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WO2024191988A1 - 3,4-fused bicyclic pyrrolidine and 3,4-fused bicyclic pyrrolidinone compounds - Google Patents

3,4-fused bicyclic pyrrolidine and 3,4-fused bicyclic pyrrolidinone compounds Download PDF

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Publication number
WO2024191988A1
WO2024191988A1 PCT/US2024/019513 US2024019513W WO2024191988A1 WO 2024191988 A1 WO2024191988 A1 WO 2024191988A1 US 2024019513 W US2024019513 W US 2024019513W WO 2024191988 A1 WO2024191988 A1 WO 2024191988A1
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Prior art keywords
alkyl
compound
nra2c
methyl
halogen
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French (fr)
Inventor
Kwon Ho Hong
Jean-Marc Lapierre
Yanbin Liu
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Cyteir Therapeutics Inc
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Cyteir Therapeutics Inc
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Publication of WO2024191988A1 publication Critical patent/WO2024191988A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/06—Peri-condensed systems

Definitions

  • Double-strand breaks are repaired by two major pathways: homologous recombination (HR) and non-homologous end- joining (NHEJ).
  • HR homologous recombination
  • NHEJ non-homologous end- joining
  • salt-EJ alternative end-joining
  • MMEJ microhomology-mediated end-joining pathway
  • DNA polymerase theta is an A-family polymerase encoded by the POLQ gene. It is a multi-functional protein that exhibits a C-terminal DNA polymerase domain (Pol ⁇ -pol), a central domain, and an N-terminal helicase domain (Pol ⁇ -hel). It is an error-prone polymerase that promotes MMEJ in higher organisms.
  • the Pol ⁇ -hel domain is a member of the SF2 helicases. While it has single-stranded DNA-dependent ATPase activity that can strip Replication Protein A (RPA) from single stranded DNA, it can suppress HR pathway by disrupting Rad51 nucleoprotein complex formation after radiation exposure.
  • RPA Replication Protein A
  • This anti- recombinase activity of Pol ⁇ promotes the alt-EJ pathway.
  • the helicase domain of Pol ⁇ can bridge two single stranded DNA sequences resulting in microhomology-mediated strand annealing. Specifically, Pol ⁇ promotes end-joining in alt- EJ pathway by employing this annealing activity even when single stranded DNA overhangs possess limited homology.
  • Pol ⁇ The Rad51 interaction is followed by ATPase-mediated displacement of Rad51 from DSB damage sites during the reannealing process. Once annealed, the primer strand of DNA is extended by the polymerase domain of Pol ⁇ . It has been shown that cancer cells with deficiency in HR, NHEJ or ataxia telangiectasia-mutated (ATM) are highly dependent on Pol ⁇ expression. Pol ⁇ has limited expression in normal cells, but is overexpressed in a variety of cancer cells. Depletion of Pol ⁇ can impair cell-viability and can lead to synthetic lethality of cancer cells. As such, Pol ⁇ is an attractive target for novel synthetic lethal therapy of cancers containing DNA repair defects.
  • compositions comprising such compounds and methods of treating and/or preventing diseases, e.g., diseases such as cancer treatable by inhibition of Pol ⁇ , including homologous recombination (HR) deficient cancers.
  • diseases e.g., diseases such as cancer treatable by inhibition of Pol ⁇ , including homologous recombination (HR) deficient cancers.
  • HR homologous recombination
  • described herein is a method for treating and/or preventing a disease in a subject, such as cancer characterized by overexpression/overactivity of Pol ⁇ polymerase, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof.
  • described herein is a method for treating and/or preventing a cancer in a subject, such as cancer characterized by a deficiency in homologous recombinant (HR) or by a reduction or absence of BRCA gene expression, the absence of the BRAC gene, or reduced function of BRCA protein, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof.
  • a method for inhibiting DNA repair by Pol ⁇ in a cell comprising contacting the cell with an effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof.
  • the cell is HR deficient.
  • a compound described herein or a pharmaceutically acceptable salt or solvate thereof for inhibiting DNA repair by Pol ⁇ in a cell In some embodiments, the cell is HR deficient. In another aspect, described herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for treating and/or preventing a disease in a subject, e.g., a disease such as cancer treatable by inhibition of Pol ⁇ , including homologous recombination (HR) deficient cancers.
  • a disease in a subject e.g., a disease such as cancer treatable by inhibition of Pol ⁇ , including homologous recombination (HR) deficient cancers.
  • HR homologous recombination
  • a compound described herein or a pharmaceutically acceptable salt or solvate thereof for treating and/or preventing a disease in a subject, such as cancer characterized by overexpression/overactivity of Pol ⁇ polymerase, by a deficiency in homologous recombinant (HR), or by a reduction or absence of BRAC gene expression, the absence of the BRAC gene, or reduced function of BRAC protein.
  • a compound described herein or a pharmaceutically acceptable salt or solvate thereof for use in the manufacture of a medicament for inhibiting DNA repair by Pol ⁇ in a cell.
  • the cell is HR deficient.
  • described herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for use in the manufacture of a medicament for treating and/or preventing a disease in a subject, e.g., a disease such as cancer treatable by inhibition of Pol ⁇ , including homologous recombination (HR) deficient cancers.
  • a disease such as cancer treatable by inhibition of Pol ⁇ , including homologous recombination (HR) deficient cancers.
  • HR homologous recombination
  • described herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for use in the manufacture of a medicament for treating and/or preventing a disease in a subject, such as cancer characterized by overexpression/overactivity of Pol ⁇ polymerase, by a deficiency in homologous recombinant (HR), or by a reduction or absence of BRAC gene expression, the absence of the BRAC gene, or reduced function of BRAC protein.
  • a compound described herein or a pharmaceutically acceptable salt or solvate thereof for treating and/or preventing a cancer that is resistant to poly(ADP-ribose) polymerase (PARP) inhibitor therapy in a subject.
  • PARP poly(ADP-ribose) polymerase
  • cancers resistant to PARP-inhibitors include, but are not limited to, breast cancer, ovarian cancer, lung cancer, bladder cancer, liver cancer, head and neck cancer, pancreatic cancer, gastrointestinal cancer, and colorectal cancer.
  • the details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
  • R 1 ’ and R 2 ’ together with the carbon atoms to which they are bonded, form a ring Cy, or R1 and R1’ are bonded together to form -(CH2)n-
  • R2’ is H, C1-C6 alkyl, C1-C6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -OH, -NH 2 , -NR a2 (C 1 -C 6 alkyl), halogen, oxo, or benzyl
  • n is 1, 2, or 3
  • R1 and R2 are each independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 al
  • any group or embodiment described herein for any of ring Cy, W, X, Y 1 , Y 2 , n, A 1 , A 2 , A 3 , A 4 , R A , R N , R a1 , R a2 , R 1 , R 1 ’, R 2 , R 2 ’, R 3 , R 4 , R W , R 5 , R 6 , and R 7 can be combined with one or more groups or embodiments described herein for one or more of the remainder of ring Cy, W, X, Y1, Y2, n, A1, A2, A3, A4, RA, RN, Ra1, Ra2, R1, R1’, R2, R2’, R 3 , R 4 , R W , R 5 , R 6 , and R 7 .
  • Embodiments of the Disclosure Embodiment 1. A compound of Formula I: or a pharmaceutically acceptable salt or solvate thereof, as described above.
  • Embodiment 2. The compound of Embodiment 1, wherein R 1 ’ and R 2 ’, together with the carbon atoms to which they are bonded, form a ring Cy.
  • Embodiment 2a The compound of Embodiment 1, wherein R 1 ’ and R 2 ’, together with the carbon atoms to which they are bonded, form a ring Cy.
  • ring Cy is a 4- to 6- membered fully saturated ring optionally comprising 1-4 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C 1 -C 6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NR a2 C(X)NR a1 R a2 .
  • Embodiment 2a-1 The compound of Embodiment 1 or 2, wherein ring Cy is a 4- membered fully saturated ring optionally comprising 1-4 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -OH, -NH 2 , -NR a2 (C 1 -C 6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NRa2C(X)NRa1Ra2.
  • Embodiment 2a-2 The compound of Embodiment 1 or 2, wherein ring Cy is a 4- membered fully saturated ring optionally comprising 1-2 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -OH, -NH 2 , -NR a2 (C 1 -C 6 alkyl), -CN, halogen, oxo, -C(X)R a1 , -C(X)OR a1 , -C(X)NR a1 R a2 , -NR a2 C(X)R a1 , -NR a2 C(X)OR a1 , and - NRa2C(X)NRa1Ra2.
  • Embodiment 2a-3 The compound of Embodiment 1 or 2, wherein ring Cy is a 4- membered fully saturated ring comprising 0 heteroatoms, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1- C 6 haloalkoxy, -OH, -NH 2 , -NR a2 (C 1 -C 6 alkyl), -CN, halogen, oxo, -C(X)R a1 , -C(X)OR a1 , - C(X)NR a1 R a2 , -NR a2 C(X)R a1 , -NR a2 C(X)OR a1 , and -NR a2 C(X)NR a1 R a2 .
  • Embodiment 2a-4 The compound of Embodiment 1 or 2, wherein ring Cy is a 5- membered fully saturated ring optionally comprising 1-4 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C 1 -C 6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NR a2 C(X)NR a1 R a2 .
  • Embodiment 2a-5 The compound of Embodiment 1 or 2, wherein ring Cy is a 5- membered fully saturated ring optionally comprising 1-2 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -OH, -NH 2 , -NR a2 (C 1 -C 6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NRa2C(X)NRa1Ra2.
  • Embodiment 2a-6 The compound of Embodiment 1 or 2, wherein ring Cy is a 5- membered fully saturated ring comprising 0 heteroatoms, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1- C 6 haloalkoxy, -OH, -NH 2 , -NR a2 (C 1 -C 6 alkyl), -CN, halogen, oxo, -C(X)R a1 , -C(X)OR a1 , - C(X)NR a1 R a2 , -NR a2 C(X)R a1 , -NR a2 C(X)OR a1 , and -NR a2 C(X)NR a1 R a2 .
  • Embodiment 2a-7 The compound of Embodiment 1 or 2, wherein ring Cy is a 6- membered fully saturated ring optionally comprising 1-4 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C 1 -C 6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NR a2 C(X)NR a1 R a2 .
  • Embodiment 2a-8 The compound of Embodiment 1 or 2, wherein ring Cy is a 6- membered fully saturated ring optionally comprising 1-2 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -OH, -NH 2 , -NR a2 (C 1 -C 6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NR a2 C(X)NR a1 R a2 .
  • Embodiment 2a-9 The compound of Embodiment 1 or 2, wherein ring Cy is a 6- membered fully saturated ring comprising 0 heteroatoms, and optionally substituted with one or more groups independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 - C 6 haloalkoxy, -OH, -NH 2 , -NR a2 (C 1 -C 6 alkyl), -CN, halogen, oxo, -C(X)R a1 , -C(X)OR a1 , - C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2.
  • Embodiment 2b The compound of Embodiment 1 or 2, wherein ring Cy is a 4- to 6- membered partially saturated ring optionally comprising 1-4 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)R a1 , -C(X)OR a1 , -C(X)NR a1 R a2 , -NR a2 C(X)R a1 , -NR a2 C(X)OR a1 , and - NR a2 C(X)NR a1 R a2 .
  • Embodiment 2b-1 The compound of Embodiment 1 or 2, wherein ring Cy is a 4- membered partially saturated ring optionally comprising 1-4 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C 1 -C 6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NR a2 C(X)NR a1 R a2 .
  • Embodiment 2b-2 The compound of Embodiment 1 or 2, wherein ring Cy is a 4- membered partially saturated ring optionally comprising 1-2 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -OH, -NH 2 , -NR a2 (C 1 -C 6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NR a2 C(X)NR a1 R a2 .
  • Embodiment 2b-3 The compound of Embodiment 1 or 2, wherein ring Cy is a 4- membered partially saturated ring comprising 0 heteroatoms, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C 1 -C 6 haloalkoxy, -OH, -NH 2 , -NR a2 (C 1 -C 6 alkyl), -CN, halogen, oxo, -C(X)R a1 , -C(X)OR a1 , -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2.
  • Embodiment 2b-5 The compound of Embodiment 1 or 2, wherein ring Cy is a 5- membered partially saturated ring optionally comprising 1-2 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C 1 -C 6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NR a2 C(X)NR a1 R a2 .
  • Embodiment 2b-8 The compound of Embodiment 1 or 2, wherein ring Cy is a 6- membered partially saturated ring optionally comprising 1-2 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C 1 -C 6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)R a1 , -C(X)OR a1 , -C(X)NR a1 R a2 , -NR a2 C(X)R a1 , -NR a2 C(X)OR a1 , and - NR a2 C(X)NR a1 R a2 .
  • Embodiment 2b-9 The compound of Embodiment 1 or 2, wherein ring Cy is a 6- membered partially saturated ring comprising 0 heteroatoms, and optionally substituted with one or more groups independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2.
  • Embodiment 2c The compound of Embodiment 1 or 2, wherein ring Cy is a 5- or 6- membered aromatic ring optionally comprising 1-4 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -OH, -NH 2 , -NR a2 (C 1 -C 6 alkyl), -CN, halogen, oxo, -C(X)R a1 , -C(X)OR a1 , -C(X)NR a1 R a2 , -NR a2 C(X)R a1 , -NR a2 C(X)OR a1 , and - NRa2C(X)NRa1Ra2.
  • Embodiment 2c-2 The compound of Embodiment 1 or 2, wherein ring Cy is a 5- membered aromatic ring optionally comprising 1-2 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C 1 -C 6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)R a1 , -C(X)OR a1 , -C(X)NR a1 R a2 , -NR a2 C(X)R a1 , -NR a2 C(X)OR a1 , and - NR a2 C(X)NR a1 R a2 .
  • Embodiment 2c-3 The compound of Embodiment 1 or 2, wherein ring Cy is a 6- membered aromatic ring optionally comprising 1-4 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C 1 -C 6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NR a2 C(X)NR a1 R a2 .
  • Embodiment 2c-4 The compound of Embodiment 1 or 2, wherein ring Cy is a 6- membered aromatic ring optionally comprising 1-2 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -OH, -NH 2 , -NR a2 (C 1 -C 6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NRa2C(X)NRa1Ra2.
  • Embodiment 2c-5 The compound of Embodiment 1 or 2, wherein ring Cy is a 6- membered aromatic ring comprising 0 heteroatoms, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH 2 , -NR a2 (C 1 -C 6 alkyl), -CN, halogen, oxo, -C(X)R a1 , -C(X)OR a1 , - C(X)NR a1 R a2 , -NR a2 C(X)R a1 , -NR a2 C(X)OR a1 , and -NR a2 C(X)NR a1 R a2 .
  • Embodiment 3 The compound of Embodiment 1, wherein R1 and R1’ are bonded together to form -(CH 2 ) 1-3 -, and R 2 ’ is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -OH, -NH 2 , -NR a2 (C 1 -C 6 alkyl), halogen, oxo, or benzyl.
  • Embodiment 3a is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -OH, -NH 2 , -NR a2 (C 1 -C 6 alkyl), halogen, oxo, or benzyl.
  • a 1 and A 4 are each independently N or CR A ;
  • A2 and A3 are each independently absent, N, or CRA; and each RA is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH 2 , -NR a2 (C 1 -C 6 alkyl), -CN, halogen, oxo, -C(X)R a1 , -C(X)OR a1 , - C(X)NR a1 R a2 , -NR a2 C(X)R a1 , -NR a2 C(X)OR a1 , or -NR a2 C(X)NR a1 R a2 .
  • Embodiment 5 The compound of any of Embodiments 1-2c-5 and 4, of Formula IIa or IIb: or a pharmaceutically acceptable salt or solvate thereof, wherein: A1 and A4 are each independently N or CRA; A 2 and A 3 are each independently absent, N, or CR A ; and each RA is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, - C(X)NR a1 R a2 , -NR a2 C(X)R a1 , -NR a2 C(X)OR a1 , or -NR a2 C(X)NR a1 R a2 .
  • Embodiment 6 The compound of Embodiment 4 or 5, wherein A 1 , A 2 , A 3 , and A 4 are each CRA.
  • Embodiment 7. The compound of Embodiment 4 or 5, wherein one of A1, A2, A3, and A 4 is N.
  • Embodiment 8. The compound of Embodiment 7, wherein A1 is N.
  • Embodiment 9. The compound of Embodiment 7, wherein A2 is N.
  • Embodiment 10. The compound of Embodiment 7, wherein A3 is N.
  • Embodiment 11 The compound of Embodiment 7, wherein A4 is N.
  • Embodiment 12. The compound of Embodiment 4 or 5, wherein two of A 1 , A 2 , A 3 , and A4 are N.
  • Embodiment 12 wherein A1 and A2 are N.
  • Embodiment 14. The compound of Embodiment 12, wherein A 1 and A 3 are N.
  • Embodiment 15. The compound of Embodiment 12, wherein A 1 and A 4 are N.
  • Embodiment 16. The compound of Embodiment 12, wherein A2 and A3 are N.
  • Embodiment 17. The compound of Embodiment 12, wherein A 2 and A 4 are N.
  • Embodiment 18 The compound of Embodiment 12, wherein A 3 and A 4 are N.
  • Embodiment 19 The compound of Embodiment 4 or 5, wherein one of A1, A2, A3, and A4 is CRA.
  • Embodiment 20 The compound of Embodiment 19, wherein A 1 is CR A .
  • Embodiment 21 The compound of Embodiment 19, wherein A2 is CRA.
  • Embodiment 22 The compound of Embodiment 19, wherein A3 is CRA.
  • Embodiment 23 The compound of Embodiment 19, wherein A 4 is CR A .
  • Embodiment 24 The compound of Embodiment 4 or 5, wherein A 2 is absent or A 3 is absent.
  • Embodiment 25 The compound of Embodiment 4 or 5, wherein A 2 is absent and A 3 is absent.
  • Embodiment 26 The compound of Embodiment 1, of Formula III: Embodiment 26a.
  • the compound of Embodiment 1 or 26, wherein n is 1.
  • Embodiment 26b The compound of Embodiment 1 or 26, wherein n is 2.
  • Embodiment 26c The compound of Embodiment 1 or 26, wherein n is 3.
  • Embodiment 27. The compound of any of previous Embodiments to the extent applicable, wherein Y 1 is O and Y 2 is -NR 3 R 4 .
  • Embodiment 28. The compound of any of previous Embodiments to the extent applicable, wherein Y1 and Y2, together with the carbon atom to which they are bonded, form .
  • Embodiment 30. The compound of any of previous Embodiments to the extent applicable, wherein W is CR W .
  • R3 is C6-C10 aryl optionally substituted with one or more groups independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, - OH, -NH 2 , -NR a2 (C 1 -C 6 alkyl), -CN, halogen, oxo, -C(X)R a1 , -C(X)OR a1 , -C(X)NR a1 R a2 , - NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2.
  • Embodiment 32 The compound of any of previous Embodiments to the extent applicable, wherein R 3 phenyl optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, - NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, - NR a2 C(X)OR a1 , and -NR a2 C(X)NR a1 R a2 .
  • Embodiment 33 The compound of any of previous Embodiments to the extent applicable, wherein R3 is heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, - OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, - NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2.
  • Embodiment 34 The compound of any of previous Embodiments to the extent applicable, wherein R3 is heteroaryl comprising one 5- or 6-membered ring and 1-4 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, - OH, -NH 2 , -NR a2 (C 1 -C 6 alkyl), -CN, halogen, oxo, -C(X)R a1 , -C(X)OR a1 , -C(X)NR a1 R a2 , - NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2.
  • Embodiment 34a The compound of any of previous Embodiments to the extent applicable, wherein R 3 is heteroaryl comprising one 5- or 6-membered ring and 1-2 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, - OH, -NH 2 , -NR a2 (C 1 -C 6 alkyl), -CN, halogen, oxo, -C(X)R a1 , -C(X)OR a1 , -C(X)NR a1 R a2 , - NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2.
  • Embodiment 34b The compound of any of previous Embodiments to the extent applicable, wherein R 3 is heteroaryl comprising one 5-membered ring and 1-2 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, - NR a2 (C 1 -C 6 alkyl), -CN, halogen, oxo, -C(X)R a1 , -C(X)OR a1 , -C(X)NR a1 R a2 , -NR a2 C(X)R a1 , - NR a2 C(X)OR a1 , and -NR a2 C(X)NR a1 R a2 .
  • Embodiment 34c The compound of any of previous Embodiments to the extent applicable, wherein R3 is heteroaryl comprising one 6-membered ring and 1-2 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, - NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, - NR a2 C(X)OR a1 , and -NR a2 C(X)NR a1 R a2 .
  • Embodiment 34d The compound of any of previous Embodiments to the extent applicable, wherein R3 is heteroaryl comprising two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, - OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, - NR a2 C(X)R a1 , -NR a2 C(X)OR a1 , and -NR a2 C(X)NR a1 R a2 .
  • Embodiment 35 The compound of any of previous Embodiments to the extent applicable, wherein R4 is H or C1-C6 alkyl optionally substituted with one or more groups independently selected from C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, C 6 -C 10 aryl, and heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1- C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -OH, -NH 2 , -NR a2 (C 1 -C 6 alkyl), -CN, halogen, oxo, -C(X)R
  • Embodiment 35a The compound of any of previous Embodiments to the extent applicable, wherein R 4 is C 1 -C 6 alkyl optionally substituted with one or more groups independently selected from C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, C6-C10 aryl, and heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1- C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)R a1 , -
  • Embodiment 35 The compound of any of previous Embodiments to the extent applicable, wherein R 4 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, optionally substituted with one or more groups independently selected from C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -OH, - NH2, -NRa2(C1-C6 alkyl), -CN, halogen, C6-C10 aryl, and heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from C 1 - C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl
  • Embodiment 36 The compound of any of previous Embodiments to the extent applicable, wherein R4 is C6-C10 aryl, or heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from C 1 -C 6 alkyl, C 1 - C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)R a1 , -C(X)OR a1 , -C(X)NR a1 R a2 , -NR a2 C(X)R a1 , -NR a2 C(X)OR a1 , and - NR a2 C(X)NR
  • Embodiment 37 The compound of any of previous Embodiments to the extent applicable, wherein R4 is C6-C10 aryl, optionally substituted with one or more groups independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, - OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, - NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2.
  • Embodiment 37a The compound of any of previous Embodiments to the extent applicable, wherein R 4 is phenyl, optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, - OH, -NH 2 , -NR a2 (C 1 -C 6 alkyl), -CN, halogen, oxo, -C(X)R a1 , -C(X)OR a1 , -C(X)NR a1 R a2 , - NR a2 C(X)R a1 , -NR a2 C(X)OR a1 , and -NR a2 C(X)NR a1 R a2 .
  • Embodiment 38 The compound of any of previous Embodiments to the extent applicable, wherein R4 is heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, - OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, - NR a2 C(X)R a1 , -NR a2 C(X)OR a1 , and -NR a2 C(X)NR a1 R a2 .
  • Embodiment 39 The compound of any of previous Embodiments to the extent applicable, wherein R4 is heteroaryl comprising one 5- or 6-membered ring and 1-4 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, - OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, - NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2.
  • Embodiment 39a The compound of any of previous Embodiments to the extent applicable, wherein R4 is heteroaryl comprising one 5- or 6-membered ring and 1-2 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, - OH, -NH 2 , -NR a2 (C 1 -C 6 alkyl), -CN, halogen, oxo, -C(X)R a1 , -C(X)OR a1 , -C(X)NR a1 R a2 , - NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2.
  • Embodiment 39b The compound of any of previous Embodiments to the extent applicable, wherein R 4 is heteroaryl comprising one 5-membered ring and 1-2 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -OH, -NH 2 , - NR a2 (C 1 -C 6 alkyl), -CN, halogen, oxo, -C(X)R a1 , -C(X)OR a1 , -C(X)NR a1 R a2 , -NR a2 C(X)R a1 , - NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2.
  • Embodiment 39c The compound of any of previous Embodiments to the extent applicable, wherein R 4 is heteroaryl comprising one 6-membered ring and 1-2 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, - NR a2 (C 1 -C 6 alkyl), -CN, halogen, oxo, -C(X)R a1 , -C(X)OR a1 , -C(X)NR a1 R a2 , -NR a2 C(X)R a1 , - NR a2 C(X)OR a1 , and -NR a2 C(X)NR a1 R a2 .
  • Embodiment 39d The compound of any of previous Embodiments to the extent applicable, wherein R 4 is heteroaryl comprising two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, - OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, - NR a2 C(X)R a1 , -NR a2 C(X)OR a1 , and -NR a2 C(X)NR a1 R a2 .
  • Embodiment 40 The compound of any of previous Embodiments to the extent applicable, wherein R1 and R2 are each H.
  • Embodiment 41 The compound of any of previous Embodiments to the extent applicable, wherein one of R 1 and R 2 is H, and the other is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 - C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), halogen, oxo, or benzyl.
  • Embodiment 42 Embodiment 42.
  • R 1 and R 2 are each independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), halogen, oxo, or benzyl.
  • Embodiment 43 The compound of any of previous Embodiments to the extent applicable, wherein R 1 and R 2 are each independently C 1 -C 6 alkyl.
  • Embodiment 44a The compound of any of previous Embodiments to the extent applicable, wherein RW is H. Embodiment 44b.
  • R W is C 1 -C 6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s- butyl, t-butyl, pentyl, or hexyl), C1-C6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, substituted with one or more halogen (e.g., F, Cl, Br, or I), C 1 -C 6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pent
  • Embodiment 44c The compound of any of previous Embodiments to the extent applicable, wherein RW is -OH, -NH2, -NRa2(C1-C6 alkyl) (wherein the alkyl is methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), -CN, or halogen (e.g., F, Cl, Br, or I).
  • RW is -OH, -NH2, -NRa2(C1-C6 alkyl) (wherein the alkyl is methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), -CN, or halogen (e.g., F, Cl
  • Embodiment 45a The compound of any of previous Embodiments to the extent applicable, wherein RW is -NRa2C(X)Ra1, -NRa2C(X)ORa1, or -NRa2C(X)NRa1Ra2.
  • Embodiment 45a The compound of any of previous Embodiments to the extent applicable, wherein R5, R6, and R7 are each H.
  • Embodiment 45b The compound of any of previous Embodiments to the extent applicable, wherein R5, R6, and R7 are each H.
  • R 5 , R 6 , and R 7 is C 1 -C 6 alkyl (e.g., methyl, ethyl, propyl, i- propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), C 1 -C 6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, substituted with one or more halogen (e.g., F, Cl, Br, or I), C 1 -C 6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy,
  • Embodiment 45c The compound of any of previous Embodiments to the extent applicable, wherein at least one of R5, R6, and R7 is -OH, -NH2, -NRa2(C1-C6 alkyl) (wherein the alkyl is methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), -CN, or halogen (e.g., F, Cl, Br, or I).
  • Embodiment 45d Embodiment 45d.
  • Embodiment 46a The compound of any of previous Embodiments to the extent applicable, wherein at least one of R 5 , R 6 , and R 7 is -NR a2 C(X)R a1 , -NR a2 C(X)OR a1 , or - NRa2C(X)NRa1Ra2.
  • Embodiment 46a The compound of any of previous Embodiments to the extent applicable, wherein R a1 is H.
  • Embodiment 46b The compound of any of previous Embodiments to the extent applicable, wherein R a1 is H.
  • Ra1 is C1-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s- butyl, t-butyl, pentyl, or hexyl), or C 1 -C 6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n- butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, substituted with one or more halogen (e.g., F, Cl, Br, or I).
  • halogen e.g., F, Cl, Br, or I
  • Embodiment 46c The compound of any of previous Embodiments to the extent applicable, wherein R a1 is C 1 -C 6 alkyl-C 6 -C 10 aryl, or C 1 -C 6 alkyl-heteroaryl wherein the heteroaryl comprises a 5- or 6-membered ring and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, - OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, and oxo, wherein the alkyl is methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-
  • Embodiment 46d The compound of any of previous Embodiments to the extent applicable, wherein R a1 is C 1 -C 6 alkyl-C 6 -C 10 aryl, wherein the aryl is optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C 1 -C 6 haloalkoxy, -OH, -NH 2 , -NR a2 (C 1 -C 6 alkyl), -CN, halogen, and oxo, wherein the alkyl is methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl.
  • Embodiment 46e The compound of any of previous Embodiments to the extent applicable, wherein Ra1 is C1-C6 alkyl-heteroaryl wherein the heteroaryl comprises a 5- or 6- membered ring and 1-4 heteroatoms selected from N, O, and S, wherein the heteroaryl is optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1- C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, and oxo, wherein the alkyl is methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl.
  • Embodiment 47a The compound of any of previous Embodiments to the extent applicable, wherein R a2 is H.
  • Embodiment 47b The compound of any of previous Embodiments to the extent applicable, wherein at least one Ra2 is C1-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n- butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl).
  • Embodiment 48a The compound of any of previous Embodiments to the extent applicable, wherein X is O.
  • Embodiment 48b The compound of any of previous Embodiments to the extent applicable, wherein X is O.
  • R A is C 1 -C 6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n- butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), C 1 -C 6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, substituted with one or more halogen (e.g., F, Cl, Br, or I), C1-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n- butoxy, i-butoxy, s-butoxy, t-butoxy, t-butoxy),
  • Embodiment 49c The compound of any of previous Embodiments to the extent applicable, wherein at least one R A is -OH, -NH 2 , -NR a2 (C 1 -C 6 alkyl) (wherein the alkyl is methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), -CN, or halogen (e.g., F, Cl, Br, or I).
  • R A is -OH, -NH 2 , -NR a2 (C 1 -C 6 alkyl) (wherein the alkyl is methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), -CN, or hal
  • Embodiment 50 The compound of any of previous Embodiments to the extent applicable, wherein at least one R A is -NR a2 C(X)R a1 , -NR a2 C(X)OR a1 , or -NR a2 C(X)NR a1 R a2 .
  • Embodiment 50 The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, C 1 -C 6 alkyl is methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl.
  • Embodiment 50a is methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or
  • C 1 -C 6 alkyl is methyl, ethyl, propyl, or i-propyl.
  • C 1 -C 6 haloalkyl is methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, substituted with one or more halogen (e.g., F, Cl, Br, or I).
  • halogen e.g., F, Cl, Br, or I.
  • C 1 -C 6 haloalkyl is methyl, ethyl, propyl, or i-propyl, substituted with one or more halogen (e.g., F, Cl, Br, or I).
  • C1-C6 alkoxy is methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexoxy.
  • Embodiment 52a The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, C1-C6 alkoxy is methoxy, ethoxy, propoxy, or i-propoxy.
  • Embodiment 53 The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, C1-C6 alkoxy is methoxy, ethoxy, propoxy, or i-propoxy.
  • C1-C6 haloalkoxy is methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t- butoxy, pentoxy, or hexoxy, substituted with one or more halogen (e.g., F, Cl, Br, or I).
  • halogen e.g., F, Cl, Br, or I.
  • C1-C6 haloalkoxy is methoxy, ethoxy, propoxy, or i-propoxy, substituted with one or more halogen (e.g., F, Cl, Br, or I).
  • halogen e.g., F, Cl, Br, or I.
  • Embodiment 54 The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, halogen is F, Cl, Br, or I.
  • Embodiment 54a The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, halogen is F.
  • Embodiment 54b The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, halogen is Cl.
  • non-limiting illustrative compounds of the present disclosure are listed in Table 1. Table 1: Compounds of the Present Disclosure
  • a compound of the present disclosure is a pharmaceutically acceptable salt.
  • a compound of the present disclosure e.g., a compound of any of the formulae or any individual compounds disclosed herein
  • is a solvate is present in some embodiments.
  • a compound of the present disclosure e.g., a compound of any of the formulae or any individual compounds disclosed herein
  • the compounds of the present disclosure may form salts which are also within the scope of this disclosure.
  • Reference to a compound of the formulae herein is understood to include reference to salts thereof, unless otherwise indicated.
  • salts include, e.g., water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumerate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laur
  • Solidvate means solvent addition forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds or salts have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H2O. Compounds having one or more chiral centers can exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement.
  • Stereoisomers include all diastereomeric, enantiomeric, and epimeric forms as well as racemates and mixtures thereof.
  • the term “geometric isomer” refers to cyclic compounds having at least two substituents, wherein the two substituents are both on the same side of the ring (cis) or wherein the substituents are each on opposite sides of the ring (trans).
