KINASE INHIBITORS, PREPARATION METHODS AND USES THEREOF

Abstract

Provided herein are novel compounds, for example, compounds having a structure according to Formula III-1 to III-12, or a pharmaceutically acceptable salt thereof. Also provided herein are methods of preparing the compounds and methods of using the compounds, for example, in inhibiting DGKs in a cell, and/or in treating various diseases such as cancer or viral infections.

Description

BACKGROUND

Field of the Disclosure

In various embodiments, the present disclosure generally relates to novel compounds, compositions comprising the same, methods of preparing and methods of using the same, e.g., for inhibiting DGKs and/or for treating a number of diseases or disorders, such as cancers or infections.

Background

Diacylglycerol kinases (DGKs) have been indicated as serving as intracellular checkpoints. Inhibition of DGKs are expected to enhance T cell signaling pathways and T cell activation. See e.g., Riese M. J. et al., Journal of Biological Chemistry, (2011) 7: 5254-5265; Zha Y et al., Nature Immunology, (2006) 12:1343; Olenchock B. A. et al., (2006) 11: 1174-81). DGKa (DGK alpha) and DGKz (DGK zeta) have been viewed as targets for cancer immunotherapy. There remains a need for compounds useful as inhibitors of one or both of DGKa and DGKz.

BRIEF SUMMARY

The present disclosure is based in part on Applicant's discovery of compounds that have activity as inhibitors of one or both of DGKa and DGKz. In various embodiments, the present disclosure provides novel compounds, pharmaceutical compositions, methods of preparing and using the same. Typically, the compounds herein are DGK inhibitors, such as DGKa and/or DGKz inhibitors. The compounds and compositions herein are useful for treating various diseases or disorders, such as cancer or viral infections.

In some embodiments, the present disclosure provides a compound of Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, or a pharmaceutically acceptable salt thereof, as defined herein. In some embodiments, the compound of Formula III-2 can also be characterized as having a structure according to a subformula of Formula III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a, or III-2-F-3b. In some embodiments, the compound of Formula III-3 can also be characterized as having a structure according to a subformula of Formula III-3-A. In some embodiments, the compound of Formula III-4 can also be characterized as having a structure according to a subformula of Formula III-4-A, III-4-B, III-4-C, III-4-D, III-4-C-1, III-4-C-2, III-4-C-3, III-4-C-4, III-4-D-1, III-4-D-2, III-4-C-4a, III-4-C-4b, III-4-C-4c, III-4-C-4d, III-4-C-4e, or III-4-C-4f. In some embodiments, the compound of Formula III-8 can also be characterized as having a structure according to a subformula of Formula III-8-A or III-8-B. In some embodiments, the present disclosure also provides a compound selected from the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure also provides a compound selected from Compound Nos. 1-347 herein, or a pharmaceutically acceptable salt thereof.

Certain embodiments of the present disclosure are directed to a pharmaceutical composition comprising one or more of the compounds of the present disclosure (e.g., a compound of Formula III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a, or III-2-F-3b), III-3 (e.g., III-3-A), III-4 (e.g., III-4-A, III-4-B, III-4-C, III-4-D, III-4-C-1, III-4-C-2, III-4-C-3, III-4-C-4, III-4-D-1, III-4-D-2, III-4-C-4a, III-4-C-4b, III-4-C-4c, III-4-C-4d, III-4-C-4e, or III-4-C-4f), III-5, III-6, III-7, III-8 (e.g., III-8-A or III-8-B), III-9, III-10, III-11, or III-12, any of Compound Nos. 1-347, any compound selected from the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof) and optionally a pharmaceutically acceptable excipient. The pharmaceutical composition described herein can be formulated for various routes of administration, such as oral administration, parenteral administration, or inhalation etc.

Certain embodiments are directed to a method of treating a disease or disorder associated with the activity of DGKa, DGKz, or both DGKa and DGKz. In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a, or III-2-F-3b), III-3 (e.g., III-3-A), III-4 (e.g., III-4-A, III-4-B, III-4-C, III-4-D, III-4-C-1, III-4-C-2, III-4-C-3, III-4-C-4, III-4-D-1, III-4-D-2, III-4-C-4a, III-4-C-4b, III-4-C-4c, III-4-C-4d, III-4-C-4e, or III-4-C-4f), III-5, III-6, III-7, III-8 (e.g., III-8-A or III-8-B), III-9, III-10, III-11, or III-12, any of Compound Nos. 1-347, any compound selected from the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof) or a therapeutically effective amount of a pharmaceutical composition described herein. Diseases or disorders associated with the activity of DGKa, DGKz, or both DGKa and DGKz suitable to be treated with the method include any of those described herein.

In some embodiments, a method of treating cancer is provided. In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, IT-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a, or III-2-F-3b), III-3 (e.g., III-3-A), III-4 (e.g., III-4-A, III-4-B, III-4-C, III-4-D, III-4-C-1, III-4-C-2, III-4-C-3, III-4-C-4, III-4-D-1, III-4-D-2, III-4-C-4a, III-4-C-4b, III-4-C-4c, III-4-C-4d, III-4-C-4e, or III-4-C-4f), III-5, III-6, III-7, III-8 (e.g., III-8-A or III-8-B), III-9, III-10, III-11, or III-12, any of Compound Nos. 1-347, any compound selected from the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof) or a therapeutically effective amount of a pharmaceutical composition described herein. In various embodiments, the cancer can be cancer of the colon, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, cancer of the head and neck, lymphoma, leukemia, and/or melanoma.

In some embodiments, a method of treating viral infection is provided. In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a, or III-2-F-3b), III-3 (e.g., III-3-A), III-4 (e.g., III-4-A, III-4-B, III-4-C, III-4-D, III-4-C-1, III-4-C-2, III-4-C-3, III-4-C-4, III-4-D-1, III-4-D-2, III-4-C-4a, III-4-C-4b, III-4-C-4c, III-4-C-4d, III-4-C-4e, or III-4-C-4f), III-5, III-6, III-7, III-8 (e.g., III-8-A or III-8-B), III-9, III-10, III-11, or III-12, any of Compound Nos. 1-347, any compound selected from the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof) or a therapeutically effective amount of a pharmaceutical composition described herein.

The administering in the methods herein is not limited to any particular route of administration. For example, in some embodiments, the administering can be orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperintoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally.

The compounds of the present disclosure can be used as a monotherapy or in a combination therapy. In some embodiments, the combination therapy includes treating the subject with a targeted therapeutic agent, chemotherapeutic agent, therapeutic antibody, radiation, cell therapy, and/or immunotherapy. In some embodiments, the combination therapy includes treating the subject with an immune-oncology agent herein. In some embodiments, the combination therapy includes treating the subject with one or more additional antiviral agents.

In some embodiments, the present disclosure provides the following exemplary enumerated Embodiments 1-49:

Embodiment 1. A compound of Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, or a pharmaceutically acceptable salt thereof:

wherein:

• • R¹ is hydrogen, halogen (e.g., F, Cl, or Br), CN, OH, NH₂, COOH, CONH₂, R^A, OR^A, NH(R^A), N(R^A)₂, COOR^A, CONH(R^A), CON(R^A)₂, SR^A, SOR^A, SO₂R^A, or P(O)(R^A) 2, wherein R^A at each occurrence is independently optionally substituted C_1-4 alkyl, optionally substituted C_2-4 alkenyl, optionally substituted C_2-4 alkynyl, optionally substituted C_3-6 cycloalkyl, optionally substituted 5 or 6 membered heteroaryl having 1-4 ring heteroatoms independently selected from O, S, and N, or optionally substituted 4-7 membered heterocyclyl;
  • R² is hydrogen, halogen (e.g., F, Cl, or Br), CN, OH, NH₂, R^B, OR^B, NH(R^B), or N(R^B) 2, wherein R^B at each occurrence is independently an optionally substituted C_1-4 alkyl, optionally substituted C_2-4 alkenyl, optionally substituted C_2-4 alkynyl, optionally substituted C_3-6 cycloalkyl, or optionally substituted 4-7 membered heterocyclyl;
  • R³ is hydrogen, optionally substituted C_1-4 alkyl, or optionally substituted 3-7 membered ring, such as optionally substituted C_3-6 cycloalkyl, or optionally substituted 4-7 membered heterocyclyl (such as a saturated 4-7 membered heterocyclyl);
  • J is O, CO, SO₂, NR¹⁵ or optionally substituted methylene;
  • W is absent or (W′)_p, wherein p is 1, 2, or 3, wherein W¹ at each occurrence is independently, C(O), NR¹⁵, SO₂, O, or optionally substituted methylene, provided that at most one instance of W¹ is C(O), NR¹⁵, SO₂, or O;
  • wherein R¹⁵ at each occurrence is independently hydrogen, optionally substituted C_1-6 alkyl, optionally substituted C_2-6 alkenyl, optionally substituted C_2-6 alkynyl, optionally substituted 3-6 membered ring, or nitrogen protecting group;
  • X is N or CR⁵, wherein R⁵ is hydrogen, halogen, OH, NH₂, NH(R^C), N(R^C)₂, CN, CONH₂, COOH, CONH(R^C), CON(R^C)₂, OR^C, or COOR^C, wherein R^C at each occurrence is independently an optionally substituted C_1-4 alkyl;
  • U is N or CR⁶, wherein R⁶ is hydrogen, halogen (e.g., F, Cl, or Br), CN, OH, NH₂, R^DOR^D, NH(R^D), N(R^D) 2, COOH, CONH₂, COOR^D, CONH(R^D), CON(R^D)₂, SR^D, SOR^D, SO₂R^D, or P(O)(R^D)₂, wherein R^D at each occurrence is independently an optionally substituted C_1-4 alkyl, optionally substituted C_2-4 alkenyl, optionally substituted C_2-4 alkynyl, optionally substituted C_3-6 cycloalkyl, optionally substituted 5 or 6 membered heteroaryl having 1-4 ring heteroatoms independently selected from O, S, and N, or optionally substituted 4-7 membered heterocyclyl;
  • Y is N or CR⁷, wherein R⁷ is hydrogen, F, Cl, CN, optionally substituted C_1-4 alkyl, or optionally substituted C_1-4 heteroalkyl;
  • Z is C(O), C(═N—OH), C(═N—O—(C_1-4 alkyl)), C(═N—NH₂), C(═N—NH—(C_1-4 alkyl)), C(═N—N(C_1-4 alkyl)(C_1-4 alkyl)), SO, SO₂, S(O)(═NH), or S(O)(═N—(C_1-4 alkyl);
  • Ring C is a 5 or 6 membered ring, preferably, a 5 or 6 membered heteroaryl having 2-3 ring heteroatoms, such as a 5 membered heteroaryl having 2-3 ring nitrogen atoms, for example, imidazole or triazole ring, wherein Ring C shares two ring atoms with the adjacent ring in Formula III-8;
  • L¹ is an optionally substituted 4-12 membered ring, preferably, 4-12 membered heterocyclylene having one or more rings and 1-4 ring heteroatoms each independently O, N, or S, or —N(R^E)—, wherein RE is optionally substituted C_1-4 alkyl or optionally substituted 3-7 membered ring;
  • L² is absent, O, NH, —N(R^E2)—, C(O), SO₂, an optionally substituted C_1-4 alkylene, an optionally substituted C_2-4 alkenylene, an optionally substituted C_1-4 alkynylene, optionally substituted C_1-4 heteroalkylene, or an optionally substituted 3-7 membered ring, wherein R^E2 is optionally substituted C_1-4 alkyl or optionally substituted 3-7 membered ring;
  • R³⁰ is hydrogen, an optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl, or optionally substituted 8-12 membered ring having two or more rings;
  • R⁹ at each occurrence is independently halogen, CN, OH, R^N, OR^N, NHR^N, N(R^N)₂, COOR^N, COR^N, CONH(R^N), or CON(R^N)₂, wherein R^N at each occurrence is independently an optionally substituted C_1-4 alkyl, optionally substituted C_2-4 alkenyl, optionally substituted C_2-4 alkynyl, or optionally substituted 3-7 membered ring, such as optionally substituted C_3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-7 membered heterocyclyl, or optionally substituted 5 or 6 membered heteroaryl; and
  • n1 is 0, 1, 2, or 3, preferably, n1 is 0 or 1, and R⁹ at each occurrence is independently CH₃, CH₂CH₃, CH₂CH₂CH₃, fluorine substituted C_1-3 alkyl (e.g., CF₂H), cyclopropyl, cyclobutyl, CH₂OH, CH₂OCH₃, CH₂OCH₂CH₃, CH₂NH₂, CH₂N₃, or CH₂NHC(O)OCH₃.

Embodiment 2. The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein Y is N.

Embodiment 3. The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein Y is CH.

Embodiment 4. The compound of any of Embodiments 1-3, or a pharmaceutically acceptable salt thereof, wherein U is N.

Embodiment 5. The compound of any of Embodiments 1-3, or a pharmaceutically acceptable salt thereof, wherein U is CR⁶.

Embodiment 6. The compound of Embodiment 5, or a pharmaceutically acceptable salt thereof, wherein R^b is hydrogen.

Embodiment 7. The compound of Embodiment 5, or a pharmaceutically acceptable salt thereof,

• • wherein R⁶ is C_1-4 alkoxy or

Embodiment 8. The compound of any of Embodiments 1-7, or a pharmaceutically acceptable salt thereof, wherein as applicable, R¹ is CN.

Embodiment 9. The compound of any of Embodiments 1-7, or a pharmaceutically acceptable salt thereof, wherein as applicable, (i) R¹ is halogen, e.g., F or Cl; (ii) R¹ is

(iii) R¹ is an optionally substituted 5 or 6 membered heteroaryl having 1-4 ring heteroatoms independently selected from O, S, and N, such as an optionally substituted pyrimidinyl or an optionally substituted thiazolyl, for example, R¹ is

or (iv) R¹ is SR^A1, wherein R^A1 is independently optionally substituted C_1-4 alkyl, for example, R¹ is SCH₃.

Embodiment 10. The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-4-C-1, III-4-C-2, III-4-C-3, III-4-C-4, III-4-D-1, or III-4-D-2

Embodiment 11. The compound of any of Embodiments 1-9, or a pharmaceutically acceptable salt thereof, wherein R² is hydrogen.

Embodiment 12. The compound of any of Embodiments 1-11, or a pharmaceutically acceptable salt thereof, wherein (i) R³ is an optionally substituted C_1-4 alkyl, such as CH₃, CD₃ etc; (ii) R³ is hydrogen; (iii) R³ is an optionally substituted C_1-4 alkyl, such as CH(CH₃)₂, CH₂CH₃, CH₂CHF₂ etc; or (iv) R³ is an optionally substituted C_3-6 cycloalkyl, such as cyclopropyl, cyclobutyl etc.

Embodiment 13. The compound of any of Embodiments 1-12, or a pharmaceutically acceptable salt thereof, wherein Z is C(O).

Embodiment 14. The compound of any of Embodiments 1-13, or a pharmaceutically acceptable salt thereof, wherein as applicable, R⁹ at each occurrence is independently an optionally substituted C_1-4 alkyl or optionally substituted C_3-6 cycloalkyl, preferably, CH₃, CH₂CH₃, CH₂CH₂CH₃, fluorine-substituted C_1-3 alkyl (e.g., CF₂H), cyclopropyl, cyclobutyl, CH₂OH, CH₂OCH₃, CH₂OCH₂CH₃, CH₂NH₂, CH₂N₃, or CH₂NHC(O)OCH₃.

Embodiment 15. The compound of any of Embodiments 1-14, or a pharmaceutically acceptable salt thereof, wherein as applicable, X is N.

Embodiment 16. The compound of any of Embodiments 1-14, or a pharmaceutically acceptable salt thereof, wherein as applicable, X is CR⁵, wherein R⁵ is CN.

Embodiment 17. The compound of any of Embodiments 1-14, or a pharmaceutically acceptable salt thereof, wherein as applicable, X is CR⁵, wherein R⁵ is CONH₂, COOH, CONH(R^C1) CON(R^C1)₂, or COOR^C1, wherein R^C1 at each occurrence is independently a C_1-4 alkyl, such as methyl.

Embodiment 18. The compound of any of Embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein as applicable, L¹ is

or (either of the two attaching points of the piperidine, N or C, can be attached to L²), wherein:

• • n is 0, 1, 2, 3, or 4, and
  • (1) R^9A at each occurrence is independently halogen, CN, OH, R^N, OR^N, NHR^N, N(R^N)₂, COOR^N, COR^N, CONH(R^N), or CON(R^N)₂, wherein R^N at each occurrence is independently an optionally substituted C_1-4 alkyl, optionally substituted C_2-4 alkenyl, optionally substituted C_2-4 alkynyl, or optionally substituted 3-7 membered ring, such as optionally substituted C_3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-7 membered heterocyclyl, or optionally substituted 5 or 6 membered heteroaryl; or
  • (2) two instances of R^9A can be joined to form a double bond or a 3-5 membered ring and any remaining instance(s) of R^9A are defined as in (1).

Embodiment 19. The compound of Embodiment 18, or a pharmaceutically acceptable salt thereof, wherein R^9A at each occurrence is independently CH₃, CH₂CH₃, CH₂CH₂CH₃, fluorine-substituted C_1-3 alkyl (e.g., CF₂H), cyclopropyl, cyclobutyl, CH₂OH, CH₂OCH₃, CH₂OCH₂CH₃, CH₂NH₂, CH₂N₃, or CH₂NHC(O)OCH₃.

Embodiment 20. The compound of any of Embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein as applicable, L¹ is selected from the following (the bottom attaching point, N or C, is attached to L²):

Embodiment 21. The compound of any of Embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein as applicable, L¹ is selected from the following (the bottom attaching point, N or C, is attached to L²):

Embodiment 22. The compound of any of Embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein as applicable, L¹ is an optionally substituted 7-12 membered heterocyclylene having two or more rings and 1-4 ring heteroatoms each independently O, N, or S, when substituted, the substituent(s) can be attached to any one or more of the two or more rings.

Embodiment 23. The compound of any of Embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein as applicable, L¹ is selected from the following bicyclic heterocyclylene (the bottom attaching point, N or C, is attached to L²

• • wherein in each of the bicyclic heterocyclylene, each of the two rings can be optionally substituted with 1-3 R¹⁰, wherein R¹⁰ at each occurrence is independently halogen, OH, NH₂, oxo (as applicable), R^J, OR^J, CN, NH(R′), or N(R^J)₂, wherein R^J at each occurrence is independently an optionally substituted C_1-4 alkyl, optionally substituted C_2-4 alkenyl, optionally substituted C_2-4 alkynyl, or optionally substituted 3-4 membered ring.

Embodiment 24. The compound of any of Embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein as applicable, L¹ is selected from the following bicyclic heterocyclylene (the bottom attaching point, N or C, is attached to L²)

Embodiment 25. The compound of any of Embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein as applicable, L¹ is —N(C_1-4 alkyl)-, such as —N(CH₃)—.

Embodiment 26. The compound of any of Embodiments 1-25, or a pharmaceutically acceptable salt thereof, wherein L² is absent.

Embodiment 27. The compound of any of Embodiments 1-25, or a pharmaceutically acceptable salt thereof, wherein L² is an optionally substituted C_1-4 alkylene selected from the following:

wherein:

• • R¹³ is selected from hydrogen, halogen (e.g., F, Cl, or Br), CN, OH, NH₂, COOH, CONH₂, SO₂NH₂, COR^K, COOR^K, CONH(R^K), CON(R^K)₂, SO₂R^K, SO₂NH(R^K), SO₂N(R^K)₂, R^K, OR^K, NH(R^K), N(R^K)₂, SR^K, SOR^K, SO₂R^K, or P(O)(R^K)₂, wherein R^K at each occurrence is independently optionally substituted C_1-4 alkyl, optionally substituted C_2-4 alkenyl, optionally substituted C_2-4 alkynyl, optionally substituted C_1-4 heteroalkyl, optionally substituted C_3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl having 1-4 ring heteroatoms independently selected from O, S, and N, or optionally substituted 4-7 membered heterocyclyl, wherein, when substituted, the optionally substituted C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, C_1-4 heteroalkyl, C_3-6 cycloalkyl, phenyl, 5 or 6 membered heteroaryl, or 4-7 membered heterocyclyl is substituted with 1-3 substituents independently selected from halogen (preferably F or Cl), OH, CN, C_1-4 alkyl optionally substituted with 1-3 F, C_1-4 heteroalkyl optionally substituted with 1-3 F, and 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and/or methyl.

Embodiment 28. The compound of Embodiment 27, or a pharmaceutically acceptable salt thereof, wherein R¹³ is hydrogen.

Embodiment 29. The compound of Embodiment 27, or a pharmaceutically acceptable salt thereof, wherein R¹³ is CN, OH, COOH, CONH₂, methoxy, ethoxy, cyclopropyl, cyclobutyl, optionally substituted phenyl, or optionally substituted 5 or 6 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S, wherein, when substituted, the optionally substituted phenyl or 5 or 6 membered heteroaryl is substituted with 1-3 substituents independently selected from halogen (preferably F or Cl), OH, CN, C_1-4 alkyl optionally substituted with 1-3 F, C_1-4 heteroalkyl optionally substituted with 1-3 F, and 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and/or methyl.

Embodiment 30. The compound of any of Embodiments 1-25, or a pharmaceutically acceptable salt thereof, wherein L² is 0 or C(O).

Embodiment 31. The compound of any of Embodiments 1-25, or a pharmaceutically acceptable salt thereof, wherein L² is an optionally substituted 5 or 6 membered heteroarylene, for example,

Embodiment 32. The compound of any of Embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein as applicable, L¹ is —N(R^E)—, L² is an optionally substituted phenylene, e.g.,

and R³⁰ is hydrogen.

Embodiment 33. The compound of any of Embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein as applicable, L¹, L², and R³⁰ together are:

Embodiment 34. The compound of any of Embodiments 1-31, or a pharmaceutically acceptable salt thereof, wherein R³⁰ is optionally substituted phenyl, such as a phenyl which is substituted with 1-3 (e.g., 1 or 2) R²², wherein R²² at each occurrence is independently halogen (e.g., F, Cl, or Br), CN, OH, NH₂, R^M, OR^M, COOH, CONH₂, COOR^M, CONH(R^M), CON(R^M)₂, NHCO(R^M), N(R^M)CO(R^M), SO₂R^M, SO₂NH₂, S(O)(NH)R^M, S(O)(NR^M)R^M, SO₂N(R^M)₂, NHSO₂R^M, N(R^M)SO₂R^M, P(O)(R^M)₂, P(O)(OR^M)₂, NH(R^M), N(R^M)₂, SR^M, or SF₅, wherein R^M at each occurrence is independently an optionally substituted C_1-4 alkyl, optionally substituted C_2-4 alkenyl, optionally substituted C_2-4 alkynyl, optionally substituted C_3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl having 1-4 ring heteroatoms independently selected from O, S, and N, or optionally substituted 4-7 membered heterocyclyl.

Embodiment 35. The compound of Embodiment 34, or a pharmaceutically acceptable salt thereof, wherein R³⁰ is a phenyl which is substituted with 1-3 (e.g., 1 or 2) R²², wherein R²² at each occurrence is independently halogen (e.g., F, Cl, or Br), CN, OH, R^M1, OR^M1, SO₂R^M1, P(O)(R^M1)₂, SR^M1, or SF₅, wherein R^M1 at each occurrence is independently an optionally substituted C_1-4 alkyl or an optionally substituted 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.), wherein when substituted, the optionally substituted C_1-4 alkyl or 3-4 membered ring is substituted with 1-3 substituents independently selected from halogen (preferably F or Cl), OH, CN, C_1-4 alkyl optionally substituted with 1-3 F, C_1-4 heteroalkyl optionally substituted with 1-3 F, and 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and/or methyl.

Embodiment 36. The compound of Embodiment 34, or a pharmaceutically acceptable salt thereof, wherein R³⁰ is a phenyl which is substituted with 1-3 (e.g., 1 or 2) R²², wherein R²² at each occurrence is independently F, Cl, CN, R^M2, OR^M2, SR^M2, or SF₅, wherein R^M2 at each occurrence is independently a C_1-4 alkyl optionally substituted with 1-3 F, such as CF₃.

Embodiment 37. The compound of any of Embodiments 1-31, or a pharmaceutically acceptable salt thereof, wherein R³⁰ is optionally substituted 5 or 6-membered heteroaryl, such as a pyridyl

or pyrimidinyl

which is substituted with 1-3 (e.g., 1 or 2) R²², wherein R²² at each occurrence is independently halogen (e.g., F, Cl, or Br), CN, OH, NH₂, R^M, OR^M, COOH, CONH₂, COOR^M, CONH(R^M), CON(R^M)₂, NHCO(R^M), N(R^M)CO(R^M), SO₂R^M, SO₂NH₂, S(O)(NH)R^M, S(O)(NR^M)R^M, SO₂N(R^M)₂, NHSO₂R^M, N(R^M)SO₂R^M, P(O)(R^M)₂, P(O)(OR^M)₂, NH(R^M), N(R^M)₂, SR^M, or SF₅, wherein R^M at each occurrence is independently an optionally substituted C_1-4 alkyl, optionally substituted C_2-4 alkenyl, optionally substituted C_2-4 alkynyl, optionally substituted C_3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl having 1-4 ring heteroatoms independently selected from O, S, and N, or optionally substituted 4-7 membered heterocyclyl.

