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WO2024218632A1 - Inhibiteurs de la protéine kinase erk - Google Patents

Inhibiteurs de la protéine kinase erk Download PDF

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Publication number
WO2024218632A1
WO2024218632A1 PCT/IB2024/053666 IB2024053666W WO2024218632A1 WO 2024218632 A1 WO2024218632 A1 WO 2024218632A1 IB 2024053666 W IB2024053666 W IB 2024053666W WO 2024218632 A1 WO2024218632 A1 WO 2024218632A1
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Prior art keywords
methyl
alkyl
group
optionally substituted
fluoro
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Inventor
Donald Sanford BACKOS
Tanna Marie BETTENDORF
Adam Wade Cook
John Joseph Gaudino
Ronald Jay Hinklin
Dean Russell KAHN
Oren Teague MCNULTY
David Austin MORENO
Viktor Christian POLITES
Alexandra Nicole SMITH
Kyle Adam WICKERSHAM
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Array Biopharma Inc
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Array Biopharma Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms 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

Definitions

  • the present invention relates to novel compounds.
  • the invention also relates to 5 the preparation of the compounds, intermediates used in their preparation, compositions containing the compounds, and uses of the compounds, including as inhibitors of extracellular signal-regulated kinases, for the treatment of abnormal cell growth, including for the treatment of cancer.
  • Mammalian cells respond to extracellular stimuli by activating signaling cascades 10 mediated by members of the mitogen-activated protein kinase (MAPK) family, including the extracellular signal-regulated kinase (ERK), the p38 MAPK and the c-Jun N-terminal kinases (JNKs), and that are involved in, for example, regulation of normal cell proliferation, survival and differentiation (see, for example, Roberts P. and Der C., “Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment15 of cancer”, 2007, Oncogene, 26, pp3291-3310).
  • MAPK mitogen-activated protein kinase
  • ERK extracellular signal-regulated kinase
  • JNKs c-Jun N-terminal kinases
  • the extracellular signal- regulated kinase (ERK) pathway is thought to play a central role in regulating mammalian cell growth by relaying extracellular signals from ligand-bound cell surface receptor tyrosine kinases (“RTKs”), such as the human epidermal growth factor receptor (ErbB) family, platelet-derived growth factor (PDGF)-, fibroblast growth factor (FGF)- and 20 vascular endothelial growth factor (VEGF)- receptor tyrosine kinases.
  • RTKs ligand-bound cell surface receptor tyrosine kinases
  • ErbB human epidermal growth factor receptor
  • PDGF platelet-derived growth factor
  • FGF fibroblast growth factor
  • VEGF vascular endothelial growth factor
  • Ras Activation of Ras (for example, due to upstream signaling or as a result of activating point mutations in the Ras oncogene) leads to the phosphorylation, recruitment and activation of Raf, a serine-threonine kinase.
  • Raf mitogen activated protein kinase kinase 1 and mitogen activated protein kinase kinase 2 (MAPKK1 and MAPKK2, also known as MEK1 and MEK2 respectively).
  • MEK1 and / or MEK2 dual-specificity kinases activate ERK1 and / or ERK2 by phosphorylation (also referred to as MAPK).
  • ERK1 and / or ERK2 When activated, ERK1 and / or ERK2 phosphorylate several downstream targets including regulatory proteins such as protein kinases and transcription involved in a multitude of cellular events, including cytoskeletal changes and transcriptional activation. The processes involved in tumor growth, progression, survival, angiogenesis and metastasis are also mediated by these signaling pathways when active in cancer cells.
  • the ERK/MAPK pathway is thought to be one of the most important for cell proliferation, and it is believed that the ERK/MAPK pathway is frequently activated in many tumors including, but not limited to, those of the colon, pancreas, breast, brain, ovary, lungs and skin.
  • Ras genes which are upstream of ERK1 and / or ERK 2 are mutated in several cancers, including colorectal, melanoma, breast and pancreatic tumors.
  • the high Ras activity is accompanied by elevated ERK activity in many human tumors.
  • mutations of BRAF, a serine-threonine kinase of the Raf family which is also upstream of ERK1 and / or ERK2 are associated with increased ERK 1 and / or ERK 2 activity.
  • ERK inhibitors for example that inhibit ERK more potently than another kinase, including, for example, compounds that are selective for inhibition of ERK over inhibition of cyclin- dependent kinase 2 (CDK2) / cyclin A and / or inhibition of Aurora A.
  • CDK2 cyclin- dependent kinase 2
  • Such compounds may be useful as therapeutic agents, for the treatment of abnormal cell growth and / or cancer.
  • Summary of the Invention The present invention provides, in part, compounds of Formula (I), Formula (II), Formula (III) and Formula (IV), and pharmaceutically acceptable salts thereof.
  • Such compounds of the invention may inhibit ERK, may be selective inhibitors of ERK, and may be useful in the treatment, prevention, suppression and amelioration of diseases, disorders and conditions mediated by ERK signaling including, abnormal cell growth, hyperproliferative disorders, cancer, pain and inflammation.
  • the present invention also provides, in part, pharmaceutically acceptable salts and compositions of the compounds of the invention, methods for preparing such compounds, and methods of using the foregoing.
  • pharmaceutical compositions comprising the compounds or pharmaceutically acceptable salts of the invention, alone or in combination with additional therapeutic agents.
  • a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of: (i) C 1 -C 6 alkyl, which C 1 -C 6 alkyl substituted by one, two or three substituents independently selected from the group consisting of fluoro; chloro; hydroxy; -NH 2 ; -NH(C 1 -C 4 alkyl); -N(C 1 -C 4 alkyl) 2 ; and C 1 -C 4 alkoxy, which C 1 -C 4 alkoxy is optionally substituted by one, two or three fluoro; (ii) C 3 -C 7 cycloalkyl, which C 3 -C 7 cycloalkyl is optionally substituted with one, two,
  • Embodiment 1 is identical to the embodiment of Formula (I) provided above.
  • a compound of formula (II): or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of hydrogen; and C1-C4 alkyl, which C1-C4 alkyl is optionally substituted by one, two or three fluoro; R 3 is selected from the group consisting of hydrogen; fluoro; and C1-C4 alkyl, which C1- C 4 alkyl is optionally substituted by one, two or three fluoro; R 4 is selected from the group consisting (i) hydrogen; (ii) C1-C4 alkyl, which C1-C4 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of fluoro, hydroxy, -NH2, and -OCH3; (iii) 5- to 6- membered heterocycl
  • a compound of formula (III): is selected from the group consisting of: (i) hydrogen; (ii) C 1 -C 4 alkyl, which C 1 -C 4 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of fluoro, hydroxy, -NH 2 , and -OCH 3 ; (iii) 5- to 6- membered heterocycloalkyl, which heterocycloalkyl comprises one heteroatom selected from the group consisting of N and O; and (iv) 5- or 6- membered heteroaryl, which heteroaryl comprises one, two or three heteroatoms independently selected from the group consisting of N, O and S, and which heteroaryl is optionally substituted with C1-C4 alkyl; and R 5 is selected from the group consisting of:
  • Embodiment 200 is identical to the embodiment of Formula (III) provided above.
  • a compound of formula (IV): or a pharmaceutically acceptable salt wherein R 4 is C 1 -C 4 alkyl, which C 1 -C 4 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of fluoro, hydroxy, -NH2, and -OCH 3 ; and R 5 is selected from the group consisting of: (i) C 3 -C 10 cycloalkyl, which C 3 -C 10 cycloalkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of fluoro, hydroxy, -CH 3 and -CF 3 ; (ii) 4- to 6- membered heterocycloalkyl, which heterocycloalkyl comprises one heteroatom selected from the group consisting of N and O, and which 4-
  • Embodiment 300 is identical to the embodiment of Formula (IV) provided above. It is to be understood that both general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. Detailed Description of the Invention The present invention may be understood more readily by reference to the following detailed description of the embodiments of the invention and the Examples included herein. It is to be understood that this invention is not limited to specific synthetic methods of making that may of course vary. It is also to be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting. E1 A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined above.
  • E3 A compound of Embodiment E2, or a pharmaceutically acceptable salt thereof, wherein R 1 is oxanyl.
  • R 1 is selected from the group consisting of pyrazolyl, which pyrazolyl is optionally substituted with one, two or three substituents independently selected from C1-C4 alkyl, which C 1 -C 4 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of fluoro, hydroxy and -OCH3 to form, for example, N-methylpyrazolyl, N-ethylpyrazolyl, N-isopropylpyrazolyl, or 2,4- dimethylpyrazolyl; pyrrolyl; thiophenyl, which thiophenyl is optionally substituted with C1- C 4 alkoxy to form, for example, ethoxythiophenyl; benzofuranyl, which benzofuranyl is optionally substituted with C1-C4 alkyl to form, for example, 7-methylbenzofuranyl; pyrazolyl, which pyrazolyl is optionally substituted with one, two or three
  • Embodiment E6 A compound of Embodiment E5, or a pharmaceutically acceptable salt thereof, wherein R 1 is pyrazolyl, which pyrazolyl is optionally substituted with one, two or three substituents independently selected from C 1 -C 4 alkyl, which C 1 -C 4 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of fluoro, hydroxy and -OCH 3 , to form, for example, N-methylpyrazolyl, N- ethylpyrazolyl, N-isopropylpyrazolyl, or 2,4-dimethylpyrazolyl.
  • R 1 is pyrazolyl, which pyrazolyl is optionally substituted with one, two or three substituents independently selected from C 1 -C 4 alkyl, which C 1 -C 4 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of fluoro, hydroxy and -OCH 3 ,
  • E7 A compound of Embodiment E6, or a pharmaceutically acceptable salt thereof, wherein R 1 is N-methylpyrazolyl.
  • E8 A compound of Embodiment E1, or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl, which phenyl is optionally substituted with one, two or three substituents independently selected from the group consisting of fluoro; chloro; C1-C4 alkyl, which C 1 -C 4 alkyl is optionally substituted by one, two or three fluoro; C 1 -C 4 alkoxy, which C1-C4 alkoxy is optionally substituted by one, two or three fluoro; -NH2; -NH(C1-C4 alkyl); and -N(C 1 -C 4 alkyl) 2 to form, for example, phenyl, chlorophenyl, 2,4- dichlorophenyl, 3,4-dimethoxyphenyl, 2,5-dimethoxylphenyl, or 2-d
  • R 1 is phenyl, which phenyl is optionally substituted with one, two or three substituents independently selected from the group consisting of fluoro; chloro; or C 1 -C 4 alkoxy to form, for example, phenyl, chlorophenyl, 2,4-dichlorophenyl, 3,4- dimethoxyphenyl, or 2,5-dimethoxylphenyl.
  • Embodiment E10 A compound of Embodiment E1, or a pharmaceutically acceptable salt thereof, wherein R 1 is C3-C7 cycloalkyl, which C3-C7 cycloalkyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of fluoro; chloro; C1-C4 alkyl, which C1-C4 alkyl is optionally substituted by one, two or three fluoro; and C 1 -C 4 alkoxy, which C 1 -C 4 alkoxy is optionally substituted by one, two or three fluoro.
  • R 1 is C3-C7 cycloalkyl, which C3-C7 cycloalkyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of fluoro; chloro; C1-C4 alkyl, which C1-C4 alkyl is optionally substituted by one, two or three fluoro; and C 1 -C 4 alkoxy
  • Embodiment E10 A compound of Embodiment E10, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of cyclobutyl, which cyclobutyl is optionally substittuted with C 1 -C 4 alkoxy, which C 1 -C 4 alkoxy is optionally substituted by one, two or three fluoro to form, for example, 3-methoxycyclobutyl; and bicyclo[1.1.1]pentanyl, which bicyclo[1.1.1]pentanyl is optionally substituted with C 1 -C 4 alkoxy to form, for example 3-methoxy-bicyclo[1.1.1]pentanyl.
  • R 1 is selected from the group consisting of cyclobutyl, which cyclobutyl is optionally substittuted with C 1 -C 4 alkoxy, which C 1 -C 4 alkoxy is optionally substituted by one, two or three fluoro to form, for example, 3-methoxycycl
  • E12 A compound of Embodiment E1, or a pharmaceutically acceptable salt thereof, wherein R 1 is C1-C6 alkyl, which C1-C6 alkyl is optionally substituted by one, two or three substituents independently selected from the group consisting of fluoro; chloro; hydroxy; -NH2; -NH(C1-C4 alkyl); -N(C1-C4 alkyl)2; and C1-C4 alkoxy, which C1-C4 alkoxy is optionally substituted by one, two or three fluoro.
  • R 2 is hydrogen.
  • E14 A compound of any of Embodiments E1 to E12, or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1 -C 4 alkyl, which C 1 -C 4 alkyl is optionally substituted by one, two or three fluoro, to form, for example, -CH3 or -CF3.
  • E15 A compound of Embodiment E14, or a pharmaceutically acceptable salt thereof, wherein R 2 is -CH 3 .
  • E16 A compound of any of Embodiments E1 to E12, or a pharmaceutically acceptable salt thereof, wherein R 2 is fluoro or chloro.
  • E17 A compound of any of to E16, or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen.
  • E18 A compound of any of Embodiments E1 to E16, or a pharmaceutically acceptable salt thereof, wherein R 3 is C 1 -C 4 alkyl, for example -CH 3 .
  • E19 A compound of Embodiment E18, or a pharmaceutically acceptable salt thereof, wherein R 3 is -CH3.
  • E20 A compound of any of Embodiments E1 to E19, or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen.
  • E21 A compound of any of Embodiments E1 to E19, or a pharmaceutically acceptable salt thereof, wherein R 4 is C 1 -C 4 alkyl, which C 1 -C 4 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of fluoro, hydroxy, -NH 2 , and -OCH 3 to form, for example -CH 3 , -CH 2 CH 3 , -CH 2 OH, -CH 2 CH 2 OH, - CH(OH)CH 3 , -C(CH 3 ) 2 OH, -CH 2 NH 2 , -CH 2 OCH 3 , -CH 2 CHF 2 , or -CF 3 .
  • E22 A compound of Embodiment E21, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of -CH 3 , -CH 2 CH 3 , -CH 2 OH, - CH2CH2OH, -CH(OH)CH3, -C(CH3)2OH, -CH2NH2, -CH2OCH3, -CH2CHF2, and -CF3.
  • R 4 is selected from the group consisting of -CH 3 , -CH 2 CH 3 , -CH 2 OH, - CH2CH2OH, -CH(OH)CH3, -C(CH3)2OH, -CH2NH2, -CH2OCH3, -CH2CHF2, and -CF3.
  • R 4 is selected from the group consisting of -CH 3 , -CH 2 CH 3 , -CH 2 OH, - CH2CH2OH, -CH(OH)CH3, -C(CH3)2OH, -CH2NH2, -CH
  • E25 A compound of any of Embodiments E1 to E19, or a pharmaceutically acceptable salt thereof, wherein R 4 is 5- or 6- membered heteroaryl, which heteroaryl comprises one, two or three heteroatoms independently selected from the group consisting of N, O and S, and which heteroaryl is optionally substituted with C 1 -C 4 alkyl.
  • R 4 is 5- or 6- membered heteroaryl, which heteroaryl comprises one, two or three heteroatoms independently selected from the group consisting of N, O and S, and which heteroaryl is optionally substituted with C 1 -C 4 alkyl.
  • E26 A compound of Embodiment E25, or a pharmaceutically acceptable salt thereof, wherein R 4 is pyrazolyl, which pyrazolyl is optionally substituted with C1-C4 alkyl to form, for example, N-methylpyrazolyl.
  • E27 A compound of any of to E19, or a pharmaceutically acceptable salt thereof, wherein R 4 is 5- to 6- membered heterocycloalkyl, which heterocycloalkyl comprises one heteroatom selected from the group consisting of N and O.
  • E28 A compound of Embodiment E27, or a pharmaceutically acceptable salt thereof, wherein R 4 is pyrrolidinyl, or tetrahydrofuranyl.
  • E29 A compound of any of Embodiments E1 to E16, or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen and R 4 is hydrogen.
  • E30 A compound of any of Embodiments E1 to E16, or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen and R 4 is -CH2OH.
  • E31 A compound of any of Embodiments E1 to E16, or a pharmaceutically acceptable salt thereof, wherein R 3 is -CH 3 and R 4 is -CH 3 .
  • E32 A compound of any of Embodiments E1 to E16, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 , taken together with the carbon to which they are attached, form a C3-C4 cycloalkyl, which C3-C4 cycloalkyl is optionally substituted by one, two, three or four fluoro.
  • E33 A compound of Embodiment E32, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 , taken together with the carbon to which they are attached, form cyclopropyl.
  • E34 A compound of any of Embodiments E1 to E33, or a pharmaceutically acceptable salt thereof, wherein R 5 is phenyl, which phenyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo; hydroxy; - CN; C1-C4 alkyl, which C1-C4 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of fluoro, hydroxy and - OCH3; C1-C4 alkoxy, which C1-C4 alkoxy is optionally substituted with one, two or three fluoro; -CO 2 CH 3 ; -S(C 1 -C 4 alkyl), which -S(C 1 -C 4 alkyl) is optionally substituted with one, two or three fluoro; -SO(C1-C4 alkyl); and -SO2(C1-C4 alkyl).
  • E35 A compound of Embodiment E34, or a pharmaceutically acceptable salt thereof, wherein R 5 is phenyl.