  • a disclosed compound is named or depicted by structure without indicating stereochemistry, it is understood that the name or the structure encompasses one or more of the possible stereoisomers, or geometric isomers, or a mixture of the encompassed stereoisomers or geometric isomers.
  • geometric isomer When a geometric isomer is depicted by name or structure, it is to be understood that the named or depicted isomer exists to a greater degree than another isomer, that is that the geometric isomeric purity of the named or depicted geometric isomer is greater than 50%, such as at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. Geometric isomeric purity is determined by dividing the weight of the named or depicted geometric isomer in the mixture by the total weight of all of the geometric isomers in the mixture. “Chiral isomer” means a compound with at least one chiral center.
  • a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center.
  • Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center.
  • the substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit.1966, 5, 385; errata 511; Cahn et al., Angew.
  • the compounds of the disclosure are diastereomers.
  • the compounds are the syn diastereomer.
  • the compounds are the anti diastereomer. Racemic mixture means 50% of one enantiomer and 50% of is corresponding enantiomer.
  • Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.
  • Enantiomers and diastereomers also can be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.
  • a compound When a compound is designated by a name or structure that indicates a single enantiomer, unless indicated otherwise, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as “enantiomerically pure”). Optical purity is the weight in the mixture of the named or depicted enantiomer divided by the total weight in the mixture of both enantiomers.
  • stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included.
  • stereoisomeric purity of the named or depicted stereoisomers at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight.
  • the stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers.
  • compounds of the disclosure may exist in different tautomeric forms, and all such forms are embraced within the scope of the disclosure.
  • “Tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds.
  • Tautomers exist as a mixture of a tautomeric set in solution. In solid form, usually one tautomer predominates. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertable by tautomerizations is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs.
  • Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose.
  • Common tautomeric pairs are: ketone-enol, amide-nitrile, lactam- lactim, amide-imidic acid tautomerism in heterocyclic rings (e.g., in nucleobases such as guanine, thymine and cytosine), amine-enamine and enamine-imine.
  • the disclosure also comprehends isotopically-labeled compounds, which are identical to those recited in the each of the formulae described herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.
  • isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, fluorine, such as 3 H, 11 C, 14 C, 2 H and 18 F.
  • Compounds of the disclosure that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present disclosure.
  • Isotopically-labeled compounds of the present disclosure are useful in drug and/or substrate tissue distribution assays.
  • Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are useful for their ease of preparation and detectability.
  • 11 C and 18 F isotopes are useful in PET (positron emission tomography). PET is useful in brain imaging.
  • substitution with heavier isotopes such as deuterium, i.e., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
  • Isotopically labeled compounds of the disclosure can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples described herein, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. In some embodiments, the compounds of the disclosure are not isotopically labelled. Methods for Preparing the Compounds The compounds of the present disclosure may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the Schemes given below. The compounds may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes.
  • protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry.
  • Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art.
  • the selection processes, as well as the reaction conditions and order of their execution, shall be consistent with the preparation of the compounds of the present disclosure. Those skilled in the art will recognize if a stereocenter exists in the compounds of the present disclosure.
  • the present disclosure includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compound but the individual enantiomers and/or diastereomers as well.
  • a compound When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).
  • the compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and/or enzymatic processes.
  • the compounds of the present disclosure can be prepared in a number of ways well known to those skilled in the art of organic synthesis.
  • the compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below.
  • the compounds of the present disclosure i.e., a compound of Formula I
  • alkyl refers to saturated, straight or branched-chain hydrocarbon radicals containing, In some embodiments, between one and six carbon atoms.
  • Examples of C1-C8 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, n-heptyl, and n-octyl radicals.
  • C 1 -C 6 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, and n-hexyl radicals.
  • alkylsulfonyl means a -SO2R radical where R is alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, 2-propylsulfonyl, and the like.
  • alkoxy means an alkyl radical attached through an oxygen linking atom, represented by –O-alkyl.
  • alkoxy includes methoxy, ethoxy, propoxy, and butoxy.
  • alkoxycarbonyl means a -COOR radical where R is alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, propoxy, or 2-propoxycarbonyl, or tertbutoxycarbonyl, and the like.
  • alkoxyalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one alkoxy group, as defined above, e.g., 2-methoxyethyl, 1-, 2-, or 3- methoxypropyl, 2-ethoxyethyl, and the like.
  • acyl means a -C(O)R radical where R is alkyl as defined herein, e.g., methylcarbonyl, ethylcarbonyl, and the like.
  • acylamino means a -NHC(O)R radical where R is alkyl as defined herein, e.g., methylcarbonylamino, ethylcarbonylamino, and the like.
  • amino means a -NH2.
  • haloalkyl and haloalkoxy mean alkyl or alkoxy, as the case may be, substituted with one or more halogen atoms.
  • alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms unless otherwise stated e.g., methylene, ethylene, propylene, 1-methylpropylene, 2- methylpropylene, butylene, pentylene, and the like.
  • An “alkylene group” is a saturated aliphatic branched or straight-chain divalent hydrocarbon radical. Unless otherwise specified, an alkylene group typically has 1-6 carbon atoms, e.g., (C1-C6) alkylene.
  • aryl means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms e.g., phenyl or naphthyl.
  • Bicyclic heterocyclyl means a saturated monocyclic ring having 4 to 7 ring carbon ring atoms wherein one or two ring carbon atoms is(are) replaced by a heteroatom selected from N, O, or S(O) n, (where n is an integer from 0 to 2) that is fused to phenyl, five or six-membered heteroaryl or heterocyclyl, each as defined herein.
  • Exemplary bicyclic heterocyclyl groups include, but are not limited to, and the like.
  • cycloalkyl means a monocyclic saturated hydrocarbon ring system.
  • C3-C7 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, cycloheptyl.
  • a bridged cycloalkyl means a bicyclic hydrocarbon ring system in which the two rings share at least three adjacent ring carbon atoms.
  • a bridged cycloalkyl has 6- 12 ring carbon atoms.
  • Examples include, but are not limited to, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[4.3.1]decyl, bicyclo[3.3.1]nonyl, bornyl, bornenyl, norbornyl, norbornenyl, 6,6-dimethylbicyclo [3.1.1]heptyl, and adamantyl.
  • heterocyclyl means saturated or unsaturated non-aromatic 4-10 membered ring radical containing from 1 to 4 ring heteroatoms, which may be the same or different, selected from N, O, or S. It can be monocyclic, bicyclic or tricyclic (e.g., a fused or bridged bicyclic or tricyclic ring).
  • Examples of include, but are not limited to, azetidinyl, morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, dihydroimidazole, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, dihydropyrimidinyl, dihydrothienyl, dihydrothiophenyl, dihydrothiopyranyl, tetrahydroimidazole, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, and tetrahydrothiopyranyl.
  • a heterocyclic ring optionally contains one or more double bonds and/or is optionally fused with one or more aromatic rings (for example, tetrahydronaphthyridine, indolinone, dihydropyrrolotriazole, imidazopyrimidine, quinolinone, dioxaspirodecane).
  • aromatic rings for example, tetrahydronaphthyridine, indolinone, dihydropyrrolotriazole, imidazopyrimidine, quinolinone, dioxaspirodecane.
  • 3-7 membered monocyclic heterocyclic ring examples include, but are not limited to, azetidinyl, morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, dihydroimidazole, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, dihydropyrimidinyl, dihydrothienyl, dihydrothiophenyl, dihydrothiopyranyl, tetrahydroimidazole, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, and tetra
  • bridged heterocyclyl means a saturated monocyclic ring having 5 to 7 ring carbon ring atoms in which two non-adjacent ring atoms are linked by a (CRR’)n group where n is 1 to 3 and each R and R’ is independently H or methyl (also may be referred to herein as “bridging” group) and further wherein one or two ring carbon atoms, including an atom in the bridging group, is replaced by a heteroatom selected from N, O, or S(O) n, where n is an integer from 0 to 2.
  • Bridged heterocyclyl is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, or cyano.
  • a bridged heterocyclyl means a bicyclic ring system containing from 1 to 4 ring heteroatoms in which the two rings share at least three adjacent ring atoms.
  • a bridged heterocyclyl has 6-12 ring atoms.
  • Examples include, but are not limited to, azanorbornyl, quinuclidinyl, isoquinuclidinyl, tropanyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.2.1]heptany1, 2-azabicyclo[3.2.1]octanyl, azabicyclo[3.2.1]octanyl, azabicyclo[3.2.2]nonanyl, azabicyclo[3.3.0]nonanyl, and azabicyclo [3.3.1]nonanyl.
  • deuteroalkyl means an alkyl radical as defined above wherein one to six hydrogen atoms in the alkyl radical are replaced by deuterium, e.g., -CD3, -CH2CD3, and the like.
  • dialkylamino means -NRR’ radical where R and R’ are independently alkyl as defined herein.
  • halo means fluoro, chloro, bromo, or iodo, preferably fluoro or chloro.
  • heteroaryl when used alone or as part of a larger moiety as in “heteroaralkyl” or “heteroarylalkoxy”, refers to aromatic ring groups having five to ten ring atoms selected from carbon and at least one (typically 1 to 4, more typically 1 or 2) heteroatoms (e.g., oxygen, nitrogen, or sulfur).
  • Heteroaryl includes monocyclic rings and polycyclic rings in which a monocyclic heteroaromatic ring is fused to one or more other aromatic or heteroaromatic rings. “Heteroaryl” includes monocyclic and bicyclic ring systems. “Monocyclic 5-6 membered heteroaromatic ring (or heteroaryl)” means a monocyclic heteroaromatic ring having five or six ring atoms selected from carbon and at least one (typically 1 to 3, more typically 1 or 2) heteroatoms (e.g., oxygen, nitrogen, or sulfur).
  • Examples of monocyclic 5-6 membered heteroaromatic ring groups include furanyl (e.g., 2- furanyl, 3-furanyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 2-oxadiazolyl, 5- oxadiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3- pyridyl
  • a non-hydrogen substituent replaces a hydrogen atom on a carbon or nitrogen.
  • a substituted alkyl is an alkyl wherein at least one non-hydrogen substituent is in the place of a hydrogen atom on the alkyl substituent.
  • monofluoroalkyl is alkyl substituted with a fluoro substituent
  • difluoroalkyl is alkyl substituted with two fluoro substituents. It should be recognized that if there is more than one substitution on a substituent, each non-hydrogen substituent can be identical or different (unless otherwise stated).
  • the optional substituents can be any substituents that are suitable to attach to the moiety.
  • a person of ordinary skill in the art will recognize that the compounds and definitions provided do not include impermissible substituent patterns (e.g., methyl substituted with 5 different groups, and the like). Such impermissible substitution patterns are clearly recognized by a person of ordinary skill in the art.
  • a group is optionally substituted by 1-3 substituents.
  • a group is optionally substituted by 1-2 substituents.
  • a group is optionally substituted by one substituent.
  • Suitable substituents are those which do not have a significant adverse effect on the ability of the compound.
  • Each R a’ and each R b’ are independently H or (C1 ⁇ C6) alkyl, wherein the (C1 ⁇ C6) alkyl group represented by R a’ or R b’ is optionally substituted, for example, with hydroxyl or (C1 ⁇ C3) alkoxy;
  • Suitable substituents may also include: -F, -Cl, -Br, -I, -OH, protected hydroxy, -NO2, -CN, -NH 2 , protected amino, -NH-C 1 -C 12 -alkyl, -NH-C 2 -C 12 -alkenyl, -NH-C 2 -C 12 -alkenyl, - NH -C 3 -C 12 -cycloalkyl, -NH-aryl, -NH -heteroaryl, -NH -heterocycloalkyl, -dialkylamino, - diarylamino, -diheteroarylamino, -O-C1-C12-alkyl, -O-C2-C12-alkenyl, -O-C2-C12-alkenyl, -O-C3-C 12 -cycloalkyl, -O-aryl, -O-hetero
  • a "patient” or “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or rhesus.
  • An "effective amount” or “therapeutically effective amount” when used in connection with a compound or pharmaceutical composition is an amount effective for treating or preventing a disease in a subject as described herein.
  • the term “treating" with regard to a subject refers to improving at least one symptom of the subject's disorder. Treating includes curing, improving, or at least partially ameliorating the disorder.
  • the compounds of the present disclosure can also be used to prevent a disease, condition or disorder.
  • preventing or “prevent” describes reducing or eliminating the onset of the symptoms or complications of the disease, condition or disorder.
  • disorder is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.
  • diseases or disorders in which Pol ⁇ polymerase plays a role means any disease or other deleterious condition in which Pol ⁇ polymerase is known to play a role. Accordingly, another embodiment of the present disclosure relates to treating or lessening the severity of one or more diseases in which Pol ⁇ polymerase is known to play a role.
  • compositions The compounds disclosed therein are Pol ⁇ polymerase inhibitors.
  • the pharmaceutical composition of the present disclosure comprises one or more Pol ⁇ polymerase inhibitors, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or diluent.
  • a “pharmaceutical composition” is a formulation containing the compound of the present disclosure in a form suitable for administration to a subject.
  • the pharmaceutical composition is in bulk or in unit dosage form.
  • the unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial.
  • the quantity of active ingredient (e.g., a formulation of the disclosed compound or a pharmaceutically acceptable salt or solvate thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved.
  • One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient.
  • the dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like.
  • Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers or propellants that are required.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable carrier” and “pharmaceutically acceptable diluent” refer to a substance that aids the formulation and/or administration of an active agent to and/or absorption by a subject and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the subject.
  • Non-limiting examples of pharmaceutically acceptable carriers and/or diluents include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like.
  • Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein.
  • auxiliary agents such
  • carrier encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.
  • the pharmaceutical compositions of the present teachings optionally include one or more pharmaceutically acceptable carriers and/or diluents therefor, such as lactose, starch, cellulose and dextrose.
  • excipients such as flavoring agents; sweeteners; and preservatives, such as methyl, ethyl, propyl and butyl parabens, can also be included. More complete listings of suitable excipients can be found in the Handbook of Pharmaceutical Excipients (5 th Ed., Pharmaceutical Press (2005)). A person skilled in the art would know how to prepare formulations suitable for various types of administration routes. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington’s Pharmaceutical Sciences (2003 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999.
  • compositions of the disclosure are formulated to be compatible with its intended route of administration.
  • routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), and transmucosal administration.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous disclosure can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • a compound or pharmaceutical composition of the disclosure can be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment.
  • a compound of the disclosure may be injected directly into tumors, injected into the blood stream or body cavities or taken orally or applied through the skin with patches.
  • the dose chosen should be sufficient to constitute effective treatment but not as high as to cause unacceptable side effects.
  • the state of the disease condition e.g., cancer, precancer, and the like
  • the health of the patient should preferably be closely monitored during and for a reasonable period after treatment.
  • therapeutically effective amount refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect.
  • the effect can be detected by any assay method known in the art.
  • the precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration.
  • Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.
  • the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs.
  • the animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.
  • Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED 50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD 50 /ED 50 .
  • Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration. Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect.
  • Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy.
  • Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.
  • compositions containing active compound (i.e., a compound of Formula (I)) of the present disclosure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes.
  • Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of the active compound into preparations that can be used pharmaceutically.
  • the appropriate formulation is dependent upon the route of administration chosen.
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor EL ⁇ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS).
  • the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed.
  • compositions can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • a sweetening agent such as sucrose or saccharin
  • the compound is delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
  • a suitable propellant e.g., a gas such as carbon dioxide, or a nebulizer.
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
  • Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
  • the active compound is formulated into ointments, salves, gels, or creams as generally known in the art.
  • the active compound can be prepared with pharmaceutically acceptable carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
  • the materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.
  • Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No.4,522,811. It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject 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 specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.
  • the dosages of the pharmaceutical compositions used in accordance with the disclosure vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage.
  • the dose should be sufficient to result in slowing, and preferably regressing, the growth of the tumors and also preferably causing complete regression of the cancer.
  • Dosages can range from about 0.01 mg/kg per day to about 5000 mg/kg per day.
  • An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer. For example, regression of a tumor in a subject may be measured with reference to the diameter of a tumor. Decrease in the diameter of a tumor indicates regression.
  • the term “dosage effective manner” refers to amount of an active compound to produce the desired biological effect in a subject or cell.
  • the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.
  • the dosage regimen utilizing the compound is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or pharmaceutically acceptable salt or solvate thereof employed.
  • An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • the compound described herein, and the pharmaceutically acceptable salts or solvates thereof are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent.
  • suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions.
  • the compound or pharmaceutically acceptable salts or solvates thereof will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein. All percentages and ratios used herein, unless otherwise indicated, are by weight.
  • the present disclosure provides a method of treating a subject with a disease or disorder which can be ameliorated by inhibition of Pol ⁇ polymerase or in which Pol ⁇ polymerase is involved, for example, in which the expression or activity of Pol ⁇ polymerase is dysregulated or aberrant, by administering to the subject an effective amount of one or more disclosed compounds, or a pharmaceutically acceptable salt or solvate thereof, or the corresponding pharmaceutical composition.
  • the present disclosure further relates to a method of treating a disease or disorder in which Pol ⁇ polymerase plays a role, for example, cancer.
  • the method comprises administering to a subject in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition disclosed herein.
  • described herein is a method for treating and/or preventing a disease in a subject, such as cancer characterized by overexpression/overactivity of Pol ⁇ polymerase, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof.
  • described herein is a method for treating and/or preventing a cancer in a subject, such as cancer characterized by a deficiency in homologous recombinant (HR) or by a reduction or absence of BRCA gene expression, the absence of the BRAC gene, or reduced function of BRCA protein, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof.
  • a method for inhibiting DNA repair by Pol ⁇ in a cell comprising contacting the cell with an effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof.
  • the cell is HR deficient.
  • a compound described herein or a pharmaceutically acceptable salt or solvate thereof for inhibiting DNA repair by Pol ⁇ in a cell In some embodiments, the cell is HR deficient. In another aspect, described herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for treating and/or preventing a disease in a subject, e.g., a disease such as cancer treatable by inhibition of Pol ⁇ , including homologous recombination (HR) deficient cancers.
  • a disease in a subject e.g., a disease such as cancer treatable by inhibition of Pol ⁇ , including homologous recombination (HR) deficient cancers.
  • HR homologous recombination
  • a compound described herein or a pharmaceutically acceptable salt or solvate thereof for treating and/or preventing a disease in a subject, such as cancer characterized by overexpression/overactivity of Pol ⁇ polymerase, by a deficiency in homologous recombinant (HR), or by a reduction or absence of BRAC gene expression, the absence of the BRAC gene, or reduced function of BRAC protein.
  • a compound described herein or a pharmaceutically acceptable salt or solvate thereof for use in the manufacture of a medicament for inhibiting DNA repair by Pol ⁇ in a cell.
  • the cell is HR deficient.
  • described herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for use in the manufacture of a medicament for treating and/or preventing a disease in a subject, e.g., a disease such as cancer treatable by inhibition of Pol ⁇ , including homologous recombination (HR) deficient cancers.
  • a disease such as cancer treatable by inhibition of Pol ⁇ , including homologous recombination (HR) deficient cancers.
  • HR homologous recombination
  • described herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for use in the manufacture of a medicament for treating and/or preventing a disease in a subject, such as cancer characterized by overexpression/overactivity of Pol ⁇ polymerase, by a deficiency in homologous recombinant (HR), or by a reduction or absence of BRAC gene expression, the absence of the BRAC gene, or reduced function of BRAC protein.
  • a compound described herein or a pharmaceutically acceptable salt or solvate thereof for treating and/or preventing a cancer that is resistant to poly(ADP-ribose) polymerase (PARP) inhibitor therapy in a subject.
  • PARP poly(ADP-ribose) polymerase
  • cancers resistant to PARP-inhibitors include, but are not limited to, breast cancer, ovarian cancer, lung cancer, bladder cancer, liver cancer, head and neck cancer, pancreatic cancer, gastrointestinal cancer, and colorectal cancer.
  • described herein is a method of treating cancer, the method comprising administering a therapeutically effective dose of a composition as described herein, e.g., a composition comprising a compound of the present disclosure, to a subject in need of treatment for cancer.
  • the present disclosure further relates to use of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein, in the manufacture of a medicament for the treatment of a disease or disorder in which Pol ⁇ polymerase plays a role, for example, a cancer.
  • the present disclosure provides use of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein, in the manufacture of a medicament for the treatment of a disease or disorder which can be ameliorated by inhibition of Pol ⁇ polymerase.
  • described herein is use of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein, in the manufacture of a medicament for the treatment of a cancer.
  • the present disclosure further relates to a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein, for use in treating a disease or disorder in which Pol ⁇ polymerase plays a role, for example, a cancer.
  • the present disclosure provides a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein, for use in treating a disease or disorder which can be ameliorated by inhibition of Pol ⁇ polymerase.
  • described herein is a method for treating and/or preventing a disease, such as cancer, characterized by overexpression of Pol ⁇ polymerase in a patient comprising administering to the patient a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt or solvate thereof.
  • a method for treating and/or preventing a homologous recombinant (HR) deficient cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof.
  • HR homologous recombinant
  • described herein is a method for inhibiting DNA repair by Pol ⁇ in a cancer cell comprising contacting the cell with an effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof.
  • the cancer is HR deficient cancer.
  • described herein is a method for treating and/or preventing a cancer in a patient, wherein the cancer is characterized by a reduction or absence of BRCA gene expression, the absence of the BRAC gene, or reduced function of BRCA protein, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof, optionally in a pharmaceutical composition.
  • the cancer is lymphoma, leukemia, multiple myeloma, soft tissue cancer, rhabdoid tumor, rhabdomyosarcoma, central nervous system cancer, peripheral nervous system cancer, bone cancer, uterine cancer, ovarian cancer, upper aerodigestive cancer, esophagus cancer, gastric cancer, gastrointestinal cancer, colorectal cancer, mesothelioma, breast cancer, lung cancer, bladder cancer, liver cancer, head and neck cancer, fibroblast cancer, urinary tract cancer, kidney cancer, skin cancer, prostate cancer, and pancreatic cancer.
  • an HR-deficient cancer is breast cancer.
  • Breast cancer includes, but is not limited to, lobular carcinoma in situ (LCIS), ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC), inflammatory breast cancer, Paget disease of the nipple, Phyllodes tumor, angiosarcoma, adenoid cystic carcinoma, low-grade adenosquamous carcinoma, medullary carcinoma, mucinous carcinoma, papillary carcinoma, tubular carcinoma, metaplastic carcinoma, micropapillary carcinoma, mixed carcinoma, and other breast cancer, including but not limited to, breast cancer that is triple negative, HER positive, estrogen receptor positive, progesterone receptor positive, HER and estrogen receptor positive, HER and progesterone receptor positive, estrogen and progesterone receptor positive, and/or HER and estrogen and progesterone receptor positive.
  • LCIS lobular carcinoma in situ
  • DCIS ductal carcinoma in situ
  • IDC invasive ductal carcinoma
  • inflammatory breast cancer Paget disease of the nipple
  • an HR-deficient cancer is ovarian cancer, including, but not limited to, epithelial ovarian carcinomas (EOC), maturing teratomas, dysgerminomas, endodermal sinus tumors, granulosa-theca tumors, Sertoli-Leydig cell tumors, and primary peritoneal carcinoma.
  • cancers that can be treated by the disclosed methods include cancer of the bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, gastrointestine, gum, head, kidney, liver, lung, nasopharynx, neck, ovary, prostate, skin, stomach, testis, tongue, or uterus.
  • the cancer may specifically be of the following histological type, though it is not limited to these: neoplasm, malignant; carcinoma; carcinoma, undifferentiated; giant and spindle cell carcinoma; sarcomas; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lymphoepithelial carcinoma; basal cell carcinoma; pilomatrix carcinoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; gastrinoma, malignant; cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular carcinoma and cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in adenomatous polyp; adenocarcinoma, familial polyposis coli; solid carcinoma; carcinoid tumor, malignant; branchiolo-alveolar adenocarcinoma; papillary adenocarcinoma; chro
  • treating includes inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms; or relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
  • inhibiting includes any measurable decrease or complete inhibition to achieve a desired result.
  • preventing refers to causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease.
  • homologous recombination refers to the cellular process of genetic recombination in which nucleotide sequences are exchanged between two similar or identical DNA.
  • HR deficient cancer refers to a cancer that is characterized by a reduction or absence of a functional HR repair pathway. HR deficiency may arise from absence of one or more HR-associated genes or presence of one or more mutations in one or more HR-associated genes.
  • HR-associated genes include BRCA1, BRCA2, RAD54, RAD51B, CtlP (Choline Transporter-Like Protein), PALB2 (Partner and Localizer of BRCA2), XRCC2 (X-ray repair complementing defective repair in Chinese hamster cells 2), RECQL4 (RecQ Protein-Like 4), BLM (Bloom syndrome, RecQ helicase-like), WRN (Werner syndrome , one or more HR-associated genes) Nbs 1 (Nibrin), and genes encoding Fanconi anemia (FA) proteins or FA-like genes e.g., FANCA, FANCB, FANCC, FANCD1 (BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANJ (BRIP1), FANCL, FANCM, FANCN (RALB2), FANCP (SLX4), FANCS (BRCA1), RAD51C, and XPF.
  • FANCA Fanconi anemia
  • Poly ⁇ ⁇ overexpression refers to the increased expression or activity of Pol ⁇ ⁇ in disease cells e.g., cancerous cell, relative to expression or activity of Pol ⁇ ⁇ in a normal cell (e.g., non-diseased cell of the same kind).
  • the amount of Pol ⁇ can be at least 2-fold, at least 3-fold, at least 4- fold, at least 5- fold, at least 10-fold, or more relative to the Pol ⁇ ⁇ expression in a normal cell.
  • Examples of Pol ⁇ ⁇ cancers include, but are not limited to, breast, ovarian, cervical, lung, colorectal, gastric, bladder and prostate cancers.
  • the compounds of the present disclosure can be co-administered with other therapeutic agents.
  • other therapeutic agents include chemotherapeutic agents known in the art, such as inhibitors of the DNA repair pathways (e.g., HR and NHEJ) and immunomodulatory agents.
  • chemotherapeutic agents known in the art, such as inhibitors of the DNA repair pathways (e.g., HR and NHEJ) and immunomodulatory agents.
  • co- administration is meant to encompass administration of two or more therapeutic agents to a single subject, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different times.
  • These terms encompass administration of two or more agents to the subject so that both agents and/or their metabolites are present in the subject at the same time. They include simultaneous administration in separate compositions, administration at different times in separate compositions, and/or administration in a composition in which both agents are present.
  • the compounds described herein and the other agent(s) are administered in a single composition.
  • the compounds described herein and the other agent(s) are admixed in the composition.
  • EXAMPLES Abbreviations General Procedures A: To a solution of the carboxylic acid (1.0 eq.) and substituted aniline (3.0 eq.) in a mixture of DCM /THF (1:1) was added EDCI (3.0 eq.). The mixture was stirred at 25 °C for 12 hrs, quenched by addition of H2O at 0 °C and extracted with EtOAc.
  • Example 7 Preparation of (1S,3aR,6aS)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N- methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (Compound 7) a) Synthesis of tert-butyl (1S,3aR,6aS)-1-(methyl(m- tolyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate tert-Butyl (1S,3aR,6aS)-1-(methyl(m- tolyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate was synthesized from (1S,3aR,6aS)-2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrole-1-
  • Polymerase theta polymerase domain activity assay Polymerase theta polymerase domain (amino acid residues 1819 to 2590) was expressed in E. coli as a hexahistidine fusion protein and purified by metal affinity chromatography. Polymerase activity was measured in 25 mM Tris•HCl (pH 7.5), 12.5 mM NaCl, 0.5 mM MgCl 2 , 0.01% Triton X-100, 0.1 mg/ml bovine gamma-globulin, 5% glycerol.
  • test compound dissolved in DMSO and DMSO were added to test wells to create a 9-point dilution series of test compound, no activity control wells, full activity control wells and a final DMSO volume of 100 nl.
  • 5 ⁇ l of assay buffer containing 40 nM polymerase domain was added to all wells except for no activity control wells, to which 5 ⁇ l of assay buffer was added.
  • IC50 of the Compounds of the Present Disclosure IC 50 : A: ⁇ 0.1 ⁇ M, B: 0.1 ⁇ M – 0.5 ⁇ M, C: 0.5 ⁇ M – 1 ⁇ M, D: > 1 ⁇ M

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Abstract

This application is directed to inhibitors of DNA Polymerase Theta (Polθ) activity represented by the following structural formula (I), and methods for their use, such as to treat cancer.