Embodiment 38. The compound of Embodiment 37, or a pharmaceutically acceptable salt thereof, wherein R³⁰ is a 5-membered heteroaryl

or pyridyl

or pyrimidinyl

which is substituted with 1-3 (e.g., 1 or 2) R²², as valency permits, wherein R²² at each occurrence is independently halogen (e.g., F, Cl, or Br), CN, OH, R^M1 OR^M1, SO₂R^M1, P(O)(R^M1)₂, SR^M1, or SF₅, wherein R^M1 at each occurrence is independently an optionally substituted C_1-4 alkyl or an optionally substituted 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.), wherein when substituted, the optionally substituted C_1-4 alkyl or 3-4 membered ring is substituted with 1-3 substituents independently selected from halogen (preferably F or Cl), OH, CN, C_1-4 alkyl optionally substituted with 1-3 F, C_1-4 heteroalkyl optionally substituted with 1-3 F, and 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and/or methyl.

Embodiment 39. The compound of Embodiment 37, or a pharmaceutically acceptable salt thereof, wherein R³⁰ is a 5-membered heteroaryl

or pyridyl

or pyrimidinyl

which is substituted with 1-3 (e.g., 1 or 2) R²², as valency permits, wherein R²² at each occurrence is independently F, Cl, CN, R^M2, OR^M2, SR^M2, or SF₅, wherein R^M2 at each occurrence is independently a C_1-4 alkyl optionally substituted with 1-3 F, such as CF₃.

Embodiment 40. The compound of any of Embodiments 1-31, or a pharmaceutically acceptable salt thereof, wherein R³⁰ has a structure according to S-1-A, S-1-B, S-1-C, or S-1-D:

wherein R⁸ is C_1-4 alkyl optionally substituted with 1-3 F (such as CH₃, CF₃, etc.), C_1-4 alkoxy optionally substituted with 1-3 F (such as OCH₃, OCF₃, etc.), SCF₃, SF₅, cyclopropyl, cyclobutyl, or

Embodiment 41. The compound of any of Embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein L¹, L², and R³⁰ together (i.e., L¹-L²-R³⁰) are selected from:

or L¹-L²-R³⁰ is selected from

Embodiment 42. The compound of any of Embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein L¹, L², and R³⁰ together are selected from:

or L¹-L²-R³⁰ is selected from:

Embodiment 43. The compound of any of Embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein L¹, L², and R³⁰ together are selected from:

or L¹-L²-R³⁰ is selected from:

or L¹, L², and R³⁰ together are selected from:

or L¹, L², and R³⁰ together are selected from:

Embodiment 44. The compound of any of Embodiments 1-31, or a pharmaceutically acceptable salt thereof, wherein R³⁰ is selected from the following:

• • or R³⁰ is selected from:

• • or R³⁰ is selected from:

• • or R³⁰ is selected from:

Embodiment 45. A compound selected from Compound Nos. 1-347 or any of the compounds disclosed in Table A, or a pharmaceutically acceptable salt thereof.

Embodiment 46. A pharmaceutical composition comprising the compound of any of Embodiments 1-45 or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable excipient.

Embodiment 47. A method for treating a disease comprising the administration to a subject in need thereof a therapeutically-effective amount of at least one compound according to any one of Embodiments 1 to 45, wherein said disease is cancer or a viral infection.

Embodiment 48. The method according to Embodiment 47, wherein said cancer is selected from colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, cancer of the head and neck, lymphoma, leukemia and melanoma.

Embodiment 49. A method of inhibiting activity of at least one of diacylglycerol kinase selected from diacylglycerol kinase alpha (DGKa) and diacylglycerol kinase zeta (DGKz) comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound according to any one of Embodiments 1 to 45.

It is to be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only, and are not restrictive of the invention herein.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1 shows anti-tumor activity of Compound 67 (cpd67) as a single agent and in combination with anti-mouse PD-1 antibody (mPD-1) in MC38 syngeneic tumor model.

DETAILED DESCRIPTION

In a broad aspect, the present disclosure provides compounds and compositions that are useful for inhibiting DGKs (diacylglycerol kinases), such as DGKa and/or DGKz, and/or treating or preventing various diseases or disorders described herein, e.g., cancer or infectious diseases such as viral infections.

Compounds

Some embodiments of the present disclosure are directed to novel compounds. The compounds herein typically can be a DGK inhibitor, and useful for treating various diseases or disorders, such as those described herein, e.g., cancer or viral infections.

Formula III-1 to III-12

In some embodiments, the present disclosure provides a compound of Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, or a pharmaceutically acceptable salt thereof:

wherein:

• • R¹ is hydrogen, halogen (e.g., F, Cl, or Br), CN, OH, NH₂, COOH, CONH₂, R^A, OR^A, NH(R^A), N(R^A)₂, COOR^A, CONH(R^A), CON(R^A)₂, SR^A, SOR^A, SO₂R^A, or P(O)(R^A)₂, wherein R^A at each occurrence is independently optionally substituted C_1-4 alkyl, optionally substituted C_2-4 alkenyl, optionally substituted C_2-4 alkynyl, optionally substituted C_3-6 cycloalkyl, optionally substituted 5 or 6 membered heteroaryl having 1-4 ring heteroatoms independently selected from O, S, and N, or optionally substituted 4-7 membered heterocyclyl;
  • R² is hydrogen, halogen (e.g., F, Cl, or Br), CN, OH, NH₂, R^B, OR^B, NH(R^B), or N(R^B)₂, wherein R^B at each occurrence is independently an optionally substituted C_1-4 alkyl, optionally substituted C_2-4 alkenyl, optionally substituted C_2-4 alkynyl, optionally substituted C_3-6 cycloalkyl, or optionally substituted 4-7 membered heterocyclyl;
  • R³ is hydrogen, optionally substituted C_1-4 alkyl, or optionally substituted 3-7 membered ring, such as an optionally substituted C_3-6 cycloalkyl, or optionally substituted 4-7 membered heterocyclyl (such as a saturated 4-7 membered heterocyclyl);
  • J is O, CO, SO₂, NR¹⁵ or optionally substituted methylene;
  • W is absent or —(W¹)_p—, wherein p is 1, 2, or 3, wherein W¹ at each occurrence is independently, C(O), NR¹⁵, SO₂, O, or optionally substituted methylene, provided that at most one instance of W¹ is C(O), NR¹⁵, SO₂, or O; to be clear, when W is absent, the ring containing J is a 5-membered ring; when p is 1, the ring containing J and W is a 6-membered ring; when p is 2 or 3, the ring containing J and W is a 7-membered ring or 8-membered ring, respectively;
  • wherein R¹⁵ at each occurrence is independently hydrogen, optionally substituted C_1-6 alkyl, optionally substituted C_2-6 alkenyl, optionally substituted C_2-6 alkynyl, optionally substituted 3-6 membered ring, or nitrogen protecting group;
  • X is N or CR⁵, wherein R⁵ is hydrogen, halogen, OH, NH₂, NHR^C, N(R^C)₂, CN, CONH₂, COOH, CONH(R^C), CON(R^C)₂, OR^C, NO₂, or COOR^C, wherein R^C at each occurrence is independently an optionally substituted C_1-4 alkyl;
  • U is N or CR⁶, wherein R⁶ is hydrogen, halogen (e.g., F, Cl, or Br), CN, OH, NH₂, R^DOR^D, NH(R^D), N(R^D)₂, COOH, CONH₂, COOR^D, CONH(R^D), CON(R^D)₂, SR^D, SOR^D, SO₂R^D, or P(O)(R^D)₂, wherein R^D at each occurrence is independently an optionally substituted C_1-4 alkyl, optionally substituted C_2-4 alkenyl, optionally substituted C_2-4 alkynyl, optionally substituted C_3-6 cycloalkyl, optionally substituted 5 or 6 membered heteroaryl having 1-4 ring heteroatoms independently selected from O, S, and N, or optionally substituted 4-7 membered heterocyclyl;
  • Y is N or CR⁷, wherein R⁷ is hydrogen, F, Cl, CN, optionally substituted C_1-4 alkyl, or optionally substituted C_1-4 heteroalkyl;
  • Z is C(O), C(═N—OH), C(═N—O—(C_1-4 alkyl)), C(═N—NH₂), C(═N—NH—(C_1-4 alkyl)), C(═N—N(C_1-4 alkyl)(C_1-4 alkyl)), SO, SO₂, S(O)(═NH), or S(O)(═N—(C_1-4 alkyl);
  • Ring C is a 5 or 6 membered ring, preferably, a 5 or 6 membered heteroaryl having 2-3 ring heteroatoms, such as a 5 membered heteroaryl having 2-3 ring nitrogen atoms, for example, imidazole or triazole ring, wherein Ring C shares two ring atoms with the adjacent ring in Formula III-8;
  • L¹ is an optionally substituted 4-12 membered ring, preferably, 4-12 membered heterocyclylene having one or more rings and 1-4 ring heteroatoms each independently O, N, or S, or —N(R^E)—, wherein R^E is optionally substituted C_1-4 alkyl or optionally substituted 3-7 membered ring;
  • L² is absent, 0, NH, —N(R^E2)—, C(O), SO₂, an optionally substituted C_1-4 alkylene, an optionally substituted C_2-4 alkenylene, an optionally substituted C_1-4 alkynylene, optionally substituted C_1-4 heteroalkylene, or an optionally substituted 3-7 membered ring, wherein R^E2 is optionally substituted C_1-4 alkyl or optionally substituted 3-7 membered ring;
  • R³⁰ is hydrogen, an optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl, or optionally substituted 8-12 membered ring having two or more rings;
  • R⁹ at each occurrence is independently halogen, CN, OH, R^N, OR^N, NHR^N, N(R^N)₂, COOR^N, COR^N, CONH(R^N), or CON(R^N)₂, wherein R^N at each occurrence is independently an optionally substituted C_1-4 alkyl, optionally substituted C_2-4 alkenyl, optionally substituted C_2-4 alkynyl, or optionally substituted 3-7 membered ring, such as optionally substituted C_3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-7 membered heterocyclyl, or optionally substituted 5 or 6 membered heteroaryl; and
  • n1 is 0, 1, 2, or 3.

As used herein, unless specified or otherwise obviously contrary from context, a “x-y membered ring” should be understood as encompassing any ring structure having the designated number of ring members, for example, such ring can be carbocyclic, heterocyclic, aryl or heteroaryl, which can be monocyclic, bicyclic, or having more than two rings, and each of the ring(s) can be saturated, partially unsaturated, or aromatic, and can optionally contain one or more ring heteroatoms. Further, when applicable, such “x-y membered ring” should be understood as attaching to the remainder of the molecule through one or more ring atoms.

To be clear, the term “substituted” or “unsubstituted” used in connection with a variable described herein should be understood as referring to whether the variable is substituted, without considering the required bonding of the variable with the remainder of the molecule. For example, an unsubstituted phenylene should be understood such that other than the two ring atoms of the phenylene that are attached to the remainder of the molecule, the other ring atoms of the phenylene are not substituted, whereas in a substituted phenylene, at least one ring atom, other than the two ring atoms of the phenylene that are attached to the remainder of the molecule, is substituted with a substituent described herein.

In some embodiments, the compound of Formula III-1 to III-12 can have stereoisomer(s). In such embodiments, the compound of Formula III-1 to III-12 can exist in the form of an individual enantiomer, diastereomer, atropisomer, and/or geometric isomer, as applicable, or a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. In some embodiments, when applicable, the compound of Formula III-1 to III-12 can exist as a mixture of a pair of enantiomers in any ratio, including a racemic mixture with a ratio of 1:1. In some embodiments, when applicable, the compound of Formula III-1 to III-12 can exist as an isolated or enriched individual enantiomer substantially free (e.g., with less than 20%, less than 10%, less than 5%, less than 1%, by weight, by HPLC or SFC area, or both, or with a non-detectable amount) of the other enantiomer.

In some embodiments, the present disclosure provides a compound having a structure according to Formula III-1, or a pharmaceutically acceptable salt thereof, with the variables defined and preferred herein. In some embodiments, the present disclosure provides a compound having a structure according to Formula III-2, or a pharmaceutically acceptable salt thereof, with the variables defined and preferred herein. In some embodiments, the present disclosure provides a compound having a structure according to Formula III-3, or a pharmaceutically acceptable salt thereof, with the variables defined and preferred herein. In some embodiments, the present disclosure provides a compound having a structure according to Formula III-4, or a pharmaceutically acceptable salt thereof, with the variables defined and preferred herein. In some embodiments, the present disclosure provides a compound having a structure according to Formula III-5, or a pharmaceutically acceptable salt thereof, with the variables defined and preferred herein. In some embodiments, the present disclosure provides a compound having a structure according to Formula III-6, or a pharmaceutically acceptable salt thereof, with the variables defined and preferred herein. In some embodiments, the present disclosure provides a compound having a structure according to Formula III-7, or a pharmaceutically acceptable salt thereof, with the variables defined and preferred herein. In some embodiments, the present disclosure provides a compound having a structure according to Formula III-8, or a pharmaceutically acceptable salt thereof, with the variables defined and preferred herein. In some embodiments, the compound of Formula III-8 can be characterized as having a structure according to Formula III-8-A or Formula III-8-B:

wherein the variables R¹, R², U, X, Y, L¹, L², and R³⁰ are defined herein, such as those described herein below in connection with Formula III-2 in enumerated embodiments A2-A36. In some embodiments, the present disclosure provides a compound having a structure according to Formula III-9, or a pharmaceutically acceptable salt thereof, with the variables defined and preferred herein. In some embodiments, the present disclosure provides a compound having a structure according to Formula III-10, or a pharmaceutically acceptable salt thereof, with the variables defined and preferred herein. In some embodiments, the present disclosure provides a compound having a structure according to Formula III-11, or a pharmaceutically acceptable salt thereof, with the variables defined and preferred herein. In some embodiments, the present disclosure provides a compound having a structure according to Formula III-12, or a pharmaceutically acceptable salt thereof, with the variables defined and preferred herein.

It should be also understood that the definitions and preferred definitions described herein for a variable(s) in any of Formula III-1 to III-12 are also applicable for the respective variable(s) in any of its respective subformulae, unless specifically defined in such subformulae or otherwise contradictory. For example, the definitions and preferred definitions described herein for a variable(s) in Formula III-2, are also applicable to the respective variable(s) in a subformula herein, such as Formula III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a, or III-2-F-3b, unless specifically defined in such subformula or otherwise contradictory. Similarly, the definitions and preferred definitions described herein for a variable(s) in Formula III-4, are also applicable to the respective variable(s) in a subformula herein, such as III-4-A, III-4-B, III-4-C, III-4-D, III-4-C-1, III-4-C-2, III-4-C-3, III-4-C-4, III-4-D-1, III-4-D-2, III-4-C-4a, III-4-C-4b, III-4-C-4c, III-4-C-4d, III-4-C-4e, or III-4-C-4f, unless specifically defined in such subformula or otherwise contradictory.

Typically, in Formula III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, Y is N.

In some embodiments, in Formula III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, Y is CR⁷, wherein R⁷ is hydrogen, F, Cl, CN, optionally substituted C_1-4 alkyl, or optionally substituted C_1-4 heteroalkyl. For example, in some embodiments, Y is CH.

Typically, U in Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, is CR⁶, wherein R⁶ is hydrogen, halogen (e.g., F, Cl, or Br), CN, OH, NH₂, R^D, OR^D, NH(R^D), N(R^D)₂, COOH, CONH₂, COOR^D, CONH(R^D), CON(R^D)₂, SR^D, SOR^D, SO₂R^D or P(O)(R^D)₂, wherein R^D at each occurrence is independently an optionally substituted C_1-4 alkyl, optionally substituted C_2-4 alkenyl, optionally substituted C_2-4 alkynyl, optionally substituted C_3-6 cycloalkyl, optionally substituted 5 or 6 membered heteroaryl having 1-4 ring heteroatoms independently selected from O, S, and N, or optionally substituted 4-7 membered heterocyclyl. In some preferred embodiments, R⁶ is hydrogen, i.e., U is CH. In some embodiments, R⁶ can also be halogen, such as F or Cl. In some embodiments, R⁶ can also be OR^D, wherein R^D is defined herein. In some embodiments, R⁶ can be OR^D1, wherein R^D1 is optionally substituted C_1-4 alkyl, optionally substituted C_3-6 cycloalkyl, or optionally substituted 4-7 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from O, N, and S; wherein, when substituted, the optionally substituted C_1-4 alkyl, C_3-6 cycloalkyl, or 4-7 membered heterocyclyl can be substituted with one or more (e.g., 1-3) substituents, for example, each substituent can be independently selected from halogen (e.g., F), OH, CN, C_1-4 alkyl or C_1-4 alkoxy. For example, in some embodiments, R⁶ can be C_1-4 alkoxy. In some specific embodiments, R⁶ can be

In some specific embodiments, R⁶ can be

In some specific embodiments, R⁶ can be

In some embodiments, in Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, U is N.

Various groups are suitable as R¹ for Formula III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12. For example, in some embodiments, R¹ can be OH, COOH, CONH₂, NH₂, R^A, OR^A, COOR^A, NH(R^A), N(R^A)₂, CONH(R^A), CON(R^A)₂, SR^A, SOR^A, SO₂R^A, or P(O)(R^A)₂, wherein R^A is defined herein. In some embodiments, R^A at each occurrence can be optionally substituted C_1-4 alkyl.

In some preferred embodiments, in Formula III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, R¹ is CN.

In some preferred embodiments, R¹ in Formula III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, is halogen, preferably F or Cl.

In some embodiments, R¹ in Formula III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, is a C_2-3 alkynyl, such as

In some embodiments, R¹ in in Formula III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, I-11, or III-12, is optionally substituted 5 or 6 membered heteroaryl having 1-4 ring heteroatoms independently selected from O, S, and N. For example, in some embodiments, R¹ can be an optionally substituted pyrimidinyl or an optionally substituted thiazolyl, for example, R¹ is

In some embodiments, R¹ in Formula III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, is SR^A, wherein R^A is defined herein. For example, in some embodiments, R¹ can be SR^A1, wherein R^A1 is independently optionally substituted C_1-4 alkyl, for example, R¹ is SCH₃. Other suitable R¹ are described herein.

In some embodiments, R¹ in Formula III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-1, or III-12, can be characterized in that (i) R¹ is halogen, e.g., F or Cl; (ii) R¹ is ; (iii) R¹ is an optionally substituted 5 or 6 membered heteroaryl having 1-4 ring heteroatoms independently selected from O, S, and N, such as an optionally substituted pyrimidinyl or an

optionally substituted thiazolyl, for example, R¹ is N or N; or (iv) R¹ is SR^A1, wherein R^A1 is independently optionally substituted C_1-4 alkyl, for example, R¹ is SCH₃.

Typically, R² in Formula III-1, III-2, III-3, III-4, III-6, III-7, or III-8, is hydrogen. In some embodiments, R² can be halogen (e.g., F, Cl, or Br), CN, OH, NH₂, R^B, OR^B, NH(R^B), or N(R^B)₂, wherein R^B is defined herein. In some embodiments, R^B can be an optionally substituted C_1-4 alkyl or optionally substituted 3-4 membered cycloalkyl.

Typically, R³ in Formula III-1, III-3, III-4, III-6, or III-7, is an optionally substituted C_1-4 alkyl, such as CH₃, CD₃ etc. In some preferred embodiments, R³ is CH₃. In some preferred embodiments, R³ is CD₃. In some preferred embodiments, R³ is CH₂CH₃. In some preferred embodiments, R³ is CH(CH₃)₂. In some preferred embodiments, R³ is CH₂CHF₂. In some embodiments, R³ can also be an optionally substituted C_3-6 cycloalkyl. In some preferred embodiments, R³ is cyclopropyl. In some preferred embodiments, R³ is cyclobutyl. In some preferred embodiments, R³ is hydrogen.

Typically, Z in Formula III-1, III-3, III-4, III-5, III-6, III-7, III-9, III-11, or III-12, is C(O).

In some embodiments, Z in Formula III-1, III-3, III-4, III-5, III-6, III-7, III-9, 11-11, or III-12, can also be S(O)₂.

In some typical embodiments, X in Formula III-1, III-2, III-5, III-6, III-7, III-8, or III-9, is N.

In some embodiments, X in Formula III-1, III-2, III-5, III-8, or III-9, is CR⁵, wherein R⁵ is defined herein. In some embodiments, X is CR⁵, wherein R⁵ is CN. In some embodiments, X is CR⁵, wherein R⁵ is CONH₂, COOH, CONH(R^C1), CON(R^C1)₂, or COOR^C1, wherein R^C1 at each occurrence is independently a C_1-4 alkyl, such as methyl.

In some embodiments, n1 is 0. In some embodiments, n1 is 1. In some embodiments, R⁹ at each occurrence is independently CH₃, CH₂CH₃, CH₂CH₂CH₃, fluorine-substituted C_1-3 alkyl (e.g., CF₂H), cyclopropyl, or cyclobutyl, CH₂OH, CH₂OCH₃, CH₂OCH₂CH₃, CH₂NH₂, CH₂N₃, or CH₂NHC(O)OCH₃.

In some embodiments, in Formula III-6 or III-7, J is NR¹⁵, wherein R¹⁵ is defined herein. For example, in some embodiments, J is N(C_1-4 alkyl), such as NCH₃.

In some embodiments, in Formula III-6 or III-7, J is an optionally substituted methylene. For example, in some embodiments, J is CH₂. In some embodiments, J is CF₂, CHCH₃, C(CH₃)₂, CHOH, etc.

In some embodiments, in Formula III-6 or III-7, J is O. In some embodiments, in Formula III-6 or III-7, J is NH or NCH₃.

In some embodiments, in Formula III-6 or III-7, W is absent. Thus, the ring containing J is a 5 membered ring.

In some embodiments, in Formula III-6 or III-7, p is 1 and W is W¹, wherein W¹ is defined herein. For example, in some embodiments, W¹ is C(O), SO₂, CH₂, CF₂, CHCH₃, C(CH₃)₂, CHOH, etc. In such embodiments, the ring containing J and W is a 6-membered ring.

In some embodiments, in Formula III-6 or III-7, p is 2 and W is —W¹—W¹—, wherein each W¹ is defined herein. For example, in some embodiments, each W¹ is independently C(O), SO₂, CH₂, CF₂, CHCH₃, C(CH₃)₂, CHOH, etc. In some embodiments, both W¹ can be CH₂. In some embodiments, one W¹ is O, and the other W¹ is CH₂. In some embodiments, one W¹ is C(O), and the other W¹ is O, NH, NCH₃, or CH₂. In such embodiments, the ring containing J and W is a 7-membered ring.

Typically, in Formula III-1, III-2, III-5, III-8, or III-9, L¹ is an optionally substituted 4-12 membered heterocyclylene herein. In some embodiments, L¹ in Formula III-1, III-2, III-5, III-8, or III-9, is an optionally substituted 4-12 membered heterocyclylene having one or more rings and 1-4 ring heteroatoms each independently O, N, or S. In some embodiments, L¹ in Formula III-1, III-2, III-5, III-8, or III-9, can be —N(R^E)—, wherein R^E is optionally substituted C_1-4 alkyl or optionally substituted 3-7 membered ring. For example, in some embodiments, L¹ is —N(C_1-4 alkyl)-, such as —N(CH₃)—.

In some embodiments, L¹ in Formula III-1, III-2, III-5, III-8, or III-9, is an optionally substituted 4-7 membered monocyclic heterocyclylene having 1 or 2 ring heteroatoms each independently O, N, or S. In some embodiments, the 4-7 membered monocyclic heterocyclylene is a saturated heterocyclylene having 1 or 2 ring heteroatoms, such as 1 or 2 ring nitrogen atoms, such as a piperazine or piperidine ring. The heterocyclylene is typically attached to the remainder of the molecule through two ring nitrogen atoms or one ring nitrogen and one ring carbon atom.

In some embodiments, in Formula III-1, III-2, III-5, III-8, or III-9, L¹ can be

(either of the two attaching points of the piperidine, N or C, can be attached to L²),

• • wherein:
  • n is 0, 1, 2, 3, or 4, and
  • (1) R^9A at each occurrence is independently halogen, CN, OH, RN, OR^N, NHR^N, N(R^N)₂, COOR^N, CORN, CONH(R^N), or CON(R^N)₂, wherein R^N at each occurrence is independently an optionally substituted C_1-4 alkyl, optionally substituted C_2-4 alkenyl, optionally substituted C_2-4 alkynyl, optionally substituted 3-7 membered ring, such as optionally substituted C_3-6 cycloalkyl, optionally substituted 4-7 membered heterocyclyl, optionally substituted phenyl, or optionally substituted 5 or 6 membered heteroaryl; or
  • (2) two instances of R^9A can be joined to form a double bond or a 3-5 membered ring and any remaining instance(s) of R^9A are defined as in (1).