  • E36 A compound of Embodiment a pharmaceutically acceptable salt thereof, wherein R 5 is phenyl, which phenyl is substituted with one substituent selected from the group consisting of fluoro; chloro; bromo; -OH; -CN; -CH 3 ; -CH 2 CH 3 ; -CH(CH 3 ) 2 ; -CH 2 OH; -CH(CH3)OH; -C(CH3)2OH; -CH2F; -CHF2; -CF3; -CH2OCH3; -OCH3; -OCHF2; -OCF3; - CO 2 CH 3 ; -SCH 3 ; -SCH 2 CH 3 ; -SCHF 2 ; -SOCH 3 ; and -SO 2 (CH 3 ).
  • Embodiment E34 A compound of Embodiment E34, or a pharmaceutically acceptable salt thereof, wherein R 5 is phenyl, which phenyl is substituted with two substituents independently selected from the group consisting of fluoro; chloro; bromo; -CH 3 ; -CH 2 OH; -CH 2 F; - CH2OCH3; and -OCH3 to form, for example difluorophenyl, dichlorophenyl, chloro- fluorophenyl, bromo-chlorophenyl, bromo-fluorophenyl, fluoro-methylphenyl, fluoro- fluoromethylphenyl, bromo-hydroxymethylphenyl, chloro-hydroxymethylphenyl, fluoro- hydroxymethylphenyl, dimethoxyphenyl, chloro-methoxyphenyl, fluoro-methoxyphenyl, bromo-methoxyphenyl, bromo-methoxymethylphenyl
  • E40 A compound of any of to E33, or a pharmaceutically acceptable salt thereof, wherein R 5 is C1-C4 alkyl.
  • E41 A compound of Embodiment E40, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from the group consisting of -CHC(CH 3 ) 2 and -C(CH 3 ) 3 .
  • E42 A compound of any of Embodiments E1 to E33, or a pharmaceutically acceptable salt thereof, wherein R 5 is C3-C10 cycloalkyl, which C3-C10 cycloalkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of fluoro, hydroxy, -CH3 and -CF3.
  • Embodiment E42 A compound of Embodiment E42, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from the group consisting of cyclopropyl; cyclobutyl; cyclopentyl; bicyclo[1.1.1]pentyl; cyclohexyl, which cyclohexyl is optionally substituted by one substituent selected from the group consisting of hydroxy and -CH3; bicyclo[2.2.1]heptanyl; and adamantanyl.
  • R 5 is selected from the group consisting of cyclopropyl; cyclobutyl; cyclopentyl; bicyclo[1.1.1]pentyl; cyclohexyl, which cyclohexyl is optionally substituted by one substituent selected from the group consisting of hydroxy and -CH3; bicyclo[2.2.1]heptanyl; and adamantanyl.
  • Embodiment E45 A compound of Embodiment E44, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from the group consisting of oxetanyl; azetidinyl, which azetidinyl is optionally substituted with -CH3; tetrahydrofuranyl; and tetrahydropyranyl.
  • E46 A compound of any of Embodiments E1 to E33, or a pharmaceutically acceptable salt thereof, wherein R 5 is –C(R 15 ) 2 -phenyl, which phenyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo; hydroxy; -CN; C 1 -C 4 alkyl, which C 1 -C 4 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of fluoro, hydroxy and -OCH 3 ; C 1 -C 4 alkoxy, which C 1 -C 4 alkoxy is optionally substituted with one, two or three fluoro; -CO2CH3; -S(C1-C4 alkyl), which -S(C1-C4 alkyl) is optionally substituted with one, two or three fluoro; -SO(C 1 -C 4 alkyl); and -SO 2 (C 1 -C 4 alkyl).
  • E47 A compound of Embodiment a pharmaceutically acceptable salt thereof, wherein R 5 is –C(R 15 )2-phenyl, which phenyl is optionally substituted with one substituent selected from the group consisting of fluoro, chloro -OCH 3 , and -SCH 3 ; and wherein R 15 is independently at each occurrence selected from the group consisting of hydrogen, hydroxy and -CH 3 to form, for example, -CH 2 -phenyl, -CH(OH)-phenyl, -CH 2 - methoxyphenyl, -CH2-chlorophenyl, -CH2-fluorophenyl, -CH2-(SCH3)phenyl, or -C(CH3)2- phenyl.
  • R 5 is selected from the group consisting of –C(R 15 ) 2 -imidazolyl, which imidazolyl is optionally substituted with -CH3; –C(R 15 )2-pyrazolyl, which pyrazolyl is optionally substituted with one or two -CH 3 ; –C(R 15 ) 2 -1,2,3-triazolyl, which triazolyl is optionally substituted with -CH3; –C(R 15 )2-oxazolyl; –C(R 15 )2-isoxazolyl; –C(R 15 )2-pyrimidinyl; and – C(R 15 ) 2 - pyridinyl; and wherein R 15 is independently at each occurrence hydrogen to form, for example, –CH2-pyrimidinyl, –CH2-pyridinyl, -CH2-N-methylimidazolyl,
  • E50 A compound of any of Embodiments E1 to E31, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 , taken together with the carbon to which they are attached, form a C3-C6 cycloalkyl, which C3-C6 cycloalkyl is optionally substituted with phenyl, and which phenyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo; hydroxy; -CN; C1-C4 alkyl, which C 1 -C 4 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of fluoro, hydroxy and -OCH3; C1-C4 alkoxy, which C 1 -C 4 alkoxy is optionally substituted with one, two or three fluoro; and - CO2CH3.
  • E51 A compound of Embodiment a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 , taken together with the carbon to which they are attached, form a C3- C 6 cycloalkyl, which C 3 -C 6 cycloalkyl is substituted with phenyl.
  • E52 A compound of any of Embodiments E1 to E51, or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen.
  • E53 A compound of any of Embodiments E1 to E51, or a pharmaceutically acceptable salt thereof, wherein R 6 is -CH 3 .
  • E100 A compound of Formula (II), or a pharmaceutically acceptable salt thereof, as defined above.
  • E101 A compound of Embodiment E100, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen.
  • E102 A compound of Embodiment E100, or a pharmaceutically acceptable salt thereof, wherein R 2 is -CH 3 .
  • E103 A compound of any of Embodiments E100 to E102, or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen.
  • E104 A compound of any of Embodiments E100 to E102, or a pharmaceutically acceptable salt thereof, wherein R 3 is -CH 3 .
  • E105 A compound of any of Embodiments E100 to E104, or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen.
  • E106 A compound of any of Embodiments E100 to E104, or a pharmaceutically acceptable salt thereof, wherein R 4 is C1-C4 alkyl, which C1- alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of fluoro, hydroxy, -NH2, and -OCH3.
  • E107 A compound of Embodiment E106, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of -CH 3 ; -CH 2 CH 3 ; -CH 2 OH; - CH(OH)CH3; -C(CH3)2OH; -CH2CH2OH; -CH2NH2; -CH2OCH3; -CH2CHF2; and -CF3.
  • R 4 A compound of Embodiment a pharmaceutically acceptable salt thereof, wherein R 4 is -CH3.
  • E109 A compound of Embodiment E107, or a pharmaceutically acceptable salt thereof, wherein R 4 is -CH 2 OH.
  • E110 A compound of any of Embodiments E100 to E104, or a pharmaceutically acceptable salt thereof, wherein R 4 is 5- or 6- membered heteroaryl, which heteroaryl comprises one, two or three heteroatoms independently selected from the group consisting of N, O and S, and which heteroaryl is optionally substituted with C1-C4 alkyl.
  • R 4 is 5- or 6- membered heteroaryl, which heteroaryl comprises one, two or three heteroatoms independently selected from the group consisting of N, O and S, and which heteroaryl is optionally substituted with C1-C4 alkyl.
  • E111 A compound of Embodiment E110, or a pharmaceutically acceptable salt thereof, wherein R 4 is pyrazolyl, which pyrazolyl is optionally substituted with -CH 3 .
  • E112 A compound of any of Embodiments E100 to E104, or a pharmaceutically acceptable salt thereof, wherein R 4 is 5- to 6- membered heterocycloalkyl, which heterocycloalkyl comprises one heteroatom selected from the group consisting of N and O.
  • E113 A compound of Embodiment E112, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of pyrrolidinyl and tetrahydrofuranyl.
  • E114 A compound of any of Embodiments E100 to E102, or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen and R 4 is hydrogen.
  • E115 A compound of any of Embodiments E100 to E102, or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen and R 4 is -CH2OH.
  • E116 A compound of any of Embodiments E100 to E102, or a pharmaceutically acceptable salt thereof, wherein R 3 is -CH 3 and R 4 is -CH 3 .
  • E117 A compound of any of Embodiments E100 to E102, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 , taken together with the carbon to which they are attached, form cyclopropyl.
  • E118 A compound of any of Embodiments E100 to E117, or a pharmaceutically acceptable salt thereof, wherein R 5 is phenyl, which phenyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo; hydroxy; -CN; C 1 -C 4 alkyl, which C 1 -C 4 is optionally substituted with one, two or three substituents independently selected from the group consisting of fluoro, hydroxy and -OCH 3 ; C 1 -C 4 alkoxy, which C 1 -C 4 alkoxy is optionally substituted with one, two or three fluoro; -CO2CH3; -S(C1-C4 alkyl), which -S(C1-C4 alkyl) is optionally substituted with one, two or three fluoro; -SO(C 1 -C 4 alkyl); and -SO 2 (C 1 -C 4 alkyl).
  • R 5 is phenyl, which phen
  • E119 A compound of Embodiment E118, or a pharmaceutically acceptable salt thereof, wherein R 5 is phenyl.
  • E120 A compound of Embodiment E118, or a pharmaceutically acceptable salt thereof, wherein R 5 is phenyl, which phenyl is substituted with one substituent selected from the group consisting of fluoro; chloro; bromo; -OH; -CN; -CH3; -CH2CH3; -CH(CH3)2; -CH2OH; -CH(CH 3 )OH; -C(CH 3 ) 2 OH; -CH 2 F; -CHF 2 ; -CF 3 ; -CH 2 OCH 3 ; -OCH 3 ; -OCHF 2 ; -OCF 3 ; - CO2CH3; -SCH3; -SCH2CH3; -SCHF2; -SOCH3; and -SO2(CH3).
  • Embodiment E118 A compound of Embodiment E118, or a pharmaceutically acceptable salt thereof, wherein R 5 is phenyl, which phenyl is substituted with two substituents independently selected from the group consisting of fluoro; chloro; bromo; -CH3; -CH2OH; -CH2F; - CH2OCH3; and -OCH3 to form, for example difluorophenyl, dichlorophenyl, chloro- fluorophenyl, bromo-chlorophenyl, bromo-fluorophenyl, fluoro-methylphenyl, fluoro- fluoromethylphenyl, bromo-hydroxymethylphenyl, chloro-hydroxymethylphenyl, fluoro- hydroxymethylphenyl, dimethoxyphenyl, chloro-methoxyphenyl, fluoro-methoxyphenyl, bromo-methoxyphenyl, bromo-methoxymethylphenyl, chlor
  • E124 A compound of any of Embodiments E100 to E117, or a pharmaceutically acceptable salt thereof, wherein R 5 is C1-C4 alkyl.
  • E125 A compound of Embodiment E124, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from the group consisting of -CHC(CH 3 ) 2 and -C(CH 3 ) 3 .
  • E126 A compound of any of Embodiments E100 to E117, or a pharmaceutically acceptable salt thereof, wherein R 5 is C3-C10 cycloalkyl, which C3-C10 cycloalkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of fluoro, hydroxy, -CH3 and -CF3.
  • Embodiment E126 A compound of Embodiment E126, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from the group consisting of cyclopropyl; cyclobutyl; cyclopentyl; bicyclo[1.1.1]pentyl; cyclohexyl, which cyclohexyl is optionally substituted by one substituent selected from the group consisting of hydroxy and -CH3; bicyclo[2.2.1]heptanyl; and adamantanyl.
  • R 5 is selected from the group consisting of cyclopropyl; cyclobutyl; cyclopentyl; bicyclo[1.1.1]pentyl; cyclohexyl, which cyclohexyl is optionally substituted by one substituent selected from the group consisting of hydroxy and -CH3; bicyclo[2.2.1]heptanyl; and adamantanyl.
  • E129 A compound of Embodiment E128, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from the group consisting of oxetanyl; azetidinyl, which azetidinyl is optionally substituted with -CH3; tetrahydrofuranyl; and tetrahydropyranyl.
  • E130 A compound of any of E100 to E117, or a pharmaceutically acceptable salt thereof, wherein R 5 is –C(R 15 )2-phenyl, which phenyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo; hydroxy; -CN; C1-C4 alkyl, which C1-C4 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of fluoro, hydroxy and -OCH3; C1-C4 alkoxy, which C1-C4 alkoxy is optionally substituted with one, two or three fluoro; -CO 2 CH 3 ; -S(C 1 -C 4 alkyl), which -S(C 1 -C 4 alkyl) is optionally substituted with one, two or three fluoro; -SO(C1-C4 alkyl); and -SO2(C1-C4 alkyl).
  • E131 A compound of Embodiment E130, or a pharmaceutically acceptable salt thereof, wherein R 5 is –C(R 15 ) 2 -phenyl, which phenyl is optionally substituted with one substituent selected from the group consisting of fluoro, chloro -OCH3, and -SCH3; and wherein R 15 is independently at each occurrence selected from the group consisting of hydrogen, hydroxy and -CH3 to form, for example, -CH2-phenyl, -CH(OH)-phenyl, -CH2- methoxyphenyl, -CH 2 -chlorophenyl, -CH 2 -fluorophenyl, -CH 2 -(SCH 3 )phenyl, or -C(CH 3 ) 2 - phenyl.
  • E133 A compound of Embodiment E132, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from the group consisting of –C(R 15 )2-imidazolyl, which imidazolyl is optionally substituted with -CH 3 ; –C(R 15 ) 2 -pyrazolyl, which pyrazolyl is optionally substituted with one or two -CH3; –C(R 15 )2-1,2,3-triazolyl, which triazolyl is optionally substituted with -CH 3 ; –C(R 15 ) 2 -oxazolyl; –C(R 15 ) 2 -isoxazolyl; –C(R 15 ) 2 -pyrimidinyl; and – C(R 15 )2- pyridinyl; and wherein R 15 is independently at each occurrence hydrogen to form, for example, –CH 2 -pyrimidinyl, –CH 2 -pyridinyl, -CH 2 -
  • E134 A compound of any of E100 to E113, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 , taken together with the carbon to which they are attached, form cyclopropyl, which cyclopropyl is optionally substituted with phenyl.
  • E135 A compound of any of Embodiments E100 to E134, or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen.
  • E136 A compound of any of Embodiments E100 to E134, or a pharmaceutically acceptable salt thereof, wherein R 6 is C 1 -C 4 alkyl.
  • E136 A compound of Embodiment E135, or a pharmaceutically acceptable salt thereof, wherein R 6 is -CH3.
  • E137 A compound of any of Embodiments E100 to E136, or a pharmaceutically acceptable salt thereof, wherein R 7 is C 1 -C 4 alkyl.
  • E138 A compound of Embodiment E137, or a pharmaceutically acceptable salt thereof, wherein R 7 is -CH 3 .
  • E200 A compound of Formula (III), or a pharmaceutically acceptable salt thereof, as defined above.
  • E201 A compound of Embodiment E200, or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen.
  • Embodiment E200 A compound of Embodiment E200, or a pharmaceutically acceptable salt thereof, wherein R 4 is C1-C4 alkyl, which C1-C4 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of fluoro, hydroxy, -NH2, and -OCH3.
  • E203 A compound of Embodiment E202, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of -CH3; -CH2CH3; -CH2OH; - CH(OH)CH 3 ; -C(CH 3 ) 2 OH; -CH 2 CH 2 OH; -CH 2 NH 2 ; -CH 2 OCH 3 ; -CH 2 CHF 2 ; and -CF 3 .
  • E204 A compound of Embodiment E203, or a pharmaceutically acceptable salt thereof, wherein R 4 is -CH3.
  • E205 A compound of Embodiment a pharmaceutically acceptable salt thereof, wherein R 4 is -CH2OH.
  • E206 A compound of Embodiment E200, or a pharmaceutically acceptable salt thereof, wherein R 4 is 5- or 6- membered heteroaryl, which heteroaryl comprises one, two or three heteroatoms independently selected from the group consisting of N, O and S, and which heteroaryl is optionally substituted with C 1 -C 4 alkyl.
  • E207 A compound of Embodiment E206, or a pharmaceutically acceptable salt thereof, wherein R 4 is pyrazolyl, which pyrazolyl is optionally substituted with -CH3.
  • E208 A compound of Embodiment E200, or a pharmaceutically acceptable salt thereof, wherein R 4 is 5- to 6- membered heterocycloalkyl, which heterocycloalkyl comprises one heteroatom selected from the group consisting of N and O.
  • E209 A compound of Embodiment E200, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of pyrrolidinyl and tetrahydrofuranyl.
  • E210 A compound of any of Embodiments E200 to E209, or a pharmaceutically acceptable salt thereof, wherein R 5 is phenyl, which phenyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo; hydroxy; -CN; C 1 -C 4 alkyl, which C 1 -C 4 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of fluoro, hydroxy and -OCH 3 ; C 1 -C 4 alkoxy, which C 1 -C 4 alkoxy is optionally substituted with one, two or three fluoro; -CO2CH3; -S(C1-C4 alkyl), which -S(C1-C4 alkyl) is optionally substituted with one, two or three fluoro; -SO(C 1 -C 4 alkyl); and -SO 2 (C 1 -C 4 alkyl).