Description

3,4-FUSED BICYCLIC PYRROLIDINE AND 3,4-FUSED BICYCLIC PYRROLIDINONE COMPOUNDS CROSS-REFERENCE TO RELATED APPLICATION This application claims priority to, and the benefit of, U.S. Provisional Application No.63/451,938, filed on March 14, 2023, the entire contents of which are incorporated herein by reference. BACKGROUND DNA lesions can occur as a result of exogenous and endogenous DNA-damaging agents. To maintain genomic stability and to limit the progression of DNA lesions, cells evolved DNA damage response (DDR) mechanisms. Double-strand breaks (DSBs) are repaired by two major pathways: homologous recombination (HR) and non-homologous end- joining (NHEJ). When NHEJ or HR are compromised, alternative end-joining (alt-EJ), also known as microhomology-mediated end-joining (MMEJ) pathway, can serve as a backup repair pathway. DNA polymerase theta (Polθ) is an A-family polymerase encoded by the POLQ gene. It is a multi-functional protein that exhibits a C-terminal DNA polymerase domain (Polθ-pol), a central domain, and an N-terminal helicase domain (Polθ-hel). It is an error-prone polymerase that promotes MMEJ in higher organisms. The Polθ-hel domain is a member of the SF2 helicases. While it has single-stranded DNA-dependent ATPase activity that can strip Replication Protein A (RPA) from single stranded DNA, it can suppress HR pathway by disrupting Rad51 nucleoprotein complex formation after radiation exposure. This anti- recombinase activity of Polθ promotes the alt-EJ pathway. The helicase domain of Polθ can bridge two single stranded DNA sequences resulting in microhomology-mediated strand annealing. Specifically, Polθ promotes end-joining in alt- EJ pathway by employing this annealing activity even when single stranded DNA overhangs possess limited homology. The Rad51 interaction is followed by ATPase-mediated displacement of Rad51 from DSB damage sites during the reannealing process. Once annealed, the primer strand of DNA is extended by the polymerase domain of Polθ. It has been shown that cancer cells with deficiency in HR, NHEJ or ataxia telangiectasia-mutated (ATM) are highly dependent on Polθ expression. Polθ has limited expression in normal cells, but is overexpressed in a variety of cancer cells. Depletion of Polθ can impair cell-viability and can lead to synthetic lethality of cancer cells. As such, Polθ is an attractive target for novel synthetic lethal therapy of cancers containing DNA repair defects. In view of the connection between the overexpression of Polθ in cancer cells, there is a need for compounds that inhibit Polθ polymerase activity. The present disclosure addresses the need. SUMMARY Disclosed herein are certain substituted 3,4-fused bicyclic pyrrolidine and 3,4-fused bicyclic pyrrolidinone compounds that inhibit DNA Polymerase Theta (Polθ) activity, in particular inhibit the activity of the polymerase domain of Polθ. In one aspect, described herein is a compound of Formula I:
Figure imgf000003_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein W, Y1, Y2, R1, R1’, R2, R2’, R5, R6, and R7 are described herein. Also disclosed are pharmaceutical compositions comprising such compounds and methods of treating and/or preventing diseases, e.g., diseases such as cancer treatable by inhibition of Polθ, including homologous recombination (HR) deficient cancers. In another aspect, described herein is a method for treating and/or preventing a disease in a subject, such as cancer characterized by overexpression/overactivity of Polθ polymerase, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof. In another aspect, described herein is a method for treating and/or preventing a cancer in a subject, such as cancer characterized by a deficiency in homologous recombinant (HR) or by a reduction or absence of BRCA gene expression, the absence of the BRAC gene, or reduced function of BRCA protein, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof. In another aspect, described herein is a method for inhibiting DNA repair by Polθ in a cell, comprising contacting the cell with an effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the cell is HR deficient. In another aspect, provided herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for inhibiting DNA repair by Polθ in a cell. In some embodiments, the cell is HR deficient. In another aspect, described herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for treating and/or preventing a disease in a subject, e.g., a disease such as cancer treatable by inhibition of Polθ, including homologous recombination (HR) deficient cancers. In another aspect, described herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for treating and/or preventing a disease in a subject, such as cancer characterized by overexpression/overactivity of Polθ polymerase, by a deficiency in homologous recombinant (HR), or by a reduction or absence of BRAC gene expression, the absence of the BRAC gene, or reduced function of BRAC protein. In another aspect, provided herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for use in the manufacture of a medicament for inhibiting DNA repair by Polθ in a cell. In some embodiments, the cell is HR deficient. In another aspect, described herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for use in the manufacture of a medicament for treating and/or preventing a disease in a subject, e.g., a disease such as cancer treatable by inhibition of Polθ, including homologous recombination (HR) deficient cancers. In another aspect, described herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for use in the manufacture of a medicament for treating and/or preventing a disease in a subject, such as cancer characterized by overexpression/overactivity of Polθ polymerase, by a deficiency in homologous recombinant (HR), or by a reduction or absence of BRAC gene expression, the absence of the BRAC gene, or reduced function of BRAC protein. In another aspect, described herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for treating and/or preventing a cancer that is resistant to poly(ADP-ribose) polymerase (PARP) inhibitor therapy in a subject. Examples of cancers resistant to PARP-inhibitors include, but are not limited to, breast cancer, ovarian cancer, lung cancer, bladder cancer, liver cancer, head and neck cancer, pancreatic cancer, gastrointestinal cancer, and colorectal cancer. The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties. DETAILED DESCRIPTION Compounds of the Disclosure The present disclosure relates to a compound of Formula I:
Figure imgf000005_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein: R1’ and R2’, together with the carbon atoms to which they are bonded, form a ring Cy, or R1 and R1’ are bonded together to form -(CH2)n-, and R2’ is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), halogen, oxo, or benzyl; n is 1, 2, or 3; R1 and R2 are each independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1- C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), halogen, oxo, or benzyl; ring Cy is a 4- to 6-membered fully saturated or partially saturated, or 5- or 6- membered aromatic ring optionally comprising 1-4 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NRa2C(X)NRa1Ra2; X is NRN, O, or S; RN is H or C1-C6 alkyl; Y1 is O and Y2 is -NR3R4, or Y1 and Y2, together with the carbon atom to which they are bonded, form
Figure imgf000006_0001
R3 is C6-C10 aryl or heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NRa2C(X)NRa1Ra2; R4 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, or heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, - C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2; and wherein the alkyl, alkenyl, or alkynyl is optionally substituted with one or more groups independently selected from C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, - NH2, -NRa2(C1-C6 alkyl), -CN, halogen, C6-C10 aryl, and heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, - NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, - NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2; W is N or CRW; RW, R5, R6, and R7 are each independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, -C(X)Ra1, - C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, or -NRa2C(X)NRa1Ra2; each Ra1 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-C6-C10 aryl, or C1-C6 alkyl-heteroaryl wherein the heteroaryl comprises a 5- or 6-membered ring and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, and oxo; and each Ra2 is independently H or C1-C6 alkyl, provided that when R1 or R2 is oxo, Y1 is O and Y2 is -NR3R4, and W is CH, then R1’ and R2’ are not bonded to form a methylenedioxy, wherein one or more hydrogen atoms in any of Ra1, Ra2, R1, R1’, R2, R2’, R3, R4, RN, RW, R5, R6, and R7 may be replaced with one or more deuterium atoms. Various embodiments of the compounds of the present disclosure, including embodiments of the various groups defined for any of ring Cy, W, X, Y1, Y2, n, A1, A2, A3, A4, RA, RN, Ra1, Ra2, R1, R1’, R2, R2’, R3, R4, RW, R5, R6, and R7 are described herein, such as below. It is understood that any group or embodiment described herein for any of ring Cy, W, X, Y1, Y2, n, A1, A2, A3, A4, RA, RN, Ra1, Ra2, R1, R1’, R2, R2’, R3, R4, RW, R5, R6, and R7 can be combined with one or more groups or embodiments described herein for one or more of the remainder of ring Cy, W, X, Y1, Y2, n, A1, A2, A3, A4, RA, RN, Ra1, Ra2, R1, R1’, R2, R2’, R3, R4, RW, R5, R6, and R7. Embodiments of the Disclosure Embodiment 1. A compound of Formula I:
Figure imgf000007_0001
or a pharmaceutically acceptable salt or solvate thereof, as described above. Embodiment 2. The compound of Embodiment 1, wherein R1’ and R2’, together with the carbon atoms to which they are bonded, form a ring Cy. Embodiment 2a. The compound of Embodiment 1 or 2, wherein ring Cy is a 4- to 6- membered fully saturated ring optionally comprising 1-4 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NRa2C(X)NRa1Ra2. Embodiment 2a-1. The compound of Embodiment 1 or 2, wherein ring Cy is a 4- membered fully saturated ring optionally comprising 1-4 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NRa2C(X)NRa1Ra2. Embodiment 2a-2. The compound of Embodiment 1 or 2, wherein ring Cy is a 4- membered fully saturated ring optionally comprising 1-2 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NRa2C(X)NRa1Ra2. Embodiment 2a-3. The compound of Embodiment 1 or 2, wherein ring Cy is a 4- membered fully saturated ring comprising 0 heteroatoms, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1- C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, - C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2. Embodiment 2a-4. The compound of Embodiment 1 or 2, wherein ring Cy is a 5- membered fully saturated ring optionally comprising 1-4 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NRa2C(X)NRa1Ra2. Embodiment 2a-5. The compound of Embodiment 1 or 2, wherein ring Cy is a 5- membered fully saturated ring optionally comprising 1-2 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NRa2C(X)NRa1Ra2. Embodiment 2a-6. The compound of Embodiment 1 or 2, wherein ring Cy is a 5- membered fully saturated ring comprising 0 heteroatoms, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1- C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, - C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2. Embodiment 2a-7. The compound of Embodiment 1 or 2, wherein ring Cy is a 6- membered fully saturated ring optionally comprising 1-4 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NRa2C(X)NRa1Ra2. Embodiment 2a-8. The compound of Embodiment 1 or 2, wherein ring Cy is a 6- membered fully saturated ring optionally comprising 1-2 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NRa2C(X)NRa1Ra2. Embodiment 2a-9. The compound of Embodiment 1 or 2, wherein ring Cy is a 6- membered fully saturated ring comprising 0 heteroatoms, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1- C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, - C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2. Embodiment 2b. The compound of Embodiment 1 or 2, wherein ring Cy is a 4- to 6- membered partially saturated ring optionally comprising 1-4 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NRa2C(X)NRa1Ra2. Embodiment 2b-1. The compound of Embodiment 1 or 2, wherein ring Cy is a 4- membered partially saturated ring optionally comprising 1-4 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NRa2C(X)NRa1Ra2. Embodiment 2b-2. The compound of Embodiment 1 or 2, wherein ring Cy is a 4- membered partially saturated ring optionally comprising 1-2 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NRa2C(X)NRa1Ra2. Embodiment 2b-3. The compound of Embodiment 1 or 2, wherein ring Cy is a 4- membered partially saturated ring comprising 0 heteroatoms, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2. Embodiment 2b-4. The compound of Embodiment 1 or 2, wherein ring Cy is a 5- membered partially saturated ring optionally comprising 1-4 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NRa2C(X)NRa1Ra2. Embodiment 2b-5. The compound of Embodiment 1 or 2, wherein ring Cy is a 5- membered partially saturated ring optionally comprising 1-2 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NRa2C(X)NRa1Ra2. Embodiment 2b-6. The compound of Embodiment 1 or 2, wherein ring Cy is a 5- membered partially saturated ring comprising 0 heteroatoms, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2. Embodiment 2b-7. The compound of Embodiment 1 or 2, wherein ring Cy is a 6- membered partially saturated ring optionally comprising 1-4 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NRa2C(X)NRa1Ra2. Embodiment 2b-8. The compound of Embodiment 1 or 2, wherein ring Cy is a 6- membered partially saturated ring optionally comprising 1-2 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NRa2C(X)NRa1Ra2. Embodiment 2b-9. The compound of Embodiment 1 or 2, wherein ring Cy is a 6- membered partially saturated ring comprising 0 heteroatoms, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2. Embodiment 2c. The compound of Embodiment 1 or 2, wherein ring Cy is a 5- or 6- membered aromatic ring optionally comprising 1-4 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NRa2C(X)NRa1Ra2. Embodiment 2c-1. The compound of Embodiment 1 or 2, wherein ring Cy is a 5- membered aromatic ring optionally comprising 1-4 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NRa2C(X)NRa1Ra2. Embodiment 2c-2. The compound of Embodiment 1 or 2, wherein ring Cy is a 5- membered aromatic ring optionally comprising 1-2 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NRa2C(X)NRa1Ra2. Embodiment 2c-3. The compound of Embodiment 1 or 2, wherein ring Cy is a 6- membered aromatic ring optionally comprising 1-4 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NRa2C(X)NRa1Ra2. Embodiment 2c-4. The compound of Embodiment 1 or 2, wherein ring Cy is a 6- membered aromatic ring optionally comprising 1-2 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NRa2C(X)NRa1Ra2. Embodiment 2c-5. The compound of Embodiment 1 or 2, wherein ring Cy is a 6- membered aromatic ring comprising 0 heteroatoms, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, - C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2. Embodiment 3. The compound of Embodiment 1, wherein R1 and R1’ are bonded together to form -(CH2)1-3-, and R2’ is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), halogen, oxo, or benzyl. Embodiment 3a. The compound of Embodiment 1, wherein R1 and R1’ are bonded together to form -(CH2)1-, and R2’ is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), halogen, oxo, or benzyl. Embodiment 3b. The compound of Embodiment 1, wherein R1 and R1’ are bonded together to form -(CH2)2-, and R2’ is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), halogen, oxo, or benzyl. Embodiment 3c. The compound of Embodiment 1, wherein R1 and R1’ are bonded together to form -(CH2)3-, and R2’ is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), halogen, oxo, or benzyl. Embodiment 4. The compound of Embodiment 1, of Formula II:
Figure imgf000013_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein: A1 and A4 are each independently N or CRA; A2 and A3 are each independently absent, N, or CRA; and each RA is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, - C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, or -NRa2C(X)NRa1Ra2. Embodiment 5. The compound of any of Embodiments 1-2c-5 and 4, of Formula IIa or IIb:
Figure imgf000013_0002
or a pharmaceutically acceptable salt or solvate thereof, wherein: A1 and A4 are each independently N or CRA; A2 and A3 are each independently absent, N, or CRA; and each RA is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, - C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, or -NRa2C(X)NRa1Ra2. Embodiment 6. The compound of Embodiment 4 or 5, wherein A1, A2, A3, and A4 are each CRA. Embodiment 7. The compound of Embodiment 4 or 5, wherein one of A1, A2, A3, and A4 is N. Embodiment 8. The compound of Embodiment 7, wherein A1 is N. Embodiment 9. The compound of Embodiment 7, wherein A2 is N. Embodiment 10. The compound of Embodiment 7, wherein A3 is N. Embodiment 11. The compound of Embodiment 7, wherein A4 is N. Embodiment 12. The compound of Embodiment 4 or 5, wherein two of A1, A2, A3, and A4 are N. Embodiment 13. The compound of Embodiment 12, wherein A1 and A2 are N. Embodiment 14. The compound of Embodiment 12, wherein A1 and A3 are N. Embodiment 15. The compound of Embodiment 12, wherein A1 and A4 are N. Embodiment 16. The compound of Embodiment 12, wherein A2 and A3 are N. Embodiment 17. The compound of Embodiment 12, wherein A2 and A4 are N. Embodiment 18. The compound of Embodiment 12, wherein A3 and A4 are N. Embodiment 19. The compound of Embodiment 4 or 5, wherein one of A1, A2, A3, and A4 is CRA. Embodiment 20. The compound of Embodiment 19, wherein A1 is CRA. Embodiment 21. The compound of Embodiment 19, wherein A2 is CRA. Embodiment 22. The compound of Embodiment 19, wherein A3 is CRA. Embodiment 23. The compound of Embodiment 19, wherein A4 is CRA. Embodiment 24. The compound of Embodiment 4 or 5, wherein A2 is absent or A3 is absent. Embodiment 25. The compound of Embodiment 4 or 5, wherein A2 is absent and A3 is absent. Embodiment 26. The compound of Embodiment 1, of Formula III:
Figure imgf000014_0001
Embodiment 26a. The compound of Embodiment 1 or 26, wherein n is 1. Embodiment 26b. The compound of Embodiment 1 or 26, wherein n is 2. Embodiment 26c. The compound of Embodiment 1 or 26, wherein n is 3. Embodiment 27. The compound of any of previous Embodiments to the extent applicable, wherein Y1 is O and Y2 is -NR3R4. Embodiment 28. The compound of any of previous Embodiments to the extent applicable, wherein Y1 and Y2, together with the carbon atom to which they are bonded, form
Figure imgf000015_0001
. Embodiment 29. The compound of any of previous Embodiments to the extent applicable, wherein W is N. Embodiment 30. The compound of any of previous Embodiments to the extent applicable, wherein W is CRW. Embodiment 31. The compound of any of previous Embodiments to the extent applicable, wherein R3 is C6-C10 aryl optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, - OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, - NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2. Embodiment 32. The compound of any of previous Embodiments to the extent applicable, wherein R3 phenyl optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, - NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, - NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2. Embodiment 33. The compound of any of previous Embodiments to the extent applicable, wherein R3 is heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, - OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, - NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2. Embodiment 34. The compound of any of previous Embodiments to the extent applicable, wherein R3 is heteroaryl comprising one 5- or 6-membered ring and 1-4 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, - OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, - NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2. Embodiment 34a. The compound of any of previous Embodiments to the extent applicable, wherein R3 is heteroaryl comprising one 5- or 6-membered ring and 1-2 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, - OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, - NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2. Embodiment 34b. The compound of any of previous Embodiments to the extent applicable, wherein R3 is heteroaryl comprising one 5-membered ring and 1-2 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, - NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, - NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2. Embodiment 34c. The compound of any of previous Embodiments to the extent applicable, wherein R3 is heteroaryl comprising one 6-membered ring and 1-2 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, - NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, - NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2. Embodiment 34d. The compound of any of previous Embodiments to the extent applicable, wherein R3 is heteroaryl comprising two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, - OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, - NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2. Embodiment 35. The compound of any of previous Embodiments to the extent applicable, wherein R4 is H or C1-C6 alkyl optionally substituted with one or more groups independently selected from C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, C6-C10 aryl, and heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1- C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NRa2C(X)NRa1Ra2. Embodiment 35a. The compound of any of previous Embodiments to the extent applicable, wherein R4 is C1-C6 alkyl optionally substituted with one or more groups independently selected from C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, C6-C10 aryl, and heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1- C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NRa2C(X)NRa1Ra2. Embodiment 35’. The compound of any of previous Embodiments to the extent applicable, wherein R4 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, optionally substituted with one or more groups independently selected from C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, - NH2, -NRa2(C1-C6 alkyl), -CN, halogen, C6-C10 aryl, and heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from C1- C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), - CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2. Embodiment 36. The compound of any of previous Embodiments to the extent applicable, wherein R4 is C6-C10 aryl, or heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1- C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NRa2C(X)NRa1Ra2. Embodiment 37. The compound of any of previous Embodiments to the extent applicable, wherein R4 is C6-C10 aryl, optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, - OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, - NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2. Embodiment 37a. The compound of any of previous Embodiments to the extent applicable, wherein R4 is phenyl, optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, - OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, - NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2. Embodiment 38. The compound of any of previous Embodiments to the extent applicable, wherein R4 is heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, - OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, - NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2. Embodiment 39. The compound of any of previous Embodiments to the extent applicable, wherein R4 is heteroaryl comprising one 5- or 6-membered ring and 1-4 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, - OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, - NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2. Embodiment 39a. The compound of any of previous Embodiments to the extent applicable, wherein R4 is heteroaryl comprising one 5- or 6-membered ring and 1-2 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, - OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, - NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2. Embodiment 39b. The compound of any of previous Embodiments to the extent applicable, wherein R4 is heteroaryl comprising one 5-membered ring and 1-2 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, - NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, - NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2. Embodiment 39c. The compound of any of previous Embodiments to the extent applicable, wherein R4 is heteroaryl comprising one 6-membered ring and 1-2 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, - NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, - NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2. Embodiment 39d. The compound of any of previous Embodiments to the extent applicable, wherein R4 is heteroaryl comprising two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, - OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, - NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2. Embodiment 40. The compound of any of previous Embodiments to the extent applicable, wherein R1 and R2 are each H. Embodiment 41. The compound of any of previous Embodiments to the extent applicable, wherein one of R1 and R2 is H, and the other is C1-C6 alkyl, C1-C6 haloalkyl, C1- C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), halogen, oxo, or benzyl. Embodiment 42. The compound of any of previous Embodiments to the extent applicable, wherein R1 and R2 are each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), halogen, oxo, or benzyl. Embodiment 43. The compound of any of previous Embodiments to the extent applicable, wherein R1 and R2 are each independently C1-C6 alkyl. Embodiment 44a. The compound of any of previous Embodiments to the extent applicable, wherein RW is H. Embodiment 44b. The compound of any of previous Embodiments to the extent applicable, wherein RW is C1-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s- butyl, t-butyl, pentyl, or hexyl), C1-C6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, substituted with one or more halogen (e.g., F, Cl, Br, or I), C1-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexoxy), or C1-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, i- propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexoxy, substituted with one or more halogen (e.g., F, Cl, Br, or I)). Embodiment 44c. The compound of any of previous Embodiments to the extent applicable, wherein RW is -OH, -NH2, -NRa2(C1-C6 alkyl) (wherein the alkyl is methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), -CN, or halogen (e.g., F, Cl, Br, or I). Embodiment 44d. The compound of any of previous Embodiments to the extent applicable, wherein RW is -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, - NRa2C(X)ORa1, or -NRa2C(X)NRa1Ra2. Embodiment 44e. The compound of any of previous Embodiments to the extent applicable, wherein RW is -C(X)Ra1, -C(X)ORa1, or -C(X)NRa1Ra2. Embodiment 44f. The compound of any of previous Embodiments to the extent applicable, wherein RW is -NRa2C(X)Ra1, -NRa2C(X)ORa1, or -NRa2C(X)NRa1Ra2. Embodiment 45a. The compound of any of previous Embodiments to the extent applicable, wherein R5, R6, and R7 are each H. Embodiment 45b. The compound of any of previous Embodiments to the extent applicable, wherein at least one of R5, R6, and R7 is C1-C6 alkyl (e.g., methyl, ethyl, propyl, i- propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), C1-C6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, substituted with one or more halogen (e.g., F, Cl, Br, or I), C1-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexoxy), or C1-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexoxy, substituted with one or more halogen (e.g., F, Cl, Br, or I)). Embodiment 45c. The compound of any of previous Embodiments to the extent applicable, wherein at least one of R5, R6, and R7 is -OH, -NH2, -NRa2(C1-C6 alkyl) (wherein the alkyl is methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), -CN, or halogen (e.g., F, Cl, Br, or I). Embodiment 45d. The compound of any of previous Embodiments to the extent applicable, wherein at least one of R5, R6, and R7 is -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, - NRa2C(X)Ra1, -NRa2C(X)ORa1, or -NRa2C(X)NRa1Ra2. Embodiment 45e. The compound of any of previous Embodiments to the extent applicable, wherein at least one of R5, R6, and R7 is -C(X)Ra1, -C(X)ORa1, or -C(X)NRa1Ra2. Embodiment 45f. The compound of any of previous Embodiments to the extent applicable, wherein at least one of R5, R6, and R7 is -NRa2C(X)Ra1, -NRa2C(X)ORa1, or - NRa2C(X)NRa1Ra2. Embodiment 46a. The compound of any of previous Embodiments to the extent applicable, wherein Ra1 is H. Embodiment 46b. The compound of any of previous Embodiments to the extent applicable, wherein Ra1 is C1-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s- butyl, t-butyl, pentyl, or hexyl), or C1-C6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n- butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, substituted with one or more halogen (e.g., F, Cl, Br, or I). Embodiment 46c. The compound of any of previous Embodiments to the extent applicable, wherein Ra1 is C1-C6 alkyl-C6-C10 aryl, or C1-C6 alkyl-heteroaryl wherein the heteroaryl comprises a 5- or 6-membered ring and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, - OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, and oxo, wherein the alkyl is methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl. Embodiment 46d. The compound of any of previous Embodiments to the extent applicable, wherein Ra1 is C1-C6 alkyl-C6-C10 aryl, wherein the aryl is optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, and oxo, wherein the alkyl is methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl. Embodiment 46e. The compound of any of previous Embodiments to the extent applicable, wherein Ra1 is C1-C6 alkyl-heteroaryl wherein the heteroaryl comprises a 5- or 6- membered ring and 1-4 heteroatoms selected from N, O, and S, wherein the heteroaryl is optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1- C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, and oxo, wherein the alkyl is methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl. Embodiment 47a. The compound of any of previous Embodiments to the extent applicable, wherein Ra2 is H. Embodiment 47b. The compound of any of previous Embodiments to the extent applicable, wherein at least one Ra2 is C1-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n- butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl). Embodiment 48a. The compound of any of previous Embodiments to the extent applicable, wherein X is O. Embodiment 48b. The compound of any of previous Embodiments to the extent applicable, wherein X is S. Embodiment 48c. The compound of any of previous Embodiments to the extent applicable, wherein X is NRN. Embodiment 49a. The compound of any of previous Embodiments to the extent applicable, wherein each RA is H. Embodiment 49b. The compound of any of previous Embodiments to the extent applicable, wherein at least one RA is C1-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n- butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), C1-C6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, substituted with one or more halogen (e.g., F, Cl, Br, or I), C1-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n- butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexoxy), or C1-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexoxy, substituted with one or more halogen (e.g., F, Cl, Br, or I)). Embodiment 49c. The compound of any of previous Embodiments to the extent applicable, wherein at least one RA is -OH, -NH2, -NRa2(C1-C6 alkyl) (wherein the alkyl is methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), -CN, or halogen (e.g., F, Cl, Br, or I). Embodiment 49d. The compound of any of previous Embodiments to the extent applicable, wherein at least one RA is -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, - NRa2C(X)ORa1, or -NRa2C(X)NRa1Ra2. Embodiment 49e. The compound of any of previous Embodiments to the extent applicable, wherein at least one RA is -C(X)Ra1, -C(X)ORa1, or -C(X)NRa1Ra2. Embodiment 49f. The compound of any of previous Embodiments to the extent applicable, wherein at least one RA is -NRa2C(X)Ra1, -NRa2C(X)ORa1, or -NRa2C(X)NRa1Ra2. Embodiment 50. The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, C1-C6 alkyl is methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl. Embodiment 50a. The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, C1-C6 alkyl is methyl, ethyl, propyl, or i-propyl. Embodiment 51. The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, C1-C6 haloalkyl is methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, substituted with one or more halogen (e.g., F, Cl, Br, or I). Embodiment 51a. The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, C1-C6 haloalkyl is methyl, ethyl, propyl, or i-propyl, substituted with one or more halogen (e.g., F, Cl, Br, or I). Embodiment 52. The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, C1-C6 alkoxy is methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexoxy. Embodiment 52a. The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, C1-C6 alkoxy is methoxy, ethoxy, propoxy, or i-propoxy. Embodiment 53. The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, C1-C6 haloalkoxy is methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t- butoxy, pentoxy, or hexoxy, substituted with one or more halogen (e.g., F, Cl, Br, or I). Embodiment 53a. The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, C1-C6 haloalkoxy is methoxy, ethoxy, propoxy, or i-propoxy, substituted with one or more halogen (e.g., F, Cl, Br, or I). Embodiment 54. The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, halogen is F, Cl, Br, or I. Embodiment 54a. The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, halogen is F. Embodiment 54b. The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, halogen is Cl. In some embodiments, non-limiting illustrative compounds of the present disclosure are listed in Table 1. Table 1: Compounds of the Present Disclosure