In some embodiments, R^9A at each occurrence is independently RN. In some embodiments, R^9A at each occurrence is independently an optionally substituted C_1-4 alkyl, and when substituted, the substituents can be independently selected from F, OH, C_1-4 heteroalkyl having 1 or 2 heteroatoms, which is optionally substituted with F, or 3-4 membered ring (e.g., cyclopropyl or cyclobutyl, etc.). In some embodiments, R^9A at each occurrence is independently CH₃, CH₂CH₃, CH₂CH₂CH₃, fluorine-substituted C_1-3 alkyl (e.g., CF₂H), cyclopropyl, or cyclobutyl, CH₂OH, CH₂OCH₃, CH₂OCH₂CH₃, CH₂NH₂, CH₂N₃, or CH₂NHC(O)OCH₃. Preferably, R^9A at each occurrence is independently CH₃, CH₂CH₃, or CH₂CH₂CH₃, more preferably, R^9A at each occurrence is CH₂CH₃. Typically, in Formula III-1, III-2, III-5, III-8, III-9, III-10, III-11, or III-12, n is 0, 1, or 2. For example, L¹ can be selected from:

wherein either of the two attaching points can be attached to L².

In some preferred embodiments, in Formula III-1, III-2, III-5, III-8, or III-9, L¹ can be selected from the following (the bottom attaching point, N or C, is attached to L²):

In some preferred embodiments, in Formula III-1, III-2, III-5, III-8, or III-9, L¹ can be selected from the following (the bottom attaching point, N or C, is attached to L²):

In some embodiments, L¹ in Formula III-1, III-2, III-5, III-8, or III-9 can also be an optionally substituted 7-12 membered heterocyclylene having two or more rings and 1-4 ring heteroatoms each independently O, N, or S, when substituted, the substituent(s) can be attached to any one or more of the two or more rings. For example, in some embodiments, L¹ can be an optionally substituted 8-12 membered fused, spiro, or bridged bicyclic heterocyclylene having 1-4 ring heteroatoms each independent O, N, or S, wherein each ring of the bicyclic heterocyclylene can be saturated, partially unsaturated, or aromatic, and each ring of the bicyclic heterocyclylene can have 0, 1, 2, or 3 ring heteroatoms, provided that the bicyclic heterocyclylene as a whole is not fully aromatic and the total number of heteroatoms in the bicyclic heterocyclylene does not exceed 4. In some embodiments, L¹ can be an optionally substituted 8-11 membered fused bicyclic heterocyclylene having 1-3 ring heteroatoms each independent O, N, or S, wherein (1) one of the two fused rings is phenyl or 5 or 6 membered heteroaryl, and (2) the other of the two fused rings is a 5-7 membered heterocycle having one or two ring heteroatoms each independently O, N, or S, preferably, the 5-7 membered heterocycle has at least one ring nitrogen atom. In some embodiments, L¹ can be an optionally substituted 8-11 (e.g., 8, 9, or 10) membered spiro bicyclic heterocyclylene having 1-4 ring heteroatoms each independent O, N, or S, wherein (1) one of the two spiro rings is a 5-7 membered heterocycle having one or two ring heteroatoms each independently O, N, or S, preferably, the 5-7 membered heterocycle has one ring nitrogen atom, and (2) the other of the two spiro rings is a 4-6 membered heterocycle having 1-3 ring heteroatoms each independently O, N, or S, for example, one of the two spiro rings is a pyrrolidine, piperidine, azepane ring and the other of the two spiro rings is azetidine, pyrrolidine, pyrrolidinone, piperidinone, oxazoline, isoxazoline, thiazoline, isothiazoline, etc.

For example, in some preferred embodiments, L¹ in Formula III-1, III-2, III-5, III-8, or III-9 can be selected from the following (the bottom attaching point, N or C, is attached to L²):

wherein in each of the bicyclic heterocyclylene, each of the two rings can be optionally substituted with 1-3 R¹⁰, wherein R¹⁰ at each occurrence is independently halogen, OH, NH₂, oxo (as applicable), R^J, OR^J, CN, NH(R¹), or N(R¹)₂, wherein R¹ at each occurrence is independently an optionally substituted C_1-4 alkyl, optionally substituted C_2-4 alkenyl, optionally substituted C_2-4 alkynyl, or optionally substituted 3-4 membered ring.

In some preferred embodiments, L¹ in Formula III-1, III-2, III-5, III-8, or III-9 can be selected from the following (the bottom attaching point, N or C, is attached to L²):

In some embodiments, L¹ in Formula III-1, III-2, III-5, III-8, or III-9 can also be —N(C_1-4 alkyl)-, such as —N(CH₃)—.

In some embodiments, in Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, L² can be absent.

In some embodiments, L² in Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12 can be an optionally substituted C_1-4 alkylene, such as those substituted with one or more R³ groups defined herein. In some embodiments, R¹³ at each occurrence is independently selected from halogen (e.g., F, Cl, or Br), CN, OH, NH₂, COOH, CONH₂, SO₂NH₂, COR^K, COOR^K, CONH(R^K), CON(R^K)₂, SO₂R^K, SO₂NH(R^K), SO₂N(R^K)₂, R^K, OR^K, NH(R^K), N(R^K)₂, SR^K, SOR^K, SO₂R^K, or P(O)(R^K)₂, wherein R^K at each occurrence is independently optionally substituted C_1-4 alkyl, optionally substituted C_2-4 alkenyl, optionally substituted C_2-4 alkynyl, optionally substituted C_1-4 heteroalkyl, optionally substituted C_3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl having 1-4 ring heteroatoms independently selected from O, S, and N, or optionally substituted 4-7 membered heterocyclyl.

In some embodiments, L² in Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12 can be an unsubstituted C_1-4 alkylene such as CH₂, CH(CH₃), CH(C₂H₅), CH(C₃H₇), etc.

In some embodiments, L² in Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12 can be an unsubstituted C_1-4 alkylene selected from: CH₂, or

In some embodiments, L² in Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12 can be an optionally substituted C_1-4 alkylene selected from:

wherein:

• • R¹³ is selected from hydrogen, halogen (e.g., F, Cl, or Br), CN, OH, NH₂, COOH, CONH₂, SO₂NH₂, COR^K, COOR^K, CONH(R^K), CON(R^K)₂, SO₂R^K, SO₂NH(R^K), SO₂N(R^K)₂, R^K, OR^K, NH(R^K), N(R^K)₂, SR^K, SOR^K, SO₂R^K, or P(O)(R^K)₂, wherein R^K at each occurrence is independently optionally substituted C_1-4 alkyl, optionally substituted C_2-4 alkenyl, optionally substituted C_2-4 alkynyl, optionally substituted C_1-4 heteroalkyl, optionally substituted C_3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl having 1-4 ring heteroatoms independently selected from O, S, and N, or optionally substituted 4-7 membered heterocyclyl, wherein, when substituted, the optionally substituted C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, C_1-4 heteroalkyl, C_3-6 cycloalkyl, phenyl, 5 or 6 membered heteroaryl, or 4-7 membered heterocyclyl is substituted with 1-3 substituents independently selected from halogen (preferably F or Cl), OH, CN, C_1-4 alkyl optionally substituted with 1-3 F, C_1-4 heteroalkyl optionally substituted with 1-3 F, and 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and/or methyl. For example, in some embodiments, R¹³ is hydrogen. In some embodiments, R¹³ is a C_1-4 alkyl, such as methyl, ethyl, isopropyl, etc. In some embodiments, R¹³ is methyl. In some embodiments, R¹³ is isopropyl. In some embodiments, R¹³ is R^K as defined herein. In some embodiments, R¹³ is OH or OR^K, wherein R^K is defined herein, such as a C_1-4 alkyl. In some embodiments, R¹³ is CN, OH, COOH, CONH₂, methoxy, ethoxy, cyclopropyl, cyclobutyl, optionally substituted phenyl, or optionally substituted 5 or 6 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S, wherein, when substituted, the optionally substituted phenyl or 5 or 6 membered heteroaryl is substituted with 1-3 substituents independently selected from halogen (preferably F or Cl), OH, CN, C_1-4 alkyl optionally substituted with 1-3 F, C_1-4 heteroalkyl optionally substituted with 1-3 F, and 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and/or methyl. In some embodiments, R¹³ is a 3-4 membered ring, such as cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc., which is optionally substituted, such as with F and/or methyl. For example, in some embodiments, R¹³ is cyclopropyl. In some embodiments, R¹³ is an optionally substituted phenyl or optionally substituted 5 or 6 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S, such as an optionally substituted phenyl or thiazole, which is optionally substituted with 1-3 substituents independently selected from halogen (preferably F or Cl), OH, CN, C_1-4 alkyl optionally substituted with 1-3 F, C_1-4 heteroalkyl optionally substituted with 1-3 F, and 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and/or methyl. For example, in some embodiments, R¹³ is

In some embodiments, R¹³ is OH, methoxy, cyclopropyl, phenyl,

In some embodiments, in Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, L² can be C(O). In some embodiments, in Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, L² can be O, preferably, in Formula III-4, L² is not O.

In some embodiments, in Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, L² can be an optionally substituted phenylene, e.g.,

In some embodiments, in Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, L² can be an optionally substituted 5 or 6 membered heteroarylene, for example,

In some embodiments, in Formula III-1, III-2, III-5, III-8, or III-9, L¹ can be —N(R^E)—, L² is an optionally substituted phenylene, e.g.,

and R³⁰ is hydrogen. For example, in some embodiments, L¹, L², and R³⁰ together are:

In some embodiments, in Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, R³⁰ is optionally substituted phenyl, such as a phenyl which is substituted with 1-3 (e.g., 1 or 2) R²², wherein R²² at each occurrence is independently halogen (e.g., F, Cl, or Br), CN, OH, NH₂, R^M, OR^M, COOH, CONH₂, COOR^M, CONH(R^M), CON(R^M)₂, NHCO(R^M), N(R^M)CO(R^M), SO₂R^M, SO₂NH₂, S(O)(NH)R^M, S(O)(NR^M)R^M, SO₂N(RM)₂, NHSO₂R^M, N(RM)SO₂R^M, P(O)(R^M)₂, P(O)(OR^M)₂, NH(R^M), N(R^M)₂, SR^M, or SF₅, wherein R^M at each occurrence is independently an optionally substituted C_1-4 alkyl, optionally substituted C₂. 4 alkenyl, optionally substituted C_2-4 alkynyl, optionally substituted C_3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl having 1-4 ring heteroatoms independently selected from O, S, and N, or optionally substituted 4-7 membered heterocyclyl. In some embodiments, one instance of R²² is halogen, such as F, Cl, or Br, and the remaining instance(s) of R²², if any, are defined herein. In some embodiments, two or three instances of R²² are halogen, each independently F, Cl, or Br, and the remaining instance(s) of R²², if any, are defined herein. In some embodiments, one instance of R²² is CN, and the remaining instance(s) of R²², if any, are defined herein. In some embodiments, one instance of R²² is R^M, OR^M, SR^M, SF₅, or SO₂R^M, wherein R^M is defined herein, such as a C_1-3 alkyl optionally substituted with F (e.g., CF₃, CF₂CH₃, CHF₂, etc.) or cyclopropyl, and the remaining instance(s) of R²², if any, are defined herein. For example, in some embodiments, R³⁰ is a phenyl which is substituted with 1-3 (e.g., 1 or 2) R²², wherein R²² at each occurrence is independently halogen (e.g., F, Cl, or Br), CN, OH, R^M1, OR^M1, SO₂R^M1, P(O)(R^M1)₂, SR^M1, or SF₅, wherein R^M1 at each occurrence is independently an optionally substituted C_1-4 alkyl or an optionally substituted 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.), wherein when substituted, the optionally substituted C_1-4 alkyl or 3-4 membered ring is substituted with 1-3 substituents independently selected from halogen (preferably F or Cl), OH, CN, C_1-4 alkyl optionally substituted with 1-3 F, C_1-4 heteroalkyl optionally substituted with 1-3 F, and 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and/or methyl. More preferably, R³⁰ is a phenyl which is substituted with 1-3 (e.g., 1 or 2) R²², wherein R²² at each occurrence is independently F, Cl, CN, R^M2, OR^M2, SR^M2, or SF₅, wherein R^M2 at each occurrence is independently a C_1-4 alkyl optionally substituted with 1-3 F, such as CF₃. In some embodiments, R²² at each occurrence can be independently halogen, CN, C_1-4 alkyl optionally substituted with 1-3 F (such as CH₃, CF₃, etc.), C_1-4 alkoxy optionally substituted with 1-3 F (such as OCH₃, OCF₃, etc.), SCF₃, SF₅,

cyclopropyl, cyclobutyl, or. In some preferred embodiments, R²² at each occurrence is independently F, Cl, Br, CF₃, OCF₃, SCF₃, SF₅, OMe, CN, methyl, CHF₂, CF₂CH₃, cyclopropyl, CH₃SO₂, and OCH₂-(cyclopropyl).

In some embodiments, in Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, R³⁰ is optionally substituted 5 or 6-membered heteroaryl, such as a pyridyl

or pyrimidinyl

which is substituted with 1-3 (e.g., 1 or 2) R²², wherein R²² at each occurrence is independently halogen (e.g., F, Cl, or Br), CN, OH, NH₂, R^M, OR^M, COOH, CONH₂, COOR^M, CONH(R^M), CON(R^M)₂, NHCO(R^M), N(R^M)CO(R^M), SO₂R^M, SO₂NH₂, S(O)(NH)R^M, S(O)(NR^M)R^M, SO₂N(R^M)₂, NHSO₂R^M, N(R^M)SO₂R^M, P(O)(R^M)₂, P(O)(OR^M)₂, NH(R^M), N(R^M)₂, SR^M, or SF₅, wherein R^M at each occurrence is independently an optionally substituted C_1-4 alkyl, optionally substituted C_2-4 alkenyl, optionally substituted C_2-4 alkynyl, optionally substituted C_3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl having 1-4 ring heteroatoms independently selected from O, S, and N, or optionally substituted 4-7 membered heterocyclyl. In some embodiments, one instance of R²² is halogen, such as F, Cl, or Br, and the remaining instance(s) of R²², if any, are defined herein. In some embodiments, two or three instances of R²² are halogen, each independently F, Cl, or Br, and the remaining instance(s) of R²², if any, are defined herein. In some embodiments, one instance of R²² is CN, and the remaining instance(s) of R²², if any, are defined herein. In some embodiments, one instance of R²² is R^M, OR^M, SR^M, SF₅, or SO₂R^M, wherein R^M is defined herein, such as a C_1-3 alkyl optionally substituted with F (e.g., CF₃, CF₂CH₃, CHF₂, etc.) or cyclopropyl, and the remaining instance(s) of R²², if an are defined herein. For example, in some embodiments, R³⁰ is a 5-membered heteroaryl

or pyridyl

or pyrimidinyl

which is substituted with 1-3 (e.g., 1 or 2) R²², as valency permits, wherein R²² at each occurrence is independently halogen (e.g., F, Cl, or Br), CN, OH, R^M1, OR^M1, SO₂R^M1, P(O)(R^M1)₂, SR^M1, or SF₅, wherein R^M1 at each occurrence is independently an optionally substituted C_1-4 alkyl or an optionally substituted 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.), wherein when substituted, the optionally substituted C_1-4 alkyl or 3-4 membered ring is substituted with 1-3 substituents independently selected from halogen (preferably F or Cl), OH, CN, C_1-4 alkyl optionally substituted with 1-3 F, C_1-4 heteroalkyl optionally substituted with 1-3 F, and 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and/or methyl. More preferably, R³⁰ is a 5-membered heteroaryl

or pyridyl

or pyrimidinyl

which is substituted with 1-3 (e.g., 1 or 2) R²², as valency permits, wherein R²² at each occurrence is independently F, Cl, CN, R^M2, OR^M2, SR^M2, or SF₅, wherein R^M2 at each occurrence is independently a C_1-4 alkyl optionally substituted with 1-3 F, such as CF₃. In some embodiments, R²² at each occurrence can be independently halogen, CN, C_1-4 alkyl optionally substituted with 1-3 F (such as CH₃, CF₃, etc.), C_1-4 alkoxy optionally substituted with 1-3 F (such as OCH₃, OCF₃, etc.), SCF₃, SF₅, cyclopropyl, cyclobutyl, or

In some preferred embodiments, R²² at each occurrence is independently F, Cl, Br, CF₃, OCF₃, SCF₃, SF₅, OMe, CN, methyl, CHF₂, CF₂CH₃, cyclopropyl, CH₃SO₂, and OCH₂-(cyclopropyl).

In some embodiments, in Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, R³⁰ can have a structure of formula S-1, S-2, S-3, or S-4 below:

wherein:

• • Ring B is attached to L2
  • wherein Ring B is a 5-7 membered ring containing 0, 1, or 2 ring heteroatoms, and is optionally substituted with 1-3 R^G, wherein R^G at each occurrence is independently halogen, OH, oxo, NH₂, NH(C_1-4 alkyl), N(C_1-4 alkyl)(C_1-4 alkyl), an optionally substituted C_1-4 alkyl, or optionally substituted C_1-4 alkoxy;
  • wherein the phenyl, pyridyl, or pyrimidyl in S-1, S-2, S-3, or S-4 is optionally substituted with q instance(s) of R⁸; wherein:
  • q is an integer ranging from 0-3 as valency permits, preferably, 1 or 2,
  • and R⁸ at each occurrence is independently halogen (e.g., F, Cl, or Br), CN, OH, NH₂, R^H, OR^H, NH(R^H), N(R^H)₂, SR^H, SF₅, or optionally substituted 5-8 membered carbocyclic having two or more rings, wherein R^H at each occurrence is independently optionally substituted C_1-4 alkyl, optionally substituted C_2-4 alkenyl, optionally substituted C_2-4 alkynyl, optionally substituted C_3-6 cycloalkyl, or optionally substituted 4-7 membered heterocyclyl;
  • wherein, when substituted, the optionally substituted C_1-4 alkyl, C_1-4 alkoxy, 5-8 membered carbocyclic, C_2-4 alkenyl, C_2-4 alkynyl, C_3-6 cycloalkyl, or 4-7 membered heterocyclyl can be substituted with one or more (e.g., 1-3) substituents, for example, each substituent can be independently selected from halogen (e.g., F), OH, CN, C_1-4 alkyl or C_1-4 alkoxy. To be clear, the drawing shown in S-1, S-2, S-3, or S-4 should be understood such that R⁸, if present, is to be attached on the phenyl, pyridyl, or pyrimidyl portion of the structure, i.e., not on Ring B. Ring B, if substituted, should be understood as being substituted with 1-3 R^G as defined herein.

In some embodiments, Ring B in S-1, S-2, S-3, or S-4 contains no ring heteroatoms. In some embodiments, Ring B in S-1, S-2, S-3, or S-4 contains one ring heteroatom, such as O, N, or S. In some embodiments, Ring B in S-1, S-2, S-3, or S-4 contains no ring heteroatoms and is not substituted. In some embodiments, Ring B in S-1, S-2, S-3, or S-4 contains no ring heteroatoms and is optionally substituted with one or more substituents described herein, for example, in some embodiments, Ring B is optionally substituted with 1-3 R^G1, wherein R^G1 at each occurrence is independently F, OH, C_1-4 alkyl optionally substituted with 1-3 F, or C_1-4 alkoxy optionally substituted with 1-3 F.

The phenyl, pyridyl, or pyrimidyl portion of S-1, S-2, S-3, or S-4 is typically substituted with 1 R⁸, i.e., q is 1, wherein R⁸ is defined herein. In some embodiments, the phenyl, pyridyl, or pyrimidyl portion of S-1, S-2, S-3, or S-4 can be substituted with 2 R⁸, wherein R⁸ is defined herein. In some embodiments, R⁸ at each occurrence is independently R^H1, OR^H1, SR^H1, SF₅, or optionally substituted 5-8 membered carbocyclic having two or more rings, wherein R^H1 is C_1-4 alkyl optionally substituted with 1-3 F, C_1-4 alkoxy optionally substituted with 1-3 F, or C_3-6 cycloalkyl optionally substituted with 1-3 substituents independently selected from F, OH, methyl, and methoxy, and wherein when substituted, the optionally substituted 5-8 membered carbocyclic is substituted with 1-3 substituents each independently selected from halogen (e.g., F), OH, CN, C_1-4 alkyl and C_1-4 alkoxy. In some embodiments, R⁸ can be optionally substituted 5-8 membered carbocyclic having two or more rings, such as a bicyclic carbocyclic ring. For example, in some embodiments, R⁸ can be a 5-8 membered bicyclic carbocyclic, such as a bridged bicyclic carbocyclic, such as

which is optionally substituted, wherein, when substituted, the bicyclic carbocyclic can be substituted with one or more (e.g., 1-3) substituents, for example, each substituent can be independently selected from halogen (e.g., F), OH, CN, C_1-4 alkyl or C_1-4 alkoxy. In some embodiments, R⁸ can be

In some embodiments, R⁸ at each occurrence can be independently a C_1-4 alkyl optionally substituted with 1-3 F (such as CH₃, CF₃, etc.), C_1-4 alkoxy optionally substituted with 1-3 F (such as OCH₃, OCF₃, etc.), SCF₃, SF₅, cyclopropyl, cyclobutyl, or

For example, in some embodiments, R³⁰ can have a structure according to S-1-A, S-1-B, S-1-C, or S-1-D:

wherein R⁸ is C_1-4 alkyl optionally substitute with 1-3 F (such as CH₃, CF₃, etc.), C_1-4 alkoxy optionally substituted with 1-3 F (such as OCH₃, OCF₃, etc.), SCF₃, SF₅, cyclopropyl, cyclobutyl, or

In some preferred embodiments, R³⁰ in Formula III-1 to III-12 can be selected from the following:

In some preferred embodiments, R³⁰ in Formula III-1 to III-12 can be selected from the following:

In some preferred embodiments, R³⁰ in Formula III-1 to III-12 can be selected from the following:

In some preferred embodiments, R³⁰ in Formula III-1 to III-12 can be selected from the following:

In some preferred embodiments, R³⁰ in Formula III-1 to III-12 can be selected from the following:

In some preferred embodiments, R³⁰ in Formula III-1 to III-12 can be selected from the following:

In some preferred embodiments, R³⁰ in Formula III-1 to III-12 can be selected from the following:

In some preferred embodiments, R³⁰ in Formula III-1 to III-12 can be selected from the following:

In some preferred embodiments, R³⁰ in Formula III-1 to III-12 is not selected from the following:

In some preferred embodiments, R³⁰ in Formula III-1 to III-12 can be selected from the following:

In some embodiments, in Formula III-1 to III-12, -L²-R³⁰ can be:

In some embodiments, in Formula III-1 to III-12, -L²-R³⁰ is not

In some embodiments, in Formula III-1 to III-12, -L²-R³⁰ can be selected from:

In some embodiments, in Formula III-1 to III-12, -L²-R³⁰ can be selected from:

In some embodiments, in Formula III-1 to III-12, -L²-R³⁰ can be selected from:

In some embodiments, in Formula III-1 to III-12, -L²-R³⁰ can be selected from:

In some embodiments, in Formula III-1 to III-12, -L²-R³⁰ can be:

In some embodiments, in Formula III-1 to III-12, -L²-R³⁰ is not

In some embodiments, in Formula III-1, III-2, III-5, III-8, or III-9, L¹, L², and R³⁰ (i.e., L¹-L²-R³⁰) together can be selected from:

In some embodiments, in Formula III-1, III-2, III-5, III-8, or III-9, L¹, L², and R³⁰ together can be selected from:

In some embodiments, in Formula III-1, III-2, III-5, III-8, or III-9, L¹, L², and R³⁰ together can be selected from:

In some embodiments, in Formula III-1, III-2, III-5, III-8, or III-9, L¹-L²-R³⁰ is selected from the following:

In some embodiments, in Formula III-1, III-2, III-5, III-8, or III-9, L¹, L², and R³⁰ together can be selected from:

In some embodiments, in Formula III-1, III-2, III-5, III-8, or III-9, L¹, L², and R³⁰ together can be selected from:

In some embodiments, in Formula III-1, III-2, III-5, III-8, or III-9, L¹, L², and R³⁰ together can be selected from:

In some embodiments, the present disclosure provides the following enumerated exemplified Embodiments A1-A38:

Embodiments A1-A38

Embodiment A1. A compound of Formula III-2, or a pharmaceutically acceptable salt thereof,

• • wherein the variables X, Y, U, R¹, R², L¹, L², and R³⁰ are defined herein.

Embodiment A2. The compound of Embodiment A1, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-2-A:

Embodiment A3. The compound of Embodiment A1, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-2-B:

Embodiment A4. The compound of any of Embodiments A1-A3, or a pharmaceutically acceptable salt thereof, wherein (i) R¹ is CN; (ii) R¹ is halogen, e.g., F or Cl; (iii) R¹ is

(iv) R¹ is an optionally substituted 5 or 6 membered heteroaryl having 1-4 ring heteroatoms independently selected from O, S, and N, such as an optionally substituted pyrimidinyl or an optionally substituted thiazolyl, for example, R¹ is

or (v) R¹ is SR^A1, wherein R^A1 is independently optionally substituted C_1-4 alkyl, for example, R¹ is SCH₃.

Embodiment A5. The compound of any of Embodiments A1-A4, or a pharmaceutically acceptable salt thereof, wherein L¹ is selected from the following (the bottom attaching point, N or C, is attached to L2)

Embodiment A6. The compound of any of Embodiments A1-A4, or a pharmaceutically acceptable salt thereof, wherein L¹ is selected from the following (the bottom attaching point, N or C, is attached to L²):

Embodiment A7. The compound of any of Embodiments A1-A4, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula II-2-C:

wherein n is 0, 1, 2, or 3, and R^9A is defined herein.