  • R 5 is phenyl
  • E211 A compound of Embodiment E210, or a pharmaceutically acceptable salt thereof, wherein R 5 is phenyl.
  • E212 A compound of Embodiment E210, or a pharmaceutically acceptable salt thereof, wherein R 5 is phenyl, which phenyl is substituted with one substituent selected from the group consisting of fluoro; chloro; bromo; -OH; -CN; -CH3; -CH2CH3; -CH(CH3)2; -CH2OH; -CH(CH 3 )OH; -C(CH 3 ) 2 OH; -CH 2 F; -CHF 2 ; -CF 3 ; -CH 2 OCH 3 ; -OCH 3 ; -OCHF 2 ; -OCF 3 ; - CO2CH3; -SCH3; -SCH2CH3; -SCHF2; -SOCH3; and -SO2(CH3).
  • E213 A compound of Embodiment a pharmaceutically acceptable salt thereof, wherein R 5 is phenyl, which phenyl is substituted with two substituents independently selected from the group consisting of fluoro; chloro; bromo; -CH 3 ; -CH 2 OH; -CH 2 F; - CH2OCH3; and -OCH3 to form, for example difluorophenyl, dichlorophenyl, chloro- fluorophenyl, bromo-chlorophenyl, bromo-fluorophenyl, fluoro-methylphenyl, fluoro- fluoromethylphenyl, bromo-hydroxymethylphenyl, chloro-hydroxymethylphenyl, fluoro- hydroxymethylphenyl, dimethoxyphenyl, chloro-methoxyphenyl, fluoro-methoxyphenyl, bromo-methoxyphenyl, bromo-methoxymethylphenyl, chloro-methoxy
  • E216 A compound of any of Embodiments E200 to E209, or a pharmaceutically acceptable salt thereof, wherein R 5 is C1-C4 alkyl.
  • E217 A compound of Embodiment E216, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from the group consisting of -CHC(CH 3 ) 2 and -C(CH 3 ) 3 .
  • E218 A compound of any of E200 to E209, or a pharmaceutically acceptable salt thereof, wherein R 5 is C3-C10 cycloalkyl, which C3-C10 cycloalkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of fluoro, hydroxy, -CH3 and -CF3.
  • Embodiment E2108 A compound of Embodiment E218, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from the group consisting of cyclopropyl; cyclobutyl; cyclopentyl; bicyclo[1.1.1]pentyl; cyclohexyl, which cyclohexyl is optionally substituted by one substituent selected from the group consisting of hydroxy and -CH 3 ; bicyclo[2.2.1]heptanyl; and adamantanyl.
  • R 5 is selected from the group consisting of cyclopropyl; cyclobutyl; cyclopentyl; bicyclo[1.1.1]pentyl; cyclohexyl, which cyclohexyl is optionally substituted by one substituent selected from the group consisting of hydroxy and -CH 3 ; bicyclo[2.2.1]heptanyl; and adamantanyl.
  • E221 A compound of Embodiment E220, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from the group consisting of oxetanyl; azetidinyl, which azetidinyl is optionally substituted with -CH3; tetrahydrofuranyl; and tetrahydropyranyl.
  • E300 A compound of Formula (IV), or a pharmaceutically acceptable salt thereof, as defined above.
  • E301 A compound of Embodiment E300, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of -CH3; -CH2CH3; -CH2OH; - CH(OH)CH 3 ; -C(CH 3 ) 2 OH; -CH 2 CH 2 OH; -CH 2 NH 2 ; -CH 2 OCH 3 ; -CH 2 CHF 2 ; and -CF 3 .
  • E302 A compound of Embodiment E301, or a pharmaceutically acceptable salt thereof, wherein R 4 is -CH3.
  • E303 A compound of Embodiment E301, or a pharmaceutically acceptable salt thereof, wherein R 4 is -CH2OH.
  • E304 A compound of any of E300 to E303, or a pharmaceutically acceptable salt thereof, wherein R 5 is phenyl, which phenyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo; hydroxy; -CN; C1-C4 alkyl, which C1-C4 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of fluoro, hydroxy and -OCH3; C1-C4 alkoxy, which C1-C4 alkoxy is optionally substituted with one, two or three fluoro; -CO 2 CH 3 ; -S(C 1 -C 4 alkyl), which -S(C 1 -C 4 alkyl) is optionally substituted with one, two or three fluoro; -SO(C1-C4 alkyl); and -SO2(C1-C4 alkyl).
  • R 5 is phenyl, which phenyl is optionally
  • E305 A compound of Embodiment E304, or a pharmaceutically acceptable salt thereof, wherein R 5 is phenyl.
  • E306 A compound of Embodiment E304, or a pharmaceutically acceptable salt thereof, wherein R 5 is phenyl, which phenyl is substituted with one substituent selected from the group consisting of fluoro; chloro; bromo; -OH; -CN; -CH 3 ; -CH 2 CH 3 ; -CH(CH 3 ) 2 ; -CH 2 OH; -CH(CH3)OH; -C(CH3)2OH; -CH2F; -CHF2; -CF3; -CH2OCH3; -OCH3; -OCHF2; -OCF3; - CO 2 CH 3 ; -SCH 3 ; -SCH 2 CH 3 ; -SCHF 2 ; -SOCH 3 ; and -SO 2 (CH 3 ).
  • Embodiment E304 A compound of Embodiment E304, or a pharmaceutically acceptable salt thereof, wherein R 5 is phenyl, which phenyl is substituted with two substituents independently selected from the group consisting of fluoro; chloro; bromo; -CH3; -CH2OH; -CH2F; - CH 2 OCH 3 ; and -OCH 3 to form, for example difluorophenyl, dichlorophenyl, chloro- fluorophenyl, bromo-chlorophenyl, bromo-fluorophenyl, fluoro-methylphenyl, fluoro- fluoromethylphenyl, bromo-hydroxymethylphenyl, chloro-hydroxymethylphenyl, fluoro- hydroxymethylphenyl, dimethoxyphenyl, chloro-methoxyphenyl, fluoro-methoxyphenyl, bromo-methoxyphenyl, bromo-methoxymethylphenyl,
  • E310 A compound of any of Embodiments E300 to E303, or a pharmaceutically acceptable salt thereof, wherein R 5 is C3-C10 cycloalkyl, which C3-C10 cycloalkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of fluoro, hydroxy, -CH3 and -CF3.
  • Embodiment E310 A compound of Embodiment E310, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from the group consisting of cyclopropyl; cyclobutyl; cyclopentyl; bicyclo[1.1.1]pentyl; cyclohexyl, which cyclohexyl is optionally substituted by one substituent selected from the group consisting of hydroxy and -CH 3 ; bicyclo[2.2.1]heptanyl; and adamantanyl.
  • R 5 is selected from the group consisting of cyclopropyl; cyclobutyl; cyclopentyl; bicyclo[1.1.1]pentyl; cyclohexyl, which cyclohexyl is optionally substituted by one substituent selected from the group consisting of hydroxy and -CH 3 ; bicyclo[2.2.1]heptanyl; and adamantanyl.
  • E313 A compound of Embodiment E312, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from the group consisting of oxetanyl; azetidinyl, which azetidinyl is optionally substituted with -CH3; tetrahydrofuranyl; and tetrahydropyranyl.
  • E400 A compound selected from the consisting of: (S)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-4-(5-methyl-2-((1-methyl-1H-pyrazol-5- yl)amino)pyrimidin-4-yl)oxazole-2-carboxamide; N-(3,5-difluorobenzyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)oxazole-2- carboxamide; (S)-N-(1-(3-chloro-5-fluorophenyl)-2-hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)oxazole-2-carboxamide; (S)-N-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(
  • any of the compounds described in embodiment E400, or pharmaceutically acceptable salts thereof may be claimed individually or grouped together with one or more other compounds of embodiments E1 to E53, E100 to E138, E200 to E221, E300 to E313 and E400, or pharmaceutically acceptable salts thereof.
  • E410 A compound selected from the group consisting of: (S)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-4-(5-methyl-2-((1-methyl-1H-pyrazol-5- yl)amino)pyrimidin-4-yl)oxazole-2-carboxamide; (R)-N-(1-(3-(difluoromethyl)phenyl)ethyl)-4-(5-methyl-2-((1-methyl-1H-pyrazol-5- yl)amino)pyrimidin-4-yl)oxazole-2-carboxamide; (S)-N-(1-(3-chloro-5-fluorophenyl)-2-hydroxyethyl)-4-(5-methyl-2-((1-methyl-1H-pyrazol- 5-yl)amino)pyrimidin-4-yl)oxazole-2-carboxamide; (S)-N-(2-hydroxy-1-(m-
  • E420 A pharmaceutical composition comprising a compound of any one of Embodiments E1 to E53, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • E421 A pharmaceutical composition a compound of any one of Embodiments E100 to E138, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • E422 A pharmaceutical composition comprising a compound of any one of Embodiments E200 to E221, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • E423 A pharmaceutical composition comprising a compound of any one of Embodiments E300 to E313, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • E424 A pharmaceutical composition comprising a compound of Embodiment E400, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • E425 A pharmaceutical composition comprising a compound of Embodiment E410, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • E430 A compound of any one of Embodiments E1 to E53, or a pharmaceutically acceptable salt thereof, for use as a medicament.
  • E431 A compound of any one of Embodiments E100 to E138, or a pharmaceutically salt thereof, for use as a medicament.
  • E432 A compound of any one of Embodiments E200 to E221, or a pharmaceutically acceptable salt thereof, for use as a medicament.
  • E433 A compound of any one of Embodiments E300 to E313, or a pharmaceutically acceptable salt thereof, for use as a medicament.
  • E434 A compound of Embodiment E400, or a pharmaceutically acceptable salt thereof, for use as a medicament.
  • E435 A compound of Embodiment E410, or a pharmaceutically acceptable salt thereof, for use as a medicament.
  • E440 A method of treating abnormal in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of Embodiments E1 to E53, or a pharmaceutically acceptable salt thereof.
  • E441 A method of treating abnormal cell growth in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of Embodiments E100 to E138, or a pharmaceutically acceptable salt thereof.
  • E442 A method of treating abnormal cell growth in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of Embodiments E200 to E221, or a pharmaceutically acceptable salt thereof.
  • E443 A method of treating abnormal cell growth in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of Embodiments E300 to E313, or a pharmaceutically acceptable salt thereof.
  • E444 A method of treating abnormal cell growth in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Embodiment E400, or a pharmaceutically acceptable salt thereof.
  • E445 A method of treating abnormal cell growth in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Embodiment E410, or a pharmaceutically acceptable salt thereof.
  • E446 The method of any one of Embodiments E440 to E445, wherein the abnormal cell growth is cancer.
  • Embodiment E446 The method of Embodiment E446, wherein the cancer is selected from the group consisting of melanoma, colon cancer, colorectal cancer, lung cancer (e.g., small cell lung carcinoma or non-small cell lung carcinoma), thyroid cancer (e.g., papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, or refractory differentiated thyroid cancer), breast cancer, ovarian cancer, cancer of the CNS, bone cancer, cancer of the anus, anal canal, or anorectum, cancer of the eye, bile duct cancer, ductal carcinoma in situ, gallbladder, or pleura, oral cancer, oral cavity cancer, lip cancer, oropharyngeal cancer, cancer of the nose, nasal cavity or middle ear, cancer of the vulva, esophageal cancer, cervical cancer, gastrointestinal carcinoid tumor, hypopharynx cancer, kidney cancer, larynx cancer, liver cancer, lung cancer, melanoma, n
  • E448 The method of Embodiment E447, wherein the cancer is selected from the group consisting of melanoma, colorectal cancer, thyroid cancer, lung cancer, ovarian cancer, and peripheral nervous system cancers.
  • E449 The method of Embodiment E448, wherein the cancer is melanoma.
  • E450 The method of Embodiment E448, wherein the cancer is colorectal cancer.
  • E451 The method of Embodiment E448, wherein the cancer is lung cancer, which lung cancer is non-small cell lung cancer.
  • E452 The method of any one of Embodiments E446 to E451, wherein the cancer is metastatic cancer.
  • E453 The method of any one of Embodiments E440 to E452, wherein the abnormal cell growth is an ERK-mediated cancer.
  • E454 The method of any one of Embodiments E446 to E453, wherein the abnormal cell growth has a BRAF mutation.
  • E455 The method of Embodiment E454, wherein the BRAF mutation is an activating BRAF-mutation.
  • E456 The method of any one of Embodiments E454 to E455, wherein the BRAF mutation is a BRAF V600 mutation selected from the group consisting of V600E, V600K, V600D, V600R and V600S.
  • E457 The method of Embodiment E456, wherein the BRAF mutation is V600E mutation.
  • E458 The method of any one of E440 to E453, wherein the abnormal cell growth has a BRAF fusion.
  • E459 The method of Embodiment E458, wherein the BRAF fusion is selected from the group consisting of KIAA11549-BRAF, MKRN1-BRAF, TRIM24-BRAF, AGAP3-BRAF, ZC3HAV1-BRAF, AKAP9-BRAF, CCDC6-BRAF, AGK-BRAF, EPS15-BRAF, NUP214- BRAF, ARMC10-BRAF, BTF3L4-BRAF, GHR-BRAF, ZC3HAV1-BRAF, ZNF767-BRAF, CCDC91-BRAF, DYNC112-BRAF, ZKSCAN1-BRAF, GTF2I-BRAF, MZT1-BRAF, RAD18-BRAF, CUX1-BRAF, SLC12A7-BRAF, MYRIP-BRAF, SND1-BRAF, NU
  • E460 The method of any one of Embodiments E440 to E459, wherein the subject is a human.
  • E461 The method of any one of Embodiments E440 to E460, which comprises administering an additional therapeutic agent.
  • E462 The method of Embodiment E461, wherein the additional therapeutic agent is selected from the group consisting of a BRAF inhibitor, a RAS inhibitor, an EGFR inhibitor, a SHP2 inhibitor, a PI3K inhibitor, a TAM kinase inhibitor including a MER/AXL inhibitor, an inhibitor of HER2 and/or HER3, a SOS1 inhibitor, a signal transduction pathway inhibitor, a checkpoint inhibitor, a modulator of the apoptosis pathway, a cytotoxic chemotherapeutic, an angiogenesis-targeted therapy, and an immune-targeted agent including immunotherapy.
  • the additional therapeutic agent is selected from the group consisting of a BRAF inhibitor, a RAS inhibitor, an EGFR inhibitor,
  • E463 The method of Embodiment E462, wherein the additional therapeutic agent is a BRAF inhibitor.
  • E464 The method of Embodiment E462, wherein the additional therapeutic agent is a RAS inhibitor.
  • E465 The method of Embodiment E462, wherein the additional therapeutic agent is a SHP2 inhibitor.
  • E470 A compound of any one of E1 to E53, or a pharmaceutically acceptable salt thereof, for use in the treatment of abnormal cell growth in a subject.
  • E471 A compound of any one of Embodiments E100 to E138, or a pharmaceutically acceptable salt thereof, for use in the treatment of abnormal cell growth in a subject.
  • E472 A compound of any one of Embodiments E200 to E221, or a pharmaceutically acceptable salt thereof, for use in the treatment of abnormal cell growth in a subject.
  • E473 A compound of any one of Embodiments E300 to E313, or a pharmaceutically acceptable salt thereof, for use in the treatment of abnormal cell growth in a subject.
  • E474 A compound of Embodiment E400, or a pharmaceutically acceptable salt thereof, for use in the treatment of abnormal cell growth in a subject.
  • E475 A compound of Embodiment E410, or a pharmaceutically acceptable salt thereof, for use in the treatment of abnormal cell growth in a subject.
  • E480 Use of a compound any one of Embodiments E1 to E53, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of abnormal cell growth in a subject.
  • E481 Use of a compound of any one of Embodiments E100 to 140, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of abnormal cell growth in a subject.
  • E482 Use of a compound of any one of Embodiments E200 to E221, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of abnormal cell growth in a subject.
  • E483 Use of a compound of any one of Embodiments E300 to E313, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of abnormal cell growth in a subject.
  • E484 Use of a compound of Embodiment E400, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of abnormal cell growth in a subject.
  • E485 Use of a compound of or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of abnormal cell growth in a subject.
  • E490 A method for the treatment of a disorder mediated by ERK activation in a subject, comprising administering to the subject in need thereof, a compound of any one of Embodiments E1 to E53, or a pharmaceutically acceptable salt thereof, in an amount that is effective for treating the disorder.
  • E491 A method for the treatment of a disorder mediated by ERK activation in a subject, comprising administering to the subject in need thereof, a compound of any one of Embodiments E100 to E138, or a pharmaceutically acceptable salt thereof, in an amount that is effective for treating the disorder.
  • E492 A method for the treatment of a disorder mediated by ERK activation in a subject, comprising administering to the subject in need thereof, a compound of any one of Embodiments E200 to E221, or a pharmaceutically acceptable salt thereof, in an amount that is effective for treating the disorder.
  • E493 A method for the treatment of a disorder mediated by ERK activation in a subject, comprising administering to the subject in need thereof, a compound of any one of Embodiments E300 to E313, or a pharmaceutically acceptable salt thereof, in an amount that is effective for treating the disorder.
