 together with the carbon atom to which they are attached form a 5-membered cycloalkyl or heterocycloalkyl ring.
  • R 2 and R 3 together with the carbon atom to which they are attached form a 6-membered cycloalkyl or heterocycloalkyl ring.
  • the ring is a cycloalkyl ring.
  • the ring is a heterocycloalkyl ring containing at least 1 N atom.
  • R 4 is -CF 3 , -OR 6 , -SR 6 , -NR 8 R 9 , substituted or unsubstituted C 1 -C 8 alkyl, or substituted or unsubstituted C 1 -C 8 heteroalkyl.
  • R 4 is -CF 3 , -OCH 3 , -NCH 3 , or -CH 3 .
  • R 4 is methyl.
  • R 4 is CD 3 .
  • R 3 and R 4 together with the atoms to which they are attached form a substituted or unsubstituted 7-membered cycloalkyl or heterocycloalkyl ring.
  • the ring is a cycloalkyl ring. In some embodiments, the ring is a heterocycloalkyl ring.
  • each R 5 is independently selected from halogen, CN, -CF 3 , -OR 6 , -SR 6 , -NR 7 R 8 , substituted or unsubstituted C 1 -C 8 alkyl, or substituted or unsubstituted C 1 -C 8 heteroalkyl.
  • each R 5 is independently selected from -OR 6 , -NR 7 R 8 , or substituted or unsubstituted C 2 -C 8 alkyl.
  • each R 5 is independently selected from -OCH 3 , -NCH 3 , or CH 3 .
  • each R 5 is independently halogen.
  • each R 5 is independently selected from Cl, Br, or F.
  • each R 5 is H.
  • each R 5 is independently C 1 -C 3 alkyl.
  • each R 5 is methyl.
  • R 5 is H.
  • R 5 is halogen.
  • R 5 is CN.
  • R 5 is -CF 3 .
  • R 5 is -OR 6 .
  • R 5 is -SR 6 .
  • R 5 is -NR 7 R 8 .
  • R 5 is substituted or unsubstituted C 1 -C 8 alkyl. In some embodiments, R 5 is substituted or unsubstituted C 1 -C 6 alkyl. In some embodiments, R 5 is substituted or unsubstituted C 1 -C 3 alkyl. In some embodiments, R 5 is ethyl. In some embodiments, R 5 is propyl. In some embodiments, R 5 is substituted or unsubstituted C 1 -C 8 heteroalkyl. In some embodiments, R 5 is substituted or unsubstituted C 1 -C 6 heteroalkyl.
  • R 11 is H or substituted or unsubstituted C 1 -C 8 alkyl.
  • R 11 is H.
  • R 11 is substituted or unsubstituted C 1 -C 8 alkyl.
  • R 11 is -CH 3 , CH 2 CH 3 , CH (CH 3 ) 2 , or C (CH 3 ) 3 .
  • Ring C is a substituted or unsubstituted phenyl, substituted or unsubstituted 6-membered monocyclic heteroaryl, or substituted or unsubstituted 6-membered monocyclic cycloalkyl.
  • Ring C is a substituted or unsubstituted aryl, substituted or unsubstituted 5 to 6-membered monocyclic heteroaryl.
  • ring C is a substituted or unsubstituted 6 membered heteroaryl having 1 to 4 ring heteroatoms independently selected from N, O and S.
  • Ring C is a substituted or unsubstituted phenyl, pyridyl, pyrimidyl or triazynyl.
  • Ring C is a substituted or unsubstituted phenyl. In some embodiments, Ring C is a substituted or unsubstituted pyridyl.
  • Ring C is a substituted or unsubstituted pyrimidyl.
  • Ring C is a substituted or unsubstituted triazynyl.
  • ring C is a 5-membered heteroaryl.
  • ring C is a substituted or unsubstituted 5 membered heteroaryl having 1 to 4 ring heteroatoms independently selected from N, O and S.
  • ring C is pyrrolyl, furyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, thiadiazolyl, or oxadiazolyl, each of which is optionally substituted.
  • ring C is a substituted or unsubstituted pyrrolyl.
  • ring C is a substituted or unsubstituted furyl.
  • ring C is a substituted or unsubstituted thiophenyl.
  • ring C is a substituted or unsubstituted pyrazolyl.
  • ring C is a substituted or unsubstituted imidazolyl.
  • ring C is a substituted or unsubstituted thiazolyl.
  • ring C is a substituted or unsubstituted isothiazolyl.
  • ring C is a substituted or unsubstituted triazolyl. In some embodiments, ring C is a substituted or unsubstituted tetrazolyl.
  • ring C is a substituted or unsubstituted thiadiazolyl.