Embodiment A8. The compound of Embodiment A7, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-2-C-1, III-2-C-2, III-2-C-3, or III-2-C-4:

wherein the two R^9A in Formula III-2-C-3 are independently selected.

Embodiment A9. The compound of Embodiment A7 or A8, wherein R^9A at each occurrence is independently CH₃, CH₂CH₃, CH₂CH₂CH₃, fluorine-substituted C_1-3 alkyl (e.g., CF₂H), cyclopropyl, cyclobutyl, CH₂OH, CH₂OCH₃, CH₂OCH₂CH₃, CH₂NH₂, CH₂N₃, or CH₂NHC(O)OCH₃.

Embodiment A10. The compound of any of Embodiments A1-A4, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-2-D:

wherein n is 0, 1, 2, or 3, and R^9A is defined herein.

Embodiment A11. The compound of Embodiment A10, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-2-D-1, III-2-D-2, III-2-D-3, or III-2-D-4:

wherein the two R^9A in Formula III-2-D-3 are independently selected.

Embodiment A12. The compound of Embodiment A10 or A11, or a pharmaceutically acceptable salt thereof, wherein R^9A at each occurrence is independently CH₃, CH₂CH₃, CH₂CH₂CH₃, fluorine-substituted C_1-3 alkyl (e.g., CF₂H), cyclopropyl, cyclobutyl, CH₂OH, CH₂OCH₃, CH₂OCH₂CH₃, CH₂NH₂, CH₂N₃, or CH₂NHC(O)OCH₃.

Embodiment A13. The compound of any of Embodiments A1-A12, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-2-E-1, III-2-E-2, or III-2-E-3:

wherein R¹³ is defined herein.

Embodiment A14. The compound of any of Embodiments A1-A12, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-2-E-1a, III-2-E-2a, II-2-E-3a, III-2-E-1b, III-2-E-2b, or III-2-E-3b:

wherein R¹³ is e me herein.

Embodiment A15. The compound of Embodiment A13, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a, or II-2-F-3b:

• • wherein:
  • R^9A at each occurrence is independently CH₃, CH₂CH₃, CH₂CH₂CH₃, fluorine-substituted C_1-3 alkyl (e.g., CF₂H), cyclopropyl, cyclobutyl, CH₂OH, CH₂OCH₃, CH₂OCH₂CH₃, CH₂NH₂, CH₂N₃, or CH₂NHC(O)OCH₃, preferably, R^9A at each occurrence is independently CH₃, CH₂CH₃, or CH₂CH₂CH₃, more preferably, R^9A at each occurrence is CH₂CH₃.

Embodiment A16. The compound of any of Embodiments A13-A15, or a pharmaceutically acceptable salt thereof, wherein R¹³ is hydrogen, C_1-4 alkyl, e.g., methyl, isopropyl, etc., CN, OH, COOH, CONH₂, methoxy, ethoxy, cyclopropyl, cyclobutyl, optionally substituted phenyl, or optionally substituted 5 or 6 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S, wherein, when substituted, the optionally substituted phenyl or 5 or 6 membered heteroaryl is substituted with 1-3 substituents independently selected from halogen (preferably F or Cl), OH, CN, C_1-4 alkyl optionally substituted with 1-3 F, C_1-4 heteroalkyl optionally substituted with 1-3 F, and 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and/or methyl, more preferably, R¹³ is hydrogen.

Embodiment A17. The compound of any of Embodiments A1-A12, or a pharmaceutically acceptable salt thereof, wherein L² is absent, O, or C(O).

Embodiment A18. The compound of any of Embodiments A1-A17, or a pharmaceutically acceptable salt thereof, wherein R³⁰ is an optionally substituted phenyl or 5 or 6-membered heteroaryl (e.g., such as oxadiazolyl

pyridyl

or pyrimidinyl

for example, when substituted, the phenyl or 5 or 6-membered heteroaryl can be substituted with 1-3 (e.g., 1 or 2) R²², wherein R²² at each occurrence is halogen (e.g., F, Cl, or Br), CN, C_1-4 alkyl optionally substituted with 1-3 F (such as CH₃, CF₃, etc.), C_1-4 alkoxy optionally substituted with 1-3 F (such as OCH₃, OCF₃, etc.), SCF₃, SF₅, cyclopropyl, cyclobutyl, or

Embodiment A19. The compound of any of Embodiments A1-A17, or a pharmaceutically acceptable salt thereof, wherein R³⁰ is a phenyl which is substituted with 1-3 (e.g., 1 or 2) R²², wherein R²² at each occurrence is independently halogen (e.g., F, Cl, or Br), CN, OH, R^M1, OR^M1, SO₂R^M1, P(O)(R^M1)₂, SR^M1, or SF₅, wherein R^M1 at each occurrence is independently an optionally substituted C_1-4 alkyl or an optionally substituted 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.), wherein when substituted, the optionally substituted C_1-4 alkyl or 3-4 membered ring is substituted with 1-3 substituents independently selected from halogen (preferably F or Cl), OH, CN, C_1-4 alkyl optionally substituted with 1-3 F, C_1-4 heteroalkyl optionally substituted with 1-3 F, and 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and/or methyl, preferably, R²² at each occurrence is independently F, Cl, Br, CF₃, OCF₃, SCF₃, SF₅, OMe, CN, methyl, CHF₂, CF₂CH₃, cyclopropyl, CH₃SO₂, and OCH₂-(cyclopropyl).

Embodiment A20. The compound of any of Embodiments A1-A17, or a pharmaceutically acceptable salt thereof, wherein R³⁰ is a phenyl which is substituted with 1-3 (e.g., 1 or 2) R²², wherein R²² at each occurrence is independently F, Cl, CN, R^M2, OR^M2, SR^M2, or SF₅, wherein R^M2 at each occurrence is independently a C_1-4 alkyl optionally substituted with 1-3 F, such as CF₃.

Embodiment A21. The compound of any of Embodiments A1-A17, or a pharmaceutically acceptable salt thereof, wherein R³⁰ is a 5-membered heteroaryl

or pyridyl

or pyrimidinyl

which is substituted with 1-3 (e.g., 1 or 2) R²², as valency permits, wherein R²² at each occurrence is independently halogen (e.g., F, Cl, or Br), CN, OH, R^M1, OR^M1, SO₂R^M1, P(O)(R^M1)₂, SR^M1, or SF₅, wherein R^M1 at each occurrence is independently an optionally substituted C_1-4 alkyl or an optionally substituted 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.), wherein when substituted, the optionally substituted C_1-4 alkyl or 3-4 membered ring is substituted with 1-3 substituents independently selected from halogen (preferably F or Cl), OH, CN, C_1-4 alkyl optionally substituted with 1-3 F, C_1-4 heteroalkyl optionally substituted with 1-3 F, and 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and/or methyl, preferably, R²² at each occurrence is independently F, Cl, Br, CF₃, OCF₃, SCF₃, SF₅, OMe, CN, methyl, CHF₂, CF₂CH₃, cyclopropyl, CH₃SO₂, and OCH₂-(cyclopropyl).

Embodiment A22. The compound of any of Embodiments A1-A17, or a pharmaceutically acceptable salt thereof, wherein R³⁰ is a 5-membered heteroaryl

or pyridyl

or pyrimidinyl

which is substituted with 1-3 (e.g., 1 or 2) R²², as valency permits, wherein R²² at each occurrence is independently F, Cl, CN, R^M2, OR^M2, SR^M2, or SF₅, wherein R^M2 at each occurrence is independently a C_1-4 alkyl optionally substituted with 1-3 F, such as CF₃.

Embodiment A23. The compound of any of Embodiments A1-A17, or a pharmaceutically acceptable salt thereof, wherein R³⁰ has a structure according to S-1-A, S-1-B, S-1-C, or S-1-D:

wherein R⁸ is C_1-4 alkyl optionally substituted with 1-3 F (such as CH₃, CF₃, etc.), C_1-4 alkoxy optionally substituted with 1-3 F (such as OCH₃, OCF₃, etc.), SCF₃, SF₅, cyclopropyl, cyclobutyl, or

Embodiment A24. The compound of any of Embodiments A1-A17, or a pharmaceutically acceptable salt thereof, wherein R³⁰ is selected from:

Embodiment A25. The compound of any of Embodiments A1-A17, or a pharmaceutically acceptable salt thereof, wherein R³⁰ is selected from:

Embodiment A26. The compound of any of Embodiments A1-A17, or a pharmaceutically acceptable salt thereof, R³⁰ is selected from the following:

Embodiment A27. The compound of any of Embodiments A1-A17, or a pharmaceutically acceptable salt thereof, wherein R³⁰ is selected from:

Embodiment A28. The compound of any of Embodiments A1-A17, or a pharmaceutically acceptable salt thereof, wherein R³⁰ is selected from:

Embodiment A29. The compound of any of Embodiments A1-A17, or a pharmaceutically acceptable salt thereof, wherein R³⁰ is selected from:

Embodiment A30. The compound of any of Embodiments A1-A17, or a pharmaceutically acceptable salt thereof, wherein R³⁰ is selected from:

Embodiment A31. The compound of any of Embodiments A1-A4, or a pharmaceutically acceptable salt thereof, wherein L¹-L²-R³⁰ is selected from the following:

Embodiment A32. The compound ofany of Embodiments A1-A4, or a pharmaceutically acceptable salt thereof, wherein L¹-L²-R³⁰ is selected from the following:

Embodiment A33. The compound of any of Embodiments A1-A4, or a pharmaceutically acceptable salt thereof, wherein L-L²-R³⁰ is selected from the following:

Embodiment A34. The compound of any of Embodiments A1-A4, or a pharmaceutically acceptable salt thereof, wherein L¹-L²-R³⁰ is selected from the following:

• • or, L-L²-R³⁰ is selected from the following:

• • or, L-L²-R³⁰ is selected from the following:

Embodiment A35. The compound of any of Embodiments A1-A12, or a pharmaceutically acceptable salt thereof, wherein L²-R³⁰ is selected from:

Embodiment A36. The compound of any of Embodiments A1-A12, or a pharmaceutically acceptable salt thereof, wherein L²-R³⁰ is selected from:

Embodiment A37. A compound of Formula III-8, or a pharmaceutically acceptable salt thereof, wherein Ring C is an imidazole or triazole ring, and wherein the variables X, Y, U, R¹, R², L¹, L², and R³⁰ are defined herein, including any of those shown in Embodiments A2-A36 as defined in connection with Formula III-2.

Embodiment A38. The compound of Embodiment A37, or a pharmaceutically acceptable salt thereof, characterized as having a formula according to III-8-A or III-8-B:

wherein the variables X, Y, U, R¹, R², L¹, L², and R³⁰ are defined herein, including any of those shown in Embodiments A2-A36 as defined in connection with Formula III-2.

In some embodiments, the present disclosure provides the following enumerated exemplified Embodiments B1-B45:

Embodiments B1-B45

Embodiment B1. A compound of Formula III-3, or a pharmaceutically acceptable salt thereof,

• • wherein the variables Y, U, Z, R¹, R², R³, R⁹, n1, L², and R³⁰ are defined herein.

Embodiment B2. The compound of Embodiment B1, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-3-A:

Embodiment B3. A compound of Formula III-4, or a pharmaceutically acceptable salt thereof,

• • wherein the variables Y, U, Z, R¹, R², R³, R⁹, n1, L², and R³⁰ are defined herein.

Embodiment B4. The compound of Embodiment B3, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-4-A:

Embodiment B5. The compound of Embodiment B3, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-4-B:

Embodiment B6. The compound of Embodiment B5, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-4-C or III-4-D:

Embodiment B7. The compound of Embodiment B6, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-4-C-1, III-4-C-2, III-4-C-3, III-4-C-4, III-4-D-1, or III-4-D-2:

Embodiment B8. The compound of any of Embodiments B1-B7, or a pharmaceutically acceptable salt thereof, wherein (i) R³ is an optionally substituted C_1-4 alkyl, such as CH₃, CD₃, ethyl, isopropyl, CH₂CHF₂, etc. or R³ is an optionally substituted 3-4 membered ring, such as cyclopropyl or cyclobutyl, etc., when substituted, the C_1-4 alkyl or 3-4 membered ring is typically substituted with 1-3 substituents independently deuterium, F, or methyl, preferably, R³ is methyl or CD₃; (11) R³ is hydrogen.

Embodiment B9. The compound of any of Embodiments B1-B8, or a pharmaceutically acceptable salt thereof, wherein (i) R¹ is CN; (ii) R¹ is halogen, e.g., F or Cl; (iii) R¹ is

(iv) R¹ is an optionally substituted 5 or 6 membered heteroaryl having 1-4 ring heteroatoms independently selected from O, S, and N, such as an optionally substituted pyrimidinyl or an optionally substituted thiazolyl, for example, R¹ is

or (v) R¹ is SR^A1, wherein R^A1 is independently optionally substituted C_1-4 alkyl, for example, R¹ is SCH₃.

Embodiment B10. The compound of any of Embodiments B1-B9, or a pharmaceutically acceptable salt thereof, wherein R⁹ at each occurrence is independently CH₃, CH₂CH₃, CH₂CH₂CH₃, fluorine-substituted C_1-3 alkyl (e.g., CF₂H), cyclopropyl, cyclobutyl, CH₂OH, CH₂OCH₃, CH₂OCH₂CH₃, CH₂NH₂, CH₂N₃, or CH₂NHC(O)OCH₃, preferably, R⁹ at each occurrence is independently CH₃, CH₂CH₃, or CH₂CH₂CH₃, more preferably, R⁹ at each occurrence is CH₂CH₃.

Embodiment B11. The compound of any of Embodiments B1-B10, or a pharmaceutically acceptable salt thereof, wherein L² is an optionally substituted C_1-4 alkylene.

Embodiment B12. The compound of any of Embodiments B1-B10, or a pharmaceutically acceptable salt thereof, wherein L² is selected from the following:

wherein R¹³ is defined herein.

Embodiment B13. The compound of any of Embodiments B1-B10, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-4-C-4a, III-4-C-4b, III-4-C-4c, III-4-C-4d, III-4-C-4e, or III-4-C-4f:

wherein R¹³ is defined herein.

Embodiment B14. The compound of any of Embodiments B1-B10, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-4-C-4a:

wherein R¹³ is defined herein.

Embodiment B15. The compound of Embodiment B14, or a pharmaceutically acceptable salt thereof, which is substantially stereoisomerically pure, for example, with an enantiomeric excess (“ee”) of 80% or above, such as with 90% ee, 95% ee, 98% ee, 99% ee, or above, and is substantially free of the corresponding stereoisomer according to Formula III-4-C-4b,

for example, with less than 5%, such as with less than 2%, less than 1%, less than 0.5%, or less than 0.1%, of the corresponding stereoisomer according to Formula III-4-C-4b, as determined by HPLC or SFC area % and/or by weight.

Embodiment B16. The compound of any of Embodiments B1-B10, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-4-C-4c:

wherein R¹³ is defined herein.

Embodiment B17. The compound of Embodiment B16, or a pharmaceutically acceptable salt thereof, which is substantially stereoisomerically pure, for example, with an enantiomeric excess (“ee”) of 80% or above, such as with 90% ee, 95% ee, 98% ee, 99% ee, or above, and is substantially free of the corresponding stereoisomer according to Formula III-4-C-4d,

for example, with less than 5%, such as with less than 2%, less than 1%, less than 0.5%, or less than 0.1%, of the corresponding stereoisomer according to Formula III-4-C-4d, as determined by HPLC or SFC area % and/or by weight.

Embodiment B18. The compound of any of Embodiments B1-B10, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-4-C-4e:

wherein R¹³ is defined herein.

Embodiment B19. The compound of Embodiment B18, or a pharmaceutically acceptable salt thereof, which is substantially stereoisomerically pure, for example, with an enantiomeric excess (“ee”) of 80% or above, such as with 90% ee, 95% ee, 98% ee, 99% ee, or above, and is substantially free of the corresponding stereoisomer according to Formula III-4-C-4f,

f for example, with less than 5%, such as with less than 2%, less than 1%, less than 0.5%, or less than 0.1%, of the corresponding stereoisomer according to Formula III-4-C-4f, as determined by HPLC or SFC area % and/or by weight.

Embodiment B20. The compound of any of Embodiments B12-B19, or a pharmaceutically acceptable salt thereof, wherein R¹³ is hydrogen, CN, OH, COOH, CONH₂, methoxy, ethoxy, cyclopropyl, cyclobutyl, optionally substituted phenyl, or optionally substituted 5 or 6 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S, wherein, when substituted, the optionally substituted phenyl or 5 or 6 membered heteroaryl is substituted with 1-3 substituents independently selected from halogen (preferably F or Cl), OH, CN, C_1-4 alkyl optionally substituted with 1-3 F, C_1-4 heteroalkyl optionally substituted with 1-3 F, and 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and/or methyl, more preferably, R¹³ is hydrogen.

Embodiment B21. The compound of any of Embodiments B12-B19, or a pharmaceutically acceptable salt thereof, wherein R¹³ is a C_1-4 alkyl optionally substituted with one or more substituents independently selected from F, OH, or C_1-4 alkoxy, for example, R¹³ is methyl, ethyl, isopropyl, CH₂OH, CH₂OMe, etc.

Embodiment B22. The compound of any of Embodiments B12-B19, or a pharmaceutically acceptable salt thereof, wherein R¹³ is phenyl, which is optionally substituted with 1-3 substituents independently selected from halogen (preferably F or Cl), OH, CN, C_1-4 alkyl optionally substituted with 1-3 F, C_1-4 heteroalkyl optionally substituted with 1-3 F, and 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and/or methyl, for example, R¹³ is

Embodiment B23. The compound of any of Embodiments B12-B19, or a pharmaceutically acceptable salt thereof, wherein R¹³ is a 5 or 6 membered heteroaryl, such as

which is optionally substituted with 1-3 substituents independently selected from halogen (preferably F or Cl), OH, CN, C_1-4 alkyl optionally substituted with 1-3 F, C_1-4 heteroalkyl optionally substituted with 1-3 F, and 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and/or methyl, for example, R¹³ is

Embodiment B24. The compound of any of Embodiments B1-B10, or a pharmaceutically acceptable salt thereof, wherein L² is absent, O, or C(O).

Embodiment B25. The compound of any of Embodiments B1-B24, or a pharmaceutically acceptable salt thereof, wherein R³⁰ is an optionally substituted phenyl or 5 or 6-membered heteroaryl (e.g., such as oxadiazoyl

pyridyl

or pyrimidinyl

for example, when substituted, the phenyl or 5 or 6-membered heteroaryl can be substituted with 1-3 (e.g., 1 or 2) R²², wherein R²² at each occurrence is halogen (e.g., F, Cl, or Br), CN, C_1-4 alkyl optionally substituted with 1-3 F (such as CH₃, CF₃, etc.), C_1-4 alkoxy optionally substituted with 1-3 F (such as OCH₃, OCF₃, etc.), SCF₃, SF₅, cyclopropyl, cyclobutyl, or

Embodiment B26. The compound of any of Embodiments B1-B24, or a pharmaceutically acceptable salt thereof, wherein R³⁰ is a phenyl which is substituted with 1-3 (e.g., 1 or 2) R²², wherein R²² at each occurrence is independently halogen (e.g., F, Cl, or Br), CN, OH, R^M1 OR^M1, SO₂R^M1, P(O)(R^M1)₂, SR^M1, or SF₅, wherein R^M1 at each occurrence is independently an optionally substituted C_1-4 alkyl or an optionally substituted 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.), wherein when substituted, the optionally substituted C_1-4 alkyl or 3-4 membered ring is substituted with 1-3 substituents independently selected from halogen (preferably F or Cl), OH, CN, C_1-4 alkyl optionally substituted with 1-3 F, C_1-4 heteroalkyl optionally substituted with 1-3 F, and 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and/or methyl, preferably, R²² at each occurrence is independently F, Cl, Br, CF₃, OCF₃, SCF₃, SF₅, OMe, CN, methyl, CHF₂, CF₂CH₃, cyclopropyl, CH₃SO₂, and OCH₂-(cyclopropyl).

Embodiment B27. The compound of any of Embodiments B1-B24, or a pharmaceutically acceptable salt thereof, wherein R³⁰ is a phenyl which is substituted with 1-3 (e.g., 1 or 2) R²², wherein R²² at each occurrence is independently F, Cl, CN, R^M2, OR^M2, SR^M2, or SF₅, wherein R^M2 at each occurrence is independently a C_1-4 alkyl optionally substituted with 1-3 F, such as CF₃.

Embodiment B28. The compound of any of Embodiments B1-B24, or a pharmaceutically acceptable salt thereof, wherein R³⁰ is a 5-membered heteroaryl

or pyridyl

or pyrimidinyl

which is substituted with 1-3 (e.g., 1 or 2) R²², as valency permits, wherein R²² at each occurrence is independently halogen (e.g., F, Cl, or Br), CN, OH, R^M1, OR^M1, SO₂R^M1, P(O)(R^M1)₂, SR^MI, or SF₅, wherein R^M1 at each occurrence is independently an optionally substituted C_1-4 alkyl or an optionally substituted 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.), wherein when substituted, the optionally substituted C_1-4 alkyl or 3-4 membered ring is substituted with 1-3 substituents independently selected from halogen (preferably F or Cl), OH, CN, C_1-4 alkyl optionally substituted with 1-3 F, C_1-4 heteroalkyl optionally substituted with 1-3 F, and 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and/or methyl, preferably, R²² at each occurrence is independently F, Cl, Br, CF₃, OCF₃, SCF₃, SF₅, OMe, CN, methyl, CHF₂, CF₂CH₃, cyclopropyl, CH₃SO₂, and OCH₂-(cyclopropyl).

Embodiment B29. The compound of any of Embodiments B1-B24, or a pharmaceutically acceptable salt thereof, wherein R³⁰ is a 5-membered heteroaryl

or pyridyl

or pyrimidinyl

which is substituted with 1-3 (e.g., 1 or 2) R²², as valency permits, wherein R²² at each occurrence is independently F, Cl, CN, R^M2, OR^M2, SR^M2, or SF₅, wherein R^M2 at each occurrence is independently a C_1-4 alkyl optionally substituted with 1-3 F, such as CF₃.

Embodiment B30. The compound of any of Embodiments B1-B24, or a pharmaceutically acceptable salt thereof, wherein R³⁰ has a structure according to S-1-A, S-1-B, S-1-C, or S-1-D:

wherein R¹ is C_1-4 alkyl optionally substituted with 1-3 F (such as CH₃, CF₃, etc.), C_1-4 alkoxy optionally substituted with 1-3 F (such as OCH₃, OCF₃, etc.), SCF₃, SF₅, cyclopropyl, cyclobutyl, or

Embodiment B31. The compound of any of Embodiments B1-B24, or a pharmaceutically acceptable salt thereof, wherein R³⁰ is selected from:

Embodiment B32. The compound of any of Embodiments B1-B24, or a pharmaceutically acceptable salt thereof, wherein R³⁰ is selected from:

Embodiment B33. The compound of any of Embodiments B1-B24, or a pharmaceutically acceptable salt thereof, wherein R³⁰ is selected from:

Embodiment B34. The compound of any of Embodiments B1-B24, or a pharmaceutically acceptable salt thereof, wherein R³⁰ is selected from:

Embodiment B35. The compound of any of Embodiments B1-B24, or a pharmaceutically acceptable salt thereof, wherein R³⁰ is selected from:

Embodiment B36. The compound of any of Embodiments B1-B24, or a pharmaceutically acceptable salt thereof, wherein R³⁰ is selected from:

Embodiment B37. The compound of any of Embodiments B1-B24, or a pharmaceutically acceptable salt thereof, wherein R³⁰ is selected from:

Embodiment B38. The compound of any of Embodiments B1-B10, or a pharmaceutically acceptable salt thereof, wherein L²-R³⁰ is selected from:

Embodiment B39. The compound of any of Embodiments B1-B10, or a pharmaceutically acceptable salt thereof, wherein L²-R³⁰ is selected from:

Embodiment B40. The compound of any of Embodiments B1-B10, or a pharmaceutically acceptable salt thereof, wherein L²-R³⁰ is selected from:

Embodiment B41. The compound of any of Embodiments B1-B10, or a pharmaceutically acceptable salt thereof, wherein L²-R³⁰ is selected from:

Embodiment B42. The compound of any of Embodiments B1-B124, or a pharmaceutically acceptable salt thereof, wherein R³⁰ is selected from:

Embodiment B43. The compound of any of Embodiments B1-B10, or a pharmaceutically acceptable salt thereof, wherein L²-R³⁰ is selected from:

Embodiment B44. The compound of any of Embodiments B1-B10, or a pharmaceutically acceptable salt thereof, wherein L²-R³⁰ is selected from:

Embodiment B45. A compound of Formula III-6 or III-7, or a pharmaceutically acceptable salt thereof, wherein -J-W-represents —CH₂—O—CH₂, —O—CH₂—CH₂—, —N(CH₃)—C(O)—, —NH—C(O)—, —N(CH₃)—CH₂, or —NH—CH₂, (from left to right, i.e., J is the first group from left, such as CH₂, O, NH, or NCH₃), and wherein the variables Z, Y, U, R¹, R², R³, n1, R⁹, L², and R³⁰ are defined herein, including any of those shown in Embodiments B1-B44 as defined in connection with Formula III-3 or III-4.