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0002
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
In some embodiments, a compound of the present disclosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is a pharmaceutically acceptable salt. In some embodiments, a compound of the present disclosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is a solvate. In some embodiments, a compound of the present disclosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is a hydrate. The compounds of the present disclosure may form salts which are also within the scope of this disclosure. Reference to a compound of the formulae herein is understood to include reference to salts thereof, unless otherwise indicated. Representative "pharmaceutically acceptable salts" include, e.g., water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumerate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3- naphthoate, einbonate), pantothenate, phosphate/diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts. “Solvate” means solvent addition forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds or salts have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H2O. Compounds having one or more chiral centers can exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric, enantiomeric, and epimeric forms as well as racemates and mixtures thereof. The term “geometric isomer” refers to cyclic compounds having at least two substituents, wherein the two substituents are both on the same side of the ring (cis) or wherein the substituents are each on opposite sides of the ring (trans). When a disclosed compound is named or depicted by structure without indicating stereochemistry, it is understood that the name or the structure encompasses one or more of the possible stereoisomers, or geometric isomers, or a mixture of the encompassed stereoisomers or geometric isomers. When a geometric isomer is depicted by name or structure, it is to be understood that the named or depicted isomer exists to a greater degree than another isomer, that is that the geometric isomeric purity of the named or depicted geometric isomer is greater than 50%, such as at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. Geometric isomeric purity is determined by dividing the weight of the named or depicted geometric isomer in the mixture by the total weight of all of the geometric isomers in the mixture. “Chiral isomer” means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture”. When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit.1966, 5, 385; errata 511; Cahn et al., Angew. Chem.1966, 78, 413; Cahn and Ingold, J. Chem. Soc.1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ.1964, 41, 116). In some embodiments, the compounds of the disclosure are diastereomers. In some embodiments, the compounds are the syn diastereomer. In some embodiments, the compounds are the anti diastereomer. Racemic mixture means 50% of one enantiomer and 50% of is corresponding enantiomer. When a compound with one chiral center is named or depicted without indicating the stereochemistry of the chiral center, it is understood that the name or structure encompasses both possible enantiomeric forms (e.g., both enantiomerically-pure, enantiomerically-enriched or racemic) of the compound. When a compound with two or more chiral centers is named or depicted without indicating the stereochemistry of the chiral centers, it is understood that the name or structure encompasses all possible diastereomeric forms (e.g., diastereomerically pure, diastereomerically enriched and equimolar mixtures of one or more diastereomers (e.g., racemic mixtures) of the compound. Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Enantiomers and diastereomers also can be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods. When a compound is designated by a name or structure that indicates a single enantiomer, unless indicated otherwise, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as “enantiomerically pure”). Optical purity is the weight in the mixture of the named or depicted enantiomer divided by the total weight in the mixture of both enantiomers. When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers. It is also possible that the compounds of the disclosure may exist in different tautomeric forms, and all such forms are embraced within the scope of the disclosure. “Tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solid form, usually one tautomer predominates. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertable by tautomerizations is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose. Common tautomeric pairs are: ketone-enol, amide-nitrile, lactam- lactim, amide-imidic acid tautomerism in heterocyclic rings (e.g., in nucleobases such as guanine, thymine and cytosine), amine-enamine and enamine-imine. The disclosure also comprehends isotopically-labeled compounds, which are identical to those recited in the each of the formulae described herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, fluorine, such as 3H, 11C, 14C, 2H and 18F. Compounds of the disclosure that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present disclosure. Isotopically-labeled compounds of the present disclosure, for example those into which radioactive isotopes such as 3H, 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are useful for their ease of preparation and detectability.11C and 18F isotopes are useful in PET (positron emission tomography). PET is useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of the disclosure, can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples described herein, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. In some embodiments, the compounds of the disclosure are not isotopically labelled. Methods for Preparing the Compounds The compounds of the present disclosure may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the Schemes given below. The compounds may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. In the scheme described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of their execution, shall be consistent with the preparation of the compounds of the present disclosure. Those skilled in the art will recognize if a stereocenter exists in the compounds of the present disclosure. Accordingly, the present disclosure includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compound but the individual enantiomers and/or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994). The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and/or enzymatic processes. The compounds of the present disclosure can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, the compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below. The compounds of the present disclosure (i.e., a compound of Formula I) can be synthesized by following the steps outlined in General Schemes and/or General Methods below, such as in the Examples. It is understood that the experimental conditions and starting materials and/or intermediates illustrated in the General Methods in the Examples may be adjusted according to techniques and knowledge available in the art. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated. The ability of compounds of the disclosure to inhibit Polq can be measured as described in Example 45 below, or according to methods known in the art. General Schemes General Procedure A:
Figure imgf000037_0001
  General Procedure B:
Figure imgf000037_0002
  General Procedure C: 
Figure imgf000037_0003
  Definitions The articles "a" and "an" are used in this disclosure to refer to one or more than one (i.e., at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element. The term "and/or" is used in this disclosure to mean either "and" or "or" unless indicated otherwise. The term "alkyl" as used herein, refers to saturated, straight or branched-chain hydrocarbon radicals containing, In some embodiments, between one and six carbon atoms. Examples of C1-C8 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, n-heptyl, and n-octyl radicals. Examples of C1-C6 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, and n-hexyl radicals. The term “alkylsulfonyl” means a -SO2R radical where R is alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, 2-propylsulfonyl, and the like. The term “alkoxy” means an alkyl radical attached through an oxygen linking atom, represented by –O-alkyl. For example, “(C1-C4) alkoxy” includes methoxy, ethoxy, propoxy, and butoxy. The term “alkoxycarbonyl” means a -COOR radical where R is alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, propoxy, or 2-propoxycarbonyl, or tertbutoxycarbonyl, and the like. The term “alkoxyalkyl” means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one alkoxy group, as defined above, e.g., 2-methoxyethyl, 1-, 2-, or 3- methoxypropyl, 2-ethoxyethyl, and the like. The term “acyl” means a -C(O)R radical where R is alkyl as defined herein, e.g., methylcarbonyl, ethylcarbonyl, and the like. The term “acylamino” means a -NHC(O)R radical where R is alkyl as defined herein, e.g., methylcarbonylamino, ethylcarbonylamino, and the like. The term “amino” means a -NH2. The terms “haloalkyl” and “haloalkoxy” mean alkyl or alkoxy, as the case may be, substituted with one or more halogen atoms. The term “alkylene” means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms unless otherwise stated e.g., methylene, ethylene, propylene, 1-methylpropylene, 2- methylpropylene, butylene, pentylene, and the like. An “alkylene group” is a saturated aliphatic branched or straight-chain divalent hydrocarbon radical. Unless otherwise specified, an alkylene group typically has 1-6 carbon atoms, e.g., (C1-C6) alkylene. The term “aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms e.g., phenyl or naphthyl. The term “Bicyclic heterocyclyl” means a saturated monocyclic ring having 4 to 7 ring carbon ring atoms wherein one or two ring carbon atoms is(are) replaced by a heteroatom selected from N, O, or S(O) n, (where n is an integer from 0 to 2) that is fused to phenyl, five or six-membered heteroaryl or heterocyclyl, each as defined herein. Exemplary bicyclic heterocyclyl groups include, but are not limited to,
Figure imgf000038_0001
and the like. The term “cycloalkyl” means a monocyclic saturated hydrocarbon ring system. For example, C3-C7 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, cycloheptyl. A bridged cycloalkyl means a bicyclic hydrocarbon ring system in which the two rings share at least three adjacent ring carbon atoms. For example, a bridged cycloalkyl has 6- 12 ring carbon atoms. Examples include, but are not limited to, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[4.3.1]decyl, bicyclo[3.3.1]nonyl, bornyl, bornenyl, norbornyl, norbornenyl, 6,6-dimethylbicyclo [3.1.1]heptyl, and adamantyl. The terms “heterocyclyl”, “heterocyclic ring”, and “heterocyclic group”, are used interchangeably herein, and means saturated or unsaturated non-aromatic 4-10 membered ring radical containing from 1 to 4 ring heteroatoms, which may be the same or different, selected from N, O, or S. It can be monocyclic, bicyclic or tricyclic (e.g., a fused or bridged bicyclic or tricyclic ring). Examples of include, but are not limited to, azetidinyl, morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, dihydroimidazole, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, dihydropyrimidinyl, dihydrothienyl, dihydrothiophenyl, dihydrothiopyranyl, tetrahydroimidazole, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, and tetrahydrothiopyranyl. A heterocyclic ring optionally contains one or more double bonds and/or is optionally fused with one or more aromatic rings (for example, tetrahydronaphthyridine, indolinone, dihydropyrrolotriazole, imidazopyrimidine, quinolinone, dioxaspirodecane). Examples of 3-7 membered monocyclic heterocyclic ring include, but are not limited to, azetidinyl, morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, dihydroimidazole, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, dihydropyrimidinyl, dihydrothienyl, dihydrothiophenyl, dihydrothiopyranyl, tetrahydroimidazole, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, and tetrahydrothiopyranyl. The term “bridged heterocyclyl” means a saturated monocyclic ring having 5 to 7 ring carbon ring atoms in which two non-adjacent ring atoms are linked by a (CRR’)n group where n is 1 to 3 and each R and R’ is independently H or methyl (also may be referred to herein as “bridging” group) and further wherein one or two ring carbon atoms, including an atom in the bridging group, is replaced by a heteroatom selected from N, O, or S(O) n, where n is an integer from 0 to 2. Bridged heterocyclyl is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, or cyano. Examples include, but are not limited to, 2-azabicyclo[2.2.2]octane, quinuclidine, 7-oxabicyclo[2.2.1]heptane, and the like. A bridged heterocyclyl means a bicyclic ring system containing from 1 to 4 ring heteroatoms in which the two rings share at least three adjacent ring atoms. For example, a bridged heterocyclyl has 6-12 ring atoms. Examples include, but are not limited to, azanorbornyl, quinuclidinyl, isoquinuclidinyl, tropanyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.2.1]heptany1, 2-azabicyclo[3.2.1]octanyl, azabicyclo[3.2.1]octanyl, azabicyclo[3.2.2]nonanyl, azabicyclo[3.3.0]nonanyl, and azabicyclo [3.3.1]nonanyl. The term “deuteroalkyl” means an alkyl radical as defined above wherein one to six hydrogen atoms in the alkyl radical are replaced by deuterium, e.g., -CD3, -CH2CD3, and the like. The term “dialkylamino” means -NRR’ radical where R and R’ are independently alkyl as defined herein. The term “halo” means fluoro, chloro, bromo, or iodo, preferably fluoro or chloro. The term “oxo,” as used herein, alone or in combination, refers to =(O). The terms “heteroaryl”, “heteroaromatic”, “heteroaryl ring”, “heteroaryl group”, “heteroaromatic ring”, and “heteroaromatic group”, are used interchangeably herein. “Heteroaryl”, when used alone or as part of a larger moiety as in “heteroaralkyl” or “heteroarylalkoxy”, refers to aromatic ring groups having five to ten ring atoms selected from carbon and at least one (typically 1 to 4, more typically 1 or 2) heteroatoms (e.g., oxygen, nitrogen, or sulfur). “Heteroaryl” includes monocyclic rings and polycyclic rings in which a monocyclic heteroaromatic ring is fused to one or more other aromatic or heteroaromatic rings. “Heteroaryl” includes monocyclic and bicyclic ring systems. “Monocyclic 5-6 membered heteroaromatic ring (or heteroaryl)” means a monocyclic heteroaromatic ring having five or six ring atoms selected from carbon and at least one (typically 1 to 3, more typically 1 or 2) heteroatoms (e.g., oxygen, nitrogen, or sulfur). Examples of monocyclic 5-6 membered heteroaromatic ring groups include furanyl (e.g., 2- furanyl, 3-furanyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 2-oxadiazolyl, 5- oxadiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3- pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl, triazolyl (e.g., 2-triazolyl, 5-triazolyl), tetrazolyl (e.g., tetrazolyl), and thienyl (e.g., 2-thienyl, 3-thienyl). If a group is described as being “substituted,” a non-hydrogen substituent replaces a hydrogen atom on a carbon or nitrogen. Thus, for example, a substituted alkyl is an alkyl wherein at least one non-hydrogen substituent is in the place of a hydrogen atom on the alkyl substituent. To illustrate, monofluoroalkyl is alkyl substituted with a fluoro substituent, and difluoroalkyl is alkyl substituted with two fluoro substituents. It should be recognized that if there is more than one substitution on a substituent, each non-hydrogen substituent can be identical or different (unless otherwise stated). As used herein, many moieties (e.g., alkyl, cycloalkyl, or a heterocyclic ring) are referred to as being either “substituted” or “optionally substituted”. It will be appreciated that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." When a moiety is modified by one of these terms, unless otherwise noted, it denotes that any portion of the moiety that is known to one skilled in the art as being available for substitution can be substituted, which includes one or more substituents. If more than one substituent is present, then each substituent is independently selected. Such means for substitution are well-known in the art and/or taught by the instant disclosure. The optional substituents can be any substituents that are suitable to attach to the moiety. A person of ordinary skill in the art will recognize that the compounds and definitions provided do not include impermissible substituent patterns (e.g., methyl substituted with 5 different groups, and the like). Such impermissible substitution patterns are clearly recognized by a person of ordinary skill in the art. When a group is described as being optionally substituted by “one or more” substituents, it denotes that the group is optionally substituted by one, two, three, four, five or six substituents. In some embodiments, a group is optionally substituted by 1-3 substituents. In some embodiments, a group is optionally substituted by 1-2 substituents. In some embodiments, a group is optionally substituted by one substituent. Suitable substituents are those which do not have a significant adverse effect on the ability of the compound. Where suitable substituents are not specifically enumerated, exemplary substituents include, but are not limited to, halo, CN, alkyl, alkoxy, halomethyl, halomethoxy, (C1-C5)alkyl, halo(C1-C5)alkyl, (C1-C5)alkoxy, NO2, ORc’, NRa’Rb’, S(O)iRa’, NRaS(O)iRb’, S(O)iNRa’Rb’, C(=O)ORa’, OC(=O)ORa’, C(=S)ORa’, O(C=S)Ra’, C(=O)NRa’Rb’, NRa’C(=O)Rb’, C(=S)NRa’Rb’, NRa’C(=S)Rb’, NRa’(C=O)ORb’, O(C=O)NRa’Rb’, NRa’(C=S)ORb’, O(C=S)NRa’Rb’, NRa’(C=O)NRa’Rb’, NRa’(C=S)NRa’Rb’, C(=S)Ra’, C(=O)Ra’, (C3-C6) cycloalkyl, monocyclic heteroaryl, and phenyl, wherein the (C3- C6) cycloalkyl, monocyclic heteroaryl, and phenyl substituents are optionally and independently substituted, for example, with CH3, halomethyl, halo, methoxy, or halomethoxy. Each Ra’ and each Rb’ are independently H or (C1 ^C6) alkyl, wherein the (C1 ^C6) alkyl group represented by Ra’ or Rb’ is optionally substituted, for example, with hydroxyl or (C1 ^C3) alkoxy; Rc’ is H, halo(C1 ^C6) alkyl, or (C1 ^C6) alkyl, wherein the (C1 ^C6) alkyl group represented by Rc is optionally substituted, for example with hydroxyl or (C1 ^C3) alkoxy; and i is 0, 1, or 2. =O is also a suitable substituent for alkyl, cycloalkyl, and a heterocyclic ring. Suitable substituents may also include: -F, -Cl, -Br, -I, -OH, protected hydroxy, -NO2, -CN, -NH2, protected amino, -NH-C1-C12-alkyl, -NH-C2-C12-alkenyl, -NH-C2-C12-alkenyl, - NH -C3-C12-cycloalkyl, -NH-aryl, -NH -heteroaryl, -NH -heterocycloalkyl, -dialkylamino, - diarylamino, -diheteroarylamino, -O-C1-C12-alkyl, -O-C2-C12-alkenyl, -O-C2-C12-alkenyl, -O-C3-C12-cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocycloalkyl, -C(O)-C1-C12-alkyl, - C(O)- C2-C12-alkenyl, -C(O)-C2-C12-alkenyl, -C(O)-C3-C12-cycloalkyl, -C(O)-aryl, -C(O)- heteroaryl, -C(O)-heterocycloalkyl, -CONH2, -CONH-C1-C12-alkyl, -CONH-C2-C12-alkenyl, -CONH-C2-C12-alkenyl, -CONH-C3-C12-cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl,-OCO2-C1-C12-alkyl, -OCO2-C2-C12-alkenyl, -OCO2-C2-C12- alkenyl, -OCO2-C3-C12-cycloalkyl, -OCO2-aryl, -OCO2-heteroaryl, -OCO2-heterocycloalkyl, -OCONH2, -OCONH-C1-C12-alkyl, -OCONH- C2-C12-alkenyl, -OCONH- C2-C12-alkenyl, -OCONH-C3-C12-cycloalkyl, -OCONH-aryl, -OCONH-heteroaryl, -OCONH- heterocycloalkyl, -NHC(O)-C1-C12-alkyl, -NHC(O)-C2-C12-alkenyl, -NHC(O)-C2-C12- alkenyl, -NHC(O)-C3-C12-cycloalkyl, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)- heterocycloalkyl, -NHCO2-C1-C12-alkyl, -NHCO2-C2-C12-alkenyl, -NHCO2-C2-C12-alkenyl, -NHCO2-C3-C12-cycloalkyl, -NHCO2-aryl, -NHCO2-heteroaryl, -NHCO2- heterocycloalkyl, -NHC(O)NH2, -NHC(O)NH-C1-C12-alkyl, -NHC(O)NH-C2-C12-alkenyl, -NHC(O)NH-C2-C12-alkenyl, -NHC(O)NH-C3-C12-cycloalkyl, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, NHC(O)NH-heterocycloalkyl, -NHC(S)NH2, -NHC(S)NH-C1-C12-alkyl, -NHC(S)NH-C2-C12-alkenyl, -NHC(S)NH-C2-C12-alkenyl, -NHC(S)NH-C3-C12-cycloalkyl, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, -NHC(S)NH-heterocycloalkyl, -NHC(NH)NH2, -NHC(NH)NH- C1-C12-alkyl, -NHC(NH)NH-C2-C12-alkenyl, -NHC(NH)NH-C2-C12-alkenyl, -NHC(NH)NH-C3-C12-cycloalkyl, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NHheterocycloalkyl, -NHC(NH)-C1-C12-alkyl, -NHC(NH)-C2-C12-alkenyl, -NHC(NH)-C2-C12-alkenyl, -NHC(NH)-C3-C12-cycloalkyl, -NHC(NH)-aryl, -NHC(NH)-heteroaryl, -NHC(NH)-heterocycloalkyl, -C(NH)NH-C1-C12-alkyl, -C(NH)NH-C2-C12-alkenyl, -C(NH)NH-C2-C12-alkenyl, C(NH)NH-C3-C12-cycloalkyl, -C(NH)NH-aryl, -C(NH)NH-heteroaryl, -C(NH)NHheterocycloalkyl, -S(O)-C1-C12-alkyl,- S(O)-C2-C12-alkenyl,- S(O)-C2-C12-alkenyl, -S(O)-C3-C12-cycloalkyl,- S(O)-aryl, -S(O)-heteroaryl, -S(O)-heterocycloalkyl -SO2NH2, -SO2NH-C1-C12-alkyl, -SO2NH-C2-C12-alkenyl, -SO2NH-C2-C12-alkenyl, -SO2NH-C3-C12-cycloalkyl, -SO2NH-aryl, -SO2NH-heteroaryl, -SO2NH-heterocycloalkyl, -NHSO2-C1-C12-alkyl, -NHSO2-C2-C12-alkenyl,- NHSO2-C2-C12-alkenyl, -NHSO2-C3-C12-cycloalkyl, -NHSO2-aryl, -NHSO2-heteroaryl, -NHSO2-heterocycloalkyl, -CH2NH2, -CH2SO2CH3, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -C3-C12-cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-C1-C12-alkyl, -S-C2-C12-alkenyl, -S-C2-C12-alkenyl, -S-C3-C12-cycloalkyl, -S-aryl, -S-heteroaryl, -S-heterocycloalkyl, or methylthiomethyl. A "patient" or “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or rhesus. An "effective amount" or “therapeutically effective amount” when used in connection with a compound or pharmaceutical composition is an amount effective for treating or preventing a disease in a subject as described herein. The term "treating" with regard to a subject, refers to improving at least one symptom of the subject's disorder. Treating includes curing, improving, or at least partially ameliorating the disorder. The compounds of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, can also be used to prevent a disease, condition or disorder. As used herein, “preventing” or “prevent” describes reducing or eliminating the onset of the symptoms or complications of the disease, condition or disorder. The term "disorder" is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated. As used herein, the term diseases or disorders in which Polθ polymerase plays a role means any disease or other deleterious condition in which Polθ polymerase is known to play a role. Accordingly, another embodiment of the present disclosure relates to treating or lessening the severity of one or more diseases in which Polθ polymerase is known to play a role. Pharmaceutical Compositions The compounds disclosed therein are Polθ polymerase inhibitors. The pharmaceutical composition of the present disclosure comprises one or more Polθ polymerase inhibitors, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or diluent. A “pharmaceutical composition” is a formulation containing the compound of the present disclosure in a form suitable for administration to a subject. In some embodiments, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial. The quantity of active ingredient (e.g., a formulation of the disclosed compound or a pharmaceutically acceptable salt or solvate thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In some embodiments, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers or propellants that are required. As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. “Pharmaceutically acceptable carrier” and “pharmaceutically acceptable diluent” refer to a substance that aids the formulation and/or administration of an active agent to and/or absorption by a subject and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the subject. Non-limiting examples of pharmaceutically acceptable carriers and/or diluents include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein. One of ordinary skill in the art will recognize that other pharmaceutical excipients are suitable for use with disclosed compounds. The term "carrier", as used in this disclosure, encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject. The pharmaceutical compositions of the present teachings optionally include one or more pharmaceutically acceptable carriers and/or diluents therefor, such as lactose, starch, cellulose and dextrose. Other excipients, such as flavoring agents; sweeteners; and preservatives, such as methyl, ethyl, propyl and butyl parabens, can also be included. More complete listings of suitable excipients can be found in the Handbook of Pharmaceutical Excipients (5th Ed., Pharmaceutical Press (2005)). A person skilled in the art would know how to prepare formulations suitable for various types of administration routes. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington’s Pharmaceutical Sciences (2003 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999. The carriers, diluents and/or excipients are “acceptable” in the sense of being compatible with the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof. Pharmaceutical compositions of the disclosure are formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous disclosure can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. A compound or pharmaceutical composition of the disclosure can be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment. For example, for treatment of cancers, a compound of the disclosure may be injected directly into tumors, injected into the blood stream or body cavities or taken orally or applied through the skin with patches. The dose chosen should be sufficient to constitute effective treatment but not as high as to cause unacceptable side effects. The state of the disease condition (e.g., cancer, precancer, and the like) and the health of the patient should preferably be closely monitored during and for a reasonable period after treatment. The term “therapeutically effective amount”, as used herein, refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician. For any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration. Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation. The pharmaceutical compositions containing active compound (i.e., a compound of Formula (I)) of the present disclosure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of the active compound into preparations that can be used pharmaceutically. Of course, the appropriate formulation is dependent upon the route of administration chosen. Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL ^ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. For administration by inhalation, the compound is delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer. Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compound is formulated into ointments, salves, gels, or creams as generally known in the art. The active compound can be prepared with pharmaceutically acceptable carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No.4,522,811. It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject 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 specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved. In therapeutic disclosures, the dosages of the pharmaceutical compositions used in accordance with the disclosure vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage. Generally, the dose should be sufficient to result in slowing, and preferably regressing, the growth of the tumors and also preferably causing complete regression of the cancer. Dosages can range from about 0.01 mg/kg per day to about 5000 mg/kg per day. An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer. For example, regression of a tumor in a subject may be measured with reference to the diameter of a tumor. Decrease in the diameter of a tumor indicates regression. Regression is also indicated by failure of tumors to reoccur after treatment has stopped. As used herein, the term “dosage effective manner” refers to amount of an active compound to produce the desired biological effect in a subject or cell. The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration. The dosage regimen utilizing the compound is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or pharmaceutically acceptable salt or solvate thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition. Techniques for formulation and administration of the disclosed compound of the disclosure can be found in Remington: the Science and Practice of Pharmacy, 19th edition, Mack Publishing Co., Easton, PA (1995). In some embodiments, the compound described herein, and the pharmaceutically acceptable salts or solvates thereof, are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compound or pharmaceutically acceptable salts or solvates thereof will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein. All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure. Methods of Using the Compounds The present disclosure provides a method of treating a subject with a disease or disorder which can be ameliorated by inhibition of Polθ polymerase or in which Polθ polymerase is involved, for example, in which the expression or activity of Polθ polymerase is dysregulated or aberrant, by administering to the subject an effective amount of one or more disclosed compounds, or a pharmaceutically acceptable salt or solvate thereof, or the corresponding pharmaceutical composition. Diseases which can be ameliorated by inhibition of Polθ polymerase include cancer. The present disclosure further relates to a method of treating a disease or disorder in which Polθ polymerase plays a role, for example, cancer. The method comprises administering to a subject in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition disclosed herein. In one aspect, described herein is a method for treating and/or preventing a disease in a subject, such as cancer characterized by overexpression/overactivity of Polθ polymerase, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof. In another aspect, described herein is a method for treating and/or preventing a cancer in a subject, such as cancer characterized by a deficiency in homologous recombinant (HR) or by a reduction or absence of BRCA gene expression, the absence of the BRAC gene, or reduced function of BRCA protein, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof. In another aspect, described herein is a method for inhibiting DNA repair by Polθ in a cell, comprising contacting the cell with an effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the cell is HR deficient. In another aspect, provided herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for inhibiting DNA repair by Polθ in a cell. In some embodiments, the cell is HR deficient. In another aspect, described herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for treating and/or preventing a disease in a subject, e.g., a disease such as cancer treatable by inhibition of Polθ, including homologous recombination (HR) deficient cancers. In another aspect, described herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for treating and/or preventing a disease in a subject, such as cancer characterized by overexpression/overactivity of Polθ polymerase, by a deficiency in homologous recombinant (HR), or by a reduction or absence of BRAC gene expression, the absence of the BRAC gene, or reduced function of BRAC protein. In another aspect, provided herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for use in the manufacture of a medicament for inhibiting DNA repair by Polθ in a cell. In some embodiments, the cell is HR deficient. In another aspect, described herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for use in the manufacture of a medicament for treating and/or preventing a disease in a subject, e.g., a disease such as cancer treatable by inhibition of Polθ, including homologous recombination (HR) deficient cancers. In another aspect, described herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for use in the manufacture of a medicament for treating and/or preventing a disease in a subject, such as cancer characterized by overexpression/overactivity of Polθ polymerase, by a deficiency in homologous recombinant (HR), or by a reduction or absence of BRAC gene expression, the absence of the BRAC gene, or reduced function of BRAC protein. In another aspect, described herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for treating and/or preventing a cancer that is resistant to poly(ADP-ribose) polymerase (PARP) inhibitor therapy in a subject. Examples of cancers resistant to PARP-inhibitors include, but are not limited to, breast cancer, ovarian cancer, lung cancer, bladder cancer, liver cancer, head and neck cancer, pancreatic cancer, gastrointestinal cancer, and colorectal cancer. In one aspect, described herein is a method of treating cancer, the method comprising administering a therapeutically effective dose of a composition as described herein, e.g., a composition comprising a compound of the present disclosure, to a subject in need of treatment for cancer. The present disclosure further relates to use of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein, in the manufacture of a medicament for the treatment of a disease or disorder in which Polθ polymerase plays a role, for example, a cancer. The present disclosure provides use of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein, in the manufacture of a medicament for the treatment of a disease or disorder which can be ameliorated by inhibition of Polθ polymerase. In one aspect, described herein is use of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein, in the manufacture of a medicament for the treatment of a cancer. The present disclosure further relates to a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein, for use in treating a disease or disorder in which Polθ polymerase plays a role, for example, a cancer. The present disclosure provides a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein, for use in treating a disease or disorder which can be ameliorated by inhibition of Polθ polymerase. In another aspect, described herein is a method for treating and/or preventing a disease, such as cancer, characterized by overexpression of Polθ polymerase in a patient comprising administering to the patient a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method for treating and/or preventing a homologous recombinant (HR) deficient cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method for inhibiting DNA repair by Polθ in a cancer cell comprising contacting the cell with an effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the cancer is HR deficient cancer. In some embodiments, described herein is a method for treating and/or preventing a cancer in a patient, wherein the cancer is characterized by a reduction or absence of BRCA gene expression, the absence of the BRAC gene, or reduced function of BRCA protein, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof, optionally in a pharmaceutical composition. In some embodiments, the cancer is lymphoma, leukemia, multiple myeloma, soft tissue cancer, rhabdoid tumor, rhabdomyosarcoma, central nervous system cancer, peripheral nervous system cancer, bone cancer, uterine cancer, ovarian cancer, upper aerodigestive cancer, esophagus cancer, gastric cancer, gastrointestinal cancer, colorectal cancer, mesothelioma, breast cancer, lung cancer, bladder cancer, liver cancer, head and neck cancer, fibroblast cancer, urinary tract cancer, kidney cancer, skin cancer, prostate cancer, and pancreatic cancer. In some embodiments, an HR-deficient cancer is breast cancer. Breast cancer includes, but is not limited to, lobular carcinoma in situ (LCIS), ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC), inflammatory breast cancer, Paget disease of the nipple, Phyllodes tumor, angiosarcoma, adenoid cystic carcinoma, low-grade adenosquamous carcinoma, medullary carcinoma, mucinous carcinoma, papillary carcinoma, tubular carcinoma, metaplastic carcinoma, micropapillary carcinoma, mixed carcinoma, and other breast cancer, including but not limited to, breast cancer that is triple negative, HER positive, estrogen receptor positive, progesterone receptor positive, HER and estrogen receptor positive, HER and progesterone receptor positive, estrogen and progesterone receptor positive, and/or HER and estrogen and progesterone receptor positive. In some embodiments, an HR-deficient cancer is ovarian cancer, including, but not limited to, epithelial ovarian carcinomas (EOC), maturing teratomas, dysgerminomas, endodermal sinus tumors, granulosa-theca tumors, Sertoli-Leydig cell tumors, and primary peritoneal carcinoma. In some embodiments, cancers that can be treated by the disclosed methods include cancer of the bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, gastrointestine, gum, head, kidney, liver, lung, nasopharynx, neck, ovary, prostate, skin, stomach, testis, tongue, or uterus. In addition, the cancer may specifically be of the following histological type, though it is not limited to these: neoplasm, malignant; carcinoma; carcinoma, undifferentiated; giant and spindle cell carcinoma; sarcomas; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lymphoepithelial carcinoma; basal cell carcinoma; pilomatrix carcinoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; gastrinoma, malignant; cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular carcinoma and cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in adenomatous polyp; adenocarcinoma, familial polyposis coli; solid carcinoma; carcinoid tumor, malignant; branchiolo-alveolar adenocarcinoma; papillary adenocarcinoma; chromophobe carcinoma; acidophil carcinoma; oxyphilic adenocarcinoma; basophil carcinoma; clear cell adenocarcinoma; granular cell carcinoma; follicular adenocarcinoma; papillary and follicular adenocarcinoma; nonencapsulating sclerosing carcinoma; adrenal cortical carcinoma; endometroid carcinoma; skin appendage carcinoma; apocrine adenocarcinoma; sebaceous adenocarcinoma; ceruminous adenocarcinoma; mucoepidermoid carcinoma; cystadenocarcinoma; papillary cystadenocarcinoma; papillary serous cystadenocarcinoma; mucinous cystadenocarcinoma; mucinous adenocarcinoma; signet ring cell carcinoma; infiltrating duct carcinoma; medullary carcinoma; lobular carcinoma; inflammatory carcinoma; Paget’s disease, mammary; acinar cell carcinoma; adenosquamous carcinoma; adenocarcinoma w/squamous metaplasia; thymoma, malignant; ovarian stromal tumor, malignant; thecoma, malignant; granulosa cell tumor, malignant; androblastoma, malignant; sertoli cell carcinoma; leydig cell tumor, malignant; lipid cell tumor, malignant; paraganglioma, malignant; extra-mammary paraganglioma, malignant; pheochromocytoma; glomangiosarcoma; malignant melanoma; amelanotic melanoma; superficial spreading melanoma; malig melanoma in giant pigmented nevus; epithelioid cell melanoma; blue nevus, malignant; sarcoma; fibrosarcoma; fibrous histiocytoma, malignant; myxosarcoma; liposarcoma; leiomyosarcoma; rhabdomyosarcoma; embryonal rhabdomyosarcoma; alveolar rhabdomyosarcoma; stromal sarcoma; mixed tumor, malignant; mullerian mixed tumor; nephroblastoma; hepatoblastoma; carcinosarcoma; mesenchymoma, malignant; Brenner tumor, malignant; phyllodes tumor, malignant; synovial sarcoma; mesothelioma, malignant; dysgerminoma; embryonal carcinoma; teratoma, malignant; struma ovarii, malignant; choriocarcinoma; mesonephroma, malignant; hemangiosarcoma; hemangioendothelioma, malignant; Kaposi’s sarcoma; hemangiopericytoma, malignant; lymphangiosarcoma; osteosarcoma; juxtacortical osteosarcoma; chondrosarcoma; chondroblastoma, malignant; mesenchymal chondrosarcoma; giant cell tumor of bone; Ewing’s sarcoma; odontogenic tumor, malignant; ameloblastic odontosarcoma; ameloblastoma, malignant; ameloblastic fibrosarcoma; pinealoma, malignant; chordoma; glioma, malignant; ependymoma; astrocytoma; protoplasmic astrocytoma; fibrillary astrocytoma; astroblastoma; glioblastoma; oligodendroglioma; oligodendroblastoma; primitive neuroectodermal; cerebellar sarcoma; ganglioneuroblastoma; neuroblastoma; retinoblastoma; olfactory neurogenic tumor; meningioma, malignant; neurofibrosarcoma; neurilemmoma, malignant; granular cell tumor, malignant; malignant lymphoma; Hodgkin’s disease; hodgkin’s; paragranuloma; malignant lymphoma, small lymphocytic; malignant lymphoma, large cell, diffuse; malignant lymphoma, follicular; mycosis fungoides; other specified non-Hodgkin’s lymphomas; malignant histiocytosis; multiple myeloma; mast cell sarcoma; immunoproliferative small intestinal disease; leukemia; lymphoid leukemia; plasma cell leukemia; erythroleukemia; lymphosarcoma cell leukemia; myeloid leukemia; basophilic leukemia; eosinophilic leukemia; monocytic leukemia; mast cell leukemia; megakaryoblastic leukemia; myeloid sarcoma; and hairy cell leukemia. The term “treating” or “treatment” of a disease includes inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms; or relieving the disease, i.e., causing regression of the disease or its clinical symptoms. The terms “inhibiting”, “reducing”, or any variation of these terms in relation of Polθ, includes any measurable decrease or complete inhibition to achieve a desired result. For example, there may be a decrease of about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein, reduction of Polθ activity compared to its normal activity. The term “preventing” refers to causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease. The term “homologous recombination” refers to the cellular process of genetic recombination in which nucleotide sequences are exchanged between two similar or identical DNA. The term “homologous recombination (HR) deficient cancer” refers to a cancer that is characterized by a reduction or absence of a functional HR repair pathway. HR deficiency may arise from absence of one or more HR-associated genes or presence of one or more mutations in one or more HR-associated genes. Examples of HR-associated genes include BRCA1, BRCA2, RAD54, RAD51B, CtlP (Choline Transporter-Like Protein), PALB2 (Partner and Localizer of BRCA2), XRCC2 (X-ray repair complementing defective repair in Chinese hamster cells 2), RECQL4 (RecQ Protein-Like 4), BLM (Bloom syndrome, RecQ helicase-like), WRN (Werner syndrome , one or more HR-associated genes) Nbs 1 (Nibrin), and genes encoding Fanconi anemia (FA) proteins or FA-like genes e.g., FANCA, FANCB, FANCC, FANCD1 (BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANJ (BRIP1), FANCL, FANCM, FANCN (RALB2), FANCP (SLX4), FANCS (BRCA1), RAD51C, and XPF. The term “Polθ ^overexpression” refers to the increased expression or activity of Polθ ^in disease cells e.g., cancerous cell, relative to expression or activity of Pol ^ ^in a normal cell (e.g., non-diseased cell of the same kind). The amount of Polθ can be at least 2-fold, at least 3-fold, at least 4- fold, at least 5- fold, at least 10-fold, or more relative to the Pol ^ ^expression in a normal cell. Examples of Pol ^ ^cancers include, but are not limited to, breast, ovarian, cervical, lung, colorectal, gastric, bladder and prostate cancers. In addition, the compounds of the present disclosure can be co-administered with other therapeutic agents. In some embodiments, other therapeutic agents include chemotherapeutic agents known in the art, such as inhibitors of the DNA repair pathways (e.g., HR and NHEJ) and immunomodulatory agents. As used herein, the terms “co- administration”, “administered in combination with”, and their grammatical equivalents, are meant to encompass administration of two or more therapeutic agents to a single subject, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different times. These terms encompass administration of two or more agents to the subject so that both agents and/or their metabolites are present in the subject at the same time. They include simultaneous administration in separate compositions, administration at different times in separate compositions, and/or administration in a composition in which both agents are present. Thus, in some embodiments, the compounds described herein and the other agent(s) are administered in a single composition. In some embodiments, the compounds described herein and the other agent(s) are admixed in the composition. EXAMPLES Abbreviations
Figure imgf000057_0001
Figure imgf000058_0002
General Procedures A:
Figure imgf000058_0001
  To a solution of the carboxylic acid (1.0 eq.) and substituted aniline (3.0 eq.) in a mixture of DCM /THF (1:1) was added EDCI (3.0 eq.). The mixture was stirred at 25 °C for 12 hrs, quenched by addition of H2O at 0 °C and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by prep-TLC (SiO2, Petroleum ether:EtOAc=5:1) to yield the corresponding amide. B:
Figure imgf000059_0001
  A solution of the Boc protected amide (1.0 eq.) in 4 M HCl/MeOH was stirred at 25 °C for 1 hr, concentrated and purified by prep-HPLC (column: Phenomenex Luna C1875 * 30 mm * 3 um; mobile phase: [water (TFA)-ACN]; B%: 15%-45%, 8 mins) to yield the corresponding amine as a HCl salt. C: 
Figure imgf000059_0002
  To a solution of the amine (1.0 eq.) and 2-chloropyridine (1.2 eq.) in dioxane was added DIEA (3.0 eq.). The mixture was stirred at 80 °C for 12 hrs, quenched by addition of H2O (20 mL) and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by prep-HPLC (column: Phenomenex Luna C18 75 * 30 mm * 3 um; mobile phase: [water (FA)-ACN]; B%: 65%-95%, 8 mins) to yield the corresponding product. Example 1 and Example 2. Preparation of (trans-H)-2-(3-cyano-6-methyl-4- (trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)octahydro-1H-isoindole-1- carboxamide (Compound 1) and (cis-H)-2-(3-cyano-6-methyl-4- (trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)octahydro-1H-isoindole-1- carboxamide (Compound 2)
Figure imgf000060_0001
Figure imgf000060_0002
  a) Synthesis of (trans-H)-2-(tert-butoxycarbonyl)octahydro-1H-isoindole-1- carboxylic acid and (cis-H)- 2-(tert-butoxycarbonyl)octahydro-1H-isoindole-1- carboxylic acid 
Figure imgf000060_0003
  To a solution of 2-tert-butoxycarbonylisoindoline-1-carboxylic acid (500 mg, 2 mmol, 1.0 eq.) in EtOH (3 mL) was added Rh/C (50 mg, 5% w/w) under N2 atmosphere. The mixture was stirred under H2 (50 psi.) at 50 °C for 12 hrs, filtered and concentrated to yield a mixture of (trans-H)-2-(tert-butoxycarbonyl)octahydro-1H-isoindole-1-carboxylic acid and (cis-H)- 2-(tert-butoxycarbonyl)octahydro-1H-isoindole-1-carboxylic acid (270 mg, crude) as a yellow gum. ESI [M-Boc+H] = 170.2. b) Synthesis of (trans-H)-N-methyl-N-(m-tolyl)octahydro-1H-isoindole-1- carboxamide and (cis-H)-N-methyl-N-(m-tolyl)octahydro-1H-isoindole-1- carboxamide
Figure imgf000061_0001
  To a solution of the mixture of (trans-H)-2-(tert-butoxycarbonyl)octahydro-1H- isoindole-1-carboxylic acid and (cis-H)- 2-(tert-butoxycarbonyl)octahydro-1H-isoindole-1- carboxylic acid (165 mg, 613 μmol, 1.0 eq.) and N,3-dimethylaniline (297 mg, 2 mmol, 4.0 eq.) in toluene (4 mL) was added PCl3 (421 mg, 3 mmol, 5.0 eq.). The mixture was stirred at 100 °C for 1 hr, quenched by addition of sat. aq. Na2CO3 (40 mL) at 0 °C and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to (trans-H)-N-methyl-N-(m-tolyl)octahydro-1H-isoindole-1-carboxamide and (cis-H)-N-methyl-N-(m-tolyl)octahydro-1H-isoindole-1-carboxamide (210 mg, crude) as a yellow gum. ESI [M+H] = 273.3. c) Synthesis of (trans-H)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N- methyl-N-(m-tolyl)octahydro-1H-isoindole-1-carboxamide (Compound 1) and (cis-H)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m- tolyl)octahydro-1H-isoindole-1-carboxamide (Compound 2)
Figure imgf000061_0002
  To a solution of the mixture of (trans-H)-N-methyl-N-(m-tolyl)octahydro-1H- isoindole-1-carboxamide and (cis-H)-N-methyl-N-(m-tolyl)octahydro-1H-isoindole-1- carboxamide (100 mg, ^ ^ ^ ^ μmol, 1.0 eq.) in NMP (1 mL) was added DIEA (142 mg, 1 mmol, 3.0 eq.). The mixture was stirred at 100 °C for 1 hr, quenched by addition of sat. aq. Na2CO3 (40 mL) at 0 °C and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by prep-HPLC (column: Phenomenex C1875 * 30 mm * 3 um ;mobile phase: [water(FA)-ACN]; B%: 65%-90%, 8 mins) to yield (trans-H)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N- (m-tolyl)octahydro-1H-isoindole-1-carboxamide (Compound 1) (5 mg, ^ ^ μmol, 3% yield, 92% purity) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 7.46 - 7.29 (m, 3H), 7.22 (br d, J = 7.4 Hz, 1H), 7.04 (s, 1H), 4.36 (d, J = 1.8 Hz, 1H), 3.99 (t, J = 9.1 Hz, 1H), 3.77 (t, J = 9.2 Hz, 1H), 3.16 (s, 3H), 2.52 (br s, 3H), 2.38 - 2.34 (m, 3H), 2.25 - 2.15 (m, 1H), 1.59 - 1.47 (m, 2H), 1.44 - 1.19 (m, 4H), 1.16 - 0.97 (m, 3H). ESI [M+H] = 457.2. And (cis-H)-2- (3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)octahydro-1H- isoindole-1-carboxamide (Compound 2) (19 mg, 39 μmol, 10% yield, 96% purity) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 7.45 - 7.38 (m, 1H), 7.34 - 7.22 (m, 3H), 7.07 (s, 1H), 4.65 (br d, J = 5.8 Hz, 1H), 3.87 (br t, J = 10.8 Hz, 1H), 3.60 (t, J = 8.8 Hz, 1H), 3.13 (s, 3H), 2.54 (s, 3H), 2.37 (s, 3H), 2.23 - 2.09 (m, 1H), 1.91 - 1.78 (m, 1H), 1.75 - 1.59 (m, 2H), 1.51 - 1.35 (m, 4H), 1.32 - 1.22 (m, 1H), 1.20 - 1.07 (m, 1H). ESI [M+H] = 457.2. Example 3. Preparation of (1S,3aR,6aS)-2-(3-cyano-6-methyl-4- (trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1- carboxamide (Compound 3)
Figure imgf000062_0001
  a) Synthesis of 2-benzyl 1-ethyl (1S,3aR,6aS)-hexahydrocyclopenta[c]pyrrole- 1,2(1H)-dicarboxylate
Figure imgf000063_0001
  To the solution of ethyl (1S,3
Figure imgf000063_0002
R,6aS)-octahydrocyclopenta[c]pyrrole-1-carboxylate hydrochloride (400 mg, 1.82 mmol) in H2O (20 mL) was added NaHCO3 (611 mg, 7.28 mmol), followed by the addition of CbzCl (621 mg, 3.64 mmol) in dioxane (20 mL), the mixture was sitrred at 20 °C for 16 h. LCMS showed formation of desired product. The mixture was diluted with H2O 30 mL extracted with EtOAc (30 mL x 2), the organic layer was dried with Na2SO4, filtered and concentrated by reduced pressure. The residue was used in next step directly.2-benzyl 1-ethyl (1S,3aR,6aS)-hexahydrocyclopenta[c]pyrrole-1,2(1H)- dicarboxylate (550 mg, 76% yield, 80% purity) was obtained as colorless oil. 1HNMR (400 MHz, CDCl3): δ 7.36 - 7.30 (m, 2H), 7.25 - 7.21 (m, 3H), 5.14 - 4.89 (m, 2H), 4.67 - 4.47 (m, 3H), 4.22 - 3.90 (m, 3H), 3.69 (t, J = 8.8 Hz, 1H), 3.37 - 3.20 (m, 1H), 2.68 - 2.50 (m, 2H), 1.97 - 1.85 (m, 1H), 1.81 - 1.75 (m, 1H), 1.72 - 1.61 (m, 1H), 1.58 - 1.48 (m, 2H), 1.40 (t, J = 6.4, 12.0 Hz, 1H), 1.24 - 1.02 (m, 3H). ESI [M-H] = 318. b) Synthesis of (1S,3aR,6aS)-2- ((benzyloxy)carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid
Figure imgf000063_0003
  To the solution of 2-benzyl 1-ethyl (1S,3aR,6aS)-hexahydrocyclopenta[c]pyrrole- 1,2(1H)-dicarboxylate (550 mg, 1.73 mmol) in THF (10 mL) was added LiOH (2 M, 6 mL), the mixture was stirred at 20 °C for 2 h. The reaction diluted with H2O (20 mL), extracted by EtOAc (20 mL x 2), the water layer was adjusted pH = 5 by HCl (1 M in water), extracted by EtOAc (30 mL x 3), the organic layer was dried with Na2SO4, filtered and concentrated by reduced pressure. The residue was used in next step directly. Compound (1S,3aR,6aS)-2- ((benzyloxy)carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid (300 mg, 53% yield, 90% purity) was obtained as colorless oil. 1HNMR (400 MHz, CDCl3): δ 7.40 - 7.20 (m, 5H), 5.18 - 4.98 (m, 2H), 4.23 - 4.07 (m, 1H), 3.75 - 3.58 (m, 1H), 3.42 - 3.20 (m, 1H), 2.78 - 2.60(m, 2H), 1.98 - 1.86 (m, 1H), 1.83 - 1.64 (m, 2H), 1.54 (br s, 2H), 1.45 - 1.28 (m, 1H). ESI [M-H] = 290.1. c) Synthesis of benzyl (1S,3aR,6aS)-1-(methyl(m- tolyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate
Figure imgf000064_0001
  To the solution of N,3-dimethylaniline (188 mg, 1.56 mmol) in DCM (10 mL) was added DIPEA (402 mg, 3.11 mmol) and (1S,3aR,6aS)-2- ((benzyloxy)carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid (300 mg, 1.04 mmol), followed by the addition of HATU (473 mg, 1.24 mmol), the mixture was stirred at 20 °C for 12 h. The mixture was diluted with EtOAc (60 mL), washed with water (60 mL x 3), the organic layer was dried with Na2SO4, filtered and concentrated by reduced pressure. The residue was purified with silica gel chromatography (petroleum ether: EtOAc = 1:0~3:1) to afford the product. Compound benzyl (1S,3aR,6aS)-1-(methyl(m- tolyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (280 mg, 58% yield, 85% purity) was obtained as yellow oil. ESI [M-H] = 393.2. d) Synthesis of (1S,3aR,6aS)-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1- carboxamide  
Figure imgf000064_0002
  To a solution of benzyl (1S,3aR,6aS)-1-(methyl(m- tolyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (280 mg, 713 µmol) in THF (10 mL) was added Pd/C (0.2 g, 10% w/w), the mixture was degassed with H2 for 3 times, stirred at 20 °C for 2 h under hydrogen (1.44 mg, 713 µmol) (15 PSI). The mixture was filtered, the cake was washed by THF (30 mL), the filtrate was concentrated by reduced pressure. The residue was used in next step directly. Compound (1S,3aR,6aS)-N-methyl-N- (m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (180 mg, 78% yield, 80% purity) was obtained as yellow oil. ESI [M-H] = 259.2. e) Synthesis of (1S,3aR,6aS)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)- N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (Compound 3)
Figure imgf000065_0001
  To a solution of 2-chloro-6-methyl-4-(trifluoromethyl)pyridine-3-carbonitrile (92.2 mg, 418 µmol) in NMP (3 mL) was added DIPEA (135 mg, 1.05 mmol), followed by the addition of (1S,3aR,6aS)-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (90.0 mg, 348 µmol), the mixture was stirre at 100 °C for 12 h under N2. The mixture was cooled to 20 °C, diluted with EtOAc (20 mL), washed with water (20 mL x 3), the organic layer was dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by pre-HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water(FA)-ACN]; B%: 70%-100%,12min) to afford the product. Compound (1S,3aR,6aS)-2- (3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m- tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (Compound 3) (50.2 mg, 33% yield, >99% purity) was obtained as white solid.1HNMR (400 MHz, DMSO-d6): δ 7.57 - 7.49 (m, 1H), 7.47 - 7.40 (m, 2H), 7.35 (d, J = 7.6 Hz, 1H), 7.18 (s, 1H), 4.74 (s, 1H), 4.25 (t, J = 9.6 Hz, 1H), 3.95 (dd, J = 4.4, 10.4 Hz, 1H), 3.45 (s, 3H), 3.26 (s, 3H), 3.08 - 2.93 (m, 1H), 2.87 - 2.72 (m, 2H), 2.48 (s, 3H), 1.89 (d, J = 6.6 Hz, 1H), 1.64 - 1.48 (m, 4H), 0.90 (dd, J = 6.4, 12.2 Hz, 1H). ESI [M-H] = 443.1. Example 4. Preparation of (Rac)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)- N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (Compound 4) 
Figure imgf000066_0001
  a) Synthesis of 2,4,5,6-tetrahydrocyclopenta[c]pyrrole-1-carboxylic acid
Figure imgf000066_0002
  To a solution of ethyl 2,4,5,6-tetrahydrocyclopenta[c]pyrrole-3-carboxylate (800 mg, 4 mmol, 1.0 eq.) in MeOH (10 mL) was added sat. aq. LiOH.H2O (10 mL). The mixture was stirred at 50 °C for 1 hr, quenched by addition of 1N HCl (30 mL) at 0 °C and extracted with MTBE (30 mL x 3). The organic layers were dried over Na2SO4, filtered, and concentrated to yield 2,4,5,6-tetrahydrocyclopenta[c]pyrrole-1-carboxylic acid (820 mg, crude) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.04 (br s, 1H), 6.56 (d, J = 2.6 Hz, 1H), 2.65 (t, J = 7.2 Hz, 2H), 2.53 - 2.48 (m, 2H), 2.22 (quin, J = 7.2 Hz, 2H). ESI [M-H] = 150.2. b) Synthesis of N-methyl-N-(m-tolyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrrole-1- carboxamide
Figure imgf000067_0001
  To a solution of 2,4,5,6-tetrahydrocyclopenta[c]pyrrole-1-carboxylic acid (930 mg, 6 mmol, 1.0 eq.) in THF (18 mL) and DCM (6 mL) was added EDCI (1.7 g, 9 mmol, 1.5 eq.) and N,3-dimethylaniline (894 mg, 7 mmol, 1.2 eq.) at 0 °C. The mixture was stirred at 25 °C for 1 hr, diluted with addition of H2O (10 mL) and extracted with DCM (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by column chromatography (SiO2, Petroleum ether: EtOAc= 5:1 to 3:1) to yield N-methyl-N-(m- tolyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrrole-1-carboxamide (400 mg, 1 mmol, 25% yield) as a yellow solid. ESI [M+H] = 255.4. c) Synthesis of tert-butyl 1-(methyl(m-tolyl)carbamoyl)-5,6- dihydrocyclopenta[c]pyrrole-2(4H)-carboxylate
Figure imgf000067_0002
  To a solution of N-methyl-N-(m-tolyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrrole-1- carboxamide (100 mg, 393 μmol, 1.0 eq.) in DCM (3 mL) was added TEA (119 mg, 1 mmol, 3.0 eq.), DMAP (5 mg, 39 ^ μmol, 0.1 eq.) and Boc2O (129 mg, 589 μmol, 1.5 eq.). The mixture was stirred at 25 °C for 1 hr, quenched by addition of H2O (5 mL) and extracted with DCM (10 mL x 3). The organic layers were dried over Na2SO4, filtered, concentrated and purified by prep-TLC (SiO2, Petroleum ether: EtOAc= 3:1) to yield tert-butyl 1-(methyl(m- tolyl)carbamoyl)-5,6-dihydrocyclopenta[c]pyrrole-2(4H)-carboxylate (70 mg, 197 μmol, 50% yield) as a yellow oil. ESI [M-t-Bu+H] = 299.3. d) Synthesis of tert-butyl (Rac)-1-(methyl(m- tolyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate
Figure imgf000068_0001
  To a solution of tert-butyl 1-(methyl(m-tolyl)carbamoyl)-5,6- dihydrocyclopenta[c]pyrrole-2(4H)-carboxylate (50 mg, 141 μmol, 1.0 eq.) in MeOH (10 mL) was added Pd/C (0.1 g, 10% w/w). The mixture was stirred at 30 °C for 5 hrs under N2 atmosphere, filtered and concentrated to yield tert-butyl (Rac)-1-(methyl(m- tolyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (140 mg, crude) as a white solid. ESI [M-Boc+H] = 259.4 e) Synthesis of (Rac)-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1- carboxamide
Figure imgf000068_0002