  • E494 A method for the treatment of a disorder mediated by ERK activation in a subject, comprising administering to the subject in need thereof, a compound of Embodiment E400, or a pharmaceutically acceptable salt thereof, in an amount that is effective for treating the disorder.
  • E495 A method for the treatment of a disorder mediated by ERK activation in a subject, comprising administering to the subject in need thereof, a compound of Embodiment E410, or a pharmaceutically acceptable salt thereof, in an amount that is effective for treating the disorder.
  • E500 A pharmaceutical combination comprising a compound of any one of Embodiments E1 to E53, or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent, or a pharmaceutically acceptable salt thereof.
  • E501 A pharmaceutical combination a compound of any one of Embodiments E100 to E138, or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent, or a pharmaceutically acceptable salt thereof.
  • E502 A pharmaceutical combination comprising a compound of any one of Embodiments E200 to E221, or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent, or a pharmaceutically acceptable salt thereof.
  • E503 A pharmaceutical combination comprising a compound of any one of Embodiments E300 to E313, or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent, or a pharmaceutically acceptable salt thereof.
  • E504 A pharmaceutical combination comprising a compound of Embodiment E400, or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent, or a pharmaceutically acceptable salt thereof.
  • E505 A pharmaceutical combination comprising a compound of Embodiment E410, or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent, or a pharmaceutically acceptable salt thereof.
  • E506 A pharmaceutical combination of any one of Embodiments E500 to E505, wherein the at least one additional therapeutic agent is selected from the group consisting of a BRAF inhibitor, a RAS inhibitor, an EGFR inhibitor, a SHP2 inhibitor, a PI3K inhibitor, a TAM kinase inhibitor including a MER/AXL inhibitor, an inhibitor of HER2 and/or HER3, a SOS1 inhibitor, a signal transduction pathway inhibitor, a checkpoint inhibitor, a modulator of the apoptosis pathway, a cytotoxic chemotherapeutic, an angiogenesis- targeted therapy, and an immune-targeted agent including immunotherapy.
  • the at least one additional therapeutic agent is selected from the group consisting of a BRAF inhibitor, a RAS inhibitor, an EGFR inhibitor, a SHP2 inhibitor, a PI3K inhibitor, a TAM kinase inhibitor including a MER/AXL inhibitor, an inhibitor of HER2 and/or HER3, a
  • E507 A pharmaceutical combination of Embodiment E506, wherein the at least one additional therapeutic agent is a BRAF inhibitor.
  • E508 A pharmaceutical combination of Embodiment E506, wherein the at least one additional therapeutic agent is a RAS inhibitor.
  • E509 A pharmaceutical combination of Embodiment E506, wherein the at least one additional therapeutic agent is a SHP2 inhibitor.
  • Each of the embodiments herein may be combined with any other embodiment(s) described herein not inconsistent with the embodiment(s) with which it is combined.
  • any of the compounds described in the Examples, or pharmaceutically acceptable salts thereof may be claimed individually or grouped together with one or more other compounds of the Examples, or pharmaceutically acceptable salts thereof, for any of the embodiment(s) described herein.
  • the dose of 5 mg means that the parameter may vary by as much as 10% below or above the stated for that parameter.
  • a dose of about 5 mg means 5 mg ⁇ 10%, i.e., it may vary between 4.5 mg and 5.5 mg.
  • substituents are described as being “independently selected’ from a group, each substituent is selected independently from the other. Each substituent therefore may be identical to, or different from the other substituent(s).
  • “Optional” or “optionally” means that the subsequently described event or circumstance may, but need not, occur, and the description includes instances where the event or circumstance occurs and instances in which it does not.
  • Alkyl refers to a saturated, monovalent, aliphatic hydrocarbon radical that has the specified number of carbon atoms, including straight chain and branched chain groups. Alkyl groups may contain, but not limited to, for example, 1 to 12 carbon atoms (“C1-C12 alkyl”), 1 to 8 carbon atoms (“C1-C8 alkyl”), 1 to 6 carbon atoms (“C1-C6 alkyl”), 1 to 5 carbon atoms (“C 1 -C 5 alkyl”), 1 to 4 carbon atoms (“C 1 -C 4 alkyl”), 1 to 3 carbon atoms (“C1-C3 alkyl”), or 1 to 2 carbon atoms (“C1-C2 alkyl”).
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • Alkyl may be substituted, unsubstituted, or substituted as further defined herein.
  • Alkoxy refers to an alkyl group as defined herein, that has the specified number of carbon atoms, including straight chain and branched chain groups, and is single bonded to an oxygen atom.
  • Alkoxy groups may contain, but are not limited to, for example, 1 to 8 carbon atoms (“C 1 -C 8 alkoxy”), 1 to 6 carbon atoms (“C1-C6 alkoxy”), 1 to 4 carbon atoms (“C1-C4 alkoxy”), or 1 to 3 carbon atoms (“C 1 -C 3 alkoxy”).
  • Alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isobutoxy, and the like.
  • Cycloalkyl refers to a fully saturated hydrocarbon ring system that has the specified number of carbon atoms, which may be a monocyclic, bridged or fused bicyclic or polycyclic ring system that is connected to the base molecule through a carbon atom of the cycloalkyl ring.
  • the term "cycloalkyl” also includes spirocyclic cycloalkyl groups, including multi-ring systems, joined by a single atom.
  • Cycloalkyl groups may contain, but art not limited to, for example, 3 to 12 carbon atoms (“C 3 -C 12 cycloalkyl”), 3 to 10 carbon atoms (“C3-C10 cycloalkyl”), 3 to 8 carbon atoms (“C3-C8 cycloalkyl”), 3 to 7 carbon atoms (“C 3 -C 7 cycloalkyl”), 3 to 6 carbon atoms (“C 3 -C 6 cycloalkyl”), or 3 to 4 carbon atoms (“C 3 - C4 cycloalkyl”).
  • Cycloalkyl groups may be optionally substituted, unsubstituted, or substituted, as further defined herein.
  • heterocycloalkyl refers to a fully saturated ring system containing the specific number of ring atoms as defined herein and containing at least one heteroatom as defined herein, for example a heteroatom selected from N, O and S as ring member, where ring S atoms are optionally substituted by one or two oxo groups (i.e., S(O)q, where q is 0, 1 or 2) as defined herein, and where the heterocycloalkyl ring is connected to the base molecule via a ring atom, which may be C or N.
  • Heterocycloalkyl rings include rings which are spirocyclic, bridged, or fused or more other heterocycloalkyl or cycloalkyl rings, where such spirocyclic, bridged or fused rings may themselves be saturated, partially saturated, unsaturated, or aromatic to the extent unsaturation or aromaticity makes chemical sense, provided the point of attachment to the base molecule is an atom of the heterocycloalkyl portion of the ring system.
  • Heterocycloalkyl rings may be optionally substituted, unsubstituted or substituted, as further defined herein on either a carbon atom or a ring nitrogen to the extent the substitution makes chemical sense.
  • Heterocycloalkyl rings may include, but are not limited to, for example, 3- to 8- membered heterocycloalkyl groups with 3 to 8 ring atoms, 4- to 7- membered heterocycloalkyl groups with 4 to 7 ring atoms, 5- to 6- membered heterocycloalkyl groups with 5 to 6 ring atoms, or 4- to 6- membered heterocycloalkyl groups with 4 to 6 ring atoms, in accordance with the definition herein.
  • heterocycloalkyl rings include, but are not limited to, a monovalent radical of: “Aryl” or polycyclic ring systems all carbon atoms in the ring are of sp 2 hybridization and in which the pi electrons are in conjugation.
  • Aryl groups contain 6 to 20 carbon atoms (“C6-C20 aryl”), 6 to 14 carbon atoms (“C6-C14 aryl”), 6 to 12 carbon atoms (“C 6 -C 12 aryl”), or 6 to 10 carbon atoms (“C 6 -C 10 aryl”).
  • Fused aryl groups may include an aryl ring (e.g., a phenyl ring) fused to another aryl ring.
  • Phenyl refers to the group -C6H5, and may be optionally substituted, unsubstituted or substituted as further defined herein.
  • the aryl group may be optionally substituted, unsubstituted or substituted as further defined herein.
  • heteroaryl refers to monocyclic, bicyclic (e.g., heterobiaryl, fused) or polycyclic ring systems that contain the specified number of ring atoms as defined herein and include at least one heteroatom as defined herein, for example at least one heteroatom selected from N, O and S, as a ring member, and contain at least one ring in which all the carbon atoms in the ring are of sp 2 hybridization and in which the pi electrons are in conjugation.
  • Heteroaryl groups may contain, but are not limited to, for example, 5 to 20 ring atoms (“5- to 20- membered heteroaryl”), 5 to 14 ring atoms (“5- to 14- membered heteroaryl”), 5 to 12 ring atoms (“5- to 12- membered heteroaryl”), 5 to 10 ring atoms (“5- to 10- membered heteroaryl”), or 5 to 6 ring atoms (“5- to 6- membered heteroaryl”).
  • Heteroaryl rings are attached to the base molecule via a ring atom of the aromatic ring.
  • heteroaryl radicals include, but art not to, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridizinyl, pyrimidinyl, pyrazinyl, benzofuranyl, benzothiophenyl, indolyl, benzamidazolyl, indazolyl, quinolinyl, isoquinolinyl, purinyl, triazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, qui
  • Examples of 5- or 6- membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl rings.
  • Heteroaryl groups include those where an aryl ring, which may optionally contain a heteroatom, is fused to a heterocyclic ring, which heterocyclic ring may optionally be a non-aromatic ring and which heterocyclic ring comprises a heteroatom, provided the point of attachment to the base molecule is an atom of the aryl portion of the ring system.
  • heteroaryl groups include, but are not limited to, benzo[d][1,3] dioxolyl, dihydrobenzofuranyl, oxoindolinyl and the like.
  • Heteroaryl groups may be optionally substituted, unsubstituted or substituted, as further defined herein.
  • Illustrative examples of monocyclic heteroaryl groups include, but are not limited to, a monovalent radical of:
  • fused ring heteroaryl groups include, but are not limited to, a monovalent radical of: “Amino” refers to the group -NH 2 , which is unsubstituted. Where the amino is described as substituted or optionally substituted, the term includes groups of the from - NRxRy, where each of Rx and Ry is defined as further described herein.
  • alkylamino refers to a group -NRxRy, wherein one of Rx and Ry is an alkyl moiety and the other is H
  • dialkylamino refers to -NRxRy, wherein both of Rx and Ry are alkyl moieties, where the alkyl moieties have the specified number of carbon atoms (e.g., - NH(C 1 -C 4 alkyl) or -N(C 1 -C 4 alkyl) 2 ).
  • pharmaceutically acceptable means the substance (e.g., the compounds described herein) and any salt thereof, or composition containing the substance or salt of the invention is suitable for administration to a subject or patient.
  • Salts encompassed within the term “pharmaceutically acceptable salts” refer to the compounds of this invention which are generally prepared by reacting the free base or free acid with a suitable organic or inorganic acid, or suitable organic or inorganic base, respectively, to provide a salt of the compound of the invention that is suitable for administration to a subject or patient.
  • the compounds of the invention may also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, which may be useful as intermediates for one or more of the following: 1) preparing compounds of Formula (I), Formula (II), Formula (III) or Formula (IV); 2) purifying compounds of Formula (I), Formula (II), Formula (III) or Formula (IV); 3) separating enantiomers of compounds of Formula (I), Formula (II), Formula (III) or Formula (IV); or 4) separating diastereomers of compounds of Formula (I), Formula (II), Formula (III) or Formula (IV).
  • Suitable acid addition salts are formed from acids which form non-toxic salts.
  • Examples include, but are not limited to, acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2- nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate,
  • Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts.
  • suitable salts see Paulekun, G. S. et al., Trends in Active Pharmaceutical Ingredient Salt Selection Based on Analysis of the Orange Book Database, J. Med. Chem.2007; 50(26), 6665-6672.
  • compositions of the invention may be prepared by methods well known to one skilled in the art, including, but not limited to, the following procedures: (i) by reacting a compound of the invention with the desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of a compound of the invention or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or (iii) by converting one salt of a compound of the invention to another. This may be accomplished by reaction with an appropriate acid or base or by means of a suitable ion exchange procedure. These procedures are typically carried out in solution.
  • the resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.
  • Solvates The compounds of the invention, and pharmaceutically acceptable salts thereof, may exist in both unsolvated and solvated forms.
  • solvate is used herein to describe a molecular complex comprising the compound of the invention, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable solvent molecules, for example ethanol.
  • hydrate is employed when said solvent is water.
  • the compounds of may also include other solvates of such compounds which are not necessarily pharmaceutically acceptable solvates, which may be useful as intermediates for one or more of the following: 1) preparing compounds of Formula (I), Formula (II), Formula (III) or Formula (IV); 2) purifying compounds of Formula (I), Formula (II), Formula (III) or Formula (IV); 3) separating enantiomers of compounds of Formula (I), Formula (II), Formula (III) or Formula (IV); or 4) separating diastereomers of compounds of Formula (I), Formula (II), Formula (III) or Formula (IV).
  • a currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K.
  • Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules.
  • channel hydrates the water molecules lie in lattice channels where they are next to other water molecules.
  • metal-ion coordinated hydrates the water molecules are bonded to the metal ion.
  • the complex When the solvent or water is tightly bound, the complex may have a well-defined stoichiometry independent of humidity.
  • the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content may be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.
  • Complexes Also included within the scope of the invention are multi-component complexes (other than salts and solvates) wherein the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts.
  • Complexes of this type include clathrates (drug-host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions, for example, hydrogen bonded complex (cocrystal) may be formed with either a neutral molecule or with a salt.
  • Co-crystals may be prepared by melt crystallization, by recrystallization from solvents, or by physically grinding the components together - see Chem Commun, 17;1889-1896, by O. Almarsson and M. J. Zaworotko (2004). For a general review of multi-component complexes, see J Pharm Sci, 64(8), 1269-1288, by Haleblian (August 1975).
  • Solid Form The compounds of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline.
  • the term “amorphous” refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid.
  • Such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid.
  • a change from solid to liquid properties occurs which is characterized by a change of state, typically second order (“glass transition”).
  • glass transition typically second order
  • crystalline refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks.
  • Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically first order (“melting point”).
  • the compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions.
  • the mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution) and consists of two-dimensional order on the molecular level.
  • Mesomorphism arising as the result of a change in temperature is described as ‘thermotropic’ and that resulting from the addition of a second component, such as water or another solvent, is described as “lyotropic”.
  • Compounds that have the potential to form lyotropic mesophases are described as “amphiphilic” and consist of molecules which possess an ionic (such as -COO-Na + , -COO-K + , or -SO 3 -Na + ) or non-ionic (such as -N- N + (CH3)3) polar head group.
  • Stereoisomers Compounds of the invention may exist as two or more stereoisomers. Stereoisomers may include cis and trans (geometric isomers), optical isomers such as R and S enantiomers, diastereomers, rotational isomers, atropisomers, and conformational isomers. For example, compounds of the invention containing one or more asymmetric carbon atom may exist as two or Where a compound of the invention contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible.
  • Cis/trans isomers may also exist for saturated rings.
  • the pharmaceutically acceptable salts of compounds of the invention may also contain a counterion which is optically active (e.g., d-lactate or l-lysine) or racemic (e.g. dl-tartrate or dl-arginine).
  • Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
  • HPLC high pressure liquid chromatography
  • the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where a compound of the invention contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid.
  • a suitable optically active compound for example, an alcohol, or, in the case where a compound of the invention contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid.
  • the resulting diastereomeric mixture may be separated by chromatography, fractional crystallization, or by using both of said techniques, and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
  • Chiral compounds of the invention may be obtained in enantiomerically-enriched form using chromatography, typically HPLC Concentration of the eluate affords the enriched mixture. Chiral chromatography using sub-and supercritical fluids may be employed. Methods for chiral chromatography useful in some embodiments of the present invention are known in the art (see, for example, Smith, Roger M., Loughborough University, Loughborough, UK; Chromatographic Science Series (1998), 75 (Supercritical Fluid Chromatography with Packed Columns), pp.223-249 and references cited therein). When any racemate crystallizes, crystals of two different types are possible.
  • the first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts.
  • the second type is the racemic mixture or conglomerate wherein two crystal forms are produced in equimolar amounts each comprising a single enantiomer. While both of the crystal forms present in a mixture have identical physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, Stereochemistry of Organic Compounds by E. L. Eliel and S. H. Wilen (Wiley, 1994).
  • tautomeric isomerism may occur. This may take the form of proton tautomerism in compounds of the invention containing, for example, an imino/amino, keto/enol, or oxime/nitroso group, lactam/lactim or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism. It must be emphasized that while, for conciseness, the compounds of the invention have been drawn herein in a single tautomeric form, all possible tautomeric forms are included within the scope of the invention.
  • Isotopes The present invention includes all pharmaceutically acceptable isotopically- labeled compounds of the invention wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
  • isotopes suitable for inclusion in the compounds of the invention may include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 Cl, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, and sulfur, such as 35 S.
  • Certain isotopically-labelled compounds of the invention are useful in one or both of drug or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e., 3 H, and carbon-14, i.e., 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N may be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • isotopic labeled compounds in accordance with the present invention include: (i) when a compound of the invention, or a pharmaceutically acceptable salt thereof, comprises an N-methylpyrazolyl substituent, such substituent may be isotopically labelled to form, for example, -CH 2 D-pyrazolyl, -CHD 2 - pyrazolyl or -CD3-pyrazolyl; or (ii) when a compound of the invention, or a pharmaceutically acceptable salt thereof, comprises a methylpyrimidinyl moiety, such a moiety may be isotopically labelled to form, for example, CH 2 D-pyrimidinyl, CHD 2 - pyrimidinyl or CD3-pyrimidinyl.