  • ring C is a substituted or unsubstituted oxadiazolyl.
  • Ring C is a substituted or unsubstituted phenyl, substituted or unsubstituted 6-membered monocyclic heteroaryl, or substituted or unsubstituted 6-membered monocyclic cycloalkyl.
  • Ring C is a phenyl, pyridyl, pyrimidyl or triazynyl.
  • Ring C is a phenyl.
  • Ring C is a pyridyl.
  • Ring C is a substituted or unsubstituted C 3 -C 8 cycloalkyl.
  • Ring C is a cyclopentyl or cyclohexyl
  • Ring C is a substituted or unsubstituted C 3 -C 8 cycloalkyl.
  • Ring C is a cyclopentyl or cyclohexyl.
  • Ring C is a cyclopentyl.
  • Ring C is a cyclohexyl.
  • each R 1 is independently selected from halogen, OH, -CN, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 alkoxyl, and -NR 8 R 9 . In some embodiments, each R 1 is independently selected from halogen, OH, -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyl, and -NR 8 R 9 . In some embodiments, each R 1 is independently selected from halogen, CN, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl.
  • each R 1 is independently selected from halogen, -CN, -OR 6 , -SR 6 , -NR 8 R 9 , -NO 2 , or substituted or unsubstituted C 1 -C 8 alkyl.
  • each R 1 is independently selected from Br, Cl, F, -CN, -OCH 3 , -NCH 3 , -NO 2 , or -CH 3 .
  • each R 1 is independently Cl or F.
  • each R 1 is independently Cl or F.
  • each R 1 is independently -CN.
  • each R 1 is independently -OCH 3 .
  • each R 1 is independently selected from -NCH 3.
  • each R 1 is independently -CH 3 .
  • each R 1 is independently -CF 3 .
  • R 6 , R 7 , R 8 , and R 9 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, or C 2 -C 7 heterocycloalkyl.
  • R 6 , R 7 , R 8 , and R 9 are each independently H or C 1 -C 6 alkyl. In some embodiments, R 6 , R 7 , R 8 , and R 9 are each independently H or methyl.
  • R 6 , R 7 , R 8 , and R 9 are each independently C 1 -C 6 alkyl.
  • R 6 , R 7 , R 8 , and R 9 are each independently C 1 -C 6 haloalkyl.
  • R 6 , R 7 , R 8 , and R 9 are each independently C 1 -C 6 heteroalkyl.
  • R 6 , R 7 , R 8 , and R 9 are each independently C 3 -C 8 cycloalkyl.
  • R 6 , R 7 , R 8 , and R 9 are each independently C 2 -C 7 heterocycloalkyl.
  • (A) , (A-I) , (A-II) , (II) , (II-I) , (II-II) , (III) , (B) , (IV) , (V) , (VI) , or (VII) , R 6 , R 7 , R 8 , and R 9 are each independently H.
  • one or more substituents of any of the formulas described herein can be substituted with one or more deuterium atoms.
  • one or more of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and/or R 11 groups comprise deuterium at a percentage higher than the natural abundance of deuterium.
  • a hydrogen is replaced with deuterium in one or more of the following groups R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 .
  • the abundance of deuterium in each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and/or R 11 is independently at least 1%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%of a total number of hydrogen and deuterium.
  • the abundance of deuterium in each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and/or R 11 is independently at least 1%of a total number of hydrogen and deuterium. In some embodiments, the abundance of deuterium in each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and/or R 11 is independently at least 10%of a total number of hydrogen and deuterium.
  • the abundance of deuterium in each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and/or R 11 is independently at least 20%of a total number of hydrogen and deuterium. In some embodiments, the abundance of deuterium in each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and/or R 11 is independently at least 30%of a total number of hydrogen and deuterium.
  • the abundance of deuterium in each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and/or R 11 is independently at least 40% of a total number of hydrogen and deuterium. In some embodiments, the abundance of deuterium in each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and/or R 11 is independently at least 50% of a total number of hydrogen and deuterium.
  • the abundance of deuterium in each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and/or R 11 is independently at least 60%of a total number of hydrogen and deuterium. In some embodiments, the abundance of deuterium in each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and/or R 11 is independently at least 70%of a total number of hydrogen and deuterium.
  • the abundance of deuterium in each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and/or R 11 is independently at least 80% of a total number of hydrogen and deuterium. In some embodiments, the abundance of deuterium in each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and/or R 11 is independently at least 90%of a total number of hydrogen and deuterium.
  • the compounds made in the examples below are made from racemic starting materials (and/or intermediates) and separated into the individual enantiomers by chiral chromatography as final products or intermediates. Unless otherwise stated, it is understood that the absolute configuration of the separated intermediates and final compounds as drawn is arbitrarily assigned and was not determined.