In some embodiments, the present disclosure also provides a compound selected from Compound Nos. 1-347, or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure also provides a compound selected from the compounds shown in Table A below, or a pharmaceutically acceptable salt thereof:

TABLE A
List of Compounds

Exemplary synthesis and characterization of the above compounds are shown in the Examples section. The compounds may be prepared in a racemic form, with respect to one or more of the chiral centers, which can be separated into two enantiomers, including the as-drawn enantiomer, or be prepared through chiral synthesis, in view of the present disclosure.

In some embodiments, to the extent applicable, the genus of compounds in the present disclosure also excludes any of the compounds specifically prepared and disclosed prior to this disclosure. In other words, the genus of compounds in the present disclosure can optionally have a negative limitation to exclude one or more applicable compound(s) selected from any of the compounds specifically prepared prior to this disclosure.

In some embodiments, the genus of compounds in the present disclosure, includes any of those shown in original claims 1-63 herein, Embodiments 1-49, Embodiments A1-A38, and Embodiments B1-B45.

The compounds of the present disclosure can be readily synthesized by one of ordinary skilled in the art in view of the present disclosure. Exemplified syntheses are also shown in the Examples section.

As will be apparent to those having ordinary skill in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in “Protective Groups in Organic Synthesis”, 4^th ed. P. G. M. Wuts; T. W. Greene, John Wiley, 2007, and references cited therein. The reagents for the reactions described herein are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the reagents are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures, or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (Wiley, 7^th Edition), and Larock's Comprehensive Organic Transformations (Wiley-VCH, 1999), and any of available updates as of this filing.

Pharmaceutical Compositions

Certain embodiments are directed to a pharmaceutical composition comprising one or more of the compounds of the present disclosure.

The pharmaceutical composition can optionally contain a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of the present disclosure (e.g., a compound of Formula III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a, or III-2-F-3b), III-3 (e.g., III-3-A), III-4 (e.g., III-4-A, III-4-B, III-4-C, III-4-D, III-4-C-1, III-4-C-2, III-4-C-3, III-4-C-4, III-4-D-1, III-4-D-2, III-4-C-4a, III-4-C-4b, III-4-C-4c, III-4-C-4d, III-4-C-4e, or III-4-C-4f), III-5, III-6, III-7, III-8 (e.g., III-8-A or III-8-B), III-9, III-10, III-11, or III-12, any of Compound Nos. 1-347, any compound selected from the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients are known in the art. Non-limiting suitable excipients include, for example, encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, carriers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof. See also Remington's The Science and Practice of Pharmacy, 21st Edition, A. R. Gennaro (Lippincott, Williams & Wilkins, Baltimore, Md., 2005; incorporated herein by reference), which discloses various excipients used in formulating pharmaceutical compositions and known techniques for the preparation thereof.

The pharmaceutical composition can include any one or more of the compounds of the present disclosure. For example, in some embodiments, the pharmaceutical composition comprises a compound of Formula III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a, or III-2-F-3b), III-3 (e.g., III-3-A), III-4 (e.g., III-4-A, III-4-B, III-4-C, III-4-D, III-4-C-1, III-4-C-2, III-4-C-3, III-4-C-4, III-4-D-1, III-4-D-2, III-4-C-4a, III-4-C-4b, III-4-C-4c, III-4-C-4d, III-4-C-4e, or III-4-C-4f), III-5, III-6, III-7, III-8 (e.g., III-8-A or III-8-B), III-9, III-10, III-11, or III-12, any of Compound Nos. 1-347, any compound selected from the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof, e.g., in a therapeutically effective amount. In any of the embodiments described herein, the pharmaceutical composition can comprise a therapeutically effective amount of a compound selected from Compound Nos. 1-347, or a pharmaceutically acceptable salt thereof. In any of the embodiments described herein, the pharmaceutical composition can comprise a therapeutically effective amount of a compound selected from the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof.

The pharmaceutical composition can also be formulated for delivery via any of the known routes of delivery, which include but are not limited to oral, parenteral, inhalation, etc.

In some embodiments, the pharmaceutical composition can be formulated for oral administration. The oral formulations can be presented in discrete units, such as capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. Excipients for the preparation of compositions for oral administration are known in the art. Non-limiting suitable excipients include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomers, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropylmethyl cellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate salts, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethyl cellulose, sodium phosphate salts, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acids, stearyl fumarate, sucrose, surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof.

In some embodiments, the pharmaceutical composition is formulated for parenteral administration (such as intravenous injection or infusion, subcutaneous or intramuscular injection). The parenteral formulations can be, for example, an aqueous solution, a suspension, or an emulsion. Excipients for the preparation of parenteral formulations are known in the art. Non-limiting suitable excipients include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, U.S.P. or isotonic sodium chloride solution, water and mixtures thereof.

In some embodiments, the pharmaceutical composition is formulated for inhalation. The inhalable formulations can be, for example, formulated as a nasal spray, dry powder, or an aerosol administrable through a metered-dose inhaler. Excipients for preparing formulations for inhalation are known in the art. Non-limiting suitable excipients include, for example, lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, and mixtures of these substances. Sprays can additionally contain propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

The pharmaceutical composition can include various amounts of the compounds of the present disclosure, depending on various factors such as the intended use and potency and selectivity of the compounds. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a, or III-2-F-3b), III-3 (e.g., III-3-A), III-4 (e.g., III-4-A, III-4-B, III-4-C, III-4-D, III-4-C-1, III-4-C-2, III-4-C-3, III-4-C-4, III-4-D-1, III-4-D-2, III-4-C-4a, III-4-C-4b, III-4-C-4c, III-4-C-4d, III-4-C-4e, or III-4-C-4f), III-5, III-6, III-7, III-8 (e.g., III-8-A or III-8-B), III-9, III-10, III-11, or III-12, any of Compound Nos. 1-347, any compound selected from the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof). In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound of the present disclosure and a pharmaceutically acceptable excipient. As used herein, a therapeutically effective amount of a compound of the present disclosure is an amount effective to treat a disease or disorder as described herein, which can depend on the recipient of the treatment, the disease or disorder being treated and the severity thereof, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the compound potency (e.g., for inhibiting DGKa and/or DGKz), its rate of clearance and whether or not another drug is co-administered.

For veterinary use, a compound of the present disclosure can be administered as a suitably acceptable formulation in accordance with normal veterinary practice. The veterinarian can readily determine the dosing regimen and route of administration that is most appropriate for a particular animal.

In some embodiments, all the necessary components for the treatment of DGKa and/or DGKz associated diseases or disorders using a compound of the present disclosure either alone or in combination with another agent or intervention traditionally used for the treatment of such disease can be packaged into a kit. Specifically, in some embodiments, the present invention provides a kit for use in the therapeutic intervention of the disease comprising a packaged set of medicaments that include the compound disclosed herein as well as buffers and other components for preparing deliverable forms of said medicaments, and/or devices for delivering such medicaments, and/or any agents that are used in combination therapy (e.g., any of those described herein, such as an immuno-oncology agent described herein, including for example an antagonist of a protein that inhibits T cell activation, an agonist of a protein that stimulates T cell activation, etc., in particular, one or more antibodies selected from anti-PD-1, anti-PD-L1, anti-CTLA-4, and combinations thereof) with the compound of the present disclosure, and/or instructions for the treatment of the disease packaged with the medicaments. The instructions may be fixed in any tangible medium, such as printed paper, or a computer readable magnetic or optical medium, or instructions to reference a remote computer data source such as a world wide web page accessible via the internet.

Method of Treatment

Compounds of the present disclosure are useful as therapeutic active substances for the treatment and/or prophylaxis of diseases or disorders that are associated with the activity of DGKa, DGKz, or both DGKa and DGKz, such as DGK target inhibition in T cells. Such diseases or disorders include viral and other infections (e.g., skin infections, GI infection, urinary tract infections, genito-urinary infections, systemic infections), and proliferative diseases (e.g., cancer).

In some embodiments, the present disclosure provides a method of inhibiting the activity of diacylglycerol kinase alpha and/or zeta (DGKa/z) in a cell comprising contacting a cell with an effective amount of one or more compounds of the present disclosure (e.g., a compound of Formula III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a, or III-2-F-3b), III-3 (e.g., III-3-A), III-4 (e.g., III-4-A, III-4-B, III-4-C, III-4-D, III-4-C-1, III-4-C-2, III-4-C-3, III-4-C-4, III-4-D-1, III-4-D-2, III-4-C-4a, III-4-C-4b, III-4-C-4c, III-4-C-4d, III-4-C-4e, or III-4-C-4f), III-5, III-6, III-7, III-8 (e.g., III-8-A or III-8-B), III-9, III-10, III-11, or III-12, any of Compound Nos. 1-347, any compound selected from the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof). As used herein, the term “cell” is meant to refer to a cell that is in vitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal. As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” the DGKa and DGKz enzyme with a compound of the present disclosure includes the administration of a compound of the present disclosure to a subject, such as a human, having DGKa and DGKz, as well as, for example, introducing a compound of the present disclosure into a sample containing a cellular or purified preparation containing DGKa and DGKz enzyme. The term “DGK inhibitor” such as a DGKa and/or DGKz inhibitor refers to an agent capable of inhibiting the activity of diacylglycerol kinase alpha and/or diacylglycerol kinase zeta (DGKa and/or DGKz), such as in T cells resulting in T cell stimulation.

In some embodiments, the present disclosure provides a method of treating a disease associated with activity or expression, including abnormal activity and/or overexpression, of DGKa and/or DGKz in a subject in need thereof, the method comprising administering to the subject an effective amount of one or more compounds of the present disclosure (e.g., a compound of Formula III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-E-1, II-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a, or III-2-F-3b), III-3 (e.g., III-3-A), III-4 (e.g., III-4-A, III-4-B, III-4-C, III-4-D, III-4-C-1, III-4-C-2, III-4-C-3, III-4-C-4, III-4-D-1, III-4-D-2, III-4-C-4a, III-4-C-4b, III-4-C-4c, III-4-C-4d, III-4-C-4e, or III-4-C-4f), III-5, III-6, III-7, III-8 (e.g., III-8-A or III-8-B), III-9, III-10, III-11, or III-12, any of Compound Nos. 1-347, any compound selected from the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof). Examples of diseases can include any disease, disorder or condition that is directly or indirectly linked to expression or activity of DGKa and/or DGKz enzyme, such as over expression or abnormal activity. A DGKa and/or DGKz-associated disease can also include any disease, disorder or condition that can be prevented, ameliorated, or cured by modulating DGKa and/or DGKz enzyme activity. Examples of DGKa and/or DGKz associated diseases include cancer and viral infections such as HIV infection, hepatitis B, and hepatitis C. Examples of cancer include cancer of the colon, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, cancer of the head and neck, lymphoma, leukemia, and/or melanoma.

In some embodiments, the present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of one or more compounds of the present disclosure (e.g., a compound of Formula III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a, or III-2-F-3b), III-3 (e.g., III-3-A), III-4 (e.g., III-4-A, III-4-B, III-4-C, III-4-D, III-4-C-1, III-4-C-2, III-4-C-3, III-4-C-4, III-4-D-1, III-4-D-2, III-4-C-4a, III-4-C-4b, III-4-C-4c, III-4-C-4d, III-4-C-4e, or III-4-C-4f), III-5, III-6, III-7, III-8 (e.g., III-8-A or III-8-B), III-9, III-10, III-11, or III-12, any of Compound Nos. 1-347, any compound selected from the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof) or a therapeutically effective amount of a pharmaceutical composition described herein. In some embodiments, the cancer is cancer of the colon, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, cancer of the head and neck, lymphoma, leukemia, and/or melanoma. Types of cancers that may be treated with the compound of the present disclosure include, but are not limited to, brain cancers, skin cancers, bladder cancers, ovarian cancers, breast cancers, gastric cancers, pancreatic cancers, prostate cancers, colon cancers, blood cancers, lung cancers and bone cancers. Examples of such cancer types include neuroblastoma, intestine carcinoma such as rectum carcinoma, colon carcinoma, familiar adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer, esophageal carcinoma, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, renal carcinoma, kidney parenchymal carcinoma, ovarian carcinoma, cervix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion carcinoma, pancreatic carcinoma, prostate carcinoma, testis carcinoma, breast carcinoma, urinary carcinoma, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gall bladder carcinoma, bronchial carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma, choroid melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma and plasmocytoma.

In some embodiments, the present disclosure provides a method of treating viral infection in a subject, the method comprising administering to the subject a therapeutically effective amount of one or more compounds of the present disclosure (e.g., a compound of Formula III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a, or III-2-F-3b), III-3 (e.g., III-3-A), III-4 (e.g., III-4-A, III-4-B, III-4-C, III-4-D, III-4-C-1, III-4-C-2, III-4-C-3, III-4-C-4, III-4-D-1, III-4-D-2, III-4-C-4a, III-4-C-4b, III-4-C-4c, III-4-C-4d, III-4-C-4e, or III-4-C-4f), III-5, III-6, III-7, III-8 (e.g., III-8-A or III-8-B), III-9, III-10, III-11, or III-12, any of Compound Nos. 1-347, any compound selected from the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof) or a therapeutically effective amount of a pharmaceutical composition described herein. Viral infections that may be treated include, but are not limited to, diseases caused by: hepatitis C virus (HCV), human papilloma virus (HPV), cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), varicella zoster virus, coxsackie virus, human immunodeficiency virus (HIV). In some embodiments, parasitic infections (e.g., malaria) may also be treated by the above methods.

In some embodiments, the present disclosure provides a method of treating a disease or disorder, e.g., a cancer associated with DGKa and/or DGKz in a subject in need thereof. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a, or III-2-F-3b), III-3 (e.g., III-3-A), III-4 (e.g., III-4-A, III-4-B, III-4-C, III-4-D, III-4-C-1, III-4-C-2, III-4-C-3, III-4-C-4, III-4-D-1, III-4-D-2, III-4-C-4a, III-4-C-4b, III-4-C-4c, III-4-C-4d, III-4-C-4e, or III-4-C-4f), III-5, III-6, III-7, III-8 (e.g., III-8-A or III-8-B), III-9, III-10, III-11, or III-12, any of Compound Nos. 1-347, any compound selected from the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof) or a therapeutically effective amount of a pharmaceutical composition described herein. In some embodiments, the cancer is cancer of the colon, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, cancer of the head and neck, lymphoma, leukemia, and/or melanoma. Other types of cancer suitable to be treated by the method include those described herein.

Compounds of the present disclosure can be used as a monotherapy or in a combination therapy. In some embodiments, the combination therapy includes treating the subject with a targeted therapeutic agent, chemotherapeutic agent, therapeutic antibody, radiation, cell therapy, and/or immunotherapy. In some embodiments, compounds of the present disclosure can also be co-administered with an additional pharmaceutically active compound, either concurrently or sequentially in any order, to a subject in need thereof. In some embodiments, the combination therapy includes treating the subject with one or more additional therapies such as anti-viral agents, chemotherapeutics or other anti-cancer agents, immune enhancers, immunosuppressants, radiation, anti-tumor and anti-viral vaccines, cytokine therapy (e.g., IL2 and GM-CSF), and/or tyrosine kinase inhibitors.

In some embodiments, compounds of the present disclosure can be administered concurrently or sequentially in any order with an immuno-oncology agent. Immuno-oncology agents include, for example, a small molecule drug, antibody, or other biologic or small molecule. Examples of biologic immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In some embodiments, the immuno-oncology agent is (i) an agonist of a stimulatory (including a co-stimulatory) receptor or (ii) an antagonist of an inhibitory (including a co-inhibitory) signal on T cells, both of which result in amplifying antigen-specific T cell responses (often referred to as immune checkpoint regulators). Certain of the stimulatory and inhibitory molecules are members of the immunoglobulin super family (IgSF). One important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane bound ligands that bind to co-stimulatory or co-inhibitory receptors is the TNF family of molecules that bind to cognate TNF receptor family members, which includes CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR/Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACl, APRIL, BCMA, LTbR, LIGHT, DcR3, HVEM, VEGI/TL1A, TRAMP/DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, Lymphotoxin a/TNFb, TNFR2, TNFa, LTbR, Lymphotoxin a 1b2, FAS, FASL, RELT, DR6, TROY, NGFR. T cell responses can be stimulated by a combination of a compound of the present disclosure and one or more of (i) an antagonist of a protein that inhibits T cell activation (e.g., immune checkpoint inhibitors) such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4, and (ii) an agonist of a protein that stimulates T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD28H. Other agents that can be combined with compounds of the present disclosure for the treatment of cancer include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells. For example, a compound of the present disclosure can be combined with antagonists of KIR, such as lirilumab. Other agents for combination therapies include agents that inhibit or deplete macrophages or monocytes, including but not limited to CSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155 (WO11/70024, WO11/107553, WO11/131407, WO13/87699, WO13/119716, WO13/132044) or FPA-008 (WO11/140249; WO13169264; WO14/036357). In some embodiments, a compound of the present disclosure can be used with one or more of agonistic agents that ligate positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that increase systemically the frequency of anti-tumor T cells, agents that overcome distinct immune suppressive pathways within the tumor microenvironment (e.g., block inhibitory receptor engagement (e.g., PD-L1/PD-1 interactions), deplete or inhibit Tregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibit metabolic enzymes such as IDO, or reverse/prevent T cell anergy or exhaustion) and agents that trigger innate immune activation and/or inflammation at tumor sites. In some embodiments, the immuno-oncology agent is a CTLA-4 antagonist, such as an antagonistic CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, YERVOY (ipilimumab) or tremelimumab. In some embodiments, the immuno-oncology agent is a PD-1 antagonist, such as an antagonistic PD-1 antibody. Suitable PD-1 antibodies include, for example, OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO2012/145493). The immuno-oncology agent may also include pidilizumab (CT-011), though its specificity for PD-1 binding has been questioned. Another approach to target the PD-1 receptor is the recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fe portion of IgG1, called AMP-224. In some embodiments, the immuno-oncology agent is a PD-L1 antagonist, such as an antagonistic PD-L1 antibody. Suitable PD-L1 antibodies include, for example, MPDL3280A (RG7446; WO2010/077634), durvalumab (MEDI4736), BMS-936559 (WO2007/005874), and MSB0010718C (WO2013/79174). In some embodiments, the immuno-oncology agent is a LAG-3 antagonist, such as an antagonistic LAG-3 antibody. Suitable LAG3 antibodies include, for example, BMS-986016 (WO10/19570, WO14/08218), or IMP-731 or IMP-321 (WO08/132601, WO09/44273). In some embodiments, the immuno-oncology agent is a CD137 (4-1BB) agonist, such as an agonistic CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (WO12/32433). In some embodiments, the immuno-oncology agent is a GITR agonist, such as an agonistic GITR antibody. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO06/105021, WO09/009116) and MK-4166 (WO11/028683). In some embodiments, the immuno-oncology agent is an IDO antagonist. Suitable IDO antagonists include, for example, INCB-024360 (WO2006/122150, WO07/75598, WO08/36653, WO08/36642), indoximod, BMS-986205, orNLG-919 (WO09/73620, WO09/1156652, WO11/56652, WO12/142237). In some embodiments, the immuno-oncology agent is an OX40 agonist, such as an agonistic OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469. In another aspect, the immuno-oncology agent is an OX40L antagonist, such as an antagonistic OX40 antibody. Suitable OX40L antagonists include, for example, RG-7888 (WO06/029879). In some embodiments, the immuno-oncology agent is a CD40 agonist, such as an agonistic CD40 antibody. In yet another embodiment, the immuno-oncology agent is a CD40 antagonist, such as an antagonistic CD40 antibody. Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab. In some embodiments, the immuno-oncology agent is a CD27 agonist, such as an agonistic CD27 antibody. Suitable CD27 antibodies include, for example, varlilumab. In some embodiments, the immuno-oncology agent is MGA271 (to B7H3) (WO11/109400).

Combination therapy also can include the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and/or non-drug therapies (e.g., surgery or radiation treatment.)

Suitable antiviral agents contemplated for use in combination with the compound of the present disclosure can comprise nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors and other antiviral drugs. Examples of suitable NRTIs include zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir; BCH-I0652; emitricitabine [(−)-FTC]; beta-L-FD4 (also called beta-L-D4C and named beta-L-2¢,3¢-dicleoxy-5-fluoro-cytidene); DAPD, ((−)-beta-D-2,6-diamino-purine dioxolane); and lodenosine (FddA). Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442 (1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione); and (+)-calanolide A (NSC-675451) and B. Typical suitable protease inhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir; DMP-450; BMS-2322623; ABT-378; and AG-1549. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Yissum Project No. 11607.

Additional combination therapies such as additional immune-oncology agents also include any of those described as suitable for combination with DGK inhibitors in any of the following published patent applications: WO2019005883; WO2020006016; WO2020006018; WO2021041588; WO2021105115; WO2021105116; WO2021105117; WO2021127554; WO2021130638; WO2021132422; WO2021133748; WO2021133749; WO2021133750; WO2021133751; WO2021133752; WO2021214019; or WO2021214020.

The administering herein is not limited to any particular route of administration. For example, in some embodiments, the administering can be orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperintoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In some embodiments, the administering is orally.

Dosing regimen including doses can vary and can be adjusted, which can depend on the recipient of the treatment, the disease or disorder being treated and the severity thereof, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the compound potency, its rate of clearance and whether or not another drug is co-administered.

Definitions

It is meant to be understood that proper valences are maintained for all moieties and combinations thereof.

It is also meant to be understood that a specific embodiment of a variable moiety herein can be the same or different as another specific embodiment having the same identifier.

The present disclosure encompasses all combinations of the aspects and/or embodiments of the disclosure herein. It is understood that any and all embodiments of the present disclosure may be taken in conjunction with any other embodiment or embodiments to describe additional embodiments. It is also to be understood that each individual element of the embodiments is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.

Suitable atoms or groups for the variables herein are independently selected. The definitions of the variables can be combined. Using Formula III-4 as an example, any of the definitions of one of R¹, R², R³, R⁹, R³⁰, U, Y, Z, n1, and L², in Formula III-4 can be combined with any of the definitions of the others of R¹, R², R³, R⁹, R³⁰, U, Y, Z, n1, and L², in Formula III-4. Such combination is contemplated and within the scope of the present disclosure. Non-limiting useful groups for the variables in compounds of Formula III-1 to III-12, or a subformula thereof, as applicable, include any of the respective groups, individually or in any combination, as shown in the Examples or in the specific compounds described in Table A herein.

Although well understood in the field, to be clear, when a formula herein is said to be a sub-formula of a broader formula, it should be understood that for a variable(s) that is defined in connection with the broader formula, such variable(s) for the sub-formula can have the same definition as any of those defined for the broader formula, and the preferred definition of such variable(s) for the sub-formula can also include the same preferred definition as any of those described for the broader formula, unless obviously contrary from context. Similarly, for a variable(s) that is defined in connection with the sub-formula, such variable(s) for the broader formula or a different sub-formula of the broader formula can have the same definition as any of those defined for the sub-formula, unless obviously contrary from context.

The symbol, when displayed perpendicular to (or otherwise crossing) a bond, indicates the point at which the displayed moiety is attached to the remainder of the molecule. It should be noted that for a divalent structure (or multivalent structure), the immediately connected group or groups or appropriate variable(s) shown in a formula maybe shown in the divalent structure (or multivalent structure) beyond the symbol, , to indicate direction of attachment. When the immediately connected group(s) or variable is not shown for either of the two attaching points of a divalent structure, it should mean that either direction of attachment to the remainder of the molecule is allowed, unless otherwise specified or obviously contrary from context. Using a structure of “X-A-G-B” to illustrate, for example, if G is defined as

i.e., the immediately connected group(s) or variable(s) is not shown, then the structure of “X-A-G-B” can be either

on the other hand, if G is defined as

then the structure of “X-A-G-B” should be understood as

Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5^th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3^rd Edition, Cambridge University Press, Cambridge, 1987. The disclosure is not intended to be limited in any manner by the exemplary listing of substituents described herein.

Compounds of the present disclosure can comprise one or more asymmetric centers and/or axial chirality, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer, atropisomer, or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those having ordinary skill in the art, including chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers including racemic mixtures. In embodiments herein, unless otherwise obviously contrary from context, when a stereochemistiy is specifically drawn, it should be understood that with respect to that particular chiral center or axial chirality, the compound can exist predominantly as the as-drawn stereoisomer, such as with less than 20%, less than 10%, less than 5%, less than 1%, by weight, by HPLC or SFC area, or both, or with a non-detectable amount of the other stereoisomer(s), for example, the compound can be characterized as having an enantiomeric excess (“ee”) of greater than 60%, such as greater than 80% ee, greater than 90% ee, greater than 95% ee, greater than 98% ee, or greater than 99% ee. The presence and/or amounts of stereoisomers can be determined by those having ordinary skill in the art in view of the present disclosure, including through the use of chiral HPLC or SFC. When the stereochemistry of a chiral center is not specifically drawn, it should be understood that the structure or a fragment thereof is intended to encompass all possible stereoisomers with respect to that particular chiral center.