  • Isotopically-labeled compounds of the invention may generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g., D2O, d 6 -acetone, d 6 -DMSO.
  • Prodrugs A compound of the invention may be administered in the form of a prodrug.
  • prodrugs certain derivatives of a compound of the invention which may have little or no pharmacological activity themselves may, when administered into or onto the body, be converted into a compound of the invention having the desired activity, for example by hydrolytic cleavage, particularly hydrolytic cleavage promoted by an esterase or peptidase enzyme.
  • Such derivatives are referred to as “prodrugs”. Further information on the use of prodrugs may be in ‘The Expanding Role of Prodrugs in Contemporary Drug Design and Development, Nature Reviews Drug Discovery, 17, 559- 587 (2016) (J. Rautio et al.).
  • Prodrugs in accordance with the invention may, for example, be produced by replacing appropriate functionalities present in compounds of the invention with certain moieties known to those skilled in the art as “pro-moieties” as described, for example, in ‘Design of Prodrugs’ by H. Bundgaard (Elsevier, 1985).
  • a prodrug in accordance with the invention may be (a) an ester or amide derivative of a carboxylic acid when present in a compound of the invention; (b) an ester, carbonate, carbamate, phosphate or ether derivative of a hydroxyl group when present in a compound of the invention; (c) an amide, imine, carbamate or amine derivative of an amino group when present in a compound of the invention; (d) a thioester, thiocarbonate, thiocarbamate or sulfide derivatives of a thiol group when present in a compound of the invention; or (e) an oxime or imine derivative of a carbonyl group when present in a compound of the invention.
  • Certain compounds of the invention may themselves act as prodrugs of other compounds the invention It is also possible for two compounds of the invention to be joined together in the form of a prodrug. In certain circumstances, a prodrug of a compound of the invention may be created by internally linking two functional groups in a compound of the invention, for instance by forming a lactone. Metabolites Also included within the scope of the invention are active metabolites of compounds of the invention, that is, compounds formed in vivo upon administration of the drug, often by oxidation or dealkylation.
  • Some examples of metabolites in accordance with the invention include, but are not limited to, (i) where the compound of the invention contains an alkyl group, a hydroxyalkyl derivative thereof (-CH -> -COH); (ii) where the compound of the invention contains an alkoxy group, a hydroxy derivative thereof (-OR -> -OH); (iii) where the compound of the invention contains a tertiary amino group, a secondary amino derivative thereof (-NRR ’ -> -NHR or –NHR ’ ); (iv) where the compound of the invention contains a secondary amino group, a primary derivative thereof (-NHR -> -NH2); (v) where the compound of contains a phenyl moiety, a phenol derivative thereof (-Ph -> -PhOH); (vi) where the compound of the invention contains an amide group, a carboxylic acid derivative thereof (-CONH 2 -> COOH); and (vii) where the compound contains a hydroxy or carboxylic acid
  • compositions In another embodiment, the invention comprises pharmaceutical compositions.
  • the compound per se or pharmaceutically acceptable salt thereof will simply be referred to as the compounds of the invention.
  • a "pharmaceutical composition” refers to a mixture of one or more of the compounds of the invention, or pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof as an active ingredient, and at least one pharmaceutically acceptable excipient.
  • excipient is used herein to describe any ingredient other than the compound(s) of the invention.
  • excipient includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, carrier, diluents and the like that are physiologically compatible.
  • excipients include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof, and may include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol, or sorbitol in the composition.
  • excipients include various organic solvents (such as hydrates and solvates).
  • the pharmaceutical compositions may, if desired, contain additional excipients such as flavorings, binders/binding agents, lubricating agents, disintegrants, sweetening or flavoring agents, coloring matters or dyes, and the like.
  • tablets containing various excipients such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes.
  • Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules.
  • excipients therefore, also include lactose or milk sugar and high molecular weight polyethylene glycols.
  • the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with additional excipients such as water, ethanol, propylene glycol, glycerin, or combinations thereof.
  • excipients also include pharmaceutically acceptable substances such as wetting agents or minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives, or buffers, which enhance the shelf life or effectiveness of the compound.
  • compositions of this invention may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, capsules, pills, powders, liposomes and suppositories.
  • liquid solutions e.g., injectable and infusible solutions
  • dispersions or suspensions tablets, capsules, pills, powders, liposomes and suppositories.
  • Typical compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans with antibodies in general.
  • One mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular).
  • the compound is administered by intravenous infusion or injection.
  • the compound is administered by intramuscular or subcutaneous injection.
  • Oral administration of a solid dosage form may be, for example, presented in discrete units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the invention.
  • the oral administration may be in a powder or granule form.
  • the oral dosage form is sub-lingual, such as, for example, a lozenge.
  • the compounds of the invention are ordinarily combined with one or more adjuvants.
  • Such capsules or tablets may comprise a controlled release formulation.
  • the dosage forms also may comprise buffering agents or may be prepared with enteric coatings.
  • oral administration may be in a liquid dosage form.
  • Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water). Such compositions also may comprise adjuvants, such as one or more of wetting, emulsifying, suspending, flavoring (e.g., sweetening), or perfuming agents.
  • the invention comprises a parenteral dosage form.
  • Parenteral administration includes, for example, subcutaneous injections, intravenous injections, intraperitoneally, intramuscular injections, intrasternal injections, and infusion.
  • Injectable preparations may be formulated according to the known art using one or more of suitable dispersing, wetting agents, or suspending agents.
  • the invention comprises a topical dosage form.
  • Topical administration includes, for example, dermal and transdermal administration, such as via transdermal patches or iontophoresis devices, intraocular administration, or intranasal or inhalation administration.
  • Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams.
  • a topical formulation may include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used.
  • Typical excipients include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, B. C. Finnin and T. M. Morgan, J. Pharm.
  • Formulations suitable for topical administration to the eye include, for example, eye drops wherein the compound of this invention is dissolved or suspended in a suitable excipient.
  • a typical formulation suitable for ocular or aural administration may be in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline.
  • Other formulations suitable for ocular and aural administration include ointments, biodegradable (i.e., absorbable gel sponges, collagen) and non-biodegradable (i.e., silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
  • a preservative such as benzalkonium chloride.
  • Such formulations may also be delivered by iontophoresis.
  • the compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant.
  • Formulations suitable for intranasal administration are typically administered in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1,1,1,2- tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane.
  • a suitable propellant such as 1,1,1,2- tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane.
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • a rectal dosage form may be in the form of, for example, a suppository. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
  • Other excipients and modes of administration known in the pharmaceutical art may also be used.
  • Pharmaceutical compositions of the invention may be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures. The above considerations in regard to effective formulations and administration procedures are well known in the art and are described in standard textbooks.
  • Acceptable excipients are nontoxic to subjects at the dosages and concentrations employed, and may comprise one or more of the following: 1) buffers such as phosphate, citrate, or other organic acids; 2) salts such as sodium chloride; 3) antioxidants such as ascorbic acid or methionine; 4) preservatives such as octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol; 5) alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, or m-cresol; 6) low molecular weight (less than about 10 residues) polypeptides; 7) proteins such as serum albumin, gelatin, or immunoglobulins; 8) hydrophilic polymers such as polyvinylpyrrolidone;
  • compositions may be provided in the form of tablets or capsules containing, for example, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250 or 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient.
  • a medicament typically contains from about 0.01 mg to about 500 mg of ingredient, or in another embodiment, from about 1 mg to about 100 mg of active ingredient.
  • doses may range from about 0.01 to about 10 mg/kg/minute during a constant rate infusion.
  • Liposome containing compounds of the invention may be prepared by methods known in the art (See, for example, Chang, H.I.; Yeh, M.K.; Clinical development of liposome-based drugs: formulation, characterization, and therapeutic efficacy; Int J Nanomedicine 2012; 7; 49-60).
  • Particularly useful liposomes may be generated by the reverse phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol and PEG-derivatized phosphatidylethanolamine (PEG- PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter.
  • microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
  • sustained-release preparations include semi-permeable matrices of solid hydrophobic polymers containing a compound of the invention, which matrices are in the form of shaped articles, e.g., films, or microcapsules.
  • sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or 'poly(vinylalcohol)), polylactides, copolymers of L-glutamic acid and 7 ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as those used in leuprolide acetate for depot suspension (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyric acid.
  • the formulations to be used for intravenous administration must be sterile. This is readily accomplished by, for example, filtration through sterile filtration membranes.
  • Compounds of the invention are generally placed into a container having a sterile access port, for example, an intravenous or vial having a stopper pierceable by a hypodermic injection needle.
  • Suitable emulsions may be prepared using commercially available fat emulsions, such as a lipid emulsion comprising soybean oil, a fat emulsion for intravenous administration (e.g., comprising safflower oil, soybean oil, egg phosphatides and glycerin in water), emulsions containing soya bean oil and medium-chain triglycerides, and lipid emulsions of cottonseed oil.
  • a lipid emulsion comprising soybean oil
  • a fat emulsion for intravenous administration e.g., comprising safflower oil, soybean oil, egg phosphatides and glycerin in water
  • emulsions containing soya bean oil and medium-chain triglycerides emulsions containing soya bean oil and medium-chain triglycerides
  • lipid emulsions of cottonseed oil such as a lipid emulsion comprising soybean oil, a fat
  • the active ingredient may be either dissolved in a pre-mixed emulsion composition or alternatively it may be dissolved in an oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phospholipid (e.g., egg phospholipids, soybean phospholipids or soybean lecithin) and water.
  • an oil e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil
  • a phospholipid e.g., egg phospholipids, soybean phospholipids or soybean lecithin
  • Suitable emulsions will typically contain up to 20% oil, for example, between 5 and 20%.
  • the fat emulsion may comprise fat droplets between 0.1 and 1.0 ⁇ m, particularly 0.1 and 0.5 ⁇ m, and have a pH in the range of 5.5 to 8.0.
  • the emulsion compositions may be those prepared by mixing a compound of the invention with a lipid emulsion comprising soybean oil or the components thereof (soybean oil, egg phospholipids, glycerol and water).
  • Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • compositions in preferably sterile pharmaceutically acceptable solvents may be nebulized by use of gases. Nebulized solutions may be breathed directly from the nebulizing device, or the nebulizing device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
  • a drug product intermediate (DPI) is a partly processed material that must undergo further processing steps before it becomes bulk drug product.
  • Compounds of the invention may be formulated into drug intermediate DPI containing the active ingredient in a higher free energy form than the crystalline form.
  • the drug product intermediate contains a compound of the invention isolated and stabilized in the amorphous state (for example, amorphous solid dispersions (ASDs)).
  • ASDs amorphous solid dispersions
  • ASD Advanced Driver Assistance Systems
  • SDD spray dried dispersions
  • HME melt extrudates
  • co-precipitates amorphous drug nanoparticles
  • nano-adsorbates amorphous solid dispersions
  • amorphous solid dispersions comprise a compound of the invention ⁇ and a polymer excipient.
  • Other excipients, as well as concentrations of said excipients and the compound of the invention, are well known in the art and are described in standard textbooks.
  • the compounds and compositions of the present invention may be administered as a component of an antibody-drug conjugate or other targeted delivery modality.
  • the pharmaceutical composition may be in unit dosage forms suitable for single administration of precise amounts.
  • Administration and Dosing The invention further provides therapeutic methods and uses comprising a compound of the invention, including those of Formulae (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, alone or in combination with one or more therapeutic agents or palliative agents.
  • treating embrace both preventative, i.e, prophylactic, and palliative treatment, i.e., relieve, alleviate, or slow the progression of the patient’s disease (or condition) or any tissue damage associated with the disease. With regard particularly these terms may mean that the life expectancy of an individual affected with a cancer will be increased or that one or more of the symptoms of the disease will be reduced.
  • Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable.
  • treating also includes adjuvant and neo-adjuvant treatment of a subject. “Ameliorating” means a lessening or improvement of one or more symptoms upon treatment with a combination described herein, as compared to not administering the combination.
  • “Ameliorating” also includes shortening or reduction in duration of a symptom.
  • the terms “subject”, “individual” or “patient”, used interchangeably, refer to any animal, including mammals. Mammals according to the invention include canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, humans, and the like, and encompass mammals in utero. In an embodiment, humans are suitable subjects. Human subjects may be of any gender and at any stage of development.
  • the phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which may include one or more of the following: (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease; (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting (or slowing) further development of the pathology or symptomatology or both); and (3) ameliorating the disease; for ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology or symptomatology or both
  • a compound of the invention is administered in a therapeutically effective amount, for example an amount effective to treat a condition as described herein.
  • the compounds of the invention may be administered as compound per se, or alternatively, as a pharmaceutically acceptable salt.
  • the compound per se or pharmaceutically acceptable salt thereof will simply be referred to as the compounds of the invention.
  • the compounds of the invention are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
  • the compounds of the invention may be administered orally, rectally, vaginally, parenterally, topically, intranasally, or by inhalation.
  • the compounds of the invention may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the bloodstream directly from the mouth.
  • the compounds of the invention may also be administered parenterally, for example directly into the bloodstream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors, and infusion techniques.
  • the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • the compounds of the invention may also be administered intranasally or by inhalation.
  • the compounds of the invention may be administered rectally or vaginally.
  • the compounds of the invention may also be administered directly to the eye or ear.
  • the dosage regimen for the of the invention or compositions containing said compounds is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus, the dosage regimen may vary widely.
  • the total daily dose of a compound of the invention is typically from about 0.01 to about 100 mg/kg (i.e., mg compound of the invention per kg body weight) for the treatment of the indicated conditions discussed herein.
  • total daily dose of the compound of the invention is from about 0.1 to about 50 mg/kg, and in another embodiment, from about 0.5 to about 30 mg/kg. It is not uncommon that the administration of the compounds of the invention will be repeated a plurality of times in a day (typically no greater than 4 times). The dose may be administered in a single dose, or multiple doses. Multiple doses per day typically may be used to increase the total dose, if desired.
  • dosage frequency may vary as well, for example once per day (QD), more than once per day, for example twice per day (BD), or on other dosing schedules including, but not limited to, every other day, every third day, weekly, every other week, or monthly.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated, each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the compounds of the invention may act as ERK inhibitors, and may be useful in the treatment, prevention, suppression and amelioration of diseases and disorders which can be treated with an ERK inhibitor, such as ERK-mediated diseases and disorders, e.g., for the treatment of abnormal cell growth, such as tumors, for example ERK- mediated tumors.
  • an ERK inhibitor such as ERK-mediated diseases and disorders
  • abnormal cell growth such as tumors, for example ERK- mediated tumors.
  • abnormal cell growth and “hyperproliferative disorders” are used interchangeably.
  • cancer refers to malignant and / or invasive growth or tumor caused by abnormal cell growth.
  • cancer refers to solid tumors named for the type of cells that form them initially, cancer of blood, bone marrow or the lymphatic systems. Examples of solid tumors include, but are not limited to, sarcomas, carcinomas and lymphomas. Examples of cancers of the blood includes, but are not limited to, leukemias, lymphomas and myelomas.
  • cancer includes, but is not to limited to, a primary cancer that originates at a specific site in the body, a metastatic cancer that has spread from the place in which it started to other parts of the body, a recurrence from the original primary cancer after remission, and a second primary cancer that is a new primary cancer in a person with a history of previous cancer of different type from latter one.
  • the compounds of the invention may be useful in the prevention and treatment of a variety of human hyperproliferative disorders, such a malignant or benign abnormal cell growth.
  • selective when used herein to describe a functionally-defined receptor ligand or enzyme inhibitor means selective for the defined receptor or enzyme as compared with other receptor or enzymes.
  • a selective ERK inhibitor is a compound that inhibits ERK more potently than another kinase including, for example, CDK2/cyclin A and / or Aurora A.
  • selectivity is, in one embodiment, at least 10 fold more selective with respect to ERK inhibition than that of another kinase, such as CDK2/cyclin A and / or Aurora A (as measured by conventional binding assays).
  • the compounds of the invention including those of formulae (I), (II), (III), and (IV), or pharmaceutically acceptable salts thereof, are ERK inhibitors.
  • the invention provides a compound of the invention, including those of formulae (I), (II), (III), and (IV), or a pharmaceutically acceptable salt thereof, for use as a medicament.
  • a method of treating abnormal cell growth in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • a method of treating abnormal cell growth in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a of Formula (II), or a pharmaceutically acceptable salt thereof.
  • ERK inhibitor refers to a compound that inhibits the mitogen-activated protein kinase enzymes ERK1 and/or ERK2.
  • ERK-associated and “ERK-mediated” are used interchangeably and refer to a disease or disorder having constitutive activation of an ERK kinase which can be treated with an ERK inhibitor. Examples include ERK-mediated abnormal cell growth such as ERK-mediated tumors, e.g., ERK-mediated cancers.
  • ERK-associated and / or “ERK-mediated” refers to a disease or disorder having a dysregulation of the expression or activity of a RAS protein, MEK kinase, and / or a BRAF kinase.
  • the abnormal cell growth is a tumor.
  • the tumor is a solid tumor.
  • the solid tumor is an ERK-mediated solid tumor.