  To a solution of (Rac)-1-(methyl(m-tolyl)carbamoyl)hexahydrocyclopenta[c]pyrrole- 2(1H)-carboxylate (130 mg, 362 μmol, 1.0 eq.) in HCl/MeOH (5 mL) was stirred at 25 °C for 1 hr. The reaction mixture was concentrated to yield (Rac)-N-methyl-N-(m- tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (90 mg, crude) as a yellow gum. ESI [M+H] = 259.4. f) Synthesis of (Rac)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N- methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (Compound 4)
Figure imgf000068_0003
  To a solution of (Rac)-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1- carboxamide (100 mg, 387 μmol, 1.0 eq.) and 2-chloro-6-methyl-4-(trifluoromethyl)pyridine- 3-carbonitrile (170 mg, 774 μmol, 2.0 eq.) in dioxane (5 mL) was added DIEA (150 mg, 1 mmol, 3.0 eq.). The mixture was stirred at 100 °C for 1 hr, diluted with H2O (5 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by prep-HPLC (column: Phenomenex Luna C1875 * 30 mm * 3 um; mobile phase: [water (FA)-ACN]; B%: 70% - 100%, 8 mins) to yield (Rac)-2- (3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m- tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (Compound 4) (15 mg, 35 μmol, 9% yield, >99% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.44 - 7.39 (m, 1H), 7.31 (s, 1H), 7.29 - 7.22 (m, 2H), 7.06 (s, 1H), 4.84 (d, J = 8.3 Hz, 1H), 4.01 (t, J = 9.6 Hz, 1H), 3.49 (br t, J = 9.8 Hz, 1H), 3.14 (s, 3H), 2.70 - 2.59 (m, 1H), 2.53 (s, 3H), 2.37 (s, 3H), 2.32 (br dd, J = 8.7, 17.1 Hz, 1H), 1.85 - 1.76 (m, 1H), 1.75 - 1.49 (m, 5H). ESI [M+H] = 443.2. Example 5 and Example 6. Preparation of (1S,3aS,6aR)-2-(3-cyano-6-methyl-4- (trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1- carboxamide (Compound 5) and (1R,3aR,6aS)-2-(3-cyano-6-methyl-4- (trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1- carboxamide (Compound 6)
Figure imgf000069_0001
Compound 4 was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm * 30 mm,10 um); mobile phase: [0.1% NH3H2O IPA]; B%: 18%-18%, 10 mins) to yield (1S,3aS,6aR)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m- tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (Compound 5) (34 mg, 76 μmol, 15% yield, 98% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.44 - 7.39 (m, 1H), 7.31 (s, 1H), 7.29 - 7.22 (m, 2H), 7.06 (s, 1H), 4.84 (d, J = 8.3 Hz, 1H), 4.01 (t, J = 9.6 Hz, 1H), 3.53 - 3.44 (m, 1H), 3.14 (s, 3H), 2.70 - 2.59 (m, 1H), 2.53 (s, 3H), 2.37 (s, 3H), 2.35 - 2.28 (m, 1H), 1.87 - 1.75 (m, 1H), 1.73 - 1.51 (m, 5H). ESI [M+H] = 443.2. And (1R,3aR,6aS)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m- tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (Compound 6) (35 mg, 79 μmol, 15% yield, 99% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.45 - 7.38 (m, 1H), 7.31 (s, 1H), 7.29 - 7.22 (m, 2H), 7.06 (s, 1H), 4.84 (d, J = 8.3 Hz, 1H), 4.01 (t, J = 9.5 Hz, 1H), 3.53 - 3.44 (m, 1H), 3.14 (s, 3H), 2.69 - 2.59 (m, 1H), 2.53 (s, 3H), 2.37 (s, 3H), 2.32 (br dd, J = 8.8, 17.2 Hz, 1H), 1.86 - 1.75 (m, 1H), 1.73 - 1.51 (m, 5H). ESI [M+H] = 443.2. Example 7. Preparation of (1S,3aR,6aS)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N- methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (Compound 7)
Figure imgf000070_0002
  a) Synthesis of tert-butyl (1S,3aR,6aS)-1-(methyl(m- tolyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate
Figure imgf000070_0001
  tert-Butyl (1S,3aR,6aS)-1-(methyl(m- tolyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate was synthesized from (1S,3aR,6aS)-2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid and N,3-dimethylaniline by following General procedure A and obtained as a brown gum in 81% yield. ESI [M+H] = 359.2. b) Synthesis of (1S,3aR,6aS)-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1- carboxamide
Figure imgf000071_0001
  (1S,3aR,6aS)-N-Methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide was synthesized from tert-butyl (1S,3aR,6aS)-1-(methyl(m- tolyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate by following General procedure B and obtained as a white solid as a HCl salt. ESI [M+H] = 259.2 c) Synthesis of (1S,3aR,6aS)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N- (m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (Compound 7)
Figure imgf000071_0002
  (1S,3aR,6aS)-2-(4,6-bis(Trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m- tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (Compound 7) was synthesized from (1S,3aR,6aS)-N-Methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (30 mg, 116 μmol, 1.0 eq.) and 2-chloro-4,6-bis(trifluoromethyl)pyridine (35 mg, 139 μmol, 1.2 eq.) by following General procedure C and obtained as a pale yellow solid in 24% yield.1H NMR (400 MHz, DMSO-d6) = 7.37 - 7.30 (m, 1H), 7.25 (br s, 1H), 7.23 - 7.16 (m, 3H), 7.03 (br s, 1H), 4.27 (br s, 1H), 3.72 (br t, J = 9.3 Hz, 1H), 3.37 (dd, J = 4.1, 10.3 Hz, 1H), 3.04 (s, 3H), 2.79 (td, J = 3.9, 7.8 Hz, 1H), 2.69 - 2.59 (m, 1H), 2.29 (s, 3H), 1.78 - 1.68 (m, 1H), 1.50 (br dd, J = 5.7, 11.1 Hz, 1H), 1.43 - 1.31 (m, 3H), 0.71 (br d, J = 5.0 Hz, 1H). ESI [M+H] = 472.2. Example 8. Preparation of (1S,3aR,6aS)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2- yl)-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (Compound 8)
Figure imgf000072_0002
  a) Synthesis of 2-hydroxy-4,6-bis(trifluoromethyl)nicotinonitrile
Figure imgf000072_0001
  To a solution of 1,1,1,5,5,5-hexafluoropentane-2,4-dione (1.0 g, 5 mmol, 1.0 eq.) in sulfolane (15 mL) was added 2-cyanoacetamide (404 mg, 5 mmol, 1.0 eq.). The mixture was stirred at 150 °C for 2 hrs, quenched by addition of H2O (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with sat. aq. LiCl (10 mL x 5), dried over Na2SO4, filtered and concentrated to yield 2-hydroxy-4,6- bis(trifluoromethyl)nicotinonitrile (1.2 g, crude) as a yellow oil. ESI [M-H] = 255.0. b) Synthesis of 2-chloro-4,6-bis(trifluoromethyl)nicotinonitrile
Figure imgf000072_0003
  To a solution of 2-hydroxy-4,6-bis(trifluoromethyl)nicotinonitrile (600 mg, 2 mmol, 1.0 eq.) in POCl3 (4.9 g, 32 mmol, 13.8 eq.) was added TEA (7.3 g, 72 mmol, 30.7 eq.). The mixture was stirred at 125 °C for 12 hrs, quenched by addition of ice water (100 mL) at 0 °C and extracted with EtOAc (200 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to yield 2-chloro-4,6-bis(trifluoromethyl)nicotinonitrile (600 mg, crude) as a yellow oil. ESI [M-H] = 275. c) Synthesis of (1S,3aR,6aS)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N- methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (Compound 8)
Figure imgf000073_0001
  (1S,3aR,6aS)-2-(3-Cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m- tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (Compound 8) was synthesized from 2- chloro-4,6-bis(trifluoromethyl)nicotinonitrile (149 mg, 542 ^ μmol l, 4.0 eq.) and (1S,3aR,6aS)-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (35 mg, 135 μmol, 1.0 eq.) by following General procedure C and obtained as a yellow solid in 13% yield.1H NMR (400 MHz, DMSO-d6) δ 7.47 (s, 1H), 7.43 - 7.36 (m, 1H), 7.26 (br dd, J = 7.1, 11.4 Hz, 3H), 4.59 (br s, 1H), 4.18 (br t, J = 9.5 Hz, 1H), 3.92 (br dd, J = 4.5, 10.5 Hz, 1H), 3.12 (s, 3H), 2.86 (br d, J = 2.6 Hz, 1H), 2.72 - 2.64 (m, 1H), 2.34 (s, 3H), 1.82 - 1.70 (m, 1H), 1.55 - 1.32 (m, 4H), 0.74 (br dd, J = 5.3, 11.3 Hz, 1H). ESI [M+H] = 497.2. Example 9. Preparation of (1S,3aR,6aS)-N-(3-chloro-4-fluorophenyl)-2-(3-cyano-6- methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyloctahydrocyclopenta[c]pyrrole-1- carboxamide (Compound 9)
Figure imgf000074_0001
  a) Synthesis of tert-butyl (1S,3aR,6aS)-1-((3-chloro-4- fluorophenyl)(methyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)- carboxylate
Figure imgf000074_0002
  tert-Butyl (1S,3aR,6aS)-1-((3-chloro-4- fluorophenyl)(methyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate was synthesized from (1S,3aR,6aS)-2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrole-1- carboxylic acid (90 mg, 353 μmol, 1.0 eq.) and 3-chloro-4-fluoro-N-methyl-aniline (84 mg, 529 μmol, 1.5 eq.) following General procedure A and obtained 80 mg as a yellow oil. ESI [M-Boc+H] = 297.1. b) Synthesis of (1S,3aR,6aS)-N-(3-chloro-4-fluorophenyl)-N- methyloctahydrocyclopenta[c]pyrrole-1-carboxamide
Figure imgf000075_0001
  (1S,3aR,6aS)-N-(3-Chloro-4-fluorophenyl)-N-methyloctahydrocyclopenta[c]pyrrole- 1-carboxamide was synthesized from (1S,3aR,6aS)-N-(3-chloro-4-fluorophenyl)-N- methyloctahydrocyclopenta[c]pyrrole-1-carboxamide (80 mg, 202 μmol, 1.0 eq.) following General procedure B and obtained 59 mg as a white solid. ESI [M+H] =297.2. c) Synthesis of (1S,3aR,6aS)-N-(3-chloro-4-fluorophenyl)-2-(3-cyano-6-methyl-4- (trifluoromethyl)pyridin-2-yl)-N-methyloctahydrocyclopenta[c]pyrrole-1- carboxamide (Compound 9)
Figure imgf000075_0002
  (1S,3aR,6aS)-N-(3-Chloro-4-fluorophenyl)-2-(3-cyano-6-methyl-4- (trifluoromethyl)pyridin-2-yl)-N-methyloctahydrocyclopenta[c]pyrrole-1-carboxamide (Compound 9) was synthesized from (1S,3aR,6aS)-N-(3-chloro-4-fluorophenyl)-N- methyloctahydrocyclopenta[c]pyrrole-1-carboxamide (50 mg, 169 μmol, 1.0 eq.) and 2- chloro-6-methyl-4-(trifluoromethyl)pyridine-3-carbonitrile (74 mg, 337 μmol, 2.0 eq.) following General procedure C and obtained 10 mg as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.85 - 7.80 (m, 1H), 7.64 - 7.53 (m, 2H), 7.06 (s, 1H), 4.55 (s, 1H), 4.14 (br t, J = 9.4 Hz, 1H), 3.83 (br dd, J = 4.1, 10.3 Hz, 1H), 3.14 (s, 3H), 2.91 - 2.79 (m, 1H), 2.70 (br d, J = 7.6 Hz, 1H), 2.53 - 2.50 (m, 3H), 1.84 -1.72 (m, 1H), 1.63 - 1.39 (m, 4H), 0.86 (br dd, J = 6.6, 12.3 Hz, 1H). ESI [M+H] = 481.2. Example 10. Preparation of (1S,3aR,6aS)-2-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)- N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (Compound 10)
Figure imgf000076_0001
  (1S,3aR,6aS)-2-(6-Chloro-4-(trifluoromethyl)pyridin-2-yl)-N-(m- tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (Compound 10) was synthesized from (1S,3aR,6aS)-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (55 mg, 213 μmol, 1.0 eq.) and 2,6-dichloro-4-(trifluoromethyl)pyridine (55 mg, 255 μmol, 1.2 eq.) following General procedure C and obtained 21 mg as a yellow gum.1H NMR (400 MHz, DMSO-d6) δ 7.41 - 7.31 (m, 2H), 7.27 (br d, J = 6.4 Hz, 1H), 7.18 (br d, J = 7.4 Hz, 1H), 6.87 (s, 1H), 6.65 (br s, 1H), 4.18 (br s, 1H), 3.68 (br t, J = 9.3 Hz, 1H), 3.26 (br d, J = 3.5 Hz, 1H), 3.07 (s, 3H), 2.85 - 2.71 (m, 1H), 2.62 (br d, J = 1.4 Hz, 1H), 2.31 (s, 3H), 1.76 - 1.65 (m, 1H), 1.61 - 1.47 (m, 1H), 1.44 - 1.25 (m, 3H), 0.83 - 0.67 (m, 1H). ESI [M+H] = 438.1. Example 11. Preparation of (1S,3aR,6aS)-N-methyl-2-(6-methyl-4- (trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1- carboxamide (Compound 11)
Figure imgf000076_0002
  A mixture (1S,3aR,6aS)-2-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-N-(m- tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (20 mg, 46 μmol, 1.0 eq.), 2,4,6- trimethyl-1,3,5,2,4,6-trioxatriborinane (17 mg, 137 μmol, 3.0 eq.), K3PO4 (29 mg, 137 μmol, 3.0 eq.), ditert-butyl(cyclopentyl)phosphane;dichloropalladium;iron (3 mg, 5 μmol, 0.1 eq.) in THF (3 mL) and H2O (1 mL) was stirred at 60 °C for 1 hr under N2 atmosphere. The reaction mixture was concentrated, diluted with addition of H2O (2 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by prep-HPLC (column: Phenomenex Luna C18200 * 40 mm * 10 um; mobile phase: [water (FA)-ACN]; B%: 65%-98%, 8 mins) to yield (1S,3aR,6aS)-N- methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(m- tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (Compound 11) (5 mg, 13 μmol, 28% yield, >99% purity) as a yellow gum.1H NMR (400 MHz, DMSO-d6) δ 7.40 - 7.12 (m, 4H), 6.64 (s, 1H), 6.34 (br s, 1H), 4.23 (br s, 1H), 3.65 (br t, J = 9.2 Hz, 1H), 3.20 (br d, J = 8.8 Hz, 1H), 3.04 (s, 3H), 2.76 (tt, J = 4.1, 7.9 Hz, 1H), 2.65 - 2.55 (m, 1H), 2.35 (s, 3H), 2.30 (s, 3H), 1.77 - 1.65 (m, 1H), 1.60 - 1.49 (m, 1H), 1.42 - 1.28 (m, 3H), 0.74 (br dd, J = 6.4, 12.8 Hz, 1H). ESI [M+H] = 418.2. Example 12. Preparation of (1S,3aR,6aS)-N-(3-chloro-2-fluorophenyl)-2-(3-cyano-6- methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyloctahydrocyclopenta[c]pyrrole-1- carboxamide (Compound 12)
Figure imgf000077_0002
  a) Synthesis of tert-butyl (1S,3aR,6aS)-1-((3-chloro-2- fluorophenyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate
Figure imgf000077_0001
tert-Butyl (1S,3aR,6aS)-1-((3-chloro-2- fluorophenyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate was synthesized from (1S,3aR,6aS)-2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid (150 mg, 588 μmol, 1.0 eq.) and 3-chloro-2-fluoro-aniline (171 mg, 1 mmol, 2.0 eq.) following General procedure A and obtained 290 mg as a white solid. ESI [M-Boc+H] = 283.1. b) Synthesis of tert-butyl (1S,3aR,6aS)-1-((3-chloro-2- fluorophenyl)(methyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)- carboxylate
Figure imgf000078_0001
  To a solution of tert-butyl (1S,3aR,6aS)-1-((3-chloro-2- fluorophenyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (270 mg, 705 μmol, 1.0 eq.) in DMF (5 mL) was added NaH (42 mg, 1 mmol, 60% w/w, 1.5 eq.) at 0 °C under N2, followed by addition of CH3I (400 mg, 3 mmol, 4.0 eq.). The mixture was stirred at 0 °C for 1.5 hrs, quenched by addition of sat. aq. NH4Cl (5 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with sat. aq. LiCl (50 mL x 3), dried over Na2SO4, filtered and concentrated to yield tert-butyl (1S,3aR,6aS)-1-((3-chloro-2- fluorophenyl)(methyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (280 mg, crude) as a yellow oil. ESI [M-Boc+H] = 297.1. c) Synthesis of (1S,3aR,6aS)-N-(3-chloro-2-fluorophenyl)-N- methyloctahydrocyclopenta[c]pyrrole-1-carboxamide
Figure imgf000078_0002
  (1S,3aR,6aS)-N-(3-Chloro-2-fluorophenyl)-N-methyloctahydrocyclopenta[c]pyrrole-1- carboxamide was synthesized from tert-butyl (1S,3aR,6aS)-1-((3-chloro-2- fluorophenyl)(methyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (280 mg, 706 μmol, 1.0 eq.) following General procedure B and obtained 200 mg as a yellow gum.  ESI [M+H] = 297.1. d) Synthesis of (1S,3aR,6aS)-N-(3-chloro-2-fluorophenyl)-2-(3-cyano-6-methyl-4- (trifluoromethyl)pyridin-2-yl)-N-methyloctahydrocyclopenta[c]pyrrole-1- carboxamide (Compound 12)
Figure imgf000079_0001
  (1S,3aR,6aS)-N-(3-Chloro-2-fluorophenyl)-2-(3-cyano-6-methyl-4- (trifluoromethyl)pyridin-2-yl)-N-methyloctahydrocyclopenta[c]pyrrole-1-carboxamide (Compound 12) was synthesized from (1S,3aR,6aS)-N-(3-chloro-2-fluorophenyl)-N- methyloctahydrocyclopenta[c]pyrrole-1-carboxamide (200 mg, 674 μmol, 1.0 eq.) in dioxane (4 mL) and 2-chloro-6-methyl-4-(trifluoromethyl)pyridine-3-carbonitrile (119 mg, 539 μmol, 0.8 eq.) following General procedure C and obtained 44 mg as a yellow gum.1H NMR (400 MHz, DMSO-d6) δ 7.87 - 7.45 (m, 2H), 7.37 (br s, 1H), 7.02 (s, 1H), 4.68 (br d, J = 0.8 Hz, 1H), 4.14 (br s, 1H), 3.87 (br s, 1H), 3.18 (br s, 3H), 2.89 (br s, 1H), 2.80 - 2.59 (m, 1H), 2.50 (br d, J = 1.7 Hz, 3H), 1.83 (br s, 1H), 1.50 -1.21 (m, 4H), 1.11 - 0.59 (m, 1H). ESI [M+H] = 481.1. Example 13. Preparation of (1S,3aR,6aS)-2-(3-cyano-6-methyl-4- (trifluoromethyl)pyridin-2-yl)-N-(2,4-difluorophenyl)-N- methyloctahydrocyclopenta[c]pyrrole-1-carboxamide (Compound 13)
Figure imgf000080_0001
  a) Synthesis of tert-butyl (1S,3aR,6aS)-1-((2,4- difluorophenyl)(methyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)- carboxylate
Figure imgf000080_0002
  tert-Butyl (1S,3aR,6aS)-1-((2,4- difluorophenyl)(methyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate was synthesized from (1S,3aR,6aS)-2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrole-1- carboxylic acid (100 mg, 391 μmol, 1.0 eq.) and 2,4-difluoro-N-methyl-aniline (84 mg, 587 μmol, 1.5 eq.) following General procedure A and obtained 150 mg as a yellow oil. ESI[M- Boc+H] = 281.2. b) Synthesis of (1S,3aR,6aS)-N-(2,4-difluorophenyl)-N- methyloctahydrocyclopenta[c]pyrrole-1-carboxamide
Figure imgf000081_0001
  (1S,3aR,6aS)-N-(2,4-Difluorophenyl)-N-methyloctahydrocyclopenta[c]pyrrole-1- carboxamide was synthesized from tert-butyl (1S,3aR,6aS)-1-((2,4- difluorophenyl)(methyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (150 mg, 394 μmol, 1.0 eq.) following General procedure B and obtained 120 mg as a yellow oil. ESI[M+H] = 281.2. c) Synthesis of (1S,3aR,6aS)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)- N-(2,4-difluorophenyl)-N-methyloctahydrocyclopenta[c]pyrrole-1-carboxamide (Compound 13)
Figure imgf000081_0002
  (1S,3aR,6aS)-2-(3-Cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(2,4- difluorophenyl)-N-methyloctahydrocyclopenta[c]pyrrole-1-carboxamide (Compound 13) was synthesized from (1S,3aR,6aS)-N-(2,4-difluorophenyl)-N- methyloctahydrocyclopenta[c]pyrrole-1-carboxamide (60 mg, 189 μmol, 1.0 eq.) and 2- chloro-6-methyl-4-(trifluoromethyl)pyridine-3-carbonitrile (62 mg, 284 μmol, 1.5 eq.) following General procedure C and obtained 7 mg as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 7.78 (br dd, J=3.81, 2.98Hz, 1H), 7.42 - 7.58 (m, 1H), 7.26 - 7.36 (m, 1H), 7.09 (br s, 1H), 4.74 (br s, 1H), 4.22 (br t, J=9.06 Hz, 1H), 3.87 - 4.00 (m, 1H), 3.17 - 3.25 (m, 3H), 2.90 - 3.02 (m, 2H), 2.48 - 2.56 (m, 3H), 1.86 - 1.95 (m, 1H), 1.47 - 1.64 (m, 4H), 0.86 - 1.04 (m, 1H). ESI[M+H] = 465.2. Example 14. Preparation of (1S,3aR,6aS)-2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N- methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (Compound 14)
Figure imgf000082_0001
  a) Synthesis of tert-butyl (1S,3aR,6aS)-1-(methyl(m- tolyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate
Figure imgf000082_0002
  tert-Butyl (1S,3aR,6aS)-1-(methyl(m- tolyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate was synthesized from (1S,3aR,6aS)-2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid (600 mg, 2 mmol, 1.0 eq.) and N,3-dimethylaniline (854 mg, 7 mmol, 3.0 eq.) following General procedure A and obtained 680 mg as a brown gum. ESI [M+H] = 359.2. b) Synthesis of (1S,3aR,6aS)-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1- carboxamide
Figure imgf000082_0003
  (1S,3aR,6aS)-N-Methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide was synthesized from tert-butyl (1S,3aR,6aS)-1-(methyl(m- tolyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (220 mg, 614 μmol, 1.0 eq.) following General procedure B and obtained 336 mg as yellow oil. ESI [M+H] = 259.3. c) Synthesis of (1S,3aR,6aS)-2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N- (m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (Compound 14)
Figure imgf000083_0001
  (1S,3aR,6aS)-2-(3,5-Bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m- tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (Compound 14) was synthesized from (1S,3aR,6aS)-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (20 mg, 77 μmol, 1.0 eq.) and 2-chloro-3,5-bis(trifluoromethyl)pyridine (23 mg, 93 μmol, 1.2 eq.) following General procedure C and obtained 31 mg as a pale yellow solid.1H NMR (400 MHz, CD3SOCD3, 298 K) δ 8.74 - 8.66 (m, 1H), 8.16 - 8.04 (m, 1H), 7.39 - 7.24 (m, 3H), 7.19 - 7.13 (m, 1H), 4.50 (d, J = 1.6 Hz, 1H), 3.82 (br t, J = 8.6 Hz, 1H), 3.48 - 3.36 (m, 1H), 3.07 (s, 3H), 2.84 - 2.74 (m, 1H), 2.61 - 2.51 (m, 1H), 2.30 (s, 3H), 1.79 - 1.66 (m, 1H), 1.56 - 1.44 (m, 1H), 1.41 - 1.24 (m, 3H), 0.71 (qd, J = 6.5, 12.9 Hz, 1H). ESI [M+H] = 472.2. Example 15. Preparation of (1S,3aR,6aS)-N-(3-chloro-2,4-difluorophenyl)-2-(3-cyano-6- methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyloctahydrocyclopenta[c]pyrrole-1- carboxamide (Compound 15)
Figure imgf000084_0001
  a) Synthesis of 3-chloro-2,4-difluoro-N-methylaniline
Figure imgf000084_0002
  To a solution of NaOMe (3.3 g, 61 mmol, 10.0 eq.) in MeOH (30 mL) was added HCHO (918 mg, 9 mmol, 30% purity, 1.5 eq.) and 3-chloro-2,4-difluoro-aniline (1.0 g, 6 mmol, 1.0 eq.). The mixture was stirred 25 °C for 12 hrs, followed by addition of NaBH4 (530 mg, 14 mmol, 2.3 eq.). The mixture was stirred at 25 °C for 2 hrs, quenched by addition of 1 N HCl (50 mL) at 0 °C, diluted with H2O (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by column chromatography (SiO2, Petroleum ether:EtOAc=100:1 to 50:1) to yield 3-chloro- 2,4-difluoro-N-methyl-aniline (930 mg, 5 mmol, 85% yield) as yellow solid. ESI [M+H] = 178.1. b) Synthesis of (1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1-carboxylic acid
Figure imgf000085_0001
  A solution of (1S,3aR,6aS)-2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrole-1- carboxylic acid (300 mg, 1 mmol, 1.0 eq.) in 4 M HCl/MeOH (2 mL) was stirred at 25 °C for 1 hr and concentrated to yield (1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1-carboxylic acid (350 mg, crude) as a brown gum. ESI [M+H] = 156.2. c) Synthesis of (1S,3aR,6aS)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2- yl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid
Figure imgf000085_0002
  To a solution of (1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1-carboxylic acid (280 mg, 2 mmol, 1.0 eq.) in dioxane (5 mL) was added DIEA (700 mg, 6 mmol, 3.0 eq.) and 2- chloro-6-methyl-4-(trifluoromethyl)pyridine-3-carbonitrile (477 mg, 2 mmol, 1.2 eq.). The mixture was stirred at 100 °C for 3 hrs, quenched by addition of H2O (50 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by prep-HPLC (column: Phenomenex luna C18100 * 40 mm * 3 um; mobile phase: [water (TFA)-ACN]; B%: 35%-80%, 8 mins) to yield (1S,3aR,6aS)-2-(3- cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid (190 mg, 560 μmol, 31% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 7.09 (s, 1H), 4.52 (br d, J = 3.8 Hz, 1H), 4.08 (br dd, J = 8.3, 10.5 Hz, 1H), 3.81 (br dd, J = 3.8, 10.7 Hz, 1H), 2.87 - 2.77 (m, 1H), 2.73 - 2.65 (m, 1H), 2.41 (s, 3H), 2.00 - 1.54 (m, 5H), 1.53 - 1.42 (m, 1H). ESI [M+H] = 340.1. d) Synthesis of (1S,3aR,6aS)-N-(3-chloro-2,4-difluorophenyl)-2-(3-cyano-6-methyl- 4-(trifluoromethyl)pyridin-2-yl)-N-methyloctahydrocyclopenta[c]pyrrole-1- carboxamide (Compound 15)
Figure imgf000086_0001
  To a solution of (1S,3aR,6aS)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2- yl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid (71 mg, 210 μmol, 1.0 eq.) in toluene (2 mL) was added 3-chloro-2,4-difluoro-N-methyl-aniline (44 mg, 251 μmol, 1.2 eq.) and PCl3 (173 mg, 1 mmol, 6.0 eq.) at 0 °C. The mixture was stirred at 100 °C for 1 hr, quenched by addition of sat. aq. NaHCO3 (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by prep-HPLC (column: Waters Xbridge BEH C18100 * 30 mm *10 um; mobile phase: [water (NH4HCO3)- ACN]; B%: 50%-80%, 8 mins) to yeild (1S,3aR,6aS)-N-(3-chloro-2,4-difluorophenyl)-2-(3- cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyloctahydrocyclopenta[c]pyrrole-1- carboxamide (Compound 15) (11 mg, 22 μmol, 10% yield, 97% purity) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 7.56 - 7.82 (m, 1 H), 7.28 - 7.54 (m, 1 H), 7.03 (s, 1 H), 4.57 (m, 1 H), 4.51 - 4.80 (m, 1 H), 3.75 - 4.28 (m, 1 H), 3.16 (br s, 3 H), 2.70 - 2.95 (m, 2 H), 2.51 (br d, J=1.67 Hz, 3 H), 1.85 (br s, 2 H), 1.39 - 1.79 (m, 3 H), 0.78 - 1.16 (m, 1 H). ESI [M+H] = 499.1. Example 16. Preparation of (1S,3aR,6aS)-N-methyl-2-(6-methyl-4- (trifluoromethyl)pyridin-2-yl)-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1- carboxamide (Compound 16)
Figure imgf000087_0001
  a) Synthesis of tert-butyl (1S,3aR,6aS)-1-(methyl(m- tolyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate
Figure imgf000087_0002
  tert-Butyl (1S,3aR,6aS)-1-(methyl(m- tolyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate was synthesized from (1S,3aR,6aS)-2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid (600 mg, 2 mmol, 1.0 eq.) and N,3-dimethylaniline (854 mg, 7 mmol, 3.0 eq.) following General procedure A and obtained 680 mg as a brown gum. ESI [M+H] = 359.2. b) Synthesis of tert-butyl (1S,3aR,6aS)-1-(methyl(m-tolyl)carbamoyl)-3- oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate
Figure imgf000087_0003
  To a solution of tert-butyl (1S,3aR,6aS)-1-(methyl(m- tolyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (200 mg, 558 μmol, 1.0 eq.) in H2O (2 mL)/EtOAc (4 mL) was added NaIO4 (609 mg, 3 mmol, 5.1 eq.) and NaHCO3 (309 mg, 4 mmol, 6.6 eq.), followed by addition of RuCl3 (45 mg, 218 μmol, 0.4 eq.). The mixture was stirred at 20 °C for 12 hrs, quenched by addition of H2O (20 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to yield tert-butyl (1S,3aR,6aS)-1-(methyl(m- tolyl)carbamoyl)-3-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (180 mg, crude) as a pale yellow gum. ESI [M-Boc+H] = 273.1. c) Synthesis of (1S,3aR,6aS)-N-methyl-3-oxo-N-(m- tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide
Figure imgf000088_0001
  (1S,3aR,6aS)-N-Methyl-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1- carboxamide was synthesized from tert-butyl (1S,3aR,6aS)-1-(methyl(m-tolyl)carbamoyl)-3- oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (160 mg, 430 μmol, 1.0 eq.) following General procedure B and obtained 40 mg as a pale yellow solid. ESI [M+H] = 273.2. d) Synthesis of (1S,3aR,6aS)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)- 3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (Compound 16)
Figure imgf000088_0002
To a solution of (1S,3aR,6aS)-N-methyl-3-oxo-N-(m- tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (30 mg, 110 μmol, 1.0 eq.) and 2-bromo- 6-methyl-4-(trifluoromethyl)pyridine (32 mg, 132 μmol, 1.2 eq.) in dioxane (1 mL) was added xantphos (6 mg, 11 μmol, 0.1 eq.), Cs2CO3 (108 mg, 330 u ^ μmol 3.0 eq.) and Pd2(dba)3 (10 mg, 11 μmol, 0.1 eq.). The mixture was stirred at 100 °C for 3 hrs, quenched by addition of H2O (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by prep-HPLC (column: Phenomenex Luna C1875 * 30 mm * 3um; mobile phase:[water(FA)-ACN];B%: 60%-95%, 8 mins) to yield (1S,3aR,6aS)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxo- N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (Compound 16) (25 mg, 57 μmol, 51% yield, 98% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) = 8.48 (s, 1H), 7.51 - 7.35 (m, 4H), 7.27 (d, J = 7.5 Hz, 1H), 4.61 (d, J = 0.8 Hz, 1H), 3.19 (s, 4H), 2.81 - 2.66 (m, 1H), 2.59 (s, 3H), 2.39 (s, 3H), 1.89 - 1.78 (m, 2H), 1.67 (td, J = 7.8, 12.8 Hz, 1H), 1.45 (td, J = 6.3, 12.6Hz, 1H), 1.36 - 1.16 (m, 2H), 0.93 - 0.84 (m, 1H). ESI [M+H] = 432.2. Example 17. Preparation of (1S,3aR,6aS)-N-(5-chloro-2,4-difluorophenyl)-N-methyl-2- (6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1- carboxamide (Compound 17)
Figure imgf000089_0001
  a) Synthesis of tert-butyl (1S,3aR,6aS)-1-((5-chloro-2,4- difluorophenyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate 
Figure imgf000090_0001
  tert-Butyl (1S,3aR,6aS)-1-((5-chloro-2,4- difluorophenyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate was synthesized from (1S,3aR,6aS)-2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrole-1- carboxylic acid (2.9 g, 11 mmol, 1.0 eq.) and 5-chloro-2,4-difluoroaniline (4.6 g, 28 mmol, 2.5 eq.) following General procedure A and obtained 4.o g as a yellow gum. ESI [M-Boc+H] = 300.9. b) Synthesis of tert-butyl (1S,3aR,6aS)-1-((5-chloro-2,4-difluorophenyl)carbamoyl)- 3-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate
Figure imgf000090_0002
  To a solution of tert-butyl (1S,3aR,6aS)-1-((5-chloro-2,4- difluorophenyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1.5 g, 4 mmol, 1.0 eq.) in EtOAc (10 mL)/H2O (10 mL) was added NaIO4 (3.9 g, 18 mmol, 5.0 eq.) and RuCl3 (750 mg, 3.6 mmol, 1.0 eq.). The mixture was stirred at 25 °C for 2 hrs, quenched by addition of sat. aq. Na2S2O3 (20 mL) and extracted with EtOAc (100 ml x 2). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by column chromatography (SiO2, Petroleum ether: EtOAc= 100:0 to 5:1) to yield tert-butyl (1S,3aR,6aS)-1-((5-chloro-2,4-difluorophenyl)carbamoyl)-3- oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (800 mg, 2 mmol, 53% yield) as a yellow oil. ESI [M+H] = 415. c) Synthesis of tert-butyl (1S,3aR,6aS)-1-((5-chloro-2,4- difluorophenyl)(methyl)carbamoyl)-3-oxohexahydrocyclopenta[c]pyrrole-2(1H)- carboxylate
Figure imgf000091_0001
  To a solution tert-butyl (1S,3aR,6aS)-1-((5-chloro-2,4-difluorophenyl)carbamoyl)-3- oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (320 mg, 771 μmol, 1.0 eq.) in THF (1 mL) was added NaH (46 mg, 1 mmol, 60% w/w, 1.5 eq.) at 0° C, the mixture was stirred at 0 °C for 0.5 hr and followed by addition of MeI (120 mg, 848 μmol, 1.1 eq.). The mixture was stirred at 25 °C for 1 hr, quenched by addition of sat. aq. NH4Cl (10 mL) and extracted with EtOAc (30 ml x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated to yield tert-butyl (1S,3aR,6aS)-1-((5-chloro-2,4- difluorophenyl)(methyl)carbamoyl)-3-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (330 mg, crude) as a yellow oil. ESI [M+H] = 429. d) Synthesis of (1S,3aR,6aS)-N-(5-chloro-2,4-difluorophenyl)-N-methyl-3- oxooctahydrocyclopenta[c]pyrrole-1-carboxamide
Figure imgf000091_0002
  (1S,3aR,6aS)-N-(5-Chloro-2,4-difluorophenyl)-N-methyl-3- oxooctahydrocyclopenta[c]pyrrole-1-carboxamide was synthesized from tert-butyl (1S,3aR,6aS)-1-((5-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-3- oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (330 mg, 769 μmol, 1.0 eq.) following General procedure B and obtained 220 mg as a yellow oil. ESI [M+H] = 329. e) Synthesis of (1S,3aR,6aS)-N-(5-chloro-2,4-difluorophenyl)-N-methyl-2-(6-methyl- 4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1- carboxamide (Compound 17)
Figure imgf000092_0001
  A mixture of (1S,3aR,6aS)-N-(5-Chloro-2,4-difluorophenyl)-N-methyl-3- oxooctahydrocyclopenta[c]pyrrole-1-carboxamide (170 mg, 517 μmol, 1.0 eq.), 2-bromo-6- methyl-4-(trifluoromethyl)pyridine (248 mg, 1 mmol, 2.0 eq.), Xantphos (30 mg, 51 μmol, 0.1 eq.), Pd2(dba)3 (47 mg, 51 μmol, 0.1 eq.) and Cs2CO3 (505 mg, 2 mmol, 3.0 eq.) in dioxane (5 mL) was stirred at 80 °C for 2 hrs under N2 atmosphere, quenched by addition of H2O (10 mL) and extracted with DCM (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by prep-HPLC (column: Phenomenex Luna C1875*30mm*3um; mobile phase: [H2O (0.2%FA)-ACN]; gradient: 50%-80% B over 8.0 mins ) to yield (1S,3aR,6aS)-N-(5-chloro-2,4-difluorophenyl)-N-methyl-2-(6-methyl-4- (trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1-carboxamide (Compound 17) (136 mg, 279 μmol, 54% yield, >99% purity) as a white solid.1H NMR (400 MHz, CHLOROFORM-d) δ 8.80 - 8.62 (m, 1H), 7.97 (br t, J = 7.6 Hz, 0.7H), 7.50 (br t, J = 7.0 Hz, 0.2H), 7.28 - 7.19 (m, 1H), 7.18 - 7.09 (m, 1H), 4.83 - 4.70 (m, 1H), 3.46 - 3.27 (m, 4H), 2.74 - 2.59 (m, 3H), 2.53 (s, 1H), 2.30 - 2.10 (m, 1H), 2.06 - 1.87 (m, 1H), 1.86 - 1.44 (m, 3H), 1.30 - 1.05 (m, 1H). ESI [M+H] = 488.0. Example 18. Preparation of (1S,3aR,6aS)-N-(5-chloro-2,4-difluorophenyl)-N-(methyl- d3)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1- carboxamide (Compound 18)
Figure imgf000093_0001
  a) Synthesis of tert-butyl (1S,3aR,6aS)-1-((5-chloro-2,4-difluorophenyl)(methyl- d3)carbamoyl)-3-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate
Figure imgf000093_0002