  • Non-limiting examples of compounds described herein are compounds presented in Table 1 and pharmaceutically acceptable salts or solvates thereof.
  • Non-limiting examples of compounds described herein are compounds presented in Table 2 and pharmaceutically acceptable salts or solvates thereof.
  • salts particularly pharmaceutically acceptable salts, of the compounds described herein.
  • the compounds of the present disclosure that possess a sufficiently acidic, a sufficiently basic, or both functional groups can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt.
  • compounds that are inherently charged, such as those with a quaternary nitrogen can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.
  • 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, compounds described herein are intended to include all Z-, E-and tautomeric forms as well.
  • a “tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible.
  • the compounds disclosed herein are used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, 11 C, 13 C and/or 14 C.
  • the compound is deuterated in at least one position.
  • deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.
  • compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C-or 14 C-enriched carbon are within the scope of the present disclosure.
  • the compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds.
  • the compounds may be labeled with isotopes, such as for example, deuterium ( 2 H) , tritium ( 3 H) , iodine-125 ( 125 I) or carbon-14 ( 14 C) .
  • isotopes such as for example, deuterium ( 2 H) , tritium ( 3 H) , iodine-125 ( 125 I) or carbon-14 ( 14 C) .
  • Isotopic substitution with 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, and 125 I are all contemplated. All isotopic variations of the compounds of the present disclosure, whether radioactive or not
  • the compounds disclosed herein have some or all of the 1 H atoms replaced with 2 H atoms.
  • the methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.
  • Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6 (10) ] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45 (21) , 6601-21; and Evans, E.Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64 (1-2) , 9-32.
  • Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds.
  • Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.
  • Compounds 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 described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. Where absolute stereochemistry is not specified, the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions” , John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure) . Stereoisomers may also be obtained by stereoselective synthesis.
  • compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs) .
  • the compounds described herein may be in the form of pharmaceutically acceptable salts.
  • active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure.
  • the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms of the compounds presented herein are also considered to be disclosed herein.
  • compounds or salts of the compounds may be prodrugs, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester.
  • prodrug is intended to encompass compounds which, under physiologic conditions, are converted into pharmaceutical agents of the present disclosure.
  • One method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule.
  • the prodrug is converted by an enzymatic activity of the host animal such as specific target cells in the host animal.
  • esters or carbonates e.g., esters or carbonates of alcohols or carboxylic acids and esters of phosphonic acids
  • Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds may be a prodrug for another derivative or active compound.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. Prodrugs may help enhance the cell permeability of a compound relative to the parent drug. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues or to increase drug residence inside of a cell.
  • the design of a prodrug increases the lipophilicity of the pharmaceutical agent. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269: G210-218 (1995) ; McLoed et al., Gastroenterol, 106: 405-413 (1994) ; Hochhaus et al., Biomed. Chrom., 6: 283-286 (1992) ; J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987) ; J. Larsen et al., Int. J.
  • the present disclosure provides methods of producing the above-defined compounds.
  • the compounds may be synthesized using conventional techniques.
  • these compounds are conveniently synthesized from readily available starting materials.
  • Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989) ; T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991) ; L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis (1994) ; and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995) .
  • compositions comprising a therapeutically effective amount of any compound or salt of any one of Formulas (A’) , (A) , (A-I) , (A-II) , (I) , (II) , (III) , (IV) , (B) , (V) , (VI) , and (VII) , (also referred to herein as “a pharmaceutical agent” ) .
  • compositions may be formulated using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the pharmaceutical agent into preparations which are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • a summary of pharmaceutical compositions is found, for example, in 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 &Wilkins, 1999) .
  • compositions and 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 pharmaceutical agent is preferably administered as a pharmaceutical composition comprising, for example, a pharmaceutical agent and a pharmaceutically acceptable carrier or excipient.
  • Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters.
  • the aqueous solution is pyrogen-free, or substantially pyrogen-free.
  • the excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs.
  • the pharmaceutical composition can be in dosage unit form such as tablet, capsule, granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like.
  • the composition can also be present in a transdermal delivery system, e.g., a skin patch.
  • the composition can also be present in a solution suitable for topical administration, such as an eye drop.
  • a pharmaceutically acceptable excipient can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a pharmaceutical agent.
  • physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients.
  • the choice of a pharmaceutically acceptable excipient, including a physiologically acceptable agent depends, for example, on the route of administration of the composition.
  • the preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self microemulsifying drug delivery system.
  • the pharmaceutical composition also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the disclosure.
  • Liposomes for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.