  • the tumor e.g., an ERK-mediated tumor
  • the tumor is a malignant tumor (i.e., cancer) (e.g., an ERK-mediated cancer).
  • the abnormal cell growth is cancer, which cancer (e.g.
  • an ERK-mediated cancer is selected from the group consisting of melanoma, colon cancer, colorectal cancer, lung cancer (e.g., small cell lung carcinoma or non-small cell lung carcinoma), thyroid cancer (e.g., papillary thyroid cancer, medullary thyroid cancer, thyroid cancer, recurrent thyroid cancer, or refractory differentiated thyroid cancer), breast cancer, ovarian cancer, cancer of the CNS, bone cancer, cancer of the anus, anal canal, or anorectum, cancer of the eye, bile duct cancer, ductal carcinoma in situ, liver cancer, gallbladder, or pleura, oral cancer, oral cavity cancer, lip cancer, oropharyngeal cancer, cancer of the nose, nasal cavity or middle ear, cancer of the vulva, esophageal cancer, cervical cancer, gastrointestinal carcinoid tumor, hypopharynx cancer, kidney cancer, larynx cancer, liver cancer, lung cancer, melanoma, nasopharynx cancer, peripheral nervous system cancers
  • the cancer is selected from the group consisting of melanoma, colorectal cancer, thyroid cancer, lung cancer, ovarian cancer, and peripheral nervous system cancers.
  • the cancer is melanoma.
  • the cancer is colorectal cancer.
  • the cancer is lung cancer, which lung cancer is non-small cell lung cancer.
  • the cancer is peripheral nervous system cancer, which peripheral nervous system cancer is neuroblastoma.
  • the cancer is a metastatic cancer.
  • the term “metastasis” is an art known term that refers to the spread of cancer cells from the place where they first formed (the primary site) to one or more other sites in a subject (one or more secondary sites).
  • metastatic cancer In metastasis, cancer cells break away from the original (primary) tumor, travel through the blood or lymph system, and form a new tumor (a metastatic tumor) in other organs or tissues of the body.
  • the new, metastatic tumor includes the same or similar cancer cells as the primary tumor.
  • the tumor cell may proliferate and begin the growth or colonization of a secondary tumor at this distant site.
  • the term “metastatic cancer” also known as “secondary cancer” as used herein refers to a type of cancer that originates in one tissue type, but then spreads to one or more tissues outside of the (primary) cancer’s origin.
  • Metastatic brain cancer refers to cancer in the brain, i.e., cancer which originated in a tissue other than the brain and has metastasized to the brain.
  • the tumor including an ERK-mediated tumor
  • the abnormal cell growth including a tumor, a solid tumor, an ERK-mediated tumor, a malignant tumor, an ERK-mediated malignant tumor, a cancer or an ERK-mediated cancer
  • has a BRAF mutation preferably an activating BRAF mutation.
  • BRAF mutations include BRAF V600 mutations, e.g., V600E, V600D, V600K, V600R and V600S.
  • the BRAF mutation is selected from the group consisting of V600E, V600K, V600D, V600R and V600S.
  • the BRAF mutation is V600E. In one embodiment, the BRAF mutation is V600K. In one embodiment, the abnormal cell growth, including a tumor, a solid tumor, an ERK-mediated tumor, a malignant tumor, an ERK-mediated malignant tumor, a cancer or an ERK-mediated cancer, has a BRAF fusion, e.g., a BRAF fusion disclosed herein.
  • abnormal cell growth including a tumor, a solid tumor, an ERK- mediated tumor, a malignant tumor, an ERK-mediated malignant tumor, a cancer or an ERK-mediated cancer, has one or more BRAF fusions that lead to constitutive kinase activation and transformation, including, but not limited to, a BRAF fusion selected from KIAA11549-BRAF, MKRN1-BRAF, TRIM24-BRAF, AGAP3-BRAF, ZC3HAV1-BRAF, AKAP9-BRAF, CCDC6-BRAF, AGK-BRAF, EPS15-BRAF, NUP214-BRAF, ARMC10- BRAF, BTF3L4-BRAF, GHR-BRAF, ZC3HAV1-BRAF, ZNF767-BRAF, CCDC91-BRAF, DYNC112-BRAF, ZKSCAN1-BRAF, GTF2I-BRAF, MZT1-BRAF, RAD18-BRA
  • the presence of a BRAF mutation or a BRAF fusion may be readily determined by a person skilled in the art, for through the use of a regulatory agency- approved (e.g., FDA-approved) test or assay for identifying BRAF mutation or fusion in a subject or a biopsy sample, including, but not limited to, a tumor biopsy, or a liquid biopsy, from the subject or by performing any of the non-limiting examples of assays described herein.
  • the test or assay is provided as a kit.
  • the biological sample to be used in a liquid biopsy can include CSF, blood, plasma, urine, saliva, sputum, broncho-alveolar lavage, bile, lymphatic fluid, cyst fluid, stool, ascites, and combinations thereof.
  • a liquid biopsy can be used to detect circulating tumor cells (CTCs).
  • CTCs circulating tumor cells
  • the assay may utilize next generation sequencing, pyrosequencing, immunohistochemistry, fluorescence microscopy, break apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, or PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR).
  • the assay is a regulatory agency-approved assay, e.g., FDA-approved kit.
  • the assay may also detect cell-free DNA in a liquid biopsy, for example circulating tumor DNA (ctDNA) that is derived from tumor cells.
  • ctDNA circulating tumor DNA
  • the abnormal cell growth including an ERK-mediated abnormal cell growth, is an abnormal cell growth having a BRAF-fusion protein, wherein the abnormal cell growth is selected from the group consisting of breast carcinoma (e.g., breast invasive ductal carcinoma) colorectal carcinoma (e.g., colon adenocarcinoma), esophageal carcinoma (e.g., esophagus adenocarcinoma), glioma (e.g., brain desmoplastic infantile ganglioglioma, brain pilocytic astrocytoma, brain pleomorphic xanthoastrocytoma, spinal cord low-grade glioma (NOS), anaplastic oligodendroglioma
  • breast carcinoma e.g., breast invasive ductal carcinoma
  • colorectal carcinoma e.g., colon adenocarcinoma
  • esophageal carcinoma e.g., esophagus adeno
  • the cancer including the ERK-mediated cancer, is selected from the cancers having the BRAF-fusion proteins described in Table 1 (J.S. Ross, et al., 2016, Int. J. Cancer: 138, pp881-890). Table 1.
  • Exemplary BRAF Fusion Partners and Cancers Tumor group histology tumor type fusion breast carcinoma BCAP29-BRAF breast carcinoma breast carcinoma breast carcinoma metastatic KIAA11549- BRAF colorectal colon adenocarcinoma primary MKRN1-BRAF carcinoma colorectal colon adenocarcinoma metastatic TRIM24-BRAF carcinoma colorectal colon adenocarcinoma primary AGAP3-BRAF carcinoma esophageal esophagus primary ZC3HAV1-BRAF carcinoma adenocarcinoma glioma brain desmoplastic primary KIAA11549- infantile ganglioglioma BRAF glioma brain pilocytic astrocytoma primary KIAA11549- BRAF glioma brain pleomorphic primary KIAA11549- xanthoastrocytoma BRAF glioma spinal cord low-grade primary KIAA11549- glioma (NOS) BRAF gli
  • wild-type describes a nucleic acid (e.g., a BRAF gene or a BRAF mRNA) that is typically found in a subject that does not have a disease or disorder related to the reference nucleic acid or protein.
  • wild-type BRAF describes a BRAF nucleic acid (e.g., a BRAF gene or a BRAF mRNA) or a BRAF protein that is found in a subject that does not have an activating BRAF-mutation.
  • Another embodiment relates to a method of treating neurofibromatosis in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • Another embodiment relates to a method of treating neurofibromatosis in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof.
  • Another embodiment relates to a method of treating neurofibromatosis in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt thereof.
  • Another embodiment relates to a method of treating neurofibromatosis in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (IV), or a pharmaceutically acceptable salt thereof.
  • the neurofibromatosis is neurofibromatosis type 1.
  • the neurofibromatosis is symptomatic, inoperable, plexiform neurofibromas.
  • Another embodiment relates to a method of treating pain in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • Another embodiment relates to a of treating pain in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof.
  • Another embodiment relates to a method of treating pain in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt thereof.
  • Another embodiment relates to a method of treating pain in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (IV), or a pharmaceutically acceptable salt thereof.
  • the pain is neuropathic pain.
  • Another embodiment relates to a method of treating inflammation in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • Another embodiment relates to a method of treating inflammation in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof.
  • Another embodiment relates to a method of treating inflammation in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt thereof.
  • Another embodiment relates to a method of treating inflammation in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (IV), or a pharmaceutically acceptable salt thereof.
  • These methods of the invention described herein may optionally employ a compound or salt as described herein as a component of an antibody-drug conjugate, or as a component of a particle-based delivery system.
  • Also embodied in the invention is a compound of the invention, including those of formulae (I), (II), (III), and (IV), or a pharmaceutically acceptable salt thereof, for use in the treatment of abnormal cell growth in a subject. Also embodied in the invention is of a compound of the invention, including those of formulae (I), (II), (III), and (IV), or a pharmaceutically acceptable salt thereof, for the preparation of a medicament useful in the treatment of abnormal cell growth in a subject. Co-administration A compound of the present invention, including those of formulae (I), (II), (III), and (IV), or a pharmaceutically acceptable salt thereof, may be used alone or in combination with one or more different forms of treatment.
  • the invention provides any of the uses, methods or compositions as defined herein, wherein the compound of the invention, or a pharmaceutically acceptable salt thereof, is used in combination with one or more different forms of treatment.
  • the administration of two or more compounds “in combination” means that all of the compounds are administered closely enough in time to affect treatment of the subject.
  • the two or more compounds may be administered simultaneously or sequentially, via the same or different routes of administration, on same or different administration schedules and with or without specific time limits depending on the treatment regimen. Additionally, simultaneous administration may be carried out by mixing the compounds prior to administration or by administering the compounds at the same point in time but as separate dosage forms at the same or different site of administration.
  • “in combination” examples include, but are not limited to, “concurrent administration,” “co- administration,” “simultaneous administration,” “sequential administration” and “administered simultaneously”.
  • a compound of the invention and the one or more other therapeutic agents may be administered as a fixed or non-fixed combination of the active ingredients.
  • the term "fixed combination” means a compound of the invention, or a pharmaceutically acceptable salt thereof, and the one or more therapeutic agents, are both administered to a subject simultaneously in a single composition or dosage.
  • non-fixed combination means that a compound of the invention, or a pharmaceutically acceptable salt thereof, and the one or more therapeutic agents are formulated as separate compositions or dosages such that they may be administered to a subject in need thereof simultaneously or at different times intervening time limits, wherein such administration provides effective levels of the two or more compounds in the body of the subject.
  • the compounds of the invention are administered in combination with the one or more additional anticancer therapies, for example one or more therapies independently selected from surgery, radiotherapy and additional therapeutic agents that work by the same or by a different mechanism of action.
  • the compounds of the invention are administered in combination with radiotherapy.
  • the compounds of the invention are administered in combination with surgery.
  • the compounds of the invention are administered in combination with one or more additional therapeutic agents.
  • the compounds of the invention are administered in combination with one or more additional therapeutic agents selected from the group consisting of a BRAF inhibitor, a RAS inhibitor, a EGFR inhibitor, a SHP2 inhibitor, a PI3K inhibitor, a TAM kinase inhibitor including a MER/AXL inhibitor, an inhibitor of HER2 and/or HER3, a SOS1 inhibitor, a signal transduction pathway inhibitor, a checkpoint inhibitor, a modulator of the apoptosis pathway, cytotoxic chemotherapeutics, an angiogenesis-targeted therapy, and an immune-targeted agent including immunotherapy.
  • the compounds of the invention are administered in combination with a targeted therapeutic agent.
  • a “targeted therapeutic agent” as used herein includes, refers to a molecule that blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells (e.g., with traditional cytotoxic chemotherapy), and includes but is not limited to, receptor tyrosine kinase-targeted therapeutic agents, signal transduction pathway inhibitors (for example, Ras-Raf-MEK- ERK pathway inhibitors, PI3K-Akt-mTOR-S6K pathway inhibitors (“PI3K inhibitors”)), and modulators of the apoptosis pathway.
  • PI3K inhibitors PI3K inhibitors
  • the of the invention are administered in combination with a BRAF inhibitor.
  • BRAF inhibitors include encorafenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3- ylcarbonyl)-2,4-difluorophenyl]propane-1-sulfonamide (PLX4720), and (3R)-N-(3-[[5-(2- cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl)-3- fluoropyrrolidine-1-sulfonamide (PLX8394), and pharmaceutically acceptable salts thereof, the compounds disclosed in International Application No.
  • the BRAF inhibitor is encorafenib or a pharmaceutically acceptable salt thereof.
  • the BRAF inhibitor is N-(2-chloro-3-((3,5- dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoropropane-1- sulfonamide or a pharmaceutically acceptable salt thereof.
  • the BRAF inhibitor is N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6- yl)amino)-4-fluorophenyl)-3-fluoroazetidine-1-sulfonamide or a pharmaceutically acceptable salt thereof.
  • the compounds of the invention are administered in combination with a RAS inhibitor.
  • RAS inhibitors include, but are not limited to, adagrasib, or a pharmaceutically acceptable salt thereof and sotorasib, or a pharmaceutically acceptable salt thereof.
  • the compounds of the invention are administered in combination with an EGFR inhibitor.
  • Non-limiting examples of EGFR inhibitors include cetuximab (Erbitux®), panitumumab (Vectibix®), osimertinib (merelectinib, Tagrisso®), erlotinib (Tarceva®), gefitinib (Iressa®), necitumumab (Portrazza TM ), neratinib (Nerlynx®), lapatinib (Tykerb®), vandetanib (Caprelsa®), brigatinib (Alunbrig®) and inhibitors of EGFR disclosed in International Application No. PCT/CA2018/051282, published April 18, 2019 as PCT Publication No.
  • the compounds of the invention are administered in combination with a SHP2 inhibitor.
  • SHP2 inhibitors include 6- (4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine (SHP099), [3- [(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6-(2,3-dichlorophenyl)-5- methylpyrazin-2-yl]methanol (RMC-4550) RMC-4630, TNO155, and the compounds disclosed in International Application No.
  • PCT/US2019/056786 published April 23, 2020 as PCT Publication No. WO 2020/081848; International Application No. PCT/IB2020/053019, published October 08, 2020 as PCT Publication No. WO 2020/201991; International Application published July 23, 2015 as PCT Publication No. WO 2015/107493; International Application No. PCT/IB2015/050344, published July 23, 2015 as PCT Publication No. WO 2015/107494; International Application No. PCT/IB2015/050345, published July 23, 2015 as PCT Publication No. WO 2015/107495; and International Application No. PCT/US2018/055502, published April 18, 2019 as PCT Publication No. WO 2019/075265.
  • the SHP2 inhibitor is a compound disclosed in International Application No. PCT/IB2020/053019, published October 08, 2020 as PCT Publication No. WO 2020/201991.
  • the SHP2 inhibitor is (S)-1'-(6- ((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'- piperidin]-1-amine or a pharmaceutically acceptable salt thereof.
  • the compounds of the invention are administered in combination with a PI3K inhibitor.
  • Non-limiting examples include buparlisib (BKM120), alpelisib (BYL719), samotolisib (LY3023414), 8-[(1R)-1-[(3,5- difluorophenyl)amino]ethyl]-N,N-dimethyl-2-(morpholin-4-yl)-4-oxo-4H-chromene-6- carboxamide (AZD8186), tenalisib (RP6530), voxtalisib hydrochloride (SAR-245409), gedatolisib (PF-05212384), panulisib (P-7170), taselisib (GDC-0032), trans-2-amino-8- [4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3- d]pyrimidin-7(8H)-one (PF-0469
  • the compounds of the invention are administered in combination with immunotherapy.
  • immunotherapy refers to an agent that modulates the immune system.
  • an immunotherapy can increase the expression and/or activity of a regulator of the immune system.
  • an immunotherapy can decrease the and/or activity of a regulator of the immune system.
  • an immunotherapy can recruit and/or enhance the activity of an immune cell.
  • the immunotherapy is an antibody therapy (e.g., a monoclonal antibody, a conjugated antibody).
  • the antibody therapy is bevacizumab (MvastiTM, Avastin®), trastuzumab (Herceptin®), rituximab (MabTheraTM, Rituxan®), edrecolomab (Panorex), daratumuab (Darzalex®), olaratumab (LartruvoTM), ofatumumab (Arzerra®), alemtuzumab (Campath®), cetuximab (Erbitux®), oregovomab, pembrolizumab (Keytruda®), dinutiximab (Unituxin®), obinutuzumab (Gazyva®), tremelimumab (CP-675,206), ramucirumab (Cyramza®), ublituximab (TG- 1101), panitumumab (Vectibix®), elotuzumab (EmplicitiTM),
  • the immunotherapy is an immune checkpoint inhibitor.
  • the immunotherapy includes one or more, e.g., one or two immune checkpoint inhibitors.
  • the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor or a PD-L1 inhibitor.
  • the CTLA-4 inhibitor is ipilimumab (Yervoy®) or tremelimumab (CP-675,206).
  • the PD-1 inhibitor is pembrolizumab (Keytruda®), nivolumab (Opdivo®) and sasanlimab (RN888).