  To a solution tert-butyl (1S,3aR,6aS)-1-((5-chloro-2,4-difluorophenyl)carbamoyl)-3- oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (320 mg, 771 μmol, 1.0 eq.) in THF (5 mL) was added NaH (46 mg, 1 mmol, 60% w/w, 1.5 eq.) at 0 °C,the mixture was stirred at 0 °C for 0.5 hr and followed by addition of trideuterio(iodo)methane (123 mg, 848 μmol, 1.1 eq.). The mixture was stirred at 25 °C for 1 hr, quenched by addition of sat. aq. NH4Cl (10 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated to yield tert-butyl (1S,3aR,6aS)-1-((5-chloro-2,4- difluorophenyl)(methyl-d3)carbamoyl)-3-oxohexahydrocyclopenta[c]pyrrole-2(1H)- carboxylate (330 mg, crude) as a yellow oil. ESI [M+H] = 432. b) Synthesis of (1S,3aR,6aS)-N-(5-chloro-2,4-difluorophenyl)-N-(methyl-d3)-3- oxooctahydrocyclopenta[c]pyrrole-1-carboxamide
Figure imgf000094_0001
  (1S,3aR,6aS)-N-(5-Chloro-2,4-difluorophenyl)-N-(methyl-d3)-3- oxooctahydrocyclopenta[c]pyrrole-1-carboxamide was synthesized from tert-butyl (1S,3aR,6aS)-1-((5-chloro-2,4-difluorophenyl)(methyl-d3)carbamoyl)-3- oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (330 mg, 764 μmol, 1.0 eq.) following General procedure B and obtained 250 mg as a yellow solid. ESI [M+H] = 332. c) Synthesis of (1S,3aR,6aS)-N-(5-chloro-2,4-difluorophenyl)-N-(methyl-d3)-2-(6- methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1- carboxamide (Compound 18)
Figure imgf000094_0002
  A mixture of (1S,3aR,6aS)-N-(5-chloro-2,4-difluorophenyl)-N-(methyl-d3)-3- oxooctahydrocyclopenta[c]pyrrole-1-carboxamide (180 mg, 542 μmol, 1.0 eq.), 2-bromo-6- methyl-4-(trifluoromethyl)pyridine (260 mg, 1 mmol, 2.0 eq.), Xantphos (31 mg, 54 μmol, 0.1 eq.), Pd2(dba)3 (49 mg, 54 μmol, 0.1 eq.) and Cs2CO3 (530 mg, 2 mmol, 3.0 eq.) in dioxane (5 mL) was stirred at 80 °C for 2 hrs under N2 atmosphere, quenched by addition of H2O (10 mL) and extracted with DCM (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by prep-HPLC (column: Phenomenex Luna C1875*30mm*3um; mobile phase: [H2O(0.2% FA)-ACN]; gradient: 50%-85% B over 8.0 mins) to yield (1S,3aR,6aS)-N-(5-chloro-2,4-difluorophenyl)-N-(methyl-d3)-2-(6-methyl-4- (trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1-carboxamide (Compound 18) (106 mg, 216 μmol, 39% yield, >99% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.57 - 8.45 (m, 1H), 8.20 - 8.00 (m, 1H), 7.96 - 7.62 (m, 1H), 7.46 - 7.37 (m, 1H), 5.41 (d, J = 0.9 Hz, 0.1H), 4.73 - 4.37 (m, 0.8H), 3.27 - 3.13 (m, 1H), 3.01 - 2.75 (m, 1H), 2.69 - 2.54 (m, 2H), 2.49 (s, 1H), 1.96 - 1.79 (m, 2H), 1.76 - 1.60 (m, 1H), 1.58 - 1.41 (m, 1H), 1.40 - 1.29 (m, 1H), 1.19 - 0.99 (m, 1H). ESI [M+H] = 491.0. Example 19. Preparation of 6-methyl-2-((1S,3aR,6aS)-1-(1-(m-tolyl)-1H-imidazol-2- yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(trifluoromethyl)nicotinonitrile (Compound 19)
Figure imgf000095_0002
  a) Synthesis of tert-butyl (1S,3aR,6aS)-1- (methoxy(methyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate  
Figure imgf000095_0001
  To a solution of (1S,3aR,6aS)-2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrole- 1-carboxylic acid (0.4 g, 1 mmol, 1.0 eq.), N-methoxymethanamine (239 mg, 4 mmol, 2.5 eq.) in DMF (10 mL) was added NMM (634 mg, 6 mmol, 4.0 eq.), HOBt (423 mg, 3 mmol, 2.0 eq.) and EDCI (450 mg, 2 mmol, 1.5 eq.). The mixture was stirred at 25 °C for 12 hrs, quenched by addition of H2O (20 mL) at 0 °C, and extracted with EtOAc (50 mL x 3). The organic layers were dried over Na2SO4, filtered, concentrated and purified by column chromatography (SiO2, Petroleum ether: EtOAc= 10:1 to 1:1) to yield tert-butyl (1S,3aR,6aS)-1-(methoxy(methyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)- carboxylate (0.5 g, crude) as yellow solid. ESI [M-Boc+H] = 199.2. b) Synthesis of tert-butyl (1S,3aR,6aS)-1-formylhexahydrocyclopenta[c]pyrrole- 2(1H)-carboxylate
Figure imgf000096_0001
  A mixture of tert-butyl (1S,3aR,6aS)-1- (methoxy(methyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (450 mg, 1 mmol, 1.0 eq.) in THF (10 mL) was added DIBAL-H (1 M, 2 mL, 1.5 eq.). The mixture was stirred at -78 °C for 1 hr under N2 atmosphere, quenched by seignette salt (5 g) at 0 °C, filtered and concentrated to yield tert-butyl (1S,3aR,6aS)-1- formylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (0.5 g, crude) as white oil.1H NMR (400 MHz, CHLOROFORM-d) δ 9.51 - 9.34 (m, 1H), 3.70 - 3.64 (m, 1H), 3.30 - 3.22 (m, 1H), 1.85 (br d, J = 7.8 Hz, 1H), 1.80 - 1.72 (m, 2H), 1.72 - 1.65 (m, 1H), 1.62 - 1.50 (m, 3H), 1.36 (s, 9H), 1.19 (d, J = 1.0 Hz, 2H). c) Synthesis of tert-butyl (1S,3aR,6aS)-1-(1-(m-tolyl)-1H-imidazol-2- yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate
Figure imgf000096_0002
  To a solution of tert-butyl (1S,3aR,6aS)-1-formylhexahydrocyclopenta[c]pyrrole- 2(1H)-carboxylate (0.1 g, 417 μmol, 1.0 eq.), 3-methylaniline (44 mg, 417.87 μmol, 1.0 eq.) in MeOH (2 mL) was added NH4HCO3 (33 mg, 417 μmol, 1.0 eq.) and oxaldehyde (24 mg, 417 μmol, 1.0 eq.). The mixture was stirred at 25 °C for 12 hr, quenched by addition of aq.Na2CO3 (10 mL, 10% solution) and extracted with EtOAc (20 mL x 3). The organic layers were dried over Na2SO4, filtered, concentrated and purified by prep-HPLC (column: Phenomenex Luna 80 * 30 mm * 3 um; mobile phase: [water (TFA) - ACN]; B%: 20% - 50%, 8 mins) to yield tert-butyl (1S,3aR,6aS)-1-(1-(m-tolyl)-1H-imidazol-2- yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (40 mg, crude) as a yellow solid. ESI [M-t-Bu+H] = 315.2. d) Synthesis of (1S,3aR,6aS)-1-(1-(m-tolyl)-1H-imidazol-2- yl)octahydrocyclopenta[c]pyrrole
Figure imgf000097_0001
  To a solution tert-butyl (1S,3aR,6aS)-1-(1-(m-tolyl)-1H-imidazol-2- yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (20 mg, 54 μmol, 1.0 eq.) in 4M HCl/MeOH (2 mL) was stirred at 25 °C for 1 hr. The mixture was concentrated to yield (1S,3aR,6aS)-1-(1-(m-tolyl)-1H-imidazol-2-yl)octahydrocyclopenta[c]pyrrole (20 mg, crude) as a yellow solid . ESI [M+H] = 268.2. e) Synthesis of 6-methyl-2-((1S,3aR,6aS)-1-(1-(m-tolyl)-1H-imidazol-2- yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(trifluoromethyl)nicotinonitrile (Compound 19)
Figure imgf000097_0002
  To a solution of (1S,3aR,6aS)-1-(1-(m-tolyl)-1H-imidazol-2- yl)octahydrocyclopenta[c]pyrrole (20 mg, 65 μmol, 1.0 eq., HCl), 2-chloro-6-methyl-4- (trifluoromethyl)pyridine-3-carbonitrile (17 mg, 79 μmol, 1.2 eq.) in dioxane (2 mL) was added DIEA (25 mg, 197 μmol, 3.0 eq.). The mixture was stirred at 100 °C for 2 hrs, quenched by H2O (2 mL) and extracted with EtOAc (5 mL x 3). The organic layers were dried over Na2SO4, filtered, concentrated and purified by prep-HPLC (column: Phenomenex Luna C1875 * 30 mm * 3 um; mobile phase: [water (FA)-ACN]; B%: 30%-60%, 8 mins) to yield 6-methyl-2-((1S,3aR,6aS)-1-(1-(m-tolyl)-1H-imidazol-2- yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(trifluoromethyl)nicotinonitrile (Compound 19) (2 mg, 5 μmol, 7% yield, 95% purity) as pale yellow solid.1H NMR (400 MHz, DMSO- d6) δ 7.49 - 7.44 (m, 1H), 7.34 - 7.24 (m, 3H), 7.23 (d, J = 1.1 Hz, 1H), 6.99 - 6.94 (m, 1H), 6.92 - 6.86 (m, 1H), 5.43 - 5.40 (m, 1H), 4.31 - 4.21 (m, 1H), 3.81 - 3.75 (m, 1H), 3.05 - 2.94 (m, 1H), 2.77 - 2.65 (m, 1H), 2.40 - 2.36 (m, 3H), 2.28 - 2.23 (m, 3H), 1.91 - 1.69 (m, 2H), 1.66 - 1.59 (m, 1H), 1.51 - 1.44 (m, 2H), 1.32 - 1.23 (m, 1H). ESI [M+H] = 452.2. Example 20. Preparation of (Rac)-3-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2- yl)-N-methyl-N-(m-tolyl)-3-azabicyclo[3.2.0]heptane-2-carboxamide (Compound 20)
Figure imgf000098_0001
  a) Synthesis of tert-butyl 3-azabicyclo[3.2.0]heptane-3-carboxylate
Figure imgf000098_0002
  To a solution of 3-azabicyclo[3.2.0]heptane (1.0 g, 7 mmol, 1.0 eq., HCl) in THF (5 mL) was added sat. aq. NaHCO3 (629 mg, 7 mmol, 1.0 eq.) and Boc2O (1.6 g, 7 mmol, 1.0 eq.). The mixture was stirred at 25 °C for 2 hrs, quenched by addition of H2O (50 mL) and extracted with DCM (40 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to yield tert-butyl 3-azabicyclo[3.2.0]heptane-3-carboxylate (1.2 g, crude) as a white oil.1H NMR (400 MHz, DMSO-d6) δ 3.41 (br d, J = 11.3 Hz, 2H), 3.17 (br s, 2H), 2.86 (br s, 2H), 2.21 - 2.09 (m, 2H), 1.67 - 1.57 (m, 2H), 1.43 (s, 9H). ESI [M-t- Bu+H] = 141.9. b) Synthesis of (Rac)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.2.0]heptane-2- carboxylic acid
Figure imgf000099_0002
To a solution of tert-butyl 3-azabicyclo[3.2.0]heptane-3-carboxylate (550 mg, 3 mmol, 1.0 eq.) in MTBE (20 mL) was added s-BuLi (1 M, 32 mL, 15.0 eq.) at -78 °C, then stirred at -78°C for 3 hrs under N2, followed by addition of CO2 (122 mg, 3 mmol, 1.0 eq.). The mixture was stirred at -78 °C for 1 hr, quenched by addition of H2O (100 mL), adjusted pH to 1 by 4 M HCl and extracted by EtOAc (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by prep-HPLC (column: Phenomenex C1875 * 30 mm * 3 um; mobile phase: [water (FA)-ACN]; B%: 20%-50%, 10 mins) to yield (Rac)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.2.0]heptane-2-carboxylic acid (0.1 g, 207 μmol, 4% yield) as a white gum.1H NMR (400 MHz, DMSO-d6) δ 4.19 (d, J = 8.9 Hz, 1H), 3.63 (dd, J = 8.6, 11.1 Hz, 1H), 3.35 (br s, 1H), 3.20 (br s, 1H), 2.90 (br s, 1H), 2.16 - 2.04 (m, 1H), 2.03 - 1.94 (m, 1H), 1.92 - 1.82 (m, 1H), 1.66 (td, J = 4.9, 10.1 Hz, 1H), 1.36 (br s, 9H). ESI [M-Boc+H] = 141.9. c) Synthesis of (Rac)-N-methyl-N-(m-tolyl)-3-azabicyclo[3.2.0]heptane-2- carboxamide
Figure imgf000099_0001
  To a solution of (Rac)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.2.0]heptane-2- carboxylic acid (30 mg, 124 μmol, 1.0 eq.) and N,3-dimethylaniline (30 mg, 249 μmol, 2.0 eq.) in toluene (2 mL) was added PCl3 (85 mg, 622 μmol, 5.0 eq.) under N2. The mixture was stirred at 100 °C for 12 hrs, quenched by addition of H2O (1 mL) and extracted with EtOAc (3 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated and purified by prep-HPLC (column: Phenomenex Luna 80 * 30 mm * 3 um; mobile phase: [water (TFA)-ACN]; B%: 5%-35%, 8 mins) to yield (Rac)-N-methyl-N-(m-tolyl)-3- azabicyclo[3.2.0]heptane-2-carboxamide (20 mg, 82 μmol, 65% yield) as a white solid. ESI [M-Boc+H] = 245.3. d) Synthesis of (Rac)-3-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N- methyl-N-(m-tolyl)-3-azabicyclo[3.2.0]heptane-2-carboxamide (Compound 20)
Figure imgf000100_0001
  To a solution of (Rac)-N-methyl-N-(m-tolyl)-3-azabicyclo[3.2.0]heptane-2- carboxamide (20 mg, 82 μmol, 1.0 eq.) in dioxane (1 mL) was added DIEA (32 mg, 246 μmol, 3.0 eq.) and 2-chloro-6-methyl-4-(trifluoromethyl)pyridine-3-carbonitrile (36 mg, 163 μmol, 2.0 eq.). The mixture was stirred at 100 °C for 1 hr, quenched by H2O (5 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by prep-HPLC (column: Phenomenex Luna C1875 * 30 mm *3 um; mobile phase: [water (FA)-ACN]; B%: 55%-90%, 8 mins) to yield (Rac)-3-(3- cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-3- azabicyclo[3.2.0]heptane-2-carboxamide (Compound 20) (7 mg, 15 μmol, 18% yield, 99% purity) as a yellow solid.1H NMR (400 MHz, ACETONITRILE-d3) δ 7.50 - 7.18 (m, 4H), 7.03 - 6.91 (m, 1H), 4.96 - 4.73 (m, 1H), 4.33 - 4.16 (m, 1H), 4.14 - 3.97 (m, 1H), 3.21 (d, J = 12.2 Hz, 3H), 3.10 - 2.89 (m, 1H), 2.75 (quin, J = 7.5 Hz, 1H), 2.56 (d, J = 11.6 Hz, 3H), 2.42 (d, J = 4.6 Hz, 3H), 2.18 - 2.09 (m, 2H), 1.91 - 1.66 (m, 1H), 1.38 - 1.16 (m, 1H). ESI [M+H] = 429.2. Example 21 and Example 22. Preparation of (Rac)-5-benzyl-2-(3-cyano-6-methyl-4- (trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)octahydropyrrolo[3,4-c]pyrrole-1- carboxamide (Compound 21) and (Rac)-5-benzyl-2-(3-cyano-6-methyl-4- (trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)octahydropyrrolo[3,4-c]pyrrole-1- carboxamide (Compound 22)
Figure imgf000101_0001
  a) Synthesis of tert-butyl (cis)-5-benzyl-1-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxylate
Figure imgf000101_0002
  To a solution of tert-butyl 5-oxo-2H-pyrrole-1-carboxylate (2.5 g, 14 mmol, 1.0 eq.) in DCM (20 mL) was added TFA (311 mg, 3 mmol, 0.2 eq.) at 0 °C, followed by addition of N-(methoxymethyl)-1-phenyl-N-(trimethylsilylmethyl)methanamine (3.9 g, 16 mmol, 1.2 eq.). The mixture was stirred at 25 °C for 12 hrs, quenched by addition of sat. aq. NaHCO3 (200 mL) at 0 °C and extracted with DCM (200 mL x 3). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by column chromatography (SiO2, Petroleum ether: EtOAc= 1:1 to 0:1) to yield tert-butyl (cis)-5-benzyl-1- oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (5.0 g, crude) as a pale yellow soild. 1H NMR (400 MHz, DMSO-d6) δ 7.41 - 7.20 (m, 5H), 3.90 (dd, J = 9.3, 10.9 Hz, 1H), 3.64 - 3.52 (m, 2H), 3.41 (dd, J = 3.1, 10.9 Hz, 1H), 3.14 - 3.04 (m, 1H), 2.97 (d, J = 9.1 Hz, 1H), 2.86 - 2.67 (m, 2H), 2.40 (ddd, J = 7.7, 9.1, 16.7 Hz, 2H), 1.53 - 1.46 (m, 9H). ESI [M+H] = 317.2. b) Synthesis of tert-butyl 5-benzyl-1-hydroxyhexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxylate
Figure imgf000102_0001
To a solution of tert-butyl (cis)-5-benzyl-1-oxohexahydropyrrolo[3,4-c]pyrrole- 2(1H)-carboxylate (4.7 g, 15 mmol, 1.0 eq.) in THF (100 mL) was added LiBHEt3 (1 M, 37 mL, 2.5 eq.) under N2. The mixture was stirred at -78 °C for 1 hr, quenched by addition of sat. aq. NaHCO3 (300 mL) at 0 °C and extracted with EtOAc (300 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to yield tert-butyl 5-benzyl- 1-hydroxyhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (5.8 g, crude) as a pale yellow gum. ESI [M+H] = 319.2. c) Synthesis of 5-benzyloctahydropyrrolo[3,4-c]pyrrole-1-carbonitrile
Figure imgf000102_0002
To a solution of tert-butyl 5-benzyl-1-hydroxyhexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxylate (5.2 g, 16 mmol, 1.0 eq.) in DCM (200 mL) was added TMSCN (4.4 g, 44 mmol, 2.7 eq.) and BF3.Et2O (7.0 g, 49 mmol, 3.0 eq.). The mixture was stirred at -78 °C for 4 hrs, quenched by addition of sat. aq. NaOH (100 mL) and extracted with DCM (200 mL x 3). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by prep- HPLC (column: Phenomenex C18250 * 70 mm 10 u; mobile phase: [water (TFA)-ACN]; B%: 20%-50%, 15 mins) to yield 5-benzyloctahydropyrrolo[3,4-c]pyrrole-1-carbonitrile (1.8 g, 8 mmol, 47% yield) as a pale yellow gum. ESI [M+H] = 228.2. d) Synthesis of 5-benzyloctahydropyrrolo[3,4-c]pyrrole-1-carboxylic acid
Figure imgf000103_0001
  A solution of 5-benzyloctahydropyrrolo[3,4-c]pyrrole-1-carbonitrile (1.7 g, 7 mmol, 1.0 eq.) in 6 M HCl (15 mL) was stirred at 90 °C for 2 hrs and concentrated to yield 5- benzyloctahydropyrrolo[3,4-c]pyrrole-1-carboxylic acid (1.7 g, crude) as a white solid. ESI [M+H] = 247.1. e) Synthesis of 5-benzyl-2-(tert-butoxycarbonyl)octahydropyrrolo[3,4-c]pyrrole-1- carboxylic acid
Figure imgf000103_0002
To a solution of 5-benzyloctahydropyrrolo[3,4-c]pyrrole-1-carboxylic acid (1.7 g, 7 mmol, 1.0 eq.) in dioxane (15 mL) and sat. aq. NaOH (15 mL) was added Boc2O (4.5 g, 21 mmol, 3.0 eq.). The mixture was stirred at 20 °C for 2 hrs and purified by prep-HPLC (column: Phenomenex C1875 * 30 mm * 3 um; mobile phase: [water (FA)-ACN]; gradient: 5%-35% B over 10 mins) to yield 5-benzyl-2-(tert-butoxycarbonyl)octahydropyrrolo[3,4- c]pyrrole-1-carboxylic acid (500 mg, 1 mmol, 20% yield) as a yellow gum. ESI [M+H] = 347.2. f) Synthesis of tert-butyl 5-benzyl-1-(m-tolylcarbamoyl)hexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate
Figure imgf000103_0003
To a solution of 5-benzyl-2-(tert-butoxycarbonyl)octahydropyrrolo[3,4-c]pyrrole-1- carboxylic acid (250 mg, 722 μmol, 1.0 eq.) and 3-methylaniline (155 mg, 1 mmol, 2.0 eq.) in pyridine (3 mL) was added T3P (689 mg, 1 mmol, 50% purity, 1.5 eq). The mixture was stirred at 25 °C for 12 hrs, quenched by addition of H2O (100 mL) at 0 °C and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered, concentrated u and purified by prep-TLC (SiO2, DCM: MeOH= 5:1) to yield tert-butyl 5- benzyl-1-(m-tolylcarbamoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (240 mg, 551 μmol, 76% yield) as a pale yellow solid.1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 7.54 - 7.35 (m, 3H), 7.31 - 7.25 (m, 1H), 7.22 - 7.13 (m, 1H), 6.97 - 6.79 (m, 2H), 6.42 - 6.27 (m, 2H), 4.93 (br s, 1H), 3.72 - 3.48 (m, 3H), 3.36 - 3.30 (m, 2H), 2.82 - 2.56 (m, 4H), 2.47 - 2.38 (m, 1H), 2.30 - 2.24 (m, 3H), 1.48 - 1.25 (m, 9H). ESI [M+H] = 436.3. g) Synthesis of tert-butyl 5-benzyl-1-(methyl(m- tolyl)carbamoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
Figure imgf000104_0001
To a solution of tert-butyl 5-benzyl-1-(m-tolylcarbamoyl)hexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate (100 mg, 230 μmol, 1.0 eq.) in methoxycyclopentane (3 mL) was added NaOH (17 mg, 413 μmol, 1.8 eq.) and trimethyl phosphate (96 mg, 689 μmol, 3.0 eq.). The mixture was stirred at 110 °C for 1 hr, quenched by H2O (5 mL) at 0 °C, and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by prep-HPLC (column: Phenomenex Luna C1880 * 30 mm * 3 um; mobile phase: [H2O (0.1%TFA)-ACN]; gradient: 20%-50% B over 8.0 mins) to yield tert-butyl 5-benzyl-1-(methyl(m-tolyl)carbamoyl)hexahydropyrrolo[3,4-c]pyrrole- 2(1H)-carboxylate (65 mg, 145 μmol, 63% yield) as a pale yellow solid. ESI [M+H] = 450.3. h) Synthesis of 5-benzyl-N-methyl-N-(m-tolyl)octahydropyrrolo[3,4-c]pyrrole-1- carboxamide
Figure imgf000104_0002
A solution of tert-butyl 5-benzyl-1-(methyl(m-tolyl)carbamoyl)hexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate (50 mg, 111 μmol, 1.0 eq.) in 4 M HCl/MeOH (1 mL) was stirred at 20 °C for 1 hr and concentrated to yield 5-benzyl-N-methyl-N-(m- tolyl)octahydropyrrolo[3,4-c]pyrrole-1-carboxamide (50 mg, crude) as a pale yellow gum. ESI [M+H] = 350.3. i) Synthesis of (Rac)-5-benzyl-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2- yl)-N-methyl-N-(m-tolyl)octahydropyrrolo[3,4-c]pyrrole-1-carboxamide (Compound 21) and (Rac)-5-benzyl-2-(3-cyano-6-methyl-4- (trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)octahydropyrrolo[3,4- c]pyrrole-1-carboxamide (Compound 22)
Figure imgf000105_0001
To a solution of 5-benzyl-N-methyl-N-(m-tolyl)octahydropyrrolo[3,4-c]pyrrole-1- carboxamide (45 mg, 129 μmol, 1.0 eq.) and 2-chloro-6-methyl-4-(trifluoromethyl)pyridine- 3-carbonitrile (28 mg, 129 μmol, 1.0 eq.) in dioxane (1 mL) was added DIEA (53 mg, 412 μmol, 3.2 eq.). The mixture was stirred at 80 °C for 1 hr, quenched by addition of sat. aq. Na2CO3 (3 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by prep-HPLC (column: Phenomenex Luna C18100 * 30 mm * 3 um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 25%-65% B over 8 mins) to yield (Rac)-5-benzyl-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)- N-methyl-N-(m-tolyl)octahydropyrrolo[3,4-c]pyrrole-1-carboxamide (Compound 21) (5 mg, 9 μmol, 7% yield, 95% purity) as a pale yellow solid.1H NMR (400 MHz, DMSO-d6) δ 7.38 - 7.19 (m, 6H), 7.17 - 7.02 (m, 4H), 4.74 (br s, 1H), 4.05 (br s, 2H), 3.42 (br s, 3H), 3.12 (s, 3H), 3.03 - 2.77 (m, 3H), 2.69 - 2.62 (m, 1H), 2.37 - 2.28 (m, 2H), 2.24 (br s, 3H), 1.64 - 1.51 (m, 1H), 1.24 (br s, 1H). ESI [M+H] = 534.3. And (Rac)-5-benzyl-2-(3-cyano-6-methyl-4- (trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)octahydropyrrolo[3,4-c]pyrrole-1- carboxamide (Compound 22) (7 mg, 12 μmol, 9% yield, 94% purity) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.38 - 7.20 (m, 6H), 7.17 - 7.07 (m, 4H), 4.74 (br s, 1H), 4.13 - 3.99 (m, 2H), 3.39 (br s, 3H), 3.13 (s, 3H), 3.01 - 2.78 (m, 3H), 2.65 (br t, J = 8.3 Hz, 1H), 2.32 (br dd, J = 5.1, 9.0 Hz, 2H), 2.25 (s, 3H), 1.58 (br dd, J = 3.9, 9.2 Hz, 1H), 1.24 (s, 1H). ESI [M+H] = 534.3. Example 23. Preparation of 2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N- methyl-N-(m-tolyl)isoindoline-1-carboxamide (Compound 23)
Figure imgf000106_0001
  a) Synthesis of tert-butyl 1-(methyl(m-tolyl)carbamoyl)isoindoline-2-carboxylate
Figure imgf000106_0002
To a solution of 2-tert-butoxycarbonylisoindoline-1-carboxylic acid (440 mg, 1 mmol, 1 eq.), N,3-dimethylaniline (303 mg, 2 mmol, 1.5 eq.) in pyridine (5 mL) was added POCl3 (768 mg, 5 mmol, 3.0 eq.). The mixture was stirred at 0 °C for 3 hrs, quenched by addition of H2O (30 mL) and extracted with EtOAc (50 mL x 3). The organic layers were dried over Na2SO4, filtered, concentrated and purified by column chromatography (SiO2, Petroleum ether:EtOAc=1:0 to 0:1) to yield tert-butyl 1-(methyl(m- tolyl)carbamoyl)isoindoline-2-carboxylate (280 mg, 764 μmol, 45% yield) as a colorless oil. ESI [M+H] = 367.1. b) Synthesis of N-methyl-N-(m-tolyl)isoindoline-1-carboxamide
Figure imgf000106_0003
  A solution of tert-butyl 1-(methyl(m-tolyl)carbamoyl)isoindoline-2-carboxylate (270 mg, 736 μmol, 1.0 eq.) in HCl/MeOH (4M, 2 mL) was stirred at 20 °C for 2 hrs and concentrated to yield N-methyl-N-(m-tolyl)isoindoline-1-carboxamide (260 mg, crude, HCl) as a colorless oil. ESI [M+H] = 267.1. c) Synthesis of 2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N- (m-tolyl)isoindoline-1-carboxamide (Compound 23)
Figure imgf000107_0002
  To a solution of N-methyl-N-(m-tolyl)isoindoline-1-carboxamide (100 mg, 375 μmol, 1.0 eq.) and 2-chloro-6-methyl-4-(trifluoromethyl)pyridine-3-carbonitrile (91 mg, 413 μmol, 1.1 eq.) in NMP (2 mL) was added DIEA (145 mg, 1 mmol, 3.0 eq.). The mixture was stirred at 100 °C for 1 hr, quenched by addition of H2O (10 mL) at 0 °C and extracted with EtOAc (50 mL x 3). The organic layers were dried over Na2SO4, filtered, concentrated and purified by prep-HPLC (column: Phenomenex C1875*30mm*3um; mobile phase: [water(FA)-ACN]; B%: 70%-90%, 8 mins) to yield 2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N- methyl-N-(m-tolyl)isoindoline-1-carboxamide (Compound 23) (38 mg, 86 μmol, 23% yield, >99% purity) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 7.29 - 7.42 (m, 4 H), 7.18 - 7.27 (m, 3 H), 7.04 (br s, 1 H), 7.00 (br d, J=7.58 Hz, 1 H), 6.22 (s, 1 H), 5.11 (br d, J=13.57 Hz, 1 H), 4.65 (br d, J=13.82 Hz, 1 H), 3.13 (s, 3 H), 2.61 (s, 3 H), 2.28 (s, 3 H). ESI [M+H] = 451.2. Example 24. Preparation of (S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N- methyl-N-(m-tolyl)isoindoline-1-carboxamide (Compound 24)
Figure imgf000107_0001
  a) Synthesis of (S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)isoindoline- 1-carboxylic acid
Figure imgf000108_0001
  To a solution of (S)-isoindoline-1-carboxylic acid;hydrochloride (100 mg, 500 μmol, 1.0 eq.) and 2-chloro-6-methyl-4-(trifluoromethyl)pyridine-3-carbonitrile (110 mg, 500 μmol, 1.0 eq.) in dioxane (2 mL) was added DIEA (194 mg, 1mmol, 3.0 eq.). The mixture was stirred at 100 oC for 1 hr, quenched by 1N HCl (50 mL) and extracted with EtOAc (30 mL x 3). The organic layers were dried over Na2SO4, filtered, and concentrated to yield (S)-2-(3- cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)isoindoline-1-carboxylic acid (170 mg, crude) as a brown gum. ESI [M+H] = 348.1. b) Synthesis of (S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl- N-(m-tolyl)isoindoline-1-carboxamide (Compound 24)
Figure imgf000108_0002
  To a solution of (S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)isoindoline- 1-carboxylic acid(170 mg, 489 μmol, 1.0 eq.) and N,3-dimethylaniline (296 mg, 2 mmol, 5 eq.) in toluene (4 mL) was added PCl3 (807 mg, 6 mmol, 12.0 eq.). The mixture was stirred at 100 oC for 4 hrs, quenched by addition of sat. aq. Na2CO3 (50 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by prep-HPLC (column: Phenomenex C1875 * 30 mm * 3 um; mobile phase: [water (FA) - ACN]; B%: 55%-70%, 8 mins) and flash silica gel chromatography (column: DAICEL CHIRALPAKAD(250 mm * 30 mm, 10 um); mobile phase: [0.1%NH3H2O ETOH]; B%: 20%-20%, 10 mins) to yield (S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N- methyl-N-(m-tolyl)isoindoline-1-carboxamide (Compound 24) (13 mg, 30 μmol, 6% yield) as a pale yellow solid.1H NMR (400 MHz, DMSO-d6) δ7.49 - 7.16 (m, 7H), 7.09 - 6.93 (m, 2H), 6.30 - 6.16 (m, 1H), 5.11 (br d, J = 13.8 Hz, 1H), 4.74 - 4.58 (m, 1H), 3.12 (s, 3H), 2.62 - 2.56 (m, 3H), 2.27 (s, 3H). ESI [M+H] = 451.2. Example 25. Preparation of (R)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N- methyl-N-(m-tolyl)isoindoline-1-carboxamide (Compound 25)
Figure imgf000109_0001
  (R)-2-(3-Cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m- tolyl)isoindoline-1-carboxamide (Compound 25) was synthesized from (R)-isoindoline-1- carboxylic acid;hydrochloride following the procedure for preparation of compound 24.1H NMR (400 MHz, DMSO-d6) δ 7.44 - 7.18 (m, 7H), 7.09 - 6.96 (m, 2H), 6.22 (s, 1H), 5.12 (d, J = 13.9 Hz, 1H), 4.66 (br d, J = 13.0 Hz, 1H), 3.13 (s, 3H), 2.61 (s, 3H), 2.28 (s, 3H). ESI [M+H] = 451.2. Example 26. Preparation of (S)-2-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-N-methyl- N-(m-tolyl)isoindoline-1-carboxamide (Compound 26)
Figure imgf000109_0002
  a) Synthesis of (S)-2-(tert-butoxycarbonyl)isoindoline-1-carboxylic acid
Figure imgf000110_0001
  To a solution of (S)-isoindoline-1-carboxylic acid;hydrochloride (1.0 g, 5 mmol, 1.0 eq.) in DCM (20 mL) was added TEA (1.5 g, 15 mmol, 3.0 eq.) and Boc2O (1.6 g, 8 mmol, 1.5 eq.). The mixture was stirred at 25 °C for 1 hr, quenched by addition of H2O (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by prep-HPLC (column: Phenomenex luna C18 250 * 50 mm * 10 um; mobile phase: [water (TFA)-ACN]; B%: 20%-50%, 10 mins) to yield (S)-2-(tert-butoxycarbonyl)isoindoline-1-carboxylic acid (1.2 g, 5 mmol, 91% yield) as a yellow solid. ESI [M-t-Bu+H] = 208.2. b) Synthesis of tert-butyl (S)-1-(methyl(m-tolyl)carbamoyl)isoindoline-2-carboxylate
Figure imgf000110_0002
  To a solution of S)-2-(tert-butoxycarbonyl)isoindoline-1-carboxylic acid (500 mg, 2 mmol, 1.0 eq.) in DCM (10 mL)/THF (30 mL) was added EDCI (546 mg, 3 mmol, 1.5 eq.) at 0 °C, followed by addition of N,3-dimethylaniline (690 mg, 6 mmol, 3.0 eq.). The mixture was stirred at 20 °C for 1 hr, quenched by addition of H2O (100 mL), concentrated and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to yield tert-butyl (S)-1-(methyl(m-tolyl)carbamoyl)isoindoline-2- carboxylate (500 mg, crude) as a yellow oil. ESI [M+H] = 367.2. c) Synthesis of (S)-N-methyl-N-(m-tolyl)isoindoline-1-carboxamide
Figure imgf000110_0003
  A solution of tert-butyl (S)-1-(methyl(m-tolyl)carbamoyl)isoindoline-2-carboxylate (500 mg, 1 mmol, 1.0 eq.) in 4 M HCl/MeOH (2 mL) was stirred at 25°C for 1 hr and concentrated to yield (S)-N-methyl-N-(m-tolyl)isoindoline-1-carboxamide (1.0 g, crude) as a brown solid. ESI [M+H] = 267.2. d) Synthesis of (S)-2-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m- tolyl)isoindoline-1-carboxamide (Compound 26)
Figure imgf000111_0001
A mixture of (S)-N-methyl-N-(m-tolyl)isoindoline-1-carboxamide (100 mg, 375 μmol, 1.0 eq.), 2,6-dichloro-4-(trifluoromethyl)pyridine (121 mg, 563 μmol, 1.5 eq.) and TEA (113 mg, 1 mmol, 3.0 eq.) in THF (2 mL) was stirred at 100 °C for 2 hrs under N2 atmosphere, quenched by addition of H2O (30 mL) at 0 °C and extracted with EtOAc (30 mL x 3). The organic layers were dried over Na2SO4, filtered, concentrated, and purified by prep-TLC (SiO2, Petroleum ether: EtOAc= 5:1) and prep-HPLC (column: Phenomenex Luna 80 * 30 mm * 3 um; mobile phase: [water (FA) - ACN]; B%: 70%-100%, 8 mins) to yield (S)-2-(6- chloro-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)isoindoline-1-carboxamide (Compound 26) (4 mg, 9 μmol, 2% yield, >99% purity) as yellow solid.1H NMR (400 MHz, DMSO-d6) δ 7.84 - 7.69 (m, 1H), 7.65 - 7.51 (m, 1H), 7.45 - 7.31 (m, 4H), 7.30 - 7.21 (m, 2H), 7.12 - 7.09 (m, 1H), 6.91 - 6.83 (m, 1H), 5.95 - 5.84 (m, 1H), 4.83 - 4.61 (m, 2H), 3.23 - 3.09 (m, 3H), 2.42 - 2.30 (m, 3H). ESI [M+H] = 446.1. Example 27. Preparation of (S)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)- N-(m-tolyl)isoindoline-1-carboxamide (Compound 27)
Figure imgf000111_0002
A mixture of 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (42 mg, 336 μmol, 1.5 eq.), (S)-2-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)isoindoline-1- carboxamide (100 mg, 224 μmol, 1.0 eq.), ditert- butyl(cyclopentyl)phosphane;dichloropalladium;iron (15 mg, 22 μmol, 0.1 eq.) and K3PO4 (143 mg, 673 μmol, 3.0 eq.) in THF (4 mL)/H2O (2 mL) was stirred at 80 °C for 12 hrs under N2 atmosphere, diluted with H2O (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by prep- HPLC (column: Phenomenex luna C1880 * 40 mm * 3 um; mobile phase: [water (FA)- ACN]; B%: 45%-85%, 8 mins) to yield (S)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin- 2-yl)-N-(m-tolyl)isoindoline-1-carboxamide (Compound 27) (18 mg, 43 μmol, 19% yield, >99% purity) as a pale yellow solid.1H NMR (400 MHz, DMSO-d6) δ 7.54 - 7.29 (m, 6H), 7.27 - 7.17 (m, 2H), 6.87 (s, 1H), 6.58 (s, 1H), 5.98 (br s, 1H), 4.67 (br d, J = 13.6 Hz, 1H), 4.54 - 4.38 (m, 1H), 3.15 (s, 3H), 2.55 (s, 3H), 2.34 (s, 3H). ESI [M+H] = 426.2. Example 28. Preparation of N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3- oxo-N-(m-tolyl)isoindoline-1-carboxamide (Compound 28)
Figure imgf000112_0001
  a) Synthesis of 2-(4-methoxyphenyl)-3-oxoisoindoline-1-carbonitrile  
Figure imgf000113_0001
  To a solution of methyl 2-formylbenzoate (4.0 g, 24 mmol, 1.0 eq.) in DCE (50 mL) was added 4-methoxyaniline (3.0 g, 24 mmol, 1.0 eq.). The mixture was stirred at 25 °C for 1 hr, followed by addition of TMSCN (3.2 g, 32 mmol, 1.3 eq.) and zinc trifluoromethanesulfonate (886 mg, 2 mmol, 0.1 eq.). The mixture was stirred at 25 °C for 12 hrs. Then TFA (2.8 g, 24 mmol, 1 eq.) was added and the mixture was stirred at 25°C for 12 hrs. The reaction mixture was quenched by addition of H2O (100 mL) at 0 °C and extracted with DCM (150 mL x 3). The combined organic layers was dried over Na2SO4, filtered, concentrated and purified by column chromatography (SiO2, Petroleum ether:EtOAc=10:1 to 1:1) to yield 2-(4-methoxyphenyl)-3-oxo-isoindoline-1-carbonitrile (5.6 g, 21 mmol, 87% yield) as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ 7.90 - 7.87 (m, 1H), 7.68 - 7.56 (m, 3H), 7.52 - 7.40 (m, 2H), 6.96 - 6.88 (m, 2H), 5.74 - 5.69 (m, 1H), 3.79 - 3.73 (m, 3H). ESI [M+H] = 265.1. b) Synthesis of methyl 2-(4-methoxyphenyl)-3-oxoisoindoline-1-carboxylate
Figure imgf000113_0002
  To a solution of 2-(4-methoxyphenyl)-3-oxo-isoindoline-1-carbonitrile (2.0 g, 8 mmol, 1.0 eq.) in MeOH (40 mL) was added H2SO4 (5 mL). The mixture was stirred at 80 °C for 12 hrs, quenched by addition of sat. aq. Na2CO3 (300 mL) to pH = 7, concentrated and extracted with EtOAc (200 mL x 3), dried over Na2SO4, filtered and concentrated to yield methyl 2-(4-methoxyphenyl)-3-oxoisoindoline-1-carboxylate (2.2 g, crude) as a yellow solid. ESI [M+H] = 298.1. c) Synthesis of 2-(4-methoxyphenyl)-3-oxoisoindoline-1-carboxylic acid
Figure imgf000114_0001
  To a solution of methyl 2-(4-methoxyphenyl)-3-oxo-isoindoline-1-carboxylate (2.2 g, 7 mmol, 1.0 eq.) in MeOH (20 mL)/H2O (10 mL) was added LiOH (931 mg, 22 mmol, 3.0 eq.). The mixture was stirred at 50 °C for 1 hr, quenched by addition of 1N HCl (30 mL) to pH=7, concentrated and extracted with EtOAc (80 mL x 3). The combined organic layers was dried over Na2SO4, filtered and concentrated to yield 2-(4-methoxyphenyl)-3-oxoisoindoline- 1-carboxylic acid (1.9 g, crude) as a brown oil. ESI [M+H] = 284.1. d) Synthesis of 2-(4-methoxyphenyl)-N-methyl-3-oxo-N-(m-tolyl)isoindoline-1- carboxamide
Figure imgf000114_0002