  • a pharmaceutical composition can be administered to a subject by any of a number of routes of administration including, for example, orally, for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules, including sprinkle capsules and gelatin capsules, boluses, powders, granules, pastes for application to the tongue; absorption through the oral mucosa, e.g., sublingually; anally, rectally or vaginally, for example, as a pessary, cream or foam; parenterally, including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension; nasally; intraperitoneally; subcutaneously; transdermally, for example, as a patch applied to the skin; and topically, for example, as a cream, ointment or spray applied to the skin, or as an eye drop.
  • the compound may also be formulated for inhalation.
  • a compound may also be formulated for
  • a pharmaceutical composition may be a sterile aqueous or non-aqueous solution, suspension or emulsion, e.g., a microemulsion.
  • the excipients described herein are examples and are in no way limiting.
  • An effective amount or therapeutically effective amount refers to an amount of the one or more pharmaceutical agents administered to a subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
  • Subjects may generally be monitored for therapeutic effectiveness using assays and methods suitable for the condition being treated, which assays will be familiar to those having ordinary skill in the art and are described herein.
  • Pharmacokinetics of a pharmaceutical agent, or one or more metabolites thereof, that is administered to a subject may be monitored by determining the level of the pharmaceutical agent or metabolite in a biological fluid, for example, in the blood, blood fraction, e.g., serum, and/or in the urine, and/or other biological sample or biological tissue from the subject. Any method practiced in the art and described herein to detect the agent may be used to measure the level of the pharmaceutical agent or metabolite during a treatment course.
  • a pharmaceutical agent described herein for treating a disease or disorder may depend upon the subject’s condition, that is, stage of the disease, severity of symptoms caused by the disease, general health status, as well as age, gender, and weight, and other factors apparent to a person skilled in the medical art.
  • Pharmaceutical compositions may be administered in a manner appropriate to the disease to be treated as determined by persons skilled in the medical arts.
  • suitable duration and frequency of administration of the pharmaceutical agent may also be determined or adjusted by such factors as the condition of the patient, the type and severity of the patient’s disease, the particular form of the active ingredient, and the method of administration.
  • Optimal doses of an agent may generally be determined using experimental models and/or clinical trials.
  • the optimal dose may depend upon the body mass, weight, or blood volume of the subject. The use of the minimum dose that is sufficient to provide effective therapy is usually preferred. Design and execution of pre-clinical and clinical studies for a pharmaceutical agent, including when administered for prophylactic benefit, described herein are well within the skill of a person skilled in the relevant art.
  • the optimal dose of each pharmaceutical agent may be different, such as less than when either agent is administered alone as a single agent therapy.
  • two pharmaceutical agents in combination may act synergistically or additively, and either agent may be used in a lesser amount than if administered alone.
  • An amount of a pharmaceutical agent that may be administered per day may be, for example, between about 0.01 mg/kg and 100 mg/kg, e.g., between about 0.1 to 1 mg/kg, between about 1 to 10 mg/kg, between about 10-50 mg/kg, between about 50-100 mg/kg body weight. In other embodiments, the amount of a pharmaceutical agent that may be administered per day is between about 0.01 mg/kg and 1000 mg/kg, between about 100-500 mg/kg, or between about 500-1000 mg/kg body weight.
  • the optimal dose, per day or per course of treatment may be different for the disease or disorder to be treated and may also vary with the administrative route and therapeutic regimen.
  • compositions comprising a pharmaceutical agent can be formulated in a manner appropriate for the delivery method by using techniques routinely practiced in the art.
  • the composition may be in the form of a solid, e.g., tablet, capsule, semi-solid, e.g., gel, liquid, or gas, e.g., aerosol.
  • the pharmaceutical composition is administered as a bolus infusion.
  • compositions are well known in the pharmaceutical art and described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5 th Ed., 2006, and in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005) ) .
  • exemplary pharmaceutically acceptable excipients include sterile saline and phosphate buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, and the like may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may also be used.
  • compositions described herein may be formulated as a lyophilizate.
  • a composition described herein may be lyophilized or otherwise formulated as a lyophilized product using one or more appropriate excipient solutions for solubilizing and/or diluting the pharmaceutical agent (s) of the composition upon administration.
  • the pharmaceutical agent may be encapsulated within liposomes using technology known and practiced in the art.
  • a pharmaceutical agent is not formulated within liposomes for application to a stent that is used for treating highly, though not totally, occluded arteries.
  • Pharmaceutical compositions may be formulated for any appropriate manner of administration described herein and in the art.
  • a pharmaceutical composition e.g., for oral administration or for injection, infusion, subcutaneous delivery, intramuscular delivery, intraperitoneal delivery or other method, may be in the form of a liquid.