  • the PD-L1 inhibitor is atezolizumab (Tecentriq®), or durvalumab (ImfinziTM).
  • the present invention provides a pharmaceutical composition comprising a compound of the invention, including a compound of formulae (I), (II), (III), and (IV), or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is administered in combination with a pharmaceutical composition comprising an additional therapeutic agent selected from the group consisting of a BRAF inhibitor, a RAS inhibitor, an EGFR inhibitor, a SHP2 inhibitor, a PI3K inhibitor, a TAM kinase inhibitor including a MER/AXL inhibitor, an inhibitor of HER2 and/or HER3, a SOS1 inhibitor, a signal transduction pathway inhibitor, a checkpoint inhibitor, a modulator of the apoptosis pathway, a cytotoxic chemotherapeutic, an angiogenesis- targeted therapy, and an agent including immunotherapy, simultaneously or at different times.
  • an additional therapeutic agent selected from the group
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, including a compound of formulae (I), (II), (III), and (IV), or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is administered in combination with two further pharmaceutical compositions, each additional pharmaceutical composition comprising an additional therapeutic agent independently selected from the group consisting of a BRAF inhibitor, a RAS inhibitor, an EGFR inhibitor, a SHP2 inhibitor, a PI3K inhibitor, a TAM kinase inhibitor including a MER/AXL inhibitor, an inhibitor of HER2 and/or HER3, a SOS1 inhibitor, a signal transduction pathway inhibitor, a checkpoint inhibitor, a modulator of the apoptosis pathway, a cytotoxic chemotherapeutic, an angiogenesis-targeted therapy, and an immune-targeted agent including immunotherapy, simultaneously or at different times.
  • an additional pharmaceutical composition comprising an additional therapeutic agent independently selected from the group consisting of a BRAF inhibitor,
  • kits comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt thereof.
  • a kit may include, in addition to a compound of the invention, or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, diagnostic or therapeutic agents.
  • a kit may also include instructions for use in a diagnostic or therapeutic method.
  • the kit includes a compound of the invention, or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt thereof and a diagnostic agent.
  • the kit includes a compound of the invention, or a pharmaceutically acceptable salt thereof, or comprising a compound of the invention, or a pharmaceutically acceptable salt thereof and one or more further therapeutic agents, such as a BRAF inhibitor, a RAS inhibitor, an EGFR inhibitor, a SHP2 inhibitor, a PI3K inhibitor, a TAM kinase inhibitor including a MER/AXL inhibitor, an inhibitor of HER2 and/or HER3, a SOS1 inhibitor, a signal transduction pathway inhibitor, a checkpoint inhibitor, a modulator of the apoptosis pathway, a cytotoxic chemotherapeutic, an angiogenesis-targeted therapy, or an immune-targeted agents including immunotherapy.
  • a BRAF inhibitor such as a BRAF inhibitor, a RAS inhibitor, an EGFR
  • the kit of the invention may include two or more separate pharmaceutical compositions, at least one of which contains a compound of the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
  • the invention comprises kits that are suitable for use in performing the methods of treatment described herein.
  • the kit contains a first dosage form comprising one or more of the compounds of the invention in quantities sufficient to carry out the methods of the invention.
  • the kit comprises one or more compounds of the invention in quantities sufficient to carry out the methods of the invention and a container for the dosage.
  • Synthetic Methods Compounds of the present invention may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein.
  • the starting materials are generally available from commercial sources or may be prepared using methods well known to those skilled in the art.
  • Many of the compounds used herein, are related to, or may be derived from compounds in which one more of scientific interest and / or commercial need has occurred. Accordingly, such compounds may be one or more of 1) commercially available; 2) reported in the literature; or 3) prepared from other commonly available substances by one skilled in the art using materials which have been reported in the literature.
  • the schemes depicted below provide potential routes for synthesizing the compounds of the present invention as well as key intermediates.
  • Suitable protecting groups for amine and carboxylic acid protection include those protecting groups commonly used in peptide synthesis (such as N-t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and 9- (Fmoc) for amines and lower alkyl or benzyl esters for carboxylic acids which are generally not chemically reactive under the reaction conditions described and may typically be removed without chemically altering other functionality in a compound of the invention.
  • Boc N-t-butoxycarbonyl
  • Cbz benzyloxycarbonyl
  • 9- (Fmoc) 9- (Fmoc) for amines and lower alkyl or benzyl esters for carboxylic acids which are generally not chemically reactive under the reaction conditions described and may typically be removed without chemically altering other functionality in a compound of the invention.
  • Reagents were purchased from commercial suppliers such as MilliporeSigma, Alfa Aesar, TCI, etc., and were used without further purification unless otherwise indicated.
  • the reactions set forth below were conducted generally under a positive pressure of nitrogen or argon or with a drying tube (unless otherwise stated) in anhydrous solvents, and the reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried. Column chromatography was conducted on a Biotage system (Manufacturer: Dyax Corporation) having a silica gel column or on a silica SepPak cartridge (Waters) (unless otherwise stated).
  • 1H NMR spectra were recorded on a Varian instrument operating at 400 MHz. 1 H- NMR spectra were obtained as CDCl3, CD3OD, D2O, (CD3)2SO, (CD3)2CO, C6D6, CD3CN solutions (reported in ppm), using tetramethylsilane (0.00 ppm) or residual solvent (CDCl3: 7.26 ppm; CD3OD: 3.31 ppm; D2O: 4.79 ppm; (CD3)2SO: 2.50 ppm; (CD3)2CO: 2.05 ppm; C 6 D 6 : 7.16 ppm; CD 3 CN: 1.94 ppm) as the reference standard.
  • oxazole amide is reacted with a metal pyrimidine with the appropriate catalyst (such as P(Cy3)Pd G3) to afford the chloro pyrimidine oxazole.
  • a metal pyrimidine with the appropriate catalyst (such as P(Cy3)Pd G3) to afford the chloro pyrimidine oxazole.
  • This can be reacted with an amine using a catalyst/ligand (such as Binap Pd G3) to afford the final compound.
  • compounds in these synthetic pathways may contain protecting groups, which may be appended or removed by additional steps in the synthetic sequence using conditions known in the art (March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure 8th Edition or Protecting Groups, 10 Georg Thieme Verlag, 1994). Compounds at every step may be purified by standard techniques, such as column chromatography, crystallization, or reverse phase SFC or HPLC.
  • Example 1 (S)-N-(1-(3- ((1-methyl-1H-pyrazol-5- yl)amino)pyrimidin-4-yl)oxazole-2-carboxamide Step A: MCPBA (45.0 g, 2.2 Eq, 261 mmol) was added to a stirred solution of 4-Chloro- 5-methyl-2-methylsulfanylpyrimidine (20.7 g, 1 Eq, 119 mmol) in DCM (1000 mL) under nitrogen at room temperature for 4 hours.
  • Step B 1-Methyl-1H-pyrazol-5-amine (9.02 g, 1.6 Eq, 92.9 mmol) was dissolved in THF (290 mL), cooled to 0°C and treated dropwise with lithium bis(trimethylsilyl)amide (15.5 g, 92.9 mL, 1 molar, 1.6 Eq, 92.9 mmol). The reaction mixture was stirred for 15 minutes and then was slowly cannulated into a -78°C solution of 4-chloro-5-methyl-2-(methyl sulfonyl)pyrimidine (12.0 g, 1 Eq, 58.1 mmol) in THF (290 mL).
  • Step C Potassium carbonate (2.4 g, 3.0 Eq, 17 mmol), mesylate[(di(1-adamantyl)-n- butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.21 g, 0.05 Eq, 0.29 mmol), ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole-2-carboxylate (0.93 g, 0.6 Eq, 3.5 mmol) and 4-chloro-5-methyl-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (1.3 g, 1.0 Eq, 5.8 mmol) were diluted with 2-methyltetrahydrofuran (20 mL) and water (4 mL).
  • reaction was sparged with argon and heated to 80°C. After stirring for 1 hour, additional ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole-2-carboxylate (0.93 g, 0.6 Eq, 3.5 mmol) was added. After 2 hours, additional ethyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole-2-carboxylate (0.93 g, 0.6 Eq, 3.5 mmol) was added. After stirring for 3 hours, the reaction was cooled to room temperature and partitioned between water and EtOAc.
  • Step D Sodium hydroxide (0.34 g, 4.3 mL, 2 molar, 2 Eq, 8.5 mmol) in ethanol (5 mL) was added to a stirred solution of ethyl 4-(5-methyl-2-((1-methyl-1H-pyrazol-5- yl)amino)pyrimidin-4-yl)oxazole-2- (1.4 g, 1 Eq, 4.3 mmol) in THF (43 mL). The reaction was placed under nitrogen and stirred for 30 minutes at room temperature. Upon completion the solids were filtered off and the mother liquor pH was adjusted to about 3.5 using concentrated HCl. The solids were collected by vacuum filtration and rinsed with water.
  • Step E 4-(5-Methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)oxazole-2- carboxylic acid (200 mg, 1 Eq, 666 ⁇ mol) was added to a stirred solution of (S)-2-amino- 2-(3-chlorophenyl)ethan-1-ol (229 mg, 2 Eq, 1.33 mmol), N,N-Diisopropylethylamine (172 mg, 232 ⁇ L, 2 Eq, 1.33 mmol) and HATU (507 mg, 2 Eq, 1.33 mmol) in DMF (6.5 mL) and was stirred at room temperature for 1 hour.
  • the reaction was diluted with water and extracted twice with 20% IPA in DCM. The combined organics were washed with saturated NaHCO 3 and brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified via C18 silica gel chromatography eluting with a gradient of 5% to 95% acetonitrile/water (0.1% TFA).
  • Step B 4-Bromo-N-(3,5-difluorobenzyl)oxazole-2-carboxamide (312 mg, 1 Eq, 984 ⁇ mol) was added to a stirred solution of 2-chloro-4-(tributylstannyl)pyrimidine (477 mg, 1.2 Eq, 1.18 mmol) and (2'-amino-[1,1'-biphenyl]-2-yl)(tricyclohexyl-l5- phosphaneyl)palladium(III) methane sulfonate (76.9 mg, 0.12 Eq, 118 ⁇ mol) in toluene (5 mL) and sparged for 15 minutes with argon.
  • 2-chloro-4-(tributylstannyl)pyrimidine 477 mg, 1.2 Eq, 1.18 mmol
  • the reaction was heated to 100° C under argon and stirred for 12 hours.
  • the reaction was cooled to room temperature, diluted with 20% IPA in DCM and filtered over celite.
  • the reaction was concentrated, and the crude residue was purified via silica gel chromatography, eluting with a gradient of 0% to 50% EtOAc in heptane to afford 4-(2-chloropyrimidin-4-yl)-N-(3,5-difluorobenzyl)oxazole-2- carboxamide (185 mg, 528 ⁇ mol, 53.6 %).
  • Step C 4-(2-Chloropyrimidin-4-yl)-N-(3,5-difluorobenzyl)oxazole-2-carboxamide (90 mg, 1 Eq, 0.26 mmol) was added to a stirred solution of tetrahydro-2H-pyran-4-amine (31 mg, 32 ⁇ L, 1.2 Eq, 0.31 mmol) BINAP Palladacycle Gen 3 (64 mg, 0.25 Eq, 64 ⁇ mol) and caesium carbonate (0.25 g, 3 Eq, 0.77 mmol) in dioxane (1.3 mL). The reaction was sparged with nitrogen for 15 minutes and then heated to 100° C in a sealed tube and stirred for 12 hours.
  • the reaction was then cooled to room temperature, diluted with 20% IPA in DCM and filtered over celite. The filtrate was concentrated, and the crude residue was purified via silica gel chromatography, eluting with a gradient of 0% to 100% EtOAc in DCM. The material was further purified via C18 silica gel chromatography eluting with a gradient of 5% to 95% acetonitrile/water (0.1% TFA). The desired fractions were combined and added to saturated NaHCO 3 .
  • Step B (S)-4-Bromo-N-(2-((tert-butyldimethylsilyl)oxy)-1-(3-chloro-5- fluorophenyl)ethyl)oxazole-2-carboxamide (110 mg, 1 Eq, 230 ⁇ mol) was added to a stirred solution of 2-chloro-4-(tributylstannyl)pyrimidine (111 mg, 1.2 Eq, 276 ⁇ mol) and (2'-amino-[1,1'-biphenyl]-2-yl)(tricyclohexyl-l5-phosphaneyl)palladium(III) methane sulfonate (18.0 mg, 0.12 Eq, 27.6 ⁇ mol) in toluene (1.2 mL).
  • Step C (S)-N-(2-((tert-butyldimethylsilyl)oxy)-1-(3-chloro-5-fluorophenyl)ethyl)-4-(2- chloropyrimidin-4-yl)oxazole-2-carboxamide (69 mg, 1 Eq, 0.13 mmol) was added to a stirred solution of tetrahydro-2H-pyran-4-amine (16 mg, 17 ⁇ L, 1.2 Eq, 0.16 mmol), BINAP Palladacycle Gen 3 (33 mg, 0.25 Eq, 34 ⁇ mol) and caesium carbonate (0.13 g, 3 Eq, 0.40 mmol) in dioxane (0.67 mL).
  • the reaction was purged with argon and heated to 80°C for 2 hours. The reaction was allowed to cool, diluted with ethyl acetate and water. The layers separated and the ethyl acetate was dried over MgSO 4 , filtered and concentrated. The material was purified on silica gel eluting with 10-80% ethyl acetate/heptane to afford ethyl 4-(2-chloro-5-fluoropyrimidin-4- yl)oxazole-2-carboxylate (206 mg, 758 ⁇ mol, 61.7 %).
  • Step B 1-Methyl-1H-pyrazol-5-amine (103 mg, 1.4 Eq, 1.06 mmol), (2- Dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methane sulfonate (33.2 mg, 0.05 Eq, 37.9 ⁇ mol), caesium carbonate (618 mg, 2.5 Eq, 1.90 mmol) and ethyl 4-(2-chloro-5-fluoropyrimidin-4-yl)oxazole-2-carboxylate (206 mg, 1 Eq, 758 ⁇ mol) were diluted with 1,4-dioxane (5.0 mL), purged with argon and heated to 95°C.
  • Step C NaOH (5.3 mg, 66 ⁇ L, 2.0 molar, 2.0 Eq, 0.13 mmol) was mixed with ethanol (60 uL) and added to a stirred solution of ethyl 4-(5-fluoro-2-((1-methyl-1H-pyrazol-5- yl)amino)pyrimidin-4-yl)oxazole-2-carboxylate (22 mg, 1 Eq, 66 ⁇ mol) in THF (0.8 mL) under Nitrogen. The reaction was allowed to stir for 30 minutes. Water (2 mL) was added to the reaction and the pH was adjusted ⁇ 4 with 1N HCl.
  • Step D DIEA (12 mg, 16 ⁇ L, 2.5 Eq, 90 ⁇ mol) was added to a stirred solution of 4-(5- fluoro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)oxazole-2-carboxylic acid (11 mg, 1 Eq, 36 ⁇ mol), HATU (15 mg, 1.1 Eq, 40 ⁇ mol) and (3-chlorophenyl)methanamine (5.6 mg, 4.9 ⁇ L, 1.1 Eq, 40 ⁇ mol) in DCM (0.5 mL) under Nitrogen. After stirring for 1 hour, an additional equivalent of HATU and amine were added.
  • the reaction was stirred for an additional hour.
  • the reaction was partitioned between saturated NaHCO3 (25 mL) and EtOAc (40 mL).
  • the organic layer over magnesium sulfate, filtered, and concentrated in vacuo.
  • the crude residue was purified on a c-18 silica cartridge, eluting with a gradient of 5% to 95% acetonitrile/water (0.1% TFA).
  • the pure fraction was diluted with saturated sodium bicarbonate and ethyl acetate.
  • Step B Aniline (26 mg, 1.5 Eq, 0.28 was added to a stirred solution of (2- Dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methane sulfonate (16 mg, 0.1 Eq, 19 ⁇ mol), ethyl 4-(2-chloro-5-methylpyrimidin-4- yl)oxazole-2-carboxylate (50 mg, 1 Eq, 0.19 mmol) and Cs2CO3 (0.18 g, 3 Eq, 0.56 mmol) in dioxane (1.5 mL).
  • the reaction was purged with argon, sealed, heated to 100°C and stirred for 3 hours.
  • the reaction was allowed to cool, diluted with ethyl acetate and water.
  • the material was filtered to get rid of the catalyst.
  • the layers separated and the ethyl acetate was dried over MgSO4, filtered and concentrated.
  • the material was purified on silica gel eluting with 20-70% ethyl acetate/heptane to afford ethyl 4-(5-methyl-2- (phenylamino)pyrimidin-4-yl)oxazole-2-carboxylate (25 mg, 77 ⁇ mol, 41 %).
  • Step C NaOH (12 mg, 0.15 mL, 2 molar, 4 Eq, 0.31 mmol) in ethanol (150 uL) was added to a stirred solution of ethyl 4-(5-methyl-2-(phenylamino)pyrimidin-4-yl)oxazole-2- carboxylate (25 mg, 1 Eq, 77 ⁇ mol) in THF (500 ⁇ L). After stirring for 1 hour, the reaction was diluted with water (5 mL) and the pH was adjusted to ⁇ 3 with 1N HCl. The material was extracted twice with 25%IPA/DCM.