When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example “C_1-6” is intended to encompass, C₁, C₂, C₃, C₄, C₅, C₆, C_1-6, C_1-5, C_1-4, C_1-3, C_1-2, C_2-6, C_2-5, C_2-4, C_2-3, C_3-6, C_3-5, C_3-4, C_4-6, C_4-5, and C_5-6.

As used herein, the term “compound(s) of the present disclosure” or “compound(s) of the present invention” refers to any of the compounds described herein according to III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a, or III-2-F-3b), III-3 (e.g., III-3-A), III-4 (e.g., III-4-A, III-4-B, III-4-C, III-4-D, III-4-C-1, III-4-C-2, III-4-C-3, III-4-C-4, III-4-D-1, III-4-D-2, III-4-C-4a, III-4-C-4b, III-4-C-4c, III-4-C-4d, III-4-C-4e, or III-4-C-4f), III-5, III-6, III-7, III-8 (e.g., III-8-A or III-8-B), III-9, III-10, 11-11, or III-12, any of Compound Nos. 1-347, any compound selected from the compounds shown in Table A herein, isotopically labeled compound(s) thereof (such as a deuterated analog wherein one or more of the hydrogen atoms is substituted with a deuterium atom with an abundance above its natural abundance), possible stereoisomers thereof (including diastereoisomers, enantiomers, and racemic mixtures), geometric isomers thereof, atropisomers thereof, tautomers thereof, conformational isomers thereof, and/or pharmaceutically acceptable salts thereof (e.g., acid addition salt such as HCl salt or base addition salt such as Na salt). For the avoidance of doubt, Compound Nos. 1-347 or Compounds 1-347 refers to the compounds described herein labeled as integers 1, 2, 3, . . . , 347, see for example the title compounds of Examples and Table 1. For ease of description, synthetic starting materials or intermediates may be labeled with an integer (compound number) followed by a “−” and additional numeric values, such as 2-1, 2-2, etc., see examples for details. The labeling of such synthetic starting materials or intermediates should not be confused with the compounds labeled with an integer only without the “−” and additional numeric value. Hydrates and solvates of the compounds of the present disclosure are considered compositions of the present disclosure, wherein the compound(s) is in association with water or solvent, respectively. In some embodiments, the compound of the present disclosure can be any of those defined in original claims 1-63 herein. In some embodiments, the compound of the present disclosure can be any of those defined in Embodiments 1-49 herein. In some embodiments, the compound of the present disclosure can be any of those defined in any of the enumerated embodiments A1-A38 and B1-B45.

Compounds of the present disclosure can exist in isotope-labeled or -enriched form containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most abundantly found in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, phosphorous, sulfur, fluorine, chlorine, and iodine include, but are not limited to ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, and ²⁵I. Compounds that contain other isotopes of these and/or other atoms are within the scope of this invention.

As used herein, the phrase “administration” of a compound, “administering” a compound, or other variants thereof means providing the compound or a prodrug of the compound to the individual in need of treatment.

As used herein, the term “alkyl” as used by itself or as part of another group refers to a straight- or branched-chain aliphatic saturated hydrocarbon. In some embodiments, the alkyl which can include one to twelve carbon atoms (i.e., C_1-12 alkyl) or the number of carbon atoms designated (i.e., a C₁ alkyl such as methyl, a C₂ alkyl such as ethyl, a C₃ alkyl such as propyl or isopropyl, etc.). In one embodiment, the alkyl group is a straight chain C_1-10 alkyl group. In another embodiment, the alkyl group is a branched chain C_3-10 alkyl group. In another embodiment, the alkyl group is a straight chain C_1-6 alkyl group. In another embodiment, the alkyl group is a branched chain C_3-6 alkyl group. In another embodiment, the alkyl group is a straight chain C_1-4 alkyl group. In one embodiment, the alkyl group is a C_1-4 alkyl group selected from methyl, ethyl, propyl (n-propyl), isopropyl, butyl (n-butyl), sec-butyl, tert-butyl, and iso-butyl. As used herein, the term “alkylene” as used by itself or as part of another group refers to a divalent radical derived from an alkyl group. For example, non-limiting straight chain alkylene groups include —CH₂—CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—, —CH₂—CH₂—, and the like.

As used herein, the term “alkenyl” as used by itself or as part of another group refers to a straight- or branched-chain aliphatic hydrocarbon containing one or more, such as one, two or three carbon-to-carbon double bonds. In one embodiment, the alkenyl group is a C_2-6 alkenyl group. In another embodiment, the alkenyl group is a C_2-4 alkenyl group. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

As used herein, the term “alkynyl” as used by itself or as part of another group refers to a straight- or branched-chain aliphatic hydrocarbon containing one or more, such as one to three carbon-to-carbon triple bonds. In one embodiment, the alkynyl has one carbon-carbon triple bond. In one embodiment, the alkynyl group is a C_2-6 alkynyl group. In another embodiment, the alkynyl group is a C_2-4 alkynyl group. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.

As used herein, the term “alkoxy” as used by itself or as part of another group refers to a radical of the formula OR^a1, wherein Rai is an alkyl. As used herein, the term “cycloalkoxy” as used by itself or as part of another group refers to a radical of the formula OR^a1, wherein R^a1 is a cycloalkyl.

As used herein, the term “haloalkyl” as used by itself or as part of another group refers to an alkyl substituted with one or more fluorine, chlorine, bromine and/or iodine atoms. In preferred embodiments, the haloalkyl is an alkyl group substituted with one or more fluorine atoms, alternatively referred to herein as fluorine-substituted alkyl, such as with one, two, or three fluorine atoms. In one embodiment, the haloalkyl group is a C_1-4 haloalkyl group. In one embodiment, the haloalkyl group is a fluorine-substituted C_1-4 alkyl group.

As used herein, the term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched-chain alkyl group, e.g., having from 2 to 14 carbons, such as 2 to 10 carbons in the chain, one or more of the carbons has been replaced by a heteroatom selected from S, O, P and N, and wherein the nitrogen, phosphine, and sulfur atoms can optionally be oxidized and the nitrogen heteroatom can optionally be quaternized. The heteroatom(s) S, O, P and N may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. When the heteroalkyl is said to be substituted, the substituent(s) can replace one or more hydrogen atoms attached to the carbon atom(s) and/or the heteroatom(s) of the heteroalkyl. In some embodiments, the heteroalkyl is a C_1-4 heteroalkyl, which refers to the heteroalkyl defined herein having 1-4 carbon atoms. Examples of C_1-4 heteroalkyl include, but are not limited to, C₄ heteroalkyl such as —CH₂—CH₂—N(CH₃)—CH₃, C₃ heteroalkyl such as —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, C₂ heteroalkyl such as —CH₂—CH₂—OH, —CH₂—CH₂—NH₂, —CH₂—NH(CH₃), —O—CH₂—CH₃ and C₁ heteroalkyl such as, —CH₂—OH, —CH₂—NH₂, —O—CH₃. Preferably, the C_1-4 heteroalkyl (or C_1-4 heteroalkylene) herein contains 1 or 2 heteroatoms, such as one oxygen, one nitrogen, two oxygens, two nitrogens, or one oxygen and one nitrogen. Similarly, the term “heteroalkylene” by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, —CH₂—CH₂—O—CH₂—CH₂— and —O—CH₂—CH₂—NH—CH₂—. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. Where “heteroalkyl” is recited, followed by recitations of specific heteroalkyl groups, such as —NR′R″ or the like, it will be understood that the terms heteroalkyl and —NR′R″ are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as —NR′R″ or the like.

“Carbocyclyl” or “carbocyclic” as used by itself or as part of another group refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C_3-10 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. The carbocyclyl group can be either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated. “Carbocyclyl” also includes ring systems wherein the carbocyclic ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclic ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Non-limiting exemplary carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclopentenyl, and cyclohexenyl.

In some embodiments, “carbocyclyl” is fully saturated, which is also referred to as cycloalkyl. In some embodiments, the cycloalkyl can have from 3 to 10 ring carbon atoms (“C_3-10 cycloalkyl”). In preferred embodiments, the cycloalkyl is a monocyclic ring.

“Heterocyclyl” or “heterocyclic” as used by itself or as part of another group refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 membered heterocyclyl”). Heterocyclyl or heterocyclic ring that has a ring size different from the 3-10 membered heterocyclyl is specified with a different ring size designation when applicable. Those having ordinary skill in the art would understand that such different ring-sized heterocyclyl is also a non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged, or spiro ring system, such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclic ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclic ring, or ring systems wherein the heterocyclic ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclic ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclic ring system.

Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C₆ aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

“Aryl” as used by itself or as part of another group refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C_6-14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C₆ aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C_1-4 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.

“Aralkyl” as used by itself or as part of another group refers to an alkyl substituted with one or more aryl groups, preferably, substituted with one aryl group. Examples of aralkyl include benzyl, phenethyl, etc. When an aralkyl is said to be optionally substituted, either the alkyl portion or the aryl portion of the aralkyl can be optionally substituted.

“Heteroaryl” as used by itself or as part of another group refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). Heteroaryl that has a ring size different from the 5-10 membered heteroaryl is specified with a different ring size designation when applicable. Those having ordinary skill in the art would understand that such different ring-sized heteroaryl is also a 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur. In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

“Heteroaralkyl” as used by itself or as part of another group refers to an alkyl substituted with one or more heteroaryl groups, preferably, substituted with one heteroaryl group. When a heteroaralkyl is said to be optionally substituted, either the alkyl portion or the heteroaryl portion of the heteroaralkyl can be optionally substituted.

As commonly understood in the art, alkylene, alkenylene, alkynylene, heteroalkylene, carbocyclylene, heterocyclylene, arylene, and heteroarylene refer to the corresponding divalent radicals of alkyl, alkenyl, alkynyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, respectively.

An “optionally substituted” group, such as an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl groups, refers to the respective group that is unsubstituted or substituted. In general, the term “substituted”, whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent can be the same or different at each position. Typically, when substituted, the optionally substituted groups herein can be substituted with 1-5 substituents. Substituents can be a carbon atom substituent, a nitrogen atom substituent, an oxygen atom substituent or a sulfur atom substituent, as applicable.

Unless expressly stated to the contrary, combinations of substituents and/or variables are allowable only if such combinations are chemically allowed and result in a stable compound. A “stable” compound is a compound that can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic administration to a subject).

In some embodiments, the “optionally substituted” alkyl, alkenyl, alkynyl, heteroalkyl, carbocyclic, cycloalkyl, alkoxy, cycloalkoxy, or heterocyclic group herein can be unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from F, Cl, —OH, protected hydroxyl, oxo (as applicable), NH₂, protected amino, NH(C_1-4 alkyl) or a protected derivative thereof, N(C_1-4 alkyl((C_1-4 alkyl), C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, C_1-4 alkoxy, C_3-6 cycloalkyl, C_3-6 cycloalkoxy, phenyl, 5 or 6 membered heteroaryl containing 1, 2, or 3 ring heteroatoms independently selected from O, S, and N, 3-7 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein each of the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy phenyl, heteroaryl, and heterocyclyl, is optionally substituted with 1, 2, or 3 substituents independently selected from F, —OH, oxo (as applicable), C_1-4 alkyl, fluoro-substituted C_1-4 alkyl (e.g., CF₃), C_1-4 alkoxy and fluoro-substituted C_1-4 alkoxy. In some embodiments, the “optionally substituted” aryl or heteroaryl group herein can be unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from F, Cl, —OH, —CN, NH₂, protected amino, NH(C_1-4 alkyl) or a protected derivative thereof, N(C_1-4 alkyl((C_1-4 alkyl), —S(═O)(C_1-4 alkyl), —SO₂(C_1-4 alkyl), C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, C_1-4 alkoxy, C_3-6 cycloalkyl, C_3-6 cycloalkoxy, phenyl, 5 or 6 membered heteroaryl containing 1, 2 or 3 ring heteroatoms independently selected from O, S, and N, 3-7 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein each of the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy, phenyl, heteroaryl, and heterocyclyl, is optionally substituted with 1, 2, or 3 substituents independently selected from F, —OH, oxo (as applicable), C_1-4 alkyl, fluoro-substituted C_1-4 alkyl, C_1-4 alkoxy and fluoro-substituted C_1-4 alkoxy.

Exemplary carbon atom substituents include, but are not limited to, halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^aa, —ON(R^bb)₂, —N(R^bb)₂, —N(R^bb)₃⁺X⁻, —N(OR^cc)R^bb, —SH, —SR^aa, —SSR^cc, —C(═O)R^aa, —CO₂H, —CHO, —C(OR^cc)₂, —CO₂R^aa, —OC(═O)R^aa, —OCO₂R^aa, —C(═O)N(R^bb)₂, —OC(═O)N(R^bb)₂, —NR^bbC(═O)R^aa, —NR^bbCO₂R^aa, —NR^bbC(═O)N(R^bb)₂, —C(═NR^bb)R^aa, —C(═NR^bb)OR^aa, —OC(═NR^bb)R^aa, —OC(═NR^bb)OR^aa, —C(═NR^bb)N(R^bb)₂, —OC(═NR^bb)N(R^bb)₂, —NR^bbC(═NR^bb)N(R^bb)₂, —C(═O)NR^bbSO₂R^aa, —NR^bbSO₂R^aa, —SO₂N(R^bb)₂, SO₂R^aa, —SO₂OR^aa, —OSO₂R^aa, —S(═O)R^aa, —OS(═O)R^aa, —Si(R^aa)₃, —OSi(R^aa)₃—C(═S)N(R^bb)₂, C(═O)SR^aa, —C(═S)SR^aa, —SC(═S)SR^aa, —SC(═O)SR^aa, —OC(═O)SR^aa, —SC(═O)OR^aa, —SC(═O)R^aa, —P(═O)(R^aa)₂, —P(═O)(OR^cc)₂, —OP(═O)(R^aa)₂, —OP(═O)(OR^cc)₂, —P(═O)(N(R^bb)₂)₂, —OP(═O)(N(R^bb)₂)₂, —NR^bbP(═O)(R^aa)₂, —NR^bbP(═O)(OR″ °)₂, —NR^bbP(═O)(N(R^bb)₂)₂, —P(R^cc)₂, —P(OR^cc)₂, —P(R^C)₃⁺X⁻, —P(OR^cc)₃⁺X⁻, —P(R^cc)₄, —P(OR^cc)₄, —OP(R^cc)₂, —OP(R^cc)₃⁺X⁻, —OP(OR^cc)₂, —OP(OR^cc)₃X—, —OP(R^cc)₄, —OP(OR^cc)₄, —B(R^aa)₂, —B(OR^cc)₂, —BR^aa(OR^cc), C_1-10 alkyl, C_1-10 haloalkyl, C_2-10 alkenyl, C_2-10 alkynyl, C_3-10 carbocyclyl, 3-14 membered heterocyclyl, C_6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^dd groups; wherein X⁻ is a counterion;

• • or two geminal hydrogens on a carbon atom are replaced with the group ═O, ═S, ═NN(R^bb)₂, ═NNR^bbC(═O)R^aa, ═NNR^bbC(═O)OR^aa, ═NNR^bbS(═O)₂R^aa, ═NR^bb, or ═NOR^cc;
  • each instance of R^aa is, independently, selected from C_1-10 alkyl, C_1-10 haloalkyl, C_2-10 alkenyl, C_2-10 alkynyl, C_3-10 carbocyclyl, 3-14 membered heterocyclyl, C_6-14 aryl, and 5-14 membered heteroaryl, or two R^aa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^dd groups; each instance of R^bb is, independently, selected from hydrogen, —OH, —OR^aa, —N(R^cc)₂, —CN, —C(═O)R^aa, —C(═O)N(R^cc)₂, —CO₂R^aa, —SO₂R^aa, —C(═NR^cc)OR^aa, —C(═NR^cc)N(R^cc)₂, —SO₂N(R^cc)₂, —SO₂R^cc, —SO₂OR^cc, —SOR^aa, —C(═S)N(R^cc)₂, —C(═O)SR^cc, —C(═S)SR^cc, —P(═O)(R^aa)₂, —P(═O)(OR^cc)₂, —P(═O)(N(R^cc)₂)₂, C_1-10 alkyl, C_1-10 haloalkyl, C_2-10 alkenyl, C_2-10 alkynyl, C_3-10 carbocyclyl, 3-14 membered heterocyclyl, C_6-14 aryl, and 5-14 membered heteroaryl, or two R^bb groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^dd groups; wherein X is a counterion; each instance of R^dd is, independently, selected from hydrogen, C_1-10 alkyl, C_1-10 haloalkyl, C_2-10 alkenyl, C_2-10 alkynyl, C_3-10 carbocyclyl, 3-14 membered heterocyclyl, C_6-14 aryl, and 5-14 membered heteroaryl, or two R^cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^dd groups; each instance of R^dd is, independently, selected from halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^ee, —ON(R^ff)₂, —N(R^ff)₂, —N(R^ff)₃⁺X⁻, —N(OR^ee)R^ff, —SH, —SR^ee, SSR^ee, C(═O)R^ee, CO₂H, —CO₂R^ee, OC(═O)R^ee, OCO₂R^ee, —C(═O)N(R^ff)₂, —OC(═O)N(R^ff)₂, —NR^ffC(═O)R^ee, NR^ffCO₂R^ee, —NR^ffC(═O)N(R^ff)₂, —C(═NR^ff)OR^ee, —OC(═NR^ff)R^ee, —OC(═NR^ff)OR^ee, —C(═NR^ff)N(R^ff)₂, —OC(═NR^ff)N(R^ff)₂, —NR^ffC(═NR^ff)N(R^ff)₂, —NR^ffSO₂R^ee, —SO₂N(R^ff)₂, —SO₂R^ee, —SO₂OR^ee, OSO₂R^ee, —S(═O)R^ee, —Si(R^ee)₃, —OSi(R^ee)₃, —C(═S)N(R^ff)₂, —C(═O)SR^ee, C(═S)SR^ee, —SC(═S)SR^ee, —P(═O)(OR^ee)₂, P(═O)(R^ee)₂, OP(═O)(R^ee)₂, —OP(═O)(OR^ee)₂, C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 carbocyclyl, 3-10 membered heterocyclyl, C_6-10 aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^gg groups, or two geminal R^dd substituents can be joined to form ═O or ═S; wherein X-is a counterion; each instance of R^ee is, independently, selected from C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 carbocyclyl, C_6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^gg groups;
  • each instance of R^ff is, independently, selected from hydrogen, C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 carbocyclyl, 3-10 membered heterocyclyl, C_6-10 aryl and 5-10 membered heteroaryl, or two R^ff groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^gg groups; and each instance of R^gg is, independently, halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OC_1-6 alkyl, —ON(C_1-6 alkyl)₂, —N(C_1-6 alkyl)₂, —N(C_1-6 alkyl)₃⁺X⁻, —NH(C_1-6 alkyl)₂⁺X⁻, —NH₂(C_1-6 alkyl) ⁺X⁻, —NH₃⁺X⁻, —N(OC_1-6 alkyl)(C_1-6 alkyl), —N(OH)(C_1-6 alkyl), —NH(OH), —SH, —SC_1-6 alkyl, —SS(C_1-6 alkyl), —C(═O)(C_1-6 alkyl), —CO₂H, —CO₂(C_1-6 alkyl), —OC(═O)(C_1-6 alkyl), —OCO₂(C_1-6 alkyl), —C(═O)NH₂, —C(═O)N(C_1-6 alkyl)₂, —OC(═O)NH(C_1-6 alkyl), —NHC(═O)(C_1-6 alkyl), —N(C_1-6 alkyl)C(═O)(C_1-6 alkyl), —NHCO₂(C_1-6 alkyl), —NHC(═O)N(C_1-6 alkyl)₂, —NHC(═O)NH(C_1-6 alkyl), —NHC(═O)NH₂, —C(═NH)O(C_1-6 alkyl), —OC(═NH)(C_1-6 alkyl), —OC(═NH)OC_1-6 alkyl, —C(═NH)N(C_1-6 alkyl)₂, —C(═NH)NH(C_1-6 alkyl), —C(═NH)NH₂, OC(═NH)N(C_1-6 alkyl)₂, —OC(NH)NH(C_1-6 alkyl), —OC(NH)NH₂, —NHC(NH)N(C_1-6 alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C_1-6 alkyl), —SO₂N(C_1-6 alkyl)₂, —SO₂NH(C_1-6 alkyl), —SO₂NH₂, —SO₂C_1-6 alkyl, —SO₂OC-6 alkyl, —OSO₂C_1-6 alkyl, —SOC_1-6 alkyl, —Si(C_1-6 alkyl)₃, —OSi(C_1-6 alkyl)₃-C(═S)N(C_1-6 alkyl)₂, C(═S)NH(C_1-6 alkyl), C(═S)NH₂, —C(═O)S(C_1-6 alkyl), —C(═S)SC_1-6 alkyl, —SC(═S)SC_1-6 alkyl, —P(═O)(OC_1-6 alkyl)₂, —P(═O)(C_1-6 alkyl)₂, —OP(═O)(C_1-6 alkyl)₂, —OP(═O)(OC_1-6 alkyl)₂, C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 carbocyclyl, C_6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R^gg substituents can be joined to form ═O or ═S; wherein X⁻ is a counterion.

A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may be monovalent (i.e., including one formal negative charge). An anionic counterion may also be multivalent (i.e., including more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F⁻, Cl⁻, Br⁻, I⁻), NO₃⁻, ClO₄⁻, OH⁻, H₂PO₄⁻, HSO₄⁻, sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonic acid-2-sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF₄⁻, PF₄⁻, PF₆⁻, AsF₆⁻, SbF₆⁻, B[3,5-(CF₃)₂C₆H₃]₄]⁻, BPh₄⁻, Al(OC(CF₃)₃)₄⁻, and a carborane anion (e.g., CB₁₁H₁₂⁻ or (HCB₁₁Me₅Br₆)⁻). Exemplary counterions which may be multivalent include CO₃²⁻, HPO₄²⁻, PO₄³⁻, B₄O₇²⁻, S₄²⁻, S₂O₃²⁻, carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, Sali cylate, phthalates, aspartate, glutamate, and the like), and carboranes.

“Halo” or “halogen” refers to fluorine (fluoro, —F), chlorine (chloro, —Cl), bromine (bromo, —Br), or iodine (iodo, —I).

“Acyl” refers to a moiety selected from the group consisting of —C(═O)R^aa, —CHO, —CO₂R^aa, —C(═O)N(R^bb)₂, —C(═NR^bb)R^aa, —C(═NR^bb)OR^aa, —C(═NR^bb)N(R^bb)₂, —C(═O)NR^bbSO₂R^aa, —C(═S)N(R^bb)₂, —C(═O)SR^aa, or —C(═S)SR^aa, wherein R^aa and R^bb are as defined herein.

Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, —OH, —OR^aa, —N(R^C)₂, —CN, —C(═O)R^aa, —C(═O)N(R^cc)₂, CO₂R^aa, SO₂R^aa, —C(═NR^bb)R^aa, —C(═NR^cc)OR^aa, —C(═NR^cc)N(R^cc)₂, SO₂N(R^cc)₂, —SO₂R^cc, —SO₂OR^cc, —SOR^aa, —C(═S)N(R^cc)₂, —C(═O)SR^cc, —C(═S)SR^cc, —P(═O)(OR^Cc)₂, —P(═O)(R^aa)₂, —P(═O)(N(R^cc)₂)₂, C_1-10 alkyl, C_1-10 haloalkyl, C_2-10 alkenyl, C_2-10 alkynyl, C_3-10 carbocyclyl, 3-14 membered heterocyclyl, C_6-14 aryl, and 5-14 membered heteroaryl, or two R^cc groups attached to a nitrogen atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^dd groups, and wherein R^aa, R^bb, R^cc, and R^dd are as defined above.

In certain embodiments, the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group). Nitrogen protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^rd edition, John Wiley & Sons, 1999, incorporated by reference herein. Exemplary nitrogen protecting groups include, but not limited to, those forming carbamates, such as Carbobenzyloxy (Cbz) group, p-Methoxybenzyl carbonyl (Moz or MeOZ) group, tert-Butyloxycarbonyl (BOC) group, Troc, 9-Fluorenylmethyloxycarbonyl (Fmoc) group, etc., those forming an amide, such as acetyl, benzoyl, etc., those forming a benzylic amine, such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, etc., those forming a sulfonamide, such as tosyl, Nosyl, etc., and others such as p-methoxyphenyl.

Exemplary oxygen atom substituents include, but are not limited to, —R^aa, —C(═O)SR^aa, —C(═O)R^aa, —CO₂R^aa, —C(═O)N(R^bb)₂, —C(═NR^bb)R^aa, —C(═NR^bb)OR^aa, —C(═NR^bb)N(R^bb)₂, —S(═O)R^aa, —SO₂R^aa, —Si(R^aa)₃, —P(R^cc)₂—P(R^cc)₃⁺X⁻, —P(OR^Cc)₂, —P(OR^cc)₃⁺X⁻, —P(═O)(R^cc)₂, —P(═O)(OR^cc)₂, and —P(═O)(N(R^bb)₂)₂, wherein X⁻, R^aa, R^bb, and R^cc are as defined herein. In certain embodiments, the oxygen atom substituent present on an oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^rd edition, John Wiley & Sons, 1999, incorporated herein by reference. Exemplary oxygen protecting groups include, but are not limited to, alkyl ethers or substituted alkyl ethers such as methyl, allyl, benzyl, substituted benzyls such as 4-methoxybenzyl, methoxymethyl (MOM), benzyloxymethyl (BOM), 2-methoxyethoxymethyl (MEM), etc., silyl ethers such as trymethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBDMS), etc., acetals or ketals, such as tetrahydropyranyl (THP), esters such as formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, etc., carbonates, sulfonates such as methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts), etc.