  • a liquid pharmaceutical composition may include, for example, one or more of the following: a sterile diluent such as water, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils that may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents; antioxidants; chelating agents; buffers and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • a sterile diluent such as water, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils that may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvent
  • a parenteral composition can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • physiological saline is preferred, and an injectable pharmaceutical composition is preferably sterile.
  • a liquid pharmaceutical composition may be applied to the eye in the form of eye drops.
  • a liquid pharmaceutical composition may be delivered orally.
  • At least one of the pharmaceutical agents described herein can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, and if desired, with diluents, buffering agents, moistening agents, preservatives, coloring agents, and flavoring agents.
  • the pharmaceutical agents may be formulated with a buffering agent to provide for protection of the compound from low pH of the gastric environment and/or an enteric coating.
  • a pharmaceutical agent included in a pharmaceutical composition may be formulated for oral delivery with a flavoring agent, e.g., in a liquid, solid or semi-solid formulation and/or with an enteric coating.
  • a pharmaceutical composition comprising any one of the pharmaceutical agents described herein may be formulated for sustained or slow release, also called timed release or controlled release.
  • sustained or slow release also called timed release or controlled release.
  • Such compositions may generally be prepared using well known technology and administered by, for example, oral, rectal, intradermal, or subcutaneous implantation, or by implantation at the desired target site.
  • Sustained-release formulations may contain the compound dispersed in a carrier matrix and/or contained within a reservoir surrounded by a rate controlling membrane. Excipients for use within such formulations are biocompatible, and may also be biodegradable; preferably the formulation provides a relatively constant level of active component release.
  • the amount of pharmaceutical agent contained within a sustained release formulation depends upon the site of implantation, the rate and expected duration of release, and the nature of the condition, disease or disorder to be treated or prevented.
  • the pharmaceutical compositions comprising a pharmaceutical agent are formulated for transdermal, intradermal, or topical administration.
  • the compositions can be administered using a syringe, bandage, transdermal patch, insert, or syringe-like applicator, as a powder/talc or other solid, liquid, spray, aerosol, ointment, foam, cream, gel, paste.
  • This preferably is in the form of a controlled release formulation or sustained release formulation administered topically or injected directly into the skin adjacent to or within the area to be treated, e.g., intradermally or subcutaneously.
  • the active compositions can also be delivered via iontophoresis. Preservatives can be used to prevent the growth of fungi and other microorganisms.
  • Suitable preservatives include, but are not limited to, benzoic acid, butylparaben, ethyl paraben, methyl paraben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetypyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, thimerosal, and combinations thereof.
  • compositions comprising a pharmaceutical agent can be formulated as emulsions for topical application.
  • An emulsion contains one liquid distributed in the body of a second liquid.
  • the emulsion may be an oil-in-water emulsion or a water-in-oil emulsion.
  • Either or both of the oil phase and the aqueous phase may contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients.
  • the oil phase may contain other oily pharmaceutically approved excipients.
  • Suitable surfactants include, but are not limited to, anionic surfactants, non-ionic surfactants, cationic surfactants, and amphoteric surfactants.
  • Compositions for topical application may also include at least one suitable suspending agent, antioxidant, chelating agent, emollient, or humectant.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
  • Liquid sprays may be delivered from pressurized packs, for example, via a specially shaped closure.
  • Oil-in-water emulsions can also be used in the compositions, patches, bandages and articles. These systems are semisolid emulsions, micro-emulsions, or foam emulsion systems.
  • the pharmaceutical agent described herein can be formulated as in inhalant. Inhaled methods can deliver medication directly to the airway.
  • the pharmaceutical agent can be formulated as aerosols, microspheres, liposomes, or nanoparticles.
  • the pharmaceutical agent can be formulated with solvents, gases, nitrates, or any combinations thereof.
  • Compositions described herein are optionally formulated for delivery as a liquid aerosol or inhalable dry powder.
  • Liquid aerosol formulations are optionally nebulized predominantly into particle sizes that can be delivered to the terminal and respiratory bronchioles.
  • Liquid aerosol and inhalable dry powder formulations are preferably delivered throughout the endobronchial tree to the terminal bronchioles and eventually to the parenchymal tissue.
  • Aerosolized formulations described herein are optionally delivered using an aerosol forming device, such as a jet, vibrating porous plate or ultrasonic nebulizer, preferably selected to allow the formation of aerosol particles having with a mass medium average diameter predominantly between 1 to 5 ⁇ .
  • the formulation preferably has balanced osmolarity ionic strength and chloride concentration, and the smallest aerosolizable volume able to deliver effective dose of the pharmaceutical agent.
  • the aerosolized formulation preferably does not impair negatively the functionality of the airways and does not cause undesirable side effects.