  • Step D DIEA (19 mg, 26 ⁇ L, 2.2 Eq, 0.15 mmol) was added to a stirred solution of 4-(5- methyl-2-(phenylamino)pyrimidin-4-yl)oxazole-2-carboxylic acid (20 mg, 1 Eq, 68 ⁇ mol), HATU (28 mg, 1.1 Eq, 74 ⁇ mol) and (3-chlorophenyl)methanamine (11 mg, 9.1 ⁇ L, 1.1 Eq, 74 ⁇ mol) in DCM (500 ⁇ L).
  • Step C DIEA (17 mg, 23 ⁇ L, 2.2 Eq, 0.13 mmol) was added to stirred solution of 4-(2- ((2-chlorophenyl)amino)-5-methylpyrimidin-4-yl)oxazole-2-carboxylic acid (20 mg, 1 Eq, 60 ⁇ mol), HATU (25 mg, 1.1 Eq, 67 ⁇ mol), and (3-chlorophenyl)methanamine (9.4 mg, 8.1 ⁇ L, 1.1 Eq, 67 ⁇ mol).
  • Example 9 4-(2-((2- 4-yl)-N-(3- chlorobenzyl)oxazole-2-carboxamide Step A: 2,4-Dichloro-5-methylpyrimidine (1.2 g, 1 Eq, 7.4 mmol) was diluted in 2- methyltetrahydrofuran (50.0 mL) and water (8.0 mL) then treated with ethyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole-2-carboxylate (1.2 g, 0.6 Eq, 4.4 mmol), mesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.54 g, 0.1 Eq, 0.74 mmol), and potassium carbonate (3.6 g, 3.5 Eq, 26 mmol) then sparged with argon for
  • the reaction was purged with argon, heated to 100°C and stirred for 12 hours.
  • the reaction was allowed to cool, diluted with minimal water and loaded onto a 60g C-18 column and eluted with 5-95% ACN/water (0.1% TFA).
  • the pure fractions were diluted with water and extracted with ethyl acetate.
  • the ethyl acetate was dried over MgSO 4 , filtered and concentrated to afford 4-(2-((2-chloro-4- fluorophenyl)amino)-5-methylpyrimidin-4-yl)oxazole-2-carboxylic acid (25 mg, 72 ⁇ mol, 38 %).
  • Step C DIEA (21 mg, 29 ⁇ L, 2.2 Eq, 0.16 mmol) was added to a stirred solution of 4-(2- ((2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)oxazole-2-carboxylic acid (26 mg, 1 Eq, 75 ⁇ mol), HATU (31 mg, 1.1 Eq, 82 ⁇ mol), and (3-chlorophenyl)methanamine (12 mg, 10 ⁇ L, 1.1 Eq, 82 ⁇ mol).
  • Step B A solution of ethyl 4-(2-chloro-5-methylpyrimidin-4-yl)oxazole-2-carboxylate (143 mg, 534 ⁇ mol) and 1M NaOH (5.34 mL, 5.34 mmol) in 1 mL of THF was heated to 30°C for 30 minutes. The solution was then concentrated, taken up in 3 mL of MeOH, washed with amberlyst resin, filtered, concentrated, and taken forward as is.
  • Step C A solution of 4-(2-chloro-5- 4-yl)oxazole-2-carboxylic acid (187 mg, 780 ⁇ mol), 3-Chlorobenzylamine (134 ⁇ L, 1.09 mmol), HATU (415 mg, 1.09 mmol) and DIEA (408 ⁇ L, 2.34 mmol) in 4.17 mL of DMF was stirred for 30 minutes. The solution was then taken up in EtOAc and washed three times with water. The organics were concentrated and purified by silica gel chromatography (5-95% EA / heptanes).
  • the ERK tracer used was a commercially available ERK inhibitor (MedChem Express, Cat. No. HY-136579) with an Alexa-Fluor® 647 fluorophore (Invitrogen, Cat. No. A20006) appended (prepared according to the procedure below).
  • the CDK2/cyclin A and Aurora A tracer used was commercially available Alexa-Fluor® Tracer 236 (Invitrogen Cat No. PR9078A.) See Table 1 below for concentrations of enzyme, tracer, Europium-Streptavidin and biotinylated-Anti-His antibody. Table 1.
  • the crude reaction mixture was loaded in a minimum amount of water onto a 12 gram C18 Biotage column and eluted with an acetonitrile/water/0.01 NH4OH gradient (0% to 95% acetonitrile).
  • a single dark blue band eluted from the column.
  • the single fraction dark blue color was concentrated under a stream of nitrogen to about 500 uL and then frozen and held under vacuum until a blue residue was left. That residue was transferred to a 2 dram amber vial with dichloromethane and re-concentrated under a stream of nitrogen and then under high vacuum to a blue film to afford the ERK tracer.
  • the buffer was 25 mM HEPES, 5 mM MgCl2, 1 mM DTT, 0.01% (v/v) Triton X-100, pH 7.4 in 2% (v/v) DMSO.
  • the test compounds were prepared in a threefold serial dilution in DMSO to reach the desired final concentration, with the highest concentration at 10 uM.
  • the assay plate was incubated for 60 minutes at 22°C.
  • POC Percent of Control
  • a suitable ERK inhibitor control compound such as ASN007 (MedChem Express, Cat. No. HY-136579) or the like, able to completely inhibit the enzyme activity signal.
  • the POC values were fitted using a four-parameter logistic curve.
  • the IC50 value (in nM) is defined as the point where the curve crosses 50 POC. Each compound was tested either once or in duplicate.
  • the binding affinity data (either single data point, or mean of two data points) are shown in Table 2. Table 2.
  • a compound of formula (I): is selected from the group consisting of: (i) C 1 -C 6 alkyl, which C 1 -C 6 alkyl is optionally substituted by one, two or three substituents independently selected from the group consisting of fluoro; chloro; hydroxy; -NH 2 ; -NH(C 1 -C 4 alkyl); -N(C 1 -C 4 alkyl) 2 ; and C 1 -C 4 alkoxy, which C1-C4 alkoxy is optionally substituted by one, two or three fluoro; (ii) C 3 -C 7 cycloalkyl, which C 3 -C 7 cycloalkyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of fluoro; chloro; C 1 -C 4 alkyl, which C 1 -C 4 alkyl is optionally substituted by one, two or three fluoro; and C1-C4 alkoxy
  • a compound of Clause 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is 4- to 7- membered heterocycloalkyl, which heterocycloalkyl comprises one heteroatom selected from the group consisting of N, O and S, and which heterocycloalkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of O; fluoro; chloro; C1-C4 alkyl, which C 1 -C 4 alkyl is optionally substituted by one, two or three fluoro; and C 1 -C 4 alkoxy, which C1-C4 alkoxy is optionally substituted by one, two or three fluoro..
  • R 4 is 5- or 6- membered heteroaryl, which heteroaryl comprises one, two or three heteroatoms independently selected from the group consisting of N, O and S, and which heteroaryl is optionally substituted with C1-C4 alkyl. 17.
  • R 5 is phenyl, which phenyl is substituted with one substituent selected from the group consisting of fluoro; chloro; bromo; -OH; -CN; -CH3; -CH2CH3; -CH(CH3)2; - CH 2 OH; -CH(CH 3 )OH; -C(CH 3 ) 2 OH; -CH 2 F; -CHF 2 ; -CF 3 ; -CH 2 OCH 3 ; -OCH 3 ; - OCHF2; -OCF3; -CO2CH3; -SCH3; -SCH2CH3; -SCHF2; -SOCH3; and -SO2(CH3).
  • a compound of any of Clauses 21, or a pharmaceutically acceptable salt thereof, wherein R 5 is 5- to 10- membered heteroaryl, which heteroaryl comprises one, two or three heteroatoms independently selected from the group consisting of N, O or S, and which heteroaryl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo; O; hydroxy; and C1-C4 alkyl, which C1-C4 alkyl is optionally substituted with one, two or three fluoro.
  • R 5 is C1-C4 alkyl.
  • R 5 is –C(R 15 )2-phenyl, which phenyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo; hydroxy; -CN; C1-C4 alkyl, which C1-C4 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of fluoro, hydroxy and -OCH3; C1-C4 alkoxy, which C1-C4 alkoxy is optionally substituted with one, two or three fluoro; -CO 2 CH 3 ; -S(C 1 -C 4 alkyl), which -S(C 1 - C4 alkyl) is optionally substituted with one, two or three fluoro; -SO(C1-C4 alkyl); and -SO 2 (C 1 -C 4 alkyl).
  • a compound of any of Clauses 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R 5 is –C(R 15 )2-(5- to 6- membered heteroaryl), which heteroaryl comprises one, two or three heteroatoms independently selected from the group consisting of N, O or S, and is optionally substituted with one, two or three substituents independently selected from the group consisting of halo; O; hydroxy; and C 1 -C 4 alkyl, which C 1 -C 4 alkyl is optionally substituted with one, two or three fluoro. 32.
  • a compound of Clause 36, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen. 38. A compound of Clause 36, or a pharmaceutically acceptable salt thereof, wherein R 2 is -CH 3 . 39. A compound of any of Clauses 36 to 38, or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen. 40. A compound of any of Clauses 36 to 38, or a pharmaceutically acceptable salt thereof, wherein R 3 is -CH 3 . 41. A compound of any of Clauses 36 to 40, or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen. 42. A compound of any of Clauses 36 to 40, or a pharmaceutically acceptable salt thereof, wherein R 4 is -CH3. 43.
  • R 3 is hydrogen and R 4 is -CH 2 OH.
  • R 3 is -CH3 and R 4 is -CH3.
  • R 5 is phenyl. 50.
  • R 5 is selected from the group consisting of –C(R 15 )2-imidazolyl, which imidazolyl is optionally substituted with -CH 3 ; –C(R 15 ) 2 -pyrazolyl, which pyrazolyl is optionally substituted with one or two -CH3; –C(R 15 )2-1,2,3-triazolyl, which triazolyl is optionally substituted with -CH 3 ; –C(R 15 ) 2 -oxazolyl; –C(R 15 ) 2 - isoxazolyl; –C(R 15 )2-pyrimidinyl; and –C(R 15 )2- pyridinyl; and wherein R 15 is independently at each occurrence hydrogen to form, for example, –CH 2 - pyrimidinyl, –CH2-pyridinyl, -CH2-N-methylimidazo
  • a compound of any of Clauses 36 to 57, or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen.
  • 61. A compound of any of Clauses 36 to 60, or a pharmaceutically acceptable salt thereof, wherein R 15 is hydrogen. 62.
  • a compound of formula (III): is selected from the group consisting of: (i) hydrogen; (ii) C1-C4 alkyl, which C1-C4 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of fluoro, hydroxy, -NH2, and -OCH3; (iii) 5- to 6- membered heterocycloalkyl, which heterocycloalkyl comprises one heteroatom selected from the group consisting of N and O; and (iv) 5- or 6- membered heteroaryl, which heteroaryl comprises one, two or three heteroatoms independently selected from the group consisting of N, O and S, and which heteroaryl is optionally substituted with C 1 -C 4 alkyl; and R 5 is selected from the group consisting of: (i) C 1 -C 4 alkyl; (ii) C 3 -C 10 cycloalkyl, which C 3 - is optionally substituted with one, two or three substituents
  • a compound of Clause 62, or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen.
  • a compound of Clause 62, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of -CH3; -CH2CH3; -CH2OH; -CH(OH)CH3; -C(CH3)2OH; -CH2CH2OH; -CH2NH2; -CH2OCH3; -CH2CHF2; and -CF3.
  • 65 A compound of Clause 64, or a pharmaceutically acceptable salt thereof, wherein R 4 is -CH 3 .
  • 66. A compound of Clause 64, or a pharmaceutically acceptable salt thereof, wherein R 4 is -CH2OH. 67.
  • R 4 is selected from the group consisting of pyrrolidinyl and tetrahydrofuranyl. 69.
  • R 5 is phenyl, which phenyl is substituted with one substituent selected from the group consisting of fluoro; chloro; bromo; -OH; -CN; -CH 3 ; -CH 2 CH 3 ; -CH(CH 3 ) 2 ; - CH2OH; -CH(CH3)OH; -C(CH3)2OH; -CH2F; -CHF2; -CF3; -CH2OCH3; -OCH3; -OCH3; -OCHF 2 ; -OCF 3 ; -CO 2 CH 3 ; -SCH 3 ; -SCH 2 CH 3 ; -SCHF 2 ; -SOCH 3 ; and -SO 2 (CH 3 ).
  • R 5 is selected from the group consisting of cyclopropyl; cyclobutyl; cyclopentyl; bicyclo[1.1.1]pentyl; cyclohexyl, which cyclohexyl is optionally substituted by one substituent selected from the group consisting of hydroxy and -CH3; bicyclo[2.2.1]heptanyl; and adamantanyl.
  • a compound of formula (IV): , or a pharmaceutically acceptable salt thereof, wherein R 4 is C 1 -C 4 alkyl, which C 1 -C 4 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of fluoro, hydroxy, -NH 2 , and -OCH 3 ; and R 5 is selected from the group consisting of: (i) C 3 -C 10 cycloalkyl, which C 3 -C 10 cycloalkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of fluoro, hydroxy, -CH 3 and -CF 3 ; (ii) 4- to 6- membered heterocycloalkyl, which heterocycloalkyl comprises one heteroatom selected from the group consisting of N and O, and which 4- to 6- membered heterocycloalkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of fluoro, O, hydroxy, -
  • R 5 is phenyl, which phenyl is substituted with one substituent selected from the group consisting of fluoro; chloro; bromo; -OH; -CN; -CH 3 ; - CH2CH3; -CH(CH3)2; -CH2OH; -CH(CH3)OH; -C(CH3)2OH; -CH2F; -CHF2; -CF3; - CH 2 OCH 3 ; -OCH 3 ; -OCHF 2 ; -OCF 3 ; -CO 2 CH 3 ; -SCH 3 ; -SCH 2 CH 3 ; -SCHF 2 ; - SOCH3; and -SO2(CH3).
  • a pharmaceutical composition a compound of any one of Clauses 1 to 85, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a method of treating abnormal cell growth in a subject comprising administering to the subject a therapeutically effective amount of a compound of any one of Clauses 1 to 85, or a pharmaceutically acceptable salt thereof.
  • the method of Clause 87, wherein the abnormal cell growth is cancer.
  • the cancer is selected from the group consisting of melanoma, colon cancer, colorectal cancer, lung cancer (e.g., small cell lung carcinoma or non-small cell lung carcinoma), thyroid cancer (e.g., papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, or refractory differentiated thyroid cancer), breast cancer, ovarian cancer, cancer of the CNS, bone cancer, cancer of the anus, anal canal, or anorectum, cancer of the eye, bile duct cancer, ductal carcinoma in situ, liver cancer, gallbladder, or pleura, oral cancer, oral cavity cancer, lip cancer, oropharyngeal cancer, cancer of the nose, nasal cavity or middle ear, cancer of the vulva, esophageal cancer, cervical cancer, gastrointestinal carcinoid tumor, hypopharynx cancer, kidney cancer, larynx cancer, liver cancer, lung cancer, gastrointestinal carcinoi
  • the method of Clause 89 wherein the cancer is selected from the group consisting of melanoma, colorectal cancer, thyroid cancer, lung cancer, ovarian cancer, and peripheral nervous system cancers.
  • the method of Clause 90, wherein the cancer is melanoma.
  • the method of Clause 90, wherein the cancer is colorectal cancer.
  • the method of Clause 90, wherein the cancer is lung cancer, which lung cancer is non-small cell lung cancer.
  • 94 The method of Clauses 88 to 93, the cancer is metastatic cancer.
  • the method of Clauses 88 to 94, wherein the abnormal cell growth is an ERK- mediated cancer.
  • the method of Clauses 88 to 95, wherein the abnormal cell growth has a BRAF mutation.
  • the BRAF fusion is selected from the group consisting of KIAA11549-BRAF, MKRN1-BRAF, TRIM24-BRAF, AGAP3- BRAF, ZC3HAV1-BRAF, AKAP9-BRAF, CCDC6-BRAF, AGK-BRAF, EPS15- BRAF, NUP214-BRAF, ARMC10-BRAF, BTF3L4-BRAF, GHR-BRAF, ZC3HAV1- BRAF, ZNF767-BRAF, CCDC91-BRAF, DYNC112-BRAF, ZKSCAN1-BRAF, GTF2I-BRAF, MZT1-BRAF, RAD18-BRAF, CUX1-BRAF, SLC12A7-BRAF, MYRIP-BRAF, SND1-BRAF, NUB1-BRAF, KLHL7-BRAF, TANK-BRAF, RBMS3- BRAF, STRN3-BRAF, ST
  • the additional therapeutic agent is selected from the group consisting of a BRAF inhibitor, a RAS inhibitor, an EGFR inhibitor, a SHP2 inhibitor, a PI3K inhibitor, a TAM kin

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Abstract

L'invention concerne des composés de formule (I) : et des sels pharmaceutiquement acceptables de ceux-ci, dans la formule R1, R2, R3, R4, R5 et R6 sont tels que définis dans la description ; leur utilisation en médecine ; des compositions les contenant ; des procédés pour leur préparation ; et des intermédiaires utilisés dans de tels procédés. Les composés de formule (I) peuvent inhiber l'activité de ERK et peuvent être utiles dans le traitement, la prévention, la suppression et le soulagement de maladies telles qu'une croissance cellulaire anormale, par exemple le cancer, ou des maladies, un trouble et des affections à médiation par ERK.
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