  To a solution of 2-(4-methoxyphenyl)-3-oxoisoindoline-1-carboxylic acid (0.9 g, 3 mmol, .1.0 eq.) and N,3-dimethylaniline (462 mg, 4 mmol, 1.2 eq.) in Tol. (10 mL) was added PCl3 (436 mg, 3 mmol, 1.0 eq.). The mixture was stirred at 100 °C for 1 hr, quenched by addition of sat. aq. Na2CO3 (100 mL) at 0 °C and extracted with EtOAc (50 mL x 3). The combined organic layers was dried over Na2SO4, filtered, concentrated and purified by column chromatography (SiO2, Petroleum ether:EtOAc=10:1 to 1:1) to yield 2-(4- methoxyphenyl)-N-methyl-3-oxo-N-(m-tolyl)isoindoline-1-carboxamide (320 mg, 828 μmol, 26% yield) as a yellow solid. ESI [M+H] = 387.2. e) Synthesis of N-methyl-3-oxo-N-(m-tolyl)isoindoline-1-carboxamide
Figure imgf000115_0001
  To a solution of 2-(4-methoxyphenyl)-N-methyl-3-oxo-N-(m-tolyl)isoindoline-1- carboxamide (0.3 g, 776 μmol, 1.0 eq.) in ACN (20 mL)/H2O (10 mL) was added CAN (851 mg, 2 mmol, 2.0 eq.). The mixture was stirred at 20 °C for 1 hr, quenched by H2O (100 mL) at 0 °C, extracted with EtOAc (50 mL x 3), The combined organic layers was dried over Na2SO4, filtered, concentrated and purified by prep-HPLC (column: Phenomenex Luna C18 75* 30 mm* 3 um; mobile phase: [water (TFA)- ACN]; B%: 20%-50%, 8 mins) to yield N- methyl-3-oxo-N-(m-tolyl)isoindoline-1-carboxamide (100 mg, 321 μmol, 41% yield, 90% purity) as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ 7.86 - 7.76 (m, 1H), 7.66 - 7.58 (m, 1H), 7.55 - 7.48 (m, 2H), 7.41 - 7.32 (m, 1H), 7.25 - 7.19 (m, 1H), 7.11 - 7.01 (m, 1H), 7.01 - 6.93 (m, 2H), 5.45 - 5.40 (m, 1H), 3.42 - 3.31 (m, 3H), 2.40 - 2.33 (m, 3H). ESI [M+H] = 281.2. f) Synthesis of N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxo-N-(m- tolyl)isoindoline-1-carboxamide (Compound 28)
Figure imgf000115_0002
  A mixture of N-methyl-3-oxo-N-(m-tolyl)isoindoline-1-carboxamide (40 mg, 143 μmol, 1.0 eq.), 2-bromo-6-methyl-4-(trifluoromethyl)pyridine (51 mg, 214 μmol, 1.5 eq.), Pd2(dba)3 (13 mg, 14 μmol, 0.1 eq.), K2CO3 (59 mg, 428 μmol, 3.0 eq.) and xantphos (8 mg, 14 μmol, 0.1 eq.) in dioxane (2 mL) was stirred at 100 °C for 3 hrs under N2 atmosphere, quenched by addition of H2O (20 mL) at 0 °C and extracted with EtOAc (20 mL x 3). The combined organic layers was dried over Na2SO4, filtered, concentrated and purified by prep- HPLC (column: Phenomenex Luna C1875* 30 mm* 3 um; mobile phase: [water (FA)- ACN]; B%: 55%- 95%, 8 mins) to yield N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2- yl)-3-oxo-N-(m-tolyl)isoindoline-1-carboxamide (Compound 28) (25 mg 56 μmol 39% yield, 99% purity) as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ 8.89 - 8.64 (m, 1H), 7.92 - 7.83 (m, 1H), 7.61 - 7.55 (m, 1H), 7.54 - 7.41 (m, 3H), 7.40 - 7.28 (m, 2H), 7.19 (br s, 1H), 7.17 - 7.14 (m, 1H), 6.43 - 6.35 (m, 1H), 3.33 (s, 3H), 2.71 (s, 3H), 2.40 (br s, 3H). ESI [M+H] = 440.2 Example 29 and Example 30. Preparation of (S)-N-methyl-2-(6-methyl-4- (trifluoromethyl)pyridin-2-yl)-3-oxo-N-(m-tolyl)isoindoline-1-carboxamide (Compound 29) and (R)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxo-N-(m- tolyl)isoindoline-1-carboxamide (Compound 30)
Figure imgf000116_0001
  The racemic mixture of Compound 28 was separated by SFC (Instrument: Waters SFC150AP preparative SFC; Column: REGIS(s,s) WHELK-O1250 mm*30 mm,10 um); Mobile phase: A for CO2 and B for EtOH (0.1% NH3H2O); Gradient: B%= 35% isocratic elution mode; Flow rate: 70 g/min; Wavelength: 220 nm; Column temperature: 35 degrees centigrade; System back pressure: 120 bar) to yield (S)-N-methyl-2-(6-methyl-4- (trifluoromethyl)pyridin-2-yl)-3-oxo-N-(m-tolyl)isoindoline-1-carboxamide (Compound 29) (4 mg, 9 μmol, 20% yield, >99% purity) as a pale yellow solid.1HNMR (400 MHz, CHLOROFORM-d) δ 8.76 (br s, 1H), 7.87 (br d, J = 7.5 Hz, 1H), 7.61 - 7.55 (m, 1H), 7.53 - 7.44 (m, 3H), 7.35 (br s, 2H), 7.20 (br d, J = 7.3 Hz, 1H), 7.16 (s, 1H), 6.39 (s, 1H), 3.33 (s, 3H), 2.71 (s, 3H), 2.40 (br s, 3H). ESI [M+H] = 440.2. And (R)-N-methyl-2-(6-methyl-4- (trifluoromethyl)pyridin-2-yl)-3-oxo-N-(m-tolyl)isoindoline-1-carboxamide (Compound 30) (3 mg, 8 μmol, 9% yield, 99% purity) as yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ 8.73 - 8.62 (m, 1H), 7.84 - 7.76 (m, 1H), 7.54 - 7.48 (m, 1H), 7.47 - 7.34 (m, 3H), 7.32 - 7.20 (m, 2H), 7.15 - 7.11 (m, 1H), 7.09 - 7.06 (m, 1H), 6.33 - 6.29 (m, 1H), 3.25 (s, 3H), 2.63 (s, 3H), 2.32 (br s, 3H). ESI [M+H] = 440.2. Example 31 and Example 32. Preparation of (S)-N-(5-chloro-2,4-difluorophenyl)-N- methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxoisoindoline-1-carboxamide (Compound 31) and (R)-N-(5-chloro-2,4-difluorophenyl)-N-methyl-2-(6-methyl-4- (trifluoromethyl)pyridin-2-yl)-3-oxoisoindoline-1-carboxamide (Compound 32)
Figure imgf000117_0001
  Compounds (S)-N-(5-chloro-2,4-difluorophenyl)-N-methyl-2-(6-methyl-4- (trifluoromethyl)pyridin-2-yl)-3-oxoisoindoline-1-carboxamide (Compound 31) and (R)-N-(5-chloro-2,4-difluorophenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2- yl)-3-oxoisoindoline-1-carboxamide (Compound 32) were synthesized following the synthetic procedures for synthesis of compound 28, 29 and 30 using 5-chloro-2,4- difluoroaniline instead of N,3-dimethylaniline. Compound 31: a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.70 - 8.62 (m, 1H), 7.91 (t, J = 6.4 Hz, 1H), 7.86 - 7.73 (m, 2H), 7.70 - 7.60 (m, 2H), 7.56 - 7.46 (m, 1H), 7.30 (br d, J = 7.2 Hz, 0.5H), 6.88 - 6.78 (m, 0.6H), 6.35 (s, 0.5H), 3.91 (s, 2H), 3.17 (s, 1H), 2.73 (s, 1H), 2.61 (s, 2H). ESI [M+H] = 496.1. Compound 32: a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.71 - 8.63 (m, 1H), 7.95 - 7.90 (m, 1H), 7.87 - 7.73 (m, 2H), 7.71 - 7.60 (m, 2H), 7.57 - 7.47 (m, 1H), 7.35 - 7.29 (m, 0.5H), 6.85 (s, 0.6H), 6.36 (s, 0.5H), 3.93 (s, 2H), 3.18 (s, 1H), 2.74 (s, 1H), 2.63 (s, 2H). ESI [M+H] = 496.1. Example 33 and Example 34. Preparation of (S)-N-(5-chloro-2,4-difluorophenyl)-5- fluoro-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxoisoindoline-1- carboxamide (Compound 33) and (R)-N-(5-chloro-2,4-difluorophenyl)-5-fluoro-N- methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxoisoindoline-1-carboxamide (Compound 34)
Figure imgf000118_0001
  Compounds (S)-N-(5-chloro-2,4-difluorophenyl)-5-fluoro-N-methyl-2-(6-methyl-4- (trifluoromethyl)pyridin-2-yl)-3-oxoisoindoline-1-carboxamide (Compound 33) and (R)-N- (5-chloro-2,4-difluorophenyl)-5-fluoro-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2- yl)-3-oxoisoindoline-1-carboxamide (Compound 34) were synthesized following the synthetic procedures for synthesis of compound 28, 29 and 30 using methyl 5-fluoro-2- formylbenzoate and 5-chloro-2,4-difluoroaniline. Compound 33: a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.70 - 8.57 (m, 1H), 8.04 - 7.90 (m, 1H), 7.82 - 7.45 (m, 5H), 7.38 - 7.23 (m, 0.4H), 6.86 - 6.78 (m, 0.5H), 6.38 - 6.31 (m, 0.4H), 3.99 - 3.85 (m, 2H), 3.23 - 3.13 (m, 1H), 2.78 - 2.72 (m, 1H), 2.65 - 2.59 (m, 2H). ESI [M+H] = 513.9. Compound 34: a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.70 - 8.60 (m, 1H), 8.03 - 7.92 (m, 1H), 7.80 - 7.50 (m, 5H), 7.38 - 7.29 (m, 0.4H), 6.86 - 6.77 (m, 0.6H), 6.35 - 6.27 (m, 0.4H), 3.97 - 3.88 (m, 2H), 3.21 - 3.16 (m, 1H), 2.75 - 2.71 (m, 1H), 2.66 - 2.61 (m, 2H). ESI [M+H] = 513.9. Example 35 and Example 36. Preparation of (S)-5-chloro-N-(5-chloro-2,4- difluorophenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3- oxoisoindoline-1-carboxamide (Compound 35) and (R)-5-chloro-N-(5-chloro-2,4- difluorophenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3- oxoisoindoline-1-carboxamide (Compound 36)
Figure imgf000120_0001
  Compounds (S)-5-chloro-N-(5-chloro-2,4-difluorophenyl)-N-methyl-2-(6-methyl-4- (trifluoromethyl)pyridin-2-yl)-3-oxoisoindoline-1-carboxamide (Compound 35) and (R)-5- chloro-N-(5-chloro-2,4-difluorophenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2- yl)-3-oxoisoindoline-1-carboxamide (Compound 36) were synthesized following the synthetic procedures for synthesis of compound 28, 29 and 30 using methyl 5-chloro-2- formylbenzoate and 5-chloro-2,4-difluoroaniline. Compound 35: A white solid.1H NMR (400 MHz, DMSO-d6) δ 8.75 - 8.62 (m, 1H), 8.08 - 7.91 (m, 3H), 7.83 (t, J = 7.7 Hz, 1H), 7.75 - 7.54 (m, 2H), 6.96 - 6.35 (m, 1H), 3.97 (s, 2H), 3.23 (s, 1H), 2.80 (s, 1H), 2.69 (s, 2H). ESI [M+H] = 530.1/532.1. Compound 36: a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.70 - 8.56 (m, 1H), 8.03 - 7.85 (m, 3H), 7.82 - 7.24 (m, 3H), 6.90 - 6.32 (m, 1H), 3.92 (s, 2H), 3.22 - 3.02 (m, 1H), 2.76 - 2.60 (m, 3H). ESI [M+H] = 530.1/532.1. Example 37 and Example 38. Preparation of (S)-N-(5-chloro-2,4-difluorophenyl)-5,7- dimethoxy-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxoisoindoline-1- carboxamide (Compound 37) and (R)-N-(5-chloro-2,4-difluorophenyl)-5,7-dimethoxy-N- methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxoisoindoline-1-carboxamide (Compound 38)
Figure imgf000121_0001
Compounds (S)-N-(5-chloro-2,4-difluorophenyl)-5,7-dimethoxy-N-methyl-2-(6- methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxoisoindoline-1-carboxamide (Compound 37) and (R)-N-(5-chloro-2,4-difluorophenyl)-5,7-dimethoxy-N-methyl-2-(6-methyl-4- (trifluoromethyl)pyridin-2-yl)-3-oxoisoindoline-1-carboxamide (Compound 38) were synthesized following the synthetic procedures for synthesis of compound 28, 29 and 30 using methyl methyl 2-formyl-3,5-dimethoxybenzoate and 5-chloro-2,4- difluoroaniline.Compound 37: a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.61 (br s, 1H), 7.62 - 7.27 (m, 3H), 6.94 (br d, J = 8.9 Hz, 2H), 6.55 (br d, J = 1.1 Hz, 1H), 4.09 - 3.82 (m, 9H), 2.64 (br s, 3H). ESI [M+H] = 556.2. Compound 38: a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.61 (br s, 1H), 7.60 - 7.47 (m, 1H), 7.46 - 7.33 (m, 2H), 6.94 (br d, J = 10.0 Hz, 2H), 6.55 (br s, 1H), 4.07 - 3.83 (m, 9H), 2.64 (br s, 3H). ESI [M+H] = 556.1. Example 39. Preparation of 6-methyl-2-(1-(1-(m-tolyl)-1H-imidazol-2-yl)isoindolin-2- yl)-4-(trifluoromethyl)nicotinonitrile (Compound 39)
Figure imgf000122_0002
  a) Synthesis of tert-butyl 1-(hydroxymethyl)isoindoline-2-carboxylate
Figure imgf000122_0001
  To a solution of 2-tert-butoxycarbonylisoindoline-1-carboxylic acid (3.00 g, 11.4 mmol) in THF (30 mL) was added BH3•THF (1 M, 22.8 mL) under N2 at 0 °C. The mixture was stirred under N2 at 20 °C for 3 h. The reaction mixture was quenched with saturated NaHCO3 solution (100 mL) and extracted with ethyl acetate (100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. tert-butyl 1-(Hydroxymethyl)isoindoline-2-carboxylate (3.10 g, crude) was obtained as a colorless oil.1H NMR (400 MHz, CDCl3): δ 7.35 - 7.27 (m, 3H), 7.26 (s, 1H), 5.25 (s, 1H), 4.82 - 4.57 (m, 2H), 4.06 - 3.67 (m, 2H), 1.54 (s, 9H). b) Synthesis of tert-butyl 1-formylisoindoline-2-carboxylate
Figure imgf000123_0003
To a solution of tert-butyl 1-(hydroxymethyl)isoindoline-2-carboxylate (2.70 g, 10.8 mmol) in DCM (30 mL) was added DMP (5.51 g, 13.0 mmol), the mixture was stirred at 20 °C for 16 h. The reaction mixture was filtered, diluted with saturated NaHCO3 solution (300 mL) and extracted with DCM (100 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (40 g, 0-10% petroleum ether/ethyl acetate, 40 mL/min). tert-Butyl 1-formylisoindoline-2-carboxylate (2.10 g, 78% yield) was obtained as yellow oil.1H NMR (400MHz, CDCl3): δ 9.60 - 9.30 (m, 1H), 7.41 - 7.28 (m, 4H), 5.46 - 5.16 (m, 1H), 4.91 - 4.70 (m, 2H), 1.55 (s, 9H). c) Synthesis of tert-butyl 1-(1-(m-tolyl)-1H-imidazol-2-yl)isoindoline-2-carboxylate
Figure imgf000123_0001
To a solution of tert-butyl 1-formylisoindoline-2-carboxylate (500 mg, 2.02 mmol), 3- methylaniline (238 mg, 2.22 mmol), NH4HCO3 (175 mg, 2.22 mmol) in MeOH (10 mL) was added oxaldehyde (323 mg, 2.22 mmol) under N2, the mixture was stirred at 25 °C for 16 h. The mixture was concentrated. The residue was purified by flash silica gel chromatography (20 g, 0-40% petroleum ether/ethyl acetate, 40 mL/min). tert-Butyl 1-(1-(m-tolyl)-1H- imidazol-2-yl)isoindoline-2-carboxylate (126 mg, 6% yield, 40% purity) was obtained as brown oil. LCMS (ESI) m/z: [M+H]+ calcd for C23H25N3O2, 376.19; found, 376.30. d) Synthesis of 1-(1-(m-tolyl)-1H-imidazol-2-yl)isoindoline
Figure imgf000123_0002
  To a solution of tert-butyl 1-[1-(m-tolyl)imidazol-2-yl]isoindoline-2-carboxylate (120 mg, 319.61 µmol) in DCM (2 mL) was added HCl/dioxane (4M, 2 mL), the mixture was stirred at 25°C for 1 hour. The mixture was concentrated.1-(1-(m-Tolyl)-1H-imidazol-2- yl)isoindoline (90 mg, crude) was obtained as a black solid. LCMS (ESI) m/z: [M+H]+ calcd for C18H17N3, 276.14; found, 276.0. e) Synthesis of 6-methyl-2-(1-(1-(m-tolyl)-1H-imidazol-2-yl)isoindolin-2-yl)-4- (trifluoromethyl)nicotinonitrile (Compound 39)
Figure imgf000124_0001
  To a solution of 1-[1-(m-tolyl)imidazol-2-yl]isoindoline (90.0 mg, 289 µmol) and 2- chloro-6-methyl-4-(trifluoromethyl)pyridine-3-carbonitrile (76.4 mg, 346 µmol) in NMP (3 mL) was added DIEA (187 mg, 1.44 mmol). The mixture was stirred at 100 °C in microwave for 2 h. Then the mixture was diluted with water 100 mL and extracted with EtOAc (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Boston Prime C18150*30mm*5um; mobile phase: [water (NH3•H2O+NH4HCO3)-ACN]; B%: 70%- 100%, 7min).6-Methyl-2-(1-(1-(m-tolyl)-1H-imidazol-2-yl)isoindolin-2-yl)-4- (trifluoromethyl)nicotinonitrile (6.76 mg, 5% yield, 98% purity) was obtained as a green solid.1H NMR (400 MHz, DMSO-d6): δ 7.44 - 7.26 (m, 5H), 7.13 (d, J = 10.4 Hz, 2H), 7.07 (d, J = 7.6 Hz, 1H), 6.93 (s, 1H), 6.90 - 6.81 (m, 3H), 5.05 (d, J = 13.8 Hz, 1H), 4.78 (d, J = 13.8 Hz, 1H), 2.35 (s, 3H), 2.29 (s, 3H). LCMS (ESI) m/z: [M + H]+ calcd for C26H20F3N5, 460.17; found, 460.0. Example 40 and Example 41. Preparation of (S)-6-methyl-2-(1-(1-(m-tolyl)-1H-imidazol- 2-yl)isoindolin-2-yl)-4-(trifluoromethyl)nicotinonitrile (Compound 40) and (R)-6- methyl-2-(1-(1-(m-tolyl)-1H-imidazol-2-yl)isoindolin-2-yl)-4- (trifluoromethyl)nicotinonitrile (Compound 41)  
Figure imgf000125_0001
  The racemic mixture of compound 39 was separated by SFC (Instrument: Column: DAICEL CHIRALPAK AD(250 mm * 30 mm, 10 um). Mobile phase: A for CO2 and B for IPA (0.1% NH3H2O) Gradient: B% = 15.0% isocratic elution mode Flow rate: 70.0 g/min Monitor wavelength: 220&254 nm Column temperature: 40℃ System back pressure: 100 bar) to yield (S)-6-methyl-2-(1-(1-(m-tolyl)-1H-imidazol-2-yl)isoindolin-2-yl)-4- (trifluoromethyl)nicotinonitrile (Compound 40) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 7.49 - 7.27 (m, 5H), 7.19 - 7.12 (m, 2H), 7.12 - 7.03 (m, 1H), 7.00 - 6.92 (m, 1H), 6.91 - 6.81 (m, 3H), 5.18 - 5.02 (m, 1H), 4.85 - 4.72 (m, 1H), 2.39 - 2.26 (m, 6H). ESI [M+H] = 460.2. And (R)-6-methyl-2-(1-(1-(m-tolyl)-1H-imidazol-2-yl)isoindolin-2-yl)-4- (trifluoromethyl)nicotinonitrile (Compound 41) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 7.46 - 7.29 (m, 5H), 7.16 - 7.12 (m, 2H), 7.10 - 7.05 (m, 1H), 6.95 - 6.93 (m, 1H), 6.89 - 6.82 (m, 3H), 5.10 - 5.04 (m, 1H), 4.82 - 4.75 (m, 1H), 2.36 - 2.35 (m, 3H), 2.31 - 2.28 (m, 3H). ESI [M+H] = 460.2. Example 42. Preparation of (1R,3S,4S)-2-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-N- methyl-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (Compound 42)
Figure imgf000126_0001
  a) Synthesis of tert-butyl (1R,3S,4S)-3-(methyl(m-tolyl)carbamoyl)-2- azabicyclo[2.2.1]heptane-2-carboxylate
Figure imgf000126_0002
To a solution of N,3-dimethylaniline (1.0 g, 8 mmol, 2.0 eq.) and (1R,3S,4S)-2-tert- butoxycarbonyl-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (1.0 g, 4 mmol, 1.0 eq.) in DCM (30 mL) was added DIEA (1.6 g, 12 mmol, 3.0 eq.) and T3P (6.4 g, 10 mmol, 50% purity, 2.1 eq.). The mixture was stirred at 25 °C for 2 hrs, quenched by addition of sat. aq. Na2CO3 (10 mL) at 0 °C and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with 1N HCl (30 mL x 3) and sat. aq. Na2CO3(30 mL x 3), dried over Na2SO4, filtered and concentrated to yield tert-butyl (1R,3S,4S)-3-(methyl(m- tolyl)carbamoyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.2 g, crude) as a white solid. ESI [M+H] = 345.2. b) Synthesis of (1R,3S,4S)-N-methyl-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3- carboxamide
Figure imgf000127_0002
A mixture of (1R,3S,4S)-3-(methyl(m-tolyl)carbamoyl)-2-azabicyclo[2.2.1]heptane-2- carboxylate (1.2 g, 3 mmol, 1.0 eq.) in HCl/MeOH (10 mL, 4M) was stirred at 25°C for 2 hrs under N2 atmosphere, concentrated and purified by prep-HPLC (column: Phenomenex Luna C1875*30 mm*3 um; mobile phase:[water (FA)-ACN]; B%: 5%-40%, 8 mins) to yield (1R,3S,4S)-N-methyl-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (800 mg, 2 mmol, 79% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.52 - 8.08 (m, 1H), 7.53 - 6.85 (m, 4H), 3.35 - 3.06 (m, 5H), 2.34 (s, 4H), 1.67 - 1.06 (m, 5H), 0.75 - 0.53 (m, 1H). ESI [M+H] = 245.2. c) Synthesis of (1R,3S,4S)-2-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N- (m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (Compound 42)
Figure imgf000127_0001
  To a solution of 2,6-dichloro-4-(trifluoromethyl)pyridine (31 mg, 143 μmol, 1.0 eq.)in dioxane (2 mL) was added TEA (43 mg, 429 μmol, 3.0 eq.) to (1R,3S,4S)-N-methyl-N-(m- tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (35 mg, 143 μmol, 1.0 eq.). The mixture was stirred at 100 °C for 12 hrs, quenched by addition of H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by prep-HPLC (column: Phenomenex Luna C1875*30 mm*3 um; mobile phase: [water (FA)-ACN]; B%: 45%-75%, 8 mins) to yield (1R,3S,4S)-2-(6-chloro-4- (trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3- carboxamide (Compound 42) (24 mg, 53 μmol, 37% yield, 91% purity) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 7.52 - 7.13 (m, 4H), 6.96 - 6.74 (m, 2H), 4.56 (br s, 1H), 3.73 (br s, 1H), 3.15 (br s, 3H), 2.63 (br s, 1H), 2.35 (s, 3H), 2.23 (br d, J = 8.0 Hz, 1H), 1.57 (br s, 2H), 1.33 (br d, J = 9.3 Hz, 2H), 0.75 (br s, 1H). ESI [M+H] =424.1. Example 43 Preparation of (1R,3S,4S)-N-methyl-2-(6-methyl-4- (trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (Compound 43)  
Figure imgf000128_0001
  A mixture of (1R,3S,4S)-2-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m- tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (Compound 42) (60 mg, 141 μmol, 1.0 eq.), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (53 mg, 424 μmol, 3.0 eq.), K3PO4 (90 mg, 424 μmol, 3.0 eq.) and ditert-butyl(cyclopentyl)phosphane;dichloropalladium;iron (9 mg, 14 μmol, 0.1 eq.) in THF (1.5 mL)/H2O (0.5 mL) was stirred at 80 °C for 12 hrs under N2 atmosphere, quenched by addition of H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by prep-HPLC (column: Phenomenex Luna C1875*30 mm*3 um; mobile phase: [water (FA)- ACN]; B%: 60%-95%, 8 mins) to yield (1R,3S,4S)-N-methyl-2-(6-methyl-4- (trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (Compound 43) (6 mg, 17 μmol, 12% yield, >99% purity) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 7.43 - 7.16 (m, 4H), 6.64 (s, 2H), 4.45 (br s, 1H), 3.78 (br d, J = 5.0 Hz, 1H), 3.16 (br s, 3H), 2.68 - 2.59 (m, 1H), 2.37 (br d, J = 17.0 Hz, 6H), 2.21 (br d, J = 8.5 Hz, 1H), 1.55 (br s, 2H), 1.32 - 1.23 (m, 2H), 0.74 (br s, 1H). ESI [M+H] = 404.2. Example 44. Preparation of (1R,3S,4S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin- 2-yl)-N-methyl-N-(m-tolyl)-2-azabicyclo[221]heptane-3-carboxamide (Compound 44)
Figure imgf000129_0001
  To a solution of (1R,3S,4S)-N-methyl-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3- carboxamide (100 mg, 356 μmol, 1.0 eq., HCl salt) in dioxane (2 mL) was added DIEA (138 mg, 1 mmol, 3.0 eq.) and 2-chloro-6-methyl-4-(trifluoromethyl)pyridine-3-carbonitrile (94 mg, 427 μmol, 1.2 eq.). The mixture was stirred at 100 °C for 2 hrs, quenched by addition of H2O (5 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by prep-HPLC (column: Phenomenex Luna C1875*30 mm*3 um; mobile phase: [water (FA)-ACN]; B%: 50%-85%, 8 mins) to yield (1R,3S,4S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-2- azabicyclo[2.2.1]heptane-3-carboxamide (Compound 44) (42 mg, 98 μmol, 27% yield, >99% purity) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 7.44 - 7.27 (m, 3H), 7.27 - 7.19 (m, 1H), 6.98 (s, 1H), 5.16 (br s, 1H), 4.00 (br s, 1H), 3.16 (s, 3H), 2.68 (br s, 1H), 2.49 (br s, 3H), 2.41 - 2.29 (m, 3H), 2.24 (br d, J = 3.5 Hz, 1H), 1.81 - 1.49 (m, 3H), 1.40 (br d, J = 9.6 Hz, 1H), 0.94 - 0.75 (m, 1H). ESI [M+H] = 429.2. Example 45. Polymerase theta polymerase domain activity assay Polymerase theta polymerase domain (amino acid residues 1819 to 2590) was expressed in E. coli as a hexahistidine fusion protein and purified by metal affinity chromatography. Polymerase activity was measured in 25 mM Tris•HCl (pH 7.5), 12.5 mM NaCl, 0.5 mM MgCl2, 0.01% Triton X-100, 0.1 mg/ml bovine gamma-globulin, 5% glycerol. A combination of 10 mM test compound dissolved in DMSO and DMSO were added to test wells to create a 9-point dilution series of test compound, no activity control wells, full activity control wells and a final DMSO volume of 100 nl. 5 µl of assay buffer containing 40 nM polymerase domain was added to all wells except for no activity control wells, to which 5 µl of assay buffer was added. 5 µl of assay buffer containing 20 µM each of dATP, dCTP, dGTP, dTTP and 200 nM primer (5’-GCGGCTGTCATAAG-3’)/template (5’- GCTACATTGACAATGGCATCAAATCTCAGATTGCGTCTTATGACAGCC GCG-3’) duplex (annealed at 20 µM in 20 mM Tris•HCl (pH 7.5), 50 mM NaCl) was added to all wells. Wells were covered and incubated at ambient temperature for 45 minutes. 5 µl 25 mM Tris•HCl (pH 7.5),10 mM EDTA, 3.75% picogreen fluorescent DNA dye was added to all wells and incubated for 30 minutes prior to measuring fluorescence of each well at excitation wavelength 485nm and emission wavelength 528 nm. Inhibition of polymerase activity in test wells was calculated using no activity control well fluorescence as 100 % inhibition and full activity control wells as 0% inhibition. Non-linear least squares fitting of inhibition as a function of inhibitor concentration was performed to determine maximum inhibition, minimum inhibition, IC50 and Hill slope. The biological activity of the compounds of the present application measured by the assay described above are listed in Table 2 below. Table 2: IC50 of the Compounds of the Present Disclosure IC50: A: ≤ 0.1 ^M, B: 0.1 ^M – 0.5 ^M, C: 0.5 ^M – 1 ^M, D: > 1 ^M
Figure imgf000130_0001
Figure imgf000131_0001
EQUIVALENTS The details of one or more embodiments of the disclosure are set forth in the accompanying description above. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms include plural referents unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated by reference. The foregoing description has been presented only for the purposes of illustration and is not intended to limit the disclosure to the precise form disclosed, but by the claims appended hereto.

Claims

CLAIMS 1. A compound of Formula I:
Figure imgf000133_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein: R1’ and R2’, together with the carbon atoms to which they are bonded, form a ring Cy, or R1 and R1’ are bonded together to form -(CH2)n-, and R2’ is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), halogen, oxo, or benzyl; n is 1, 2, or 3; R1 and R2 are each independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1- C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), halogen, oxo, or benzyl; ring Cy is a 4- to 6-membered fully saturated or partially saturated, or 5- or 6- membered aromatic ring optionally comprising 1-4 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NRa2C(X)NRa1Ra2; X is NRN, O, or S; RN is H or C1-C6 alkyl; Y1 is O and Y2 is -NR3R4, or Y1 and Y2, together with the carbon atom to which they are bonded, form
Figure imgf000133_0002
R3 is C6-C10 aryl or heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NRa2C(X)NRa1Ra2; R4 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, or heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, - C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2; and wherein the alkyl, alkenyl, or alkynyl is optionally substituted with one or more groups independently selected from C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, - NH2, -NRa2(C1-C6 alkyl), -CN, halogen, C6-C10 aryl, and heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, - NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, - NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2; W is N or CRW; RW, R5, R6, and R7 are each independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, -C(X)Ra1, - C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, or -NRa2C(X)NRa1Ra2; each Ra1 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-C6-C10 aryl, or C1-C6 alkyl-heteroaryl wherein the heteroaryl comprises a 5- or 6-membered ring and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, and oxo; and each Ra2 is independently H or C1-C6 alkyl, provided that when R1 or R2 is oxo, Y1 is O and Y2 is -NR3R4, and W is CH, then R1’ and R2’ are not bonded to form a methylenedioxy, wherein one or more hydrogen atoms in any of Ra1, Ra2, R1, R1’, R2, R2’, R3, R4, RN, RW, R5, R6, and R7 may be replaced with one or more deuterium atoms.
2. The compound of claim 1, wherein R1’ and R2’, together with the carbon atoms to which they are bonded, form a ring Cy.
3. The compound of claim 1 or 2, wherein ring Cy is a 4- to 6-membered fully saturated ring optionally comprising 1-4 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NRa2C(X)NRa1Ra2.
4. The compound of claim 1 or 2, wherein ring Cy is a 4- to 6-membered partially saturated ring optionally comprising 1-4 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1- C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NRa2C(X)NRa1Ra2.
5. The compound of claim 1 or 2, wherein ring Cy is a 5- or 6-membered aromatic ring optionally comprising 1-4 heteroatoms selected from N, O, and S, and optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, - C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2.
6. The compound of claim 1, wherein R1 and R1’ are bonded together to form -(CH2)1-3-, and R2’ is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, - NRa2(C1-C6 alkyl), halogen, oxo, or benzyl.
7. The compound of any one of claims 1-5, of Formula II:
Figure imgf000136_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein: A1 and A4 are each independently N or CRA; A2 and A3 are each independently absent, N, or CRA, provided that A2 and A3 are not both absent; and each RA is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, - C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, or -NRa2C(X)NRa1Ra2.
8. The compound of any one of claims 1-5 and 7, of Formula IIa or IIb:
Figure imgf000136_0002
or a pharmaceutically acceptable salt or solvate thereof, wherein: A1 and A4 are each independently N or CRA; A2 and A3 are each independently absent, N, or CRA, provided that A2 and A3 are not both absent; and each RA is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, - C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, or -NRa2C(X)NRa1Ra2.
9. The compound of claim 7 or 8, wherein A1, A2, A3, and A4 are each CRA.
10. The compound of claim 7 or 8, wherein one of A1, A2, A3, and A4 is N.
11. The compound of claim 7 or 8, wherein two of A1, A2, A3, and A4 are N.
12. The compound of claim 7 or 8, wherein one of A1, A2, A3, and A4 is CRA.
13. The compound of claim 7 or 8, wherein A2 is absent or A3 is absent.
14. The compound of claim 7 or 8, wherein A2 is absent and A3 is absent.
15. The compound of claim 1 or 6, of Formula III:
Figure imgf000137_0001
or a pharmaceutically acceptable salt or solvate thereof.
16. The compound of any one of claims 1-15, wherein Y1 is O and Y2 is -NR3R4.
17. The compound of any one of claims 1-15, wherein Y1 and Y2, together with the carbon atom to which they are bonded, form
Figure imgf000137_0002
.
18. The compound of any one of claims 1-17, wherein W is N.
19. The compound of any one of claims 1-17, wherein W is CRW.
20. The compound of any one of claims 1-19, wherein R3 is C6-C10 aryl optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NRa2C(X)NRa1Ra2.
21. The compound of any one of claims 1-20, wherein R3 phenyl optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, - C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2.
22. The compound of any one of claims 1-19, wherein R3 is heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NRa2C(X)NRa1Ra2.
23. The compound of any one of claims 1-19 and 22, wherein R3 is heteroaryl comprising one 5- or 6-membered ring and 1-4 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NRa2C(X)NRa1Ra2.
24. The compound of any one of claims 1-23, wherein R4 is H or C1-C6 alkyl optionally substituted with one or more groups independently selected from C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, C6-C10 aryl, and heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, - OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, - NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2.
25. The compound of any one of claims 1-23, wherein R4 is C6-C10 aryl, or heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, - OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, - NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2.
26. The compound of any one of claims 1-23 and 25, wherein R4 is C6-C10 aryl, optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1- C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NRa2C(X)NRa1Ra2.
27. The compound of any one of claims 1-23 and 25, wherein R4 is heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NRa2C(X)NRa1Ra2.
28. The compound of any one of claims 1-23, 25, and 27, wherein R4 is heteroaryl comprising one 5- or 6-membered ring and 1-4 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1- C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NRa2C(X)NRa1Ra2.
29. The compound of any one of claims 1-28, wherein R1 and R2 are each H.
30. The compound of any one of claims 1-28, wherein one of R1 and R2 is H, and the other is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1- C6 alkyl), or halogen.
31. The compound of any one of claims 1-28, wherein R1 and R2 are each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), or halogen.
32. The compound of any one of claims 1-28 and 31, wherein R1 and R2 are each independently C1-C6 alkyl.
33. A pharmaceutical composition comprising a compound of any one of claims 1-32 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient.
34. A method of treating or preventing a disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-32 or a pharmaceutically acceptable salt or solvate thereof.
35. Use of a compound of any one of claims 1-32 or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for treating or preventing a disease.
36. A compound of any one of claims 1-32 or a pharmaceutically acceptable salt or solvate thereof for treating or preventing a disease.
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