  • Aerosolization devices suitable for administration of aerosol formulations described herein include, for example, jet, vibrating porous plate, ultrasonic nebulizers and energized dry powder inhalers, that are able to nebulize the formulation into aerosol particle size predominantly in the size range from 1-5 ⁇ . Predominantly in this application means that at least 70%but preferably more than 90%of all generated aerosol particles are within 1-5 ⁇ range.
  • a jet nebulizer works by air pressure to break a liquid solution into aerosol droplets. Vibrating porous plate nebulizers work by using a sonic vacuum produced by a rapidly vibrating porous plate to extrude a solvent droplet through a porous plate.
  • An ultrasonic nebulizer works by a piezoelectric crystal that shears a liquid into small aerosol droplets.
  • a variety of suitable devices are available, including, for example, AeroNeb ⁇ and AeroDose ⁇ vibrating porous plate nebulizers (AeroGen, Inc., Sunnyvale, California) , nebulizers (Medic-Aid Ltd., West Wales, England) , Pari and Pari LC jet nebulizers (Pari Respiratory Equipment, Inc., Richmond, Virginia) , and Aerosonic ⁇ (DeVilbiss Medizinische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffo Kunststoffo Kunststoffo Kunststoffo Kunststoffo Kunststoffo Kunststoffo Kunststoffo Kunststoffo Kunststoffo Kunststoffo Kunststoffo Kunststoffo Kunststoffo Kunststoffo Kunststoffo Kunststoffo Kunststoffo Kunststoffo Kunststoffo Kunststoffo Kunststoffo Kunststoffo Kunststoffo Kunststoffo Kunststoffo Kunststoffo Kunststoffo Kunststoffo Kunststoffo Kunststoffo Kunststoffo Kunststoffo Kunststoffe
  • the pharmaceutical agent (s) can be formulated with oleaginous bases or ointments to form a semisolid composition with a desired shape.
  • these semisolid compositions can contain dissolved and/or suspended bactericidal agents, preservatives and/or a buffer system.
  • a petrolatum component that may be included may be any paraffin ranging in viscosity from mineral oil that incorporates isobutylene, colloidal silica, or stearate salts to paraffin waxes.
  • Absorption bases can be used with an oleaginous system.
  • Additives may include cholesterol, lanolin (lanolin derivatives, beeswax, fatty alcohols, wool wax alcohols, low HLB (hydrophobellipophobe balance) emulsifiers, and assorted ionic and nonionic surfactants, singularly or in combination.
  • lanolin lanolin derivatives, beeswax, fatty alcohols, wool wax alcohols, low HLB (hydrophobellipophobe balance) emulsifiers, and assorted ionic and nonionic surfactants, singularly or in combination.
  • Controlled or sustained release transdermal or topical formulations can be achieved by the addition of time-release additives, such as polymeric structures, matrices, that are available in the art.
  • the compositions may be administered through use of hot-melt extrusion articles, such as bioadhesive hot-melt extruded film.
  • the formulation can comprise a cross-linked polycarboxylic acid polymer formulation.
  • a cross-linking agent may be present in an amount that provides adequate adhesion to allow the system to remain attached to target epithelial or endothelial cell surfaces for a sufficient time to allow the desired release of the compound.
  • An insert, transdermal patch, bandage or article can comprise a mixture or coating of polymers that provide release of the pharmaceutical agents at a constant rate over a prolonged period of time.
  • the article, transdermal patch or insert comprises water-soluble pore forming agents, such as polyethylene glycol (PEG) that can be mixed with water insoluble polymers to increase the durability of the insert and to prolong the release of the active ingredients.
  • PEG polyethylene glycol
  • Transdermal devices may also comprise a water insoluble polymer.
  • Rate controlling polymers may be useful for administration to sites where pH change can be used to effect release. These rate controlling polymers can be applied using a continuous coating film during the process of spraying and drying with the active compound.
  • the coating formulation is used to coat pellets comprising the active ingredients that are compressed to form a solid, biodegradable insert.
  • a polymer formulation can also be utilized to provide controlled or sustained release.
  • Bioadhesive polymers described in the art may be used.
  • a sustained-release gel and the compound may be incorporated in a polymeric matrix, such as a hydrophobic polymer matrix.
  • a polymeric matrix include a microparticle.
  • the microparticles can be microspheres, and the core may be of a different material than the polymeric shell.
  • the polymer may be cast as a thin slab or film, a powder produced by grinding or other standard techniques, or a gel such as a hydrogel.
  • the polymer can also be in the form of a coating or part of a bandage, stent, catheter, vascular graft, or other device to facilitate delivery of the pharmaceutical agent.