The term “leaving group” is given its ordinary meaning in the art of synthetic organic chemistry, for example, it can refer to an atom or a group capable of being displaced by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502). Examples of suitable leaving groups include, but are not limited to, halogen (such as F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformates.

The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art.

The term “tautomers” or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base. Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.

The term “subject” (alternatively referred to herein as “patient”) as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

As used herein, the terms “treat,” “treating,” “treatment,” and the like refer to eliminating, reducing, or ameliorating a disease or condition, and/or symptoms associated therewith. Although not precluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated. As used herein, the terms “treat,” “treating,” “treatment,” and the like may include “prophylactic treatment,” which refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously-controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or condition. The term “treat” and synonyms contemplate administering a therapeutically effective amount of a compound described herein to a subject in need of such treatment.

As used herein, the singular form “a”, “an”, and “the”, includes plural references unless it is expressly stated or is unambiguously clear from the context that such is not intended.

The term “and/or” as used in a phrase such as “A and/or B” herein is intended to include both A and B; A or B; A (alone); and B (alone). Likewise, the term “and/or” as used in a phrase such as “A, B, and/or C” is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

Headings and subheadings are used for convenience and/or formal compliance only, do not limit the subject technology, and are not referred to in connection with the interpretation of the description of the subject technology. Features described under one heading or one subheading of the subject disclosure may be combined, in various embodiments, with features described under other headings or subheadings. Further it is not necessarily the case that all features under a single heading or a single subheading are used together in embodiments.

Examples

The various starting materials, intermediates, and compounds of the preferred embodiments can be isolated and purified where appropriate using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Characterization of these compounds can be performed using conventional methods such as by melting point, mass spectrum, nuclear magnetic resonance, and various other spectroscopic analyses. The examples are illustrative only and do not limit the claimed invention in any way.

Exemplary embodiments of steps for performing the synthesis of products described herein are described in greater detail infra. Some of the Examples discussed herein can be prepared by separating the corresponding racemic mixtures. As would be understood by a person of ordinary skill in the art, the compounds described in the Examples section immediately prior to the chiral separation step, e.g., by supercritical fluid chromatography (SFC), exist in racemic and/or stereoisomeric mixture forms. It should be understood that the enantiomeric excesses (“ee”) and/or diastereomeric excesses (“de”) reported for these examples are only representative from the exemplified procedures herein and not limiting; those of ordinary skill in the art would understand that such enantiomers and/or diastereomers with a different ee and/or de, such as a higher ee and/or de, can be obtained in view of the present disclosure. Typically, a “de” value is reported herein when a pair of diastereomers, having only one of the chiral centers being different, are separated from a corresponding diastereomeric mixture. In such cases, the “de” value indicates the degree of enrichment of one of the diastereomers.

The abbreviations used in the Examples section should be understood as having their ordinary meanings in the art unless specifically indicated otherwise or obviously contrary from context. The following shows certain abbreviations used in the Examples section herein.

Abbreviations Chemical Name
(Boc)2O       di-tert-butyl dicarbonate
AcOH/HOAc     Acetic acid
AcONa/NaOAc   Sodium acetate
AIBN          2,2′-Azobis(2-methylpropionitrile)
BINAP         racemic-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl
CDI           Di(1H-imidazol-1-yl)methanone
DAST          Diethylaminosulphur trifluoride
DBU           1,8-Diazabicyclo[5.4.0]undec-7-ene
DCM           dichloromethane
DEA           Diethylamine
DEAD          DiethylAzodicarboxylate
DIAD          Diisopropyl azodicarboxylate
DIPEA         N,N-Diisopropylethylamine
DMAc          N,N-dimethylacetamide
DMAP          4-Dimethylaminopyridine
DMF           N,N-dimethylformamide
DMSO          Dimethyl sulfoxide
dppf          1,1-Bis(diphenylphosphino)ferrocene
EDCI          N-Ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride
EtOH/ETOH     ethanol
FA            Formic acid
Grubbs 2nd    [1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene](dichloro){[2-(1-
catalyst      methylethoxy)phenyl methylidene} ruthenium
HATU          O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium
              hexafluorophosphate
IPA           propan-2-ol
KHMDS         Potassium bis(trimethylsilyl)amide
KOAc          Potassium acetate
LDA           Lithium diisopropylamide
mCPBA         3-Chloroperbenzoic acid
Me4t-BuXPhos  2-Di-t-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-tri-i-propyl)-1,1′-biphenyl
MeCN          acetonitrile
MeOH/MEOH     methanol
NaBH(OAc)3    Sodium triacetoxyborohydride
NBS           N-Bromosuccinimide
n-BuLi        n-butyllithium
NCS           N-Chlorosuccinimide
NMP           N-methylpyrrolidin-2-one
Pd(dppf)Cl2   [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)
Pd(OAc)2      Palladium (II) acetate
Pd(PPh3)4     Tetrakis(triphenylphosphine)palladium
Pd2(dba)3     Tris(dibenzylideneacetone)dipalladium(0)
PPA           polyphosphoric acid
PPh3          triphenylphosphine
Rh(PPh3)3Cl   Tris(triphenylphosphine)chlororhodium
Ruphos Pd G3  (2-Dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-
              1,1′-biphenyl)]palladium(II) methanesulfonate
SEM           2-(Trimethylsilyl)ethoxymethyl
SEMCl         2-(Trimethylsilyl)ethoxymethyl Chloride
SFC           Supercritical Fluid Chromatography
TBAF          Tetra-n-butylammonium fluoride
TBAI          Tetrabutylammonium iodide
TBDPSCl       tert-Butylchlorodiphenylsilane
TBSOTf        tert-Butyldimethylsilyl trifluoromethanesulfonate
t-BuBrettPhos 2-(Di-t-butylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl
t-BuONO       tert-Butyl nitrite
TEA           Triethylamine
Tf2O          Trifluoromethanesulfonic anhydride
TFA           Trifluoroacetic acid
TFAA          Trifluoroacetic anhydride
THF           Tetrahydrofuran
TIPS          Triisopropylsilyl
TIPSCl        Triisopropylsilyl Chloride
TMSCN         Trimethylsilyl cyanide
TMSI          Trimethyliodosilane
Xantphos      9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene

Example 1 Synthesis of Compound 1

Step 1: To a solution of 1-1 (2.5 g, 10.4 mmol) in dioxane (20 mL) was added tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (3.0 g, 12.45 mmol), Cs₂CO₃ (6.76 g, 20.75 mmol) and RuPhos Pd G3 (867.6 mg, 1.4 mmol). The resulting mixture was degassed with N₂ for 10 minutes, then stirred at 120° C. for 4 h. After cooled down to room temperature, the mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 3/1) to afford 1-2.

Step 2: To a solution of 1-2 (2.8 g, 7 mmol) in dioxane (20 mL) was added HCl (4.3 mL, 43 mmol). The reaction mixture was stirred at room temperature for 5 h. The pH was adjusted to 6 by addition of saturated NaHCO₃. The mixture was extracted with ethyl acetate. The organic layer was dried over Na₂SO₄, filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 0/1) to afford 1-3.

Step 3: To a solution of 1-4 (24 g, 144.4 mmol) in acetonitrile (250 mL) was added NBS (28.3 g, 158.9 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. Water was added, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over Na₂SO₄, filtered and the filtrated was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 0/1) to afford 1-5.

Step 4: To a solution of 2-cyanoacetic acid (16.6 g, 195.2 mmol) in DMF (400 mL) were added HATU (1.39 g, 3.7 mmol) and triethylamine (45.2 mL, 325.4 mmol) at room temperature. The mixture was stirred at room temperature for 15 minutes. Then 1-5 (31.9 g, 130.2 mmol) was added. The mixture was stirred at room temperature for 12 h. Water was added to the reaction mixture. The solid was collected by filtration to afford 1-6.

Step 5: To a solution of 1-6 (21.5 g, 68.9 mmol) in THF (300 mL) was added KHMDS (1M in THF, 89.6 mL, 89.6 mmol) at room temperature. The mixture was stirred at room temperature for 12 h. HCl (1 N) was added until the pH was 4. The solid was collected by filtration to afford 1-7.

Step 6: To a solution of 1-7 (15.8 g, 59.4 mmol) in DMF (200 mL) was added NaH (9.5 g, 60%, 237.6 mmol) in portions at 0. The mixture was stirred at 0 for 30 minutes. CH₃I (14.8 mL, 237.6 mmol) was added. The reaction was stirred at room temperature for 12 h, then quenched with H₂O. The pH of the reaction mixture was adjusted to 3 with HCl (1 N). The solid was collected by filtration to afford 1-8.

Step 7: To a solution of 1-8 (17.3 g, 61.8 mmol), triethylamine (25.8 mL, 185.3 mmol) and DMAP (0.8 g, 6.2 mmol) in dichloromethane (200 mL) was added Tf₂O (34.9 g, 123.5 mmol) at 0 . The mixture was stirred at 0 for 0.5 h, then quenched with H₂O and extracted with dichloromethane. The combined organic layers were dried over Na₂SO₄, filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 2/1) to afford 1-9.

Step 8: To a mixture of 1-9 (300 mg, 0.73 mmol) and 1-3 (327.9 mg, 1.1 mmol) in acetonitrile (10 mL) was added DIPEA (0.36 mL, 2.18 mmol). The mixture was stirred at 85 for 2 h. The reaction was quenched by H₂O. The aqueous layer was extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/1) to afford 1-10.

Step 9: To a solution of 1-10 (210 mg, 0.37 mmol) in NMP (8 mL) were added Zn(CN)₂ (87.7 mg, 0.75 mmol), Zn (4.9 mg, 0.075 mmol), Pd₂(dba)₃ (34.2 mg, 0.037 mmol) and dppf (12.6 mg, 0.022 mmol) under N₂. The reaction mixture was stirred at 80 for 1 h. The reaction was quenched by H₂O. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated. The residue was purified by reverse phase HPLC (Reverse phase HPLC (acetonitrile/water: 5-95%) to afford 1. LCMS (ESI, m/z): [M+H]⁺=509.4; ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 8.25 (d, J=8.8 Hz, 1H), 8.14 (d, J=8.8 Hz, 1H), 7.12 (d, J=8.4 Hz, 2H), 6.58 (d, J=9.2 Hz, 2H), 3.90-3.85 (m, 4H), 3.52 (s, 3H), 3.38-3.34 (m, 2H), 3.25 (s, 2H), 1.99 (t, J=6.8 Hz, 2H), 1.86-1.80 (m, 4H).

Example 2 Synthesis of Compound 2

Step 1: To a solution of 2-1 (19 g, 106.7 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (21.5 g, 106.7 mmol) and PPh₃ (30.8 g, 117.3 mmol) in THF (85 mL) was added DEAD (18.6 mL, 117.3 mmol) at 0 under N₂. The mixture was stirred at 20 under N₂ for 16 h. The mixture was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 4/1) to afford 2-2.

Step 2: To a solution of 2-2 (22.1 g, 61.2 mmol) in dichloromethane (20 mL) was added a solution of HCl in dioxane (4M, 61.2 mL, 244.8 mmol) at 20 . The mixture was stirred at 20 for 16 h. The mixture was concentrated under reduced pressure to afford 2-3.

Step 3: To a mixture of 1-9 (600 mg, 1.46 mmol) and 2-3 (456.4 mg, 1.75 mmol) in acetonitrile (10 mL) was added DIPEA (564.4 mg, 4.37 mmol) at room temperature. The mixture was stirred at 85 for 1 h. This mixture was concentrated and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 10/1) to afford 2-4.

Step 4: To a solution of 2-4 (300 mg, 0.57 mmol) and acetaldoxime (609.5 mg, 10.3 mmol) in toluene (15 mL) was added Rh(PPh₃)₃Cl (53.0 mg, 0.057 mmol) at room temperature. Then the mixture was heated at 110 for 12 h. The mixture was concentrated and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 10/1) to afford 2-5.

Step 5: To a mixture of 2-5 (250 mg, 0.46 mmol), Zn (6.0 mg, 0.09 mmol) and Zn(CN)₂ (108.5 mg, 0.92 mmol) in NMP (4 mL) were added Pd₂(dba)₃ (42.3 mg, 0.046 mmol A pf (12.8 mg, 0.023 mmol) at room temperature. Then the mixture was stirred at 90 for 1 h. The reaction mixture was quenched with H₂O and extracted with ethyl acetate. The combined organic layers were dried over Na₂SO₄, filtered and the filtrate was concentrated. The residue was purified by reverse phase HPLC (acetonitrile/0.05% TFA in water: 5%-80%) to afford 2 as 0.2 eq of TFA salt. LCMS (ESI, m/z): [M+H]⁺=488.4; ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 8.17 (d, J=8.8 Hz, 1H), 8.08 (d, J=8.9 Hz, 1H), 7.65 (s, 1H), 7.50 (s, 1H), 7.27 (d, J=8.6 Hz, 2H), 7.13-7.08 (m, 2H), 4.73-4.65 (m, 1H), 3.63 (s, 2H), 3.55 (s, 3H), 3.34-3.29 (m, 2H), 2.13-2.10 (m, 2H), 1.86-1.83 (m, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆, ppm): δ −57.25 (3F), −74.58 (0.6F, TFA).

Example 3 Synthesis of Compound 3

Step 1: 3-1 (10 g, 81.2 mmol) and piperidine-4-carboxylic acid (10.5 g, 81.2 mmol) were added to PPA (53.4 g, 81.2 mmol) and the mixture was stirred at 180 for 2 h. The reaction mixture was cooled to 90° C., then H₂O was added to quench the reaction. The pH of the mixture was adjusted to 12 with 50% KOH. The mixture was extracted with CH₂Cl₂. The organic layer was dried over Na₂SO₄, filtered and concentrated to afford 3-2.

Step 2: Compound 3-3 was prepared from compound 3-2 following the procedure for the synthesis of compound 1-10 in example 1.

Step 3: Compound 3 was prepared from compound 3-3 following the procedure for the synthesis of compound 1 in example 1. LCMS (ESI, m/z): [M+H]⁺=425.2; ¹H NMR (400 MHz, DMSO-d₆, ppm) δ 8.27-8.24 (m, 1H), 8.16-8.13 (m, 1H), 7.54-7.56 (m, 1H), 7.51 (s, 1H), 7.17-7.15 (m, 1H), 4.28-4.24 (m, 2H), 3.67 (t, J=11.2 Hz, 2H), 3.53 (s, 3H), 3.50-3.46 (m, 1H), 2.40 (s, 3H), 2.30-2.28 (m, 2H), 2.16-2.08 (m, 2H).

Example 4 Synthesis of Compound 4

Step 1: To a solution of 4-1 (2.5 g, 10.37 mmol) in dioxane (20 mL) was added Cs₂CO₃ (6.8 g, 20.75 mmol), Pd₂(dba)₃ (0.9 g, 1.04 mmol), BINAP (1.3 g, 2.08 mmol) and tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate (2.64 g, 12.45 mmol). The resulting mixture was degassed for 10 minutes, then stirred for 4 h at 120° C. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 3/1) to afford 4-2.

Step 2: To a solution of 4-2 (2.9 g, 7.8 mmol) in dichloromethane (20 mL) was added TFA (5 mL, 805.6 mmol). Then the reaction mixture was stirred at 25° C. for 3 h. The pH was adjusted to 6 by aqueous solution of NaHCO₃ and the mixture was extracted with ethyl acetate. The organic layer was dried over Na₂SO₄, filtered and concentrated to afford 4-3.

Step 3: Compound 4-4 was prepared from compound 4-3 following the procedure for the synthesis of compound 1-10 in example 1.

Step 4: Compound 4 was prepared as a 0.33 eq of TFA salt from compound 4-4 following the procedure for the synthesis of compound 1 in example 1. LCMS (ESI, m/z): [M+H]⁺=481.2; ¹H NMR (400 MHz, DMSO-d₆, ppm) δ 8.24-8.22 (m, 1H), 8.08-8.05 (m, 1H), 7.16-7.13 (m, 2H), 6.49-6.47 (m, 2H), 4.40 (s, 2H), 4.24 (t, J=6.7 Hz, 2H), 3.87-3.81 (m, 4H), 3.49 (s, 3H), 2.24 (t, J=6.9 Hz, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆, ppm) 6-57.34 (3F), −73.62 (1F, TFA).

Example 5 Synthesis of Compound 5

Step 1: To a solution of 5-1 (46 g, 250.6 mmol) in con. HCl (170 mL) and EtOH (510 mL) was added Fe powder (42.0 g, 751.8 mmol) at 40 in portions. Then the mixture was stirred at 80 for 1 h. The mixture was filtered and the filtrate was concentrated. The pH of the mixture was adjusted to 8 with ammonia. Then the mixture was filtered and the filtrate was extracted with ethyl acetate. The combined organic layers were dried over Na₂SO₄, filtered and the filtrate was concentrated to afford 5-2.

Step 2: To a solution of 5-2 (36 g, crude) in THF (400 mL) was added pyridine (56.6 mL, 703.3 mmol), DMAP (2.9 g, 23.4 mmol) and TFAA (73.9 g, 351.6 mmol) at 0 slowly. Then the mixture was stirred at room temperature for 0.5 h. The mixture was concentrated. H₂O was added to the residue. The mixture was extracted with ethyl acetate. The combined organic layers were dried over Na₂SO₄, filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 2/1) to afford 5-3.

Step 3: To a solution of 5-3 (47 g, 188.3 mmol) in DMF (450 mL) was added K₂CO₃ (78.1 g, 565 mmol) and CH₃I (35.2 mL, 565 mmol) at room temperature. The mixture was stirred at room temperature for 12 h, then quenched with H₂O. The mixture was extracted with ethyl acetate. The combined organic layers were dried over Na₂SO₄, filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 2/1) to afford 5-4.

Step 4: To a mixture of 5-4 (49.0 g, 175.4 mmol) and K₂CO₃ (72.7 g, 526.3 mmol) in DMSO (500 mL) was added H₂O₂ (30%, 59.7 g, 526.3 mmol) at 0 slowly. The mixture was stirred at room temperature for 2 h. H₂O was added to the mixture, the mixture was extracted with ethyl acetate. The combined organic layers were dried over Na₂SO₄, filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 2/1) to afford 5-5.

Step 5: To a solution of 5-5 (27 g, 87.3 mmol) in DMF (300 mL) was added NaH (60%, 7.0 g, 174.6 mmol) at 0 in portions. After the mixture was stirred at 0 for 1 h, CDI (21.2 g, 130.9 mmol) was added to the reaction mixture. Then the mixture was stirred at 70 for 2 h. The solid was collected by filtration and washed with ethyl acetate and methanol to afford 5-6.

Step 6: To a solution of 5-6 (1.5 g, 7.09 mmol) in toluene (15 mL) were added POCl₃ (5.27 mL, 56.71 mmol) and DIPEA (2.93 mL, 17.72 mmol) at room temperature. Then the mixture was stirred at 110 for 12 h. The mixture was concentrated to afford 5-7 which was used for the next step directly without further purification.

Step 7: To a solution of 5-7 (crude, 1.2 g) and DIPEA (2.5 mL, 15.1 mmol) in acetonitrile (10 mL) was added 2-3 (500 mg, 1.68 mmol) at room temperature. Then the mixture was stirred at 80 for 1 h. The mixture was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 1/4) to afford 5-8.

Step 8: To a solution of 5-8 (98 mg, 0.22 mmol) in NMP (6 mL) were added dppf (11.9 mg, 0.022 mmol), Zn (5.6 mg, 0.088 mmol), Zn(CN)₂ (50.6 mg, 0.43 mmol) and Pd₂(dba)₃ (19.7 mg, 0.022 mmol) at room temperature. Then the mixture was stirred at 90 for 3 h. The mixture was quenched with H₂O and extracted with ethyl acetate. The combined organic layers were dried over Na₂SO₄, filtered and the filtrate was concentrated under vacuum. The residue was purified by reverse phase HPLC (acetonitrile/0.05% TFA in water: 5%-90%) to afford 5 as a 0.4 eq of TFA salt. LCMS (ESI, m/z): [M+H]⁺=446.4; ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 8.26 (d, J=9.2 Hz, 1H), 8.02 (d, J=9.2 Hz, 1H), 7.35-7.26 (m, 2H), 7.18-7.06 (m, 2H), 4.82-4.71 (m, 1H), 3.96-3.79 (m, 4H), 3.46 (s, 3H), 2.20-2.05 (m, 2H), 1.86-1.70 (m, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆, ppm): δ −57.23 (3F), −74.35 (1.2F, TFA).

Example 6 Synthesis of Compound 12

Step 1: To a solution of 12-1 (7.4 g, 34 mmol) in DMSO (100 mL) was added 4-bromo-1H-pyrazole (5.0 g, 34 mmol), K₃PO₄ (21.7 g, 102 mmol), CuO (0.2 g, 1.7 mmol) and N₁,N₂-bis(furan-2-ylmethyl)oxalamide (0.4 g, 1.7 mmol). The reaction mixture was degassed with nitrogen 3 times, then the reaction mixture was stirred for 14 h at 120 . The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 5/1) to afford 12-2.

Step 2: To a solution of tert-butyl 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (4.7 g, 15.2 mmol) in dioxane (60 mL) was added 12-2 (3 g, 12.7 mmol) and K₂CO₃ (5.2 g, 38 mmol). The reaction mixture was degassed with nitrogen 3 times, then Pd(dppf)Cl₂ (0.9 g, 1.27 mmol) and H₂O (20 mL) were added to the reaction mixture. The reaction mixture was stirred for 14 h at 80 . The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 5/1) to afford 12-3.

Step 3: To a solution of 12-3 (973 mg, 2.9 mmol) in dichloromethane (10 mL) was added Pd/C (10%, 97.6 mg). The reaction mixture was degassed with H₂ 3 times. The reaction mixture was stirred at room temperature for 14 h under H₂ atmosphere. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 5/11) to afford 12-4.

Step 4: To a solution of 12-4 (826 mg, 2.4 mmol) in dichloromethane (5 mL) was added HCl in ethyl acetate (4M, 5 mL, 20 mmol) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to afford 12-5 which was used for the next step directly without further purification.

Compound 12 was prepared from compound 12-5 following the procedure for the synthesis of compound 5 in example 5. LCMS (ESI, m/z): [M+H]⁺=426.2; ¹H NMR (400 MHz, methanol-d₄, ppm) δ 8.11 (d, J=8.9 Hz, 1H), 8.03 (d, J=8.9 Hz, 1H), 7.74 (s, 1H), 7.68 (s, 1H), 7.39-7.36 (m, 2H), 7.33-7.30 (m, 2H), 3.61 (s, 3H), 3.36-3.34 (m, 2H), 3.32-3.29 (m, 2H), 3.17-3.11 (m, 1H), 2.28-2.21 (m, 2H), 2.20 (s, 3H), 1.94-1.81 (m, 2H).

Example 7 Synthesis of Compounds 16 and 17

Step 1: To a solution of 16-1 (1.9 g, 8.36 mmol) in methanol (12 mL) was added NaBH₄ (0.2 g, 10.87 mmol) at 0 . The mixture was stirred at 20 for 16 h. The mixture was quenched with water and concentrated. The reside was diluted with H₂O and extracted with ethyl acetate. The combined organic layers were dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 2/1) to afford 16-2 and 16-3.

Step 2: To a solution of 16-2 (604 mg, 2.63 mmol), 16-4 (563 mg, 3.16 mmol) and PPh₃ (1.04 g, 3.95 mmol) in toluene (6 mL) was added DIAD (0.78 mL, 3.95 mmol) at 0 under N₂. The mixture was stirred at 110 under N₂ for 5 h. The mixture was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 5/1) to afford 16-5.

Step 3: To a solution of 16-5 (923 mg, 2.37 mmol) in dichloromethane (5 mL) was added HCl in ethyl acetate (4M, 2.37 mL, 9.5 mmol) at 25. The mixture was stirred at 25 for 3 h. The mixture was concentrated to afford 16-6 which was used for the next step directly without further purification.

Step 4: Compound 16-7 was prepared from compound 16-6 following the procedure for the synthesis of compound 5 in example 5.