  • the matrices can be formed by solvent evaporation, spray drying, solvent extraction and other methods known to those skilled in the art.
  • Kits with unit doses of one or more of the agents described herein, usually in oral or injectable doses are provided.
  • Such kits may include a container containing the unit dose, an informational package insert describing the use and attendant benefits of the drugs in treating disease, and optionally an appliance or device for delivery of the composition.
  • the compounds described herein can be used in the preparation of medicaments for the prevention or treatment of diseases or conditions.
  • a method for treating any of the diseases or conditions described herein in a subject in need of such treatment involves administration of pharmaceutical compositions containing at least one compound described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject.
  • compositions containing the compound (s) described herein can be administered for prophylactic and/or therapeutic treatments.
  • the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician.
  • compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition.
  • a patient susceptible to or otherwise at risk of a particular disease, disorder or condition is defined to be a "prophylactically effective amount or dose.
  • dose a dose that is administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition.
  • the precise amounts also depend on the patient's state of health, weight, and the like.
  • effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
  • the administration of the compounds may be administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
  • a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • the amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease or condition and its severity, the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be determined in a manner recognized in the field according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
  • doses employed for adult human treatment will typically be in the range of about 0.02 -about 5000 mg per day, in some embodiments, about 1 –about 1500 mg per day.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • the pharmaceutical composition described herein may be in unit dosage forms suitable for single administration of precise dosages.
  • the formulation is divided into unit doses containing appropriate quantities of one or more compound.
  • the unit dosage may be in the form of a package containing discrete quantities of the formulation.
  • Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules.
  • Aqueous suspension compositions can be packaged in single-dose non-recloseable containers.
  • multiple-dose recloseable containers can be used, in which case it is typical to include a preservative in the composition.
  • formulations for parenteral injection may be presented in unit dosage form, which include, but are not limited to ampoules, or in multi-dose containers, with an added preservative.
  • Toxicity and therapeutic efficacy of such therapeutic regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD 50 (the dose lethal to 50%of the population) and the ED 50 (the dose therapeutically effective in 50%of the population) .
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD 50 and ED 50 .
  • Compounds exhibiting high therapeutic indices are preferred.
  • the data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with minimal toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • a method of modulating cyclic dependent kinase 8 and/or 19 (CDK8/19) activity in a subject comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt or solvate thereof.
  • a method of inhibiting cyclic dependent kinase 8 and/or 19 (CDK8/19) activity in a subject comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt or solvate thereof.
  • provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein.
  • the cancer is leukemia, acute myeloid leukemia (AML) , chronic myeloid leukemia, acute lymphoblastic leukemia (ALL) , non-Hodgkin lymphoma (NHL) , Hodgkin lymphoma (HL) , or multiple myeloma (MM) .
  • the cancer is leukemia.
  • the cancer is acute myeloid leukemia (AML) .
  • the cancer is chronic myeloid leukemia.
  • the cancer is acute lymphoblastic leukemia (ALL) .
  • the cancer is non-Hodgkin lymphoma (NHL) .
  • the cancer is Hodgkin lymphoma (HL) .
  • the cancer is multiple myeloma (MM) .
  • the cancer is a solid cancer.
  • the cancer is a skin cancer, ocular cancer, gastrointestinal cancer, thyroid cancer, breast cancer, ovarian cancer, central nervous system cancer, laryngeal cancer, cervical cancer, lymphatic system cancer, genitourinary tract cancer, bone cancer, biliary tract cancer, pancreatic cancer, endometrial cancer, liver cancer, lung cancer, prostate cancer, or colon cancer.
  • the cancer is a prostate cancer, breast cancer, colon cancer, pancreatic cancer, skin cancer, ocular cancer, gastrointestinal cancer, thyroid cancer, ovarian cancer, central nervous system cancer, laryngeal cancer, cervical cancer, lymphatic system cancer, genitourinary tract cancer, bone cancer, biliary tract cancer, endometrial cancer, liver cancer, lung cancer, head and neck squamous cell carcinomas, or melanoma.
  • the cancer is a prostate cancer, breast cancer, colon cancer, pancreatic cancer, head and neck squamous cell carcinomas, or melanoma.
  • the cancer is a prostate cancer.
  • the cancer is a breast cancer.
  • the cancer is a colon cancer. In some embodiments, the cancer is a pancreatic cancer. In some embodiments, the cancer is a head and neck squamous cell carcinomas. In some embodiments, the cancer is a melanoma.
  • a method of treating an autoimmune disease or disorder in a subject in need thereof comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein.
  • the method comprises administering a second therapeutic agent.
  • the second therapeutic agent is a monoclonal antibody.
  • the monoclonal antibody is selected from edrecolomab, rituximab, gemtuzumab ozogamicin, alemtuzumab, ibritumomab tiuxetan, tositumomab, cetuximab, bevacizumab, and trastuzumab.
  • the second therapeutic agent is an immune checkpoint inhibitor.
  • the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor, or a PD-L1 inhibitor.
  • the immune checkpoint inhibitor is Ipilimumab, Nivolumab, Pembrolizumab, Atezolizumab, Avelumab, Durvalumab or Cemiplimab.
  • the second therapeutic agent is chemotherapy (such as fulvestrant or cytarabine) target therapy or an immune checkpoint inhibitor.
  • the second therapeutic is fulyestrant or cytarabine.
  • the second therapeutic agent is a CDK4/6 inhibitor, BCL-2 inhibitor, EGFR inhibitor, JAK1/2 inhibitor, anti-PD-L1 inhibitor or anti-PD1 inhibitor.
  • the compounds and salts of Formulas (A’) , (A) , (A-I) , (A-II) , (B) , (I) , (II) , (III) , (IV) , (V) , (VI) , and (VII) 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 the synthesis schemes below, the steps in some cases may be performed in a different order than the order shown below. Numberings or R groups in each scheme do not necessarily correspond to that of the claims or other schemes or tables herein.
  • Step 4 Compound 1: 5- (4- (4-chlorobenzyl) -5-methyl-4H-1, 2, 4-triazol-3-yl) -3-methyl-1H-indazole
  • Step 8 5- (4- (4-chlorobenzyl) -5-methyl-4H-1, 2, 4-triazol-3-yl) -N-methyl-1H-indazol-3-amine (Compound 10)
  • the crude solid was purified by Prep-HPLC (column: YMC, C18 (250*20mm, 5 ⁇ m) ; mobile phase: [water (0.1%NH 4 HCO 3 ) -ACN] ; B%: 20ACN%-50ACN%, 20min) to afford title compound 11 (25 mg, 6%) as a white solid.
  • Step 4 5- (5- (4-chlorophenyl) -6, 7-dihydro-5H-pyrrolo [2, 1-c] [1, 2, 4] triazol-3-yl) -3-methyl-1H-indazole
  • Step 7 5- (4-chlorophenyl) -7-methyl-3- (3-methyl-1H-indazol-5-yl) -5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [4, 3-a] pyrazine

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Abstract

La divulgation concerne des composés et des procédés de modulation ou d'inhibition de CDK8/19. Dans un aspect, l'invention concerne des composés de formule (A'), (A), (A-I), (A-II), (II), (II-I), (II-II), (III), (B), (IV), (V), (VI) et (VII), et des sels et des solvates de ceux-ci. Dans un aspect, l'invention concerne des compositions pharmaceutiques comprenant un composé selon l'invention, ou un sel ou solvate de celui-ci. Dans un aspect, l'invention concerne des méthodes de traitement d'une maladie ou d'un état pathologique comprenant l'administration d'un composé selon l'invention, ou d'un sel ou d'un solvate de celui-ci.
PCT/CN2022/129486 2021-11-04 2022-11-03 Inhibiteurs doubles de cdk8/19 et leurs procédés d'utilisation WO2023078337A1 (fr)

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CNPCT/CN2022/120489 2022-09-22

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016009076A1 (fr) * 2014-07-17 2016-01-21 Merck Patent Gmbh Nouvelles naphtyridines et isoquinoléines et leur utilisation à titre d'inhibiteurs de cdk8/19
WO2016041618A1 (fr) * 2014-09-15 2016-03-24 Merck Patent Gmbh Indazoles substitués et hétérocycles associés
WO2018136202A2 (fr) * 2016-12-23 2018-07-26 Plexxikon Inc. Composés et procédés pour la modulation de cdk8, et indications associées
EP3666770A1 (fr) * 2017-08-07 2020-06-17 Joint Stock Company "Biocad" Nouveaux composés hétérocycliques comme inhibiteurs de cdk8/19

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016009076A1 (fr) * 2014-07-17 2016-01-21 Merck Patent Gmbh Nouvelles naphtyridines et isoquinoléines et leur utilisation à titre d'inhibiteurs de cdk8/19
WO2016041618A1 (fr) * 2014-09-15 2016-03-24 Merck Patent Gmbh Indazoles substitués et hétérocycles associés
WO2018136202A2 (fr) * 2016-12-23 2018-07-26 Plexxikon Inc. Composés et procédés pour la modulation de cdk8, et indications associées
EP3666770A1 (fr) * 2017-08-07 2020-06-17 Joint Stock Company "Biocad" Nouveaux composés hétérocycliques comme inhibiteurs de cdk8/19

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