Step 5: 16-7 (70 mg) was purified by SFC (column: DAICELCHIRALCEL®OZ, methanol (+0.10% 7.0 mol/1 Ammonia in methanol)/Supercritical CO₂=40/60) to afford 16 (31.8 mg) and 17 (7.02 mg). respectively. 16: SFC analysis: 99.52% ee; retention time: 1.87 min; column: DAICELCHIRALPAK®OZ, methanol (0.1% DEA) in CO₂, 40%; pressure: 1800 psi; flow rate: 1.5 mL/min. LCMS (ESI, m/z): [M+H]⁺=474.2; ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 8.28-8.23 (m, 1H), 8.04-7.99 (m, 1H), 7.33-7.29 (m, 2H), 7.11-7.07 (m, 2H), 4.85-4.77 (m, 1H), 3.47-3.43 (m, 4H), 3.37-3.29 (m, 2H), 2.17-2.02 (m, 3H), 2.01-1.89 (m, 3H), 0.87-0.79 (m, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆, ppm): δ −57.23 (3F). 17: SFC analysis: 96.6% ee; retention time: 2.14 min; column: DAICELCHIRALPAK®OZ, methanol (0.1% DEA) in CO₂, 40%; pressure: 1800 psi; flow rate: 1.5 mL/min. LCMS (ESI, m/z): [M+H]+=474.2; ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 8.23-8.17 (m, 1H), 7.99-7.92 (m, 1H), 7.30 7.22 (m, 2H), 7.10-6.98 (m, 2H), 4.81-4.71 (m, 1H), 3.40 (s, 3H), 3.34-3.32 (m, 3H), 2.13-1.83 (m, 6H1), 0.83-0.73 (m, 3H1). ¹⁹F NMR (376 MHz, DMSO-d₆, ppm): δ −57.23 (3F).

Example 8 Synthesis of Compound 21

Step 1: Compound 21-1 was prepared from compound 2-3 following the procedure for the synthesis of compound 5-8 in example 5.

Step 2: To a mixture of 21-1 (730 mg, 1.61 mmol) and (tert-butoxy)carbohydrazide (640 mg, 4.8 mmol) in dioxane (10 mL) were added Pd₂(dba)₃ (147.0 mg, 0.16 mmol), Cs₂CO₃ (1.57 g, 4.8 mmol) and t-BuBrettPhos (77.8 mg, 0.16 mmol) at room temperature. Then the mixture was stirred at 80 for 1 h. This mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (dichloromethane/methanol=1/0 to 10/1) to afford 21-2.

Step 3: To a solution of 21-2 (310 mg, 0.56 mmol) in methanol (5 mL) was added HCl in ethyl acetate (4M, 3 mL) at room temperature. Then the mixture was stirred at room temperature for 0.5 h. The mixture was concentrated to afford 21-3.

Step 4: To a solution of 21-3 (250 mg, crude) in methanol (6 mL) was added CH(OCH₃)₃ (3 mL, 0.56 mmol) at room temperature. Then the mixture was heated at 100 for 12 h. The mixture was concentrated. The residue was purified by column chromatography on silica gel (dichloromethane/methanol=1/0 to 10/1) to afford 21. LCMS (ESI, m/z): [M+H]⁺=461.4; ¹H NMR (400 MHz, DMSO-d₆, ppm) δ 9.49 (d, J=3.3 Hz, 1H), 8.26 (d, J=10.1 Hz, 1H), 7.77 (d, J=10.1 Hz, 1H), 7.33-7.26 (m, 2H), 7.15-7.08 (m, 2H), 4.73-4.65 (m, 1H), 3.68-3.50 (m, 5H), 3.44-3.36 (m, 1H), 3.29-3.22 (m, 1H), 2.17-1.87 (m, 3H), 1.78-1.65 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆, ppm): δ −57.23 (3F).

Example 9 Synthesis of Compounds 23, 24 and 25

Step 1: To a solution of LDA (2M in THF, 1.57 mL, 3.15 mmol) in THF (20 mL) was added dropwise 23-1 (550 mg, 2.42 mmol) at −68° C. After 30 minutes, a solution of 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonylmethanesulfonamide (864.44 mg, 2.42 mmol) in THF (5 mL) was added. The reaction mixture was stirred at room temperature for 16 h. The mixture was quenched with saturated NH₄Cl and extracted with ethyl acetate. The combined organic layers were dried over Na₂SO₄, filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 1/1) to afford 23-2.

Step 2: To a solution of 12-2 (1.0 g, 4.22 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.39 g, 5.48 mmol) in dioxane (20 mL) was added KOAc (0.8 g, 8.44 mmol) and Pd(dppf)Cl₂ (0.3 g, 0.42 mmol). The mixture was stirred at 100° C. for 16 h under N₂ atmosphere. The mixture was quenched with H₂O and extracted with ethyl acetate. The combined organic layers were dried over Na₂SO₄, filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 1/1) to afford 23-3.

Step 3: To a solution of 23-2 (500 mg, 1.39 mmol), 23-3 (395.4 mg, 1.39 mmol) in dioxane (20 mL) and H₂O (5 mL) was added Pd(dppf)Cl₂ (113.6 mg, 0.14 mmol) and Na₂CO₃ (295 mg, 2.78 mmol). The mixture was stirred at 90° C. for 16 h under N₂ atmosphere. The mixture was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 1/1) to afford 23-4.

Step 4: To a solution of 23-4 (310 mg, 0.84 mmol) in methanol (10 mL) was added 10% Pd/C (179.5 mg). The mixture was degassed with H₂ several times. Then the mixture was stirred at 25° C. under H₂ atmosphere (1 atm) for 16 h. The mixture was filtered and the filtrate was concentrated to afford 23-5 which was used for the next step directly without further purification.

Step 5: To a solution of 23-5 (240 mg, crude) in dichloromethane (4 mL) was added TFA (1 mL). The mixture was stirred at 25° C. for 1 h. The mixture was concentrated to afford 23-6 which was used for the next step directly without further purification.

Step 6: Compound 23-7 was prepared from compound 23-6 following the procedure for the synthesis of compound 5 in example 5.

Step 7: 23-7 (120 mg, 0.26 mmol) was purified by prep-SFC (column: DAICELCHIRALCEL®AS, methanol (+0.1% 7.0 mol/1 Ammonia in methanol)/Supercritical CO₂=40/60) to afford 23 (25.05 mg), 24 (3.11 mg) and 25 (9.99 mg). 23: SFC analysis: retention time: 1.795 min; column: DAICELCHIRALPAK®AS, methanol (0.1% of DEA) in CO₂, 40%; pressure: 1800 psi; flow rate: 1.5 mL/min; LCMS (ESI, m/z): [M+H]⁺=454.4, ¹H NMR (400 MHz, methanol-d₄, ppm): δ 8.13-8.06 (m, 1H), 8.06-7.98 (m, 1H), 7.76-7.69 (m, 1H), 7.69-7.63 (m, 1H), 7.39-7.33 (m, 2H), 7.33-7.25 (m, 2H), 6.12-5.00 (m, 2H), 3.72-3.35 (m, 4H), 3.00-2.48 (m, 1H), 2.35-1.69 (m, 9H), 1.16-0.94 (m, 3H). 24: SFC analysis: 99.76% de; retention time: 2.300 min; column: DAICELCHIRALPAK®AS, methanol (0.1% of DEA) in CO₂, 40%; pressure: 1800 psi; flow rate: 1.5 mL/min; LCMS (ESI, m/z): [M+H]⁺=454.4, ¹H NMR (400 MHz, methanol-d4, ppm): δ 8.16-8.05 (m, 1H), 8.05-7.96 (m, 1H), 7.70 (s, 1H), 7.65 (s, 1H), 7.39-7.33 (m, 2H), 7.33-7.25 (m, 2H), 6.05-5.03 (m, 2H), 3.58 (s, 3H), 3.36 (s, 1H), 2.28-2.10 (m, 6H), 2.11-1.99 (m, 1H), 1.95-1.86 (m, 1H), 1.85-1.72 (m, 1H), 1.36-1.27 (m, 1H), 1.11-0.97 (m, 3H). 25: SFC analysis: 100% de; retention time: 2.422 min; column: DAICELCHIRALPAK®AS, methanol (0.1% of DEA) in CO₂, 40%; pressure: 1800 psi; flow rate: 1.5 mL/min; LCMS (ESI, m/z): [M+H]⁺=454.4, ¹H NMR (400 MHz, methanol-d4, ppm): δ 8.19-8.06 (m, 1H), 8.05-7.96 (m, 1H), 7.75-7.70 (m, 1H), 7.67 (s, 1H), 7.40-7.34 (m, 2H), 7.34-7.27 (m, 2H), 5.17 (s, 2H), 3.61-3.55 (m, 3H), 3.55-3.44 (m, 1H), 3.00-2.81 (m, 1H), 2.65-2.51 (m, 1H), 2.36-2.22 (m, 1H), 2.22-2.16 (m, 3H), 2.14-1.98 (m, 1H), 2.01-1.85 (m, 2H), 1.78 (s, 1H), 1.13-0.97 (m, 3H).

Example 10 Synthesis of Compounds 26 and 27

Step 1: To a mixture of 26-1 (10 g, 46.29 mmol) and potassium trifluoro(vinyl)borate (7.44 g, 55.55 mmol) in THF (160 mL) and H₂O (40 mL) was added 1,1′-bis (di-t-butylphosphino)ferrocene palladium dichloride (3.0 g, 4.63 mmol) and K₃PO₄ (24.6 g, 115.73 mmol) under N₂. Then the mixture was stirred at room temperature for 16 h.

The mixture quenched by addition of water. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=5/1) to afford 26-2.

Step 2: To a mixture of methyl 26-2 (7.8 g, 47.8 mmol) in AcOH (100 mL) was added PtO₂ (2.2 g, 9.56 mmol). The mixture was degassed with H₂ several times, then the mixture was stirred at 80 for 16 h under H₂ (1 atm) atmosphere. The mixture was filtered and the filtrate was concentrated to afford 26-3 which was used for the next step directly without further purification.

Step 3: To a mixture of 26-3 (8 g, 46.72 mmol) in THF (80 mL) and H₂O (80 mL) was added NaHCO₃ (39.2 g, 467.18 mmol) and (Boc)₂O (21.47 mL, 93.44 mmol). Then the mixture was stirred at room temperature for 3 h. The mixture quenched by addition of water, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=5/1) to afford 26-4.

Step 4: To a mixture of 26-4 (9.6 g, 35.38 mmol) in THF (60 mL) and H₂O (60 mL) was added LiOH (7.4 g, 176.89 mmol). Then the mixture was stirred at room temperature for 16 h. The pH of mixture was adjusted to 4 with 1N HCl and the aqueous layer was extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over anhydrous Na₂SO₄ and concentrated to afford 26-5 which was used for the next step directly without further purification.

Step 5: A mixture of 26-5 (4.55 g, crude) and PPA (100 mL) was stirred at 180 for 2 h. After being cooled to 90° C., the reaction was quenched by water. The filtrate was adjusted pH to about 12 with 50% potassium hydroxide aqueous solution and then extracted with methylene chloride. The organic layer was dried by Na₂SO₄, filtered and concentrated to afford 26-6 which was used for the next step directly without further purification.

Step 6: Compound 26-7 was prepared from compound 26-6 following the procedure for the synthesis of compound 5 in example 5.

Step 7: 26-7 (150 mg, 0.35 mmol) was separated by reverse phase HPLC (acetonitrile/H₂O, 5-95%) to afford 26 (24.47 mg) and 27 (54.71 mg). 26: Analytical HPLC: retention time: 1.85 min; column: Waters ACQUITY BEH C18 2.1*50 mm, 1.7 um; Mobile phase A: H₂O (0.05% TFA); Mobile phase B: Acetonitrile (0.05% TFA); flow rate: 1.0 mL/min; Run time: 5 min; 95 to 5% A in 3 min, 5% A for 2 min. LCMS (ESI, m/z): [M+H]⁺=429.4; ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 8.27-8.23 (m, 1H), 8.01 (d, J=9.2 Hz, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.47 (s, 1H), 7.18-7.15 (m, 1H), 5.77-5.44 (m, 1H), 5.34-4.80 (m, 1H), 3.68-3.61 (m, 2H), 3.45 (s, 3H), 2.40 (s, 3H), 2.29-2.16 (m, 2H), 2.05-1.78 (m, 4H), 1.00-0.89 (m, 3H). 27: Analytical HPLC: retention time: 1.85 min; column: Waters ACQUITY BEH C18 2.1*50 mm, 1.7 um; Mobile phase A: H₂O (0.05% TFA); Mobile phase B: Acetonitrile (0.05% TFA); flow rate: 1.0 mL/min; Run time: 5 min; 95 to 5% A in 3 min, 5% A for 2 min. LCMS (ESI, m/z): [M+H]⁺=429.4; ¹H NMR (400 MHz, DMSO-d(, ppm): δ 8.26 (d, J=8.8 Hz, 1H), 8.00 (d, J=9.2 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.47 (s, 1H), 7.18-7.15 (m, 1H), 5.37-4.81 (m, 2H), 3.49-3.46 (m, 2H), 3.45 (s, 3H), 2.42 (s, 3H), 2.37-2.25 (m, 3H), 2.24-2.15 (m, 1H), 1.79-1.64 (m, 11H), 1.53-1.45 (m, 1H), 0.92-0.81 (m, 3H).

Example 11 Synthesis of Compounds 28 and 29

Step 1: A solution of 28-1 (4.5 g, 19.38 mmol) in THF (30 mL) at −30 was added C₂H₅MgBr (29.07 mL, 29.07 mmol, 1M in THF). The mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated aqueous ammonium chloride. The organic phase was separated, dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=4/1) to afford 28-2.

Step 2: To a solution of 28-2 (1 g, 3.81 mmol) in dichloromethane (10 mL) at 0 was added DMF (0.029 mL, 0.38 mmol) and SOCl₂ (0.42 mL, 5.72 mmol). The reaction was stirred at room temperature for 18 h. The reaction mixture was concentrated, and the residue was purified by column chromatography on silica gel (petroleum ether) to afford 28-3.

Step 3: To a stirred solution of 28-4 (100 g, 651 mmol) in dry CH₂Cl₂ (1.5 L) were added benzaldehyde (67.5 mL, 664 mmol), K₂CO₃ (90.0 g, 651 mmol) and Na₂SO₄ (92.5 g, 651 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was cooled with an ice water bath and NaBH(OAc)₃ (207.0 g, 976 mmol) was added in portions over 30 minutes. Then the mixture was stirred at room temperature for 16 h. The solid was filtered and the filtration was concentrated. The residue was washed with 1 N HCl and extracted with ethyl acetate. The aqueous layer was adjusted to pH=8.0 with NaHCO₃. Then the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated to afford 28-5 which was used in the next step directly without further purification.

Step 4: To a solution of (2R)-2-{[(tert-butoxy)carbonyl]amino}butanoic acid (124 g, crude) in DMF (1 L) were added DIPEA (137 mL, 832 mmol) and HATU (253 g, 666 mmol). The reaction was stirred at 0 for 10 minutes, then 28-5 (115 g, 555 mmol) was added to the mixture. The resulting mixture was stirred for 16 h at room temperature. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous Na₂SO₄, filtered and evaporated to afford 28-6 which was used for next step directly without further purification.

Step 5: To a solution of 28-6 (300 g, crude) in dichloromethane (1 L) was added TFA (500 mL, 764 mmol), the reaction was stirred at room temperature for 16 h. The solvent was removed to afford 28-7 which was used for next step directly without further purification.

Step 6: 28-7 (500 g, crude) was dissolved in methanol (1.5 L) and the reaction mixture was heated at 70 for 16 h. The solvent was removed, the residue was dissolved in dichloromethane and washed with saturated aqueous NaHCO₃ solution. The combined organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was dissolved in propan-2-ol (500 mL) and heated at 70 for 1 h. The mixture was filtered, the solution was cooled to −10, the solid was filtered and dried to afford 28-8.

Step 7: To a stirred solution of 28-8 (20 g, 76.82 mmol) in dry THF (500 mL) was slowly added BH₃·THF (1M, 768 mL, 768 mmol) at 0 . The reaction mixture heated at 70 for 16 h. The reaction was quenched with methanol and 1.5 N HCl. The solvent was removed, the residue was dissolved in dichloromethane and washed with saturated aqueous NaHCO₃ solution. The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated to afford 28-9 which was used in the next step directly.

Step 8: To a stirred solution of 28-9 (23 g, crude) in THF (100 mL) and H₂O (100 mL) was added NaHCO₃ (16.6 g, 198 mmol) and (Boc)₂O (34.1 mL, 148.5 mmol). The reaction mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate and washed with water and brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=20/1 to 10/1) to afford 28-10.

Step 9: To a stirred solution of 28-10 (20 g, 60.15 mmol) in ethanol (200 mL) was added Pd/C (10%, 10 g). The reaction mixture was stirred under H₂ atmosphere for 18 h at room temperature. The reaction mixture was filtered, the solvent was removed. The residue was purified by column chromatography on silica gel (dichloromethane/methanol=1/0 to 10/1) to afford 28-11.

Step 10: To a solution of 5-7 (1.63 g, crude) and DIPEA (7 mL, 42.5 mmol) in acetonitrile (40 mL) was added 28-11 (1.37 g, 5.66 mmol) at room temperature and the mixture was stirred at 80 for 1 h. Then the mixture was concentrated, the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 1/4) to afford 28-12.

Step 11: To a solution of 28-12 (800 mg, 1.84 mmol) in NMP (8 mL) was added dppf (207.2 mg, 0.37 mmol), Zn (120.0 mg, 1.84 mmol), Zn(CN)₂ (431.0 mg, 3.67 mmol) and Pd₂(dba)₃ (168.0 mg, 0.18 mmol) at room temperature. Then the mixture was heated at 90 for 12 h. The mixture was quenched with H₂O and extracted with ethyl acetate. The combined organic layers were dried over Na₂SO₄, filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 1/4) to afford 28-13.

Step 12: To a solution of 28-13 (570 mg, 1.34 mmol) in dichloromethane (5 mL) was added TFA (2 mL, 1.34 mmol) at room temperature. Then the mixture was stirred at room temperature for 1 h. The mixture was concentrated to 28-14 which was used in the next step directly without further purification.

Step 13: The mixture of 28-14 (220 mg, 0.67 mmol), 28-3 (283.8 mg, 1.01 mmol), DIPEA (1.11 mL, 6.74 mmol) and NaI (151.5 mg, 1.01 mmol) in acetonitrile (10 mL) was stirred at 90° C. for 24 h. The solvent was removed, and the residue was purified by Reverse phase HPLC (acetonitrile with 0.05% of TFA in water: 10% to 70%) to afford 28-15.

Step 14: 28-15 (170 mg) was purified by SFC (column: DAICELCHIRALPAK®IG, methanol (+0.10% 7.0 mol/l Ammonia in methanol)/Supercritical CO₂=40/60) to afford 28 (28 mg) and 29 (18 mg) respectively. 28: SFC analysis: 96.44% de; retention time: 4.29 min; column: DAICELCHIRALPAK®IB, methanol (0.1% of DEA) in CO₂, 5% to 40%; pressure: 1800 psi; flow rate: 1.5 mL/min. LCMS (ESI, m/z): [M+H]⁺=571.5. ¹H NMR (400 MHz, DMSO-d₆, ppm) δ 8.23 (d, J=8.32 Hz, 1H), 7.98 (d, J=8.86 Hz, 1H), 7.89 (d, J=8.52 Hz, 2H), 7.56 (d, J=6.04 Hz, 2H), 5.85-5.47 (m, 1H), 4.97-4.85 (m, 1H), 3.71-3.62 (m, 1H), 3.66 (s, 3H), 3.09 (d, J=12.24 Hz, 1H), 2.93-2.76 (m, 2H), 2.44-2.24 (m, 1H), 2.22-2.06 (m, 1H), 2.05-1.80 (m, 3H), 1.62-1.54 (m, 1H), 1.53-1.39 (m, 1H), 0.97-0.91 (m, 3H), 0.70-0.52 (m, 6H); ¹⁹F NMR (376 MHz, DMSO-de, ppm): δ 87.99 (1F), 64.42 (4F) 29: SFC analysis: 97.86% de; retention time: 4.44 min; column: DAICELCHIRALPAK®IB, methanol (0.1% of DEA) in CO₂, 5% to 40%; pressure: 1800 psi; flow rate: 1.5 mL/min. LCMS (ESI, m/z): [M+H]⁺=571.5. ¹H NMR (400 MHz, DMSO-de, ppm): δ 8.27-8.19 (m, 1H), 8.01-7.95 (m, 1H), 7.87 (d, J=7.88 Hz, 2H), 7.58 (d, J=8.28 Hz, 2H), 6.05-5.28 (m, 1H), 5.09-4.75 (m, 1H), 3.64-3.50 (m, 2H), 3.43 (s, 3H), 3.18-3.07 (m, 1H), 2.21-2.12 (m, 1H), 2.04-1.95 (m, 1H), 1.83-1.39 (m, 6H), 1.00-0.91 (m, 3H), 0.65-0.54 (m, 6H). ¹⁹F NMR (376 MHz, DMSO-d₆, ppm): δ 88.00 (1F), 64.37 (4F).

Example 12 Synthesis of Compound 30

Step 1: To a solution of 30-1 (5 g, 26.3 mmol) and NaOH (1.6 g, 39.5 mmol) in EtOH (30 mL) and H₂O (15 mL) was added hydroxylamine hydrochloride (2.2 g, 31.6 mmol) at 25. The mixture was stirred at 25 for 16 h. Ice was added to the reaction mixture, the solid was filtered, the filter cake was washed with H₂O and dried to afford 30-2.

Step 2: A solution of 30-2 (1.6 g, 7.8 mmol) and NCS (1.1 g, 8.6 mmol) in DMF (15 mL) was stirred at 25 for 16 h. The mixture was concentrated, the residue was diluted with ethyl acetate, washed with H₂O. The organic layer was dried over Na₂SO₄, filtered and concentrated to afford 30-3.

Step 3: To a solution of 30-3 (800 mg, 3.3 mmol) and tert-butyl 3-ethylidenepyrrolidine-1-carboxylate (795.5 mg, 4.3 mmol) in THF (20 mL) was added triethylamine (0.93 mL, 6.7 mmol) at 25 . The mixture was stirred at 25 for 4 h. The mixture was concentrated, the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 4/1) to afford 30-4.

Step 4: To a solution of 30-4 (300 mg, 0.78 mmol) in dichloromethane (5 mL) was added HCl (4 M in ethyl acetate, 2.0 mL) at 25. The mixture was stirred at 25 for 2 h. The mixture was concentrated to afford 30-5.

Step 5: Compound 30 was prepared from compound 30-5 following the procedure for the synthesis of compound 5 in example 5. LCMS (ESI, m/z): [M+H]⁺=471.2; ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 8.33-8.20 (m, 1H), 8.06-7.94 (m, 1H), 7.88-7.76 (m, 2H), 7.55-7.43 (m, 2H), 4.69-4.49 (m, 1H), 4.44-4.19 (m, 1H), 4.12-3.93 (m, 1H), 3.90-3.68 (m, 2H), 3.64-3.52 (m, 1H), 3.46 (s, 3H), 2.45-2.15 (m, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆, ppm): δ −56.74 (3F).

Example 13 Synthesis of Compounds 32 and 33

Step 1: To a solution of 32-1 (15 g, 99.25 mmol) in acetonitrile (100 mL) was added CH₃NH₂ (200 mL, 3.56 mmol, 40% in H₂O). Then the reaction mixture was stirred at 80° C. for 16 h. The reaction mixture was quenched with H₂O. The mixture was extracted with ethyl acetate. The combined organic layers were washed with H₂O. The organic layer was dried over Na₂SO₄, filtered and concentrated to afford 32-2.

Step 2: To a solution of 32-2 (8.2 g, 50.56 mmol) in acetonitrile (150 mL) was added NCS (7.4 g, 55.61 mmol), then the reaction mixture was stirred at 60° C. for 70 minutes. The mixture was quenched by addition of water. The aqueous layer was extracted with ethyl acetate. The organic layer was combined, washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 5/1) to afford 32-3.

Step 3: To a solution of 32-3 (5.0 g, 25.43 mmol) in DMSO (60 mL) were added K₂CO₃ (5.3 g, 38.14 mmol) and H₂O₂ (17.3 g, 30%, 152.6 mmol). Then the reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was quenched with H₂O. The mixture was extracted with ethyl acetate. The combined organic layers were washed with H₂O. The organic layer was dried over Na₂SO₄, filtered and the filtrate was concentrated to afford 32-4.

Step 4: To a stirred 0° C. solution of 32-4 (5 g, 23.29 mmol) in DMF (70 mL) was in portions added NaH (1.9 g, 46.59 mmol). After stirred at 0° C. for 0.5 h, CDI (5.7 g, 34.94 mmol) was added to the mixture, then the mixture was stirred at 60° C. for 16 h. The reaction mixture was quenched with H₂O. The mixture was extracted with ethyl acetate. The combined organic layer was washed with H₂O. The organic layer was dried by Na₂SO₄, filtered and the filtrate was concentrated to afford 32-5.

Step 5: To a solution of 32-5 (1 g, 4.16 mmol) in toluene (10 mL) was added DIPEA (1.2 g, 9.14 mmol) and POCl₃ (3.2 g, 20.78 mmol). The mixture was stirred at 90° C. for 3 h. The reaction mixture was concentrated to afford 32-6.

Step 6: A mixture of 32-6 (1.0 g, 3.86 mmol), 3-2 (1.00 g, 4.63 mmol) and DIPEA (7.5 g, 57.9 mmol) in propan-2-ol (15 mL) was stirred at 90° C. for 5 h. The mixture was cooled to room temperature. The precipitate was collected by filtration to afford 32-7.

Step 7: To a solution of 32-7 (1.0 g, 2.28 mmol) in dichloromethane (10 mL) under N₂ at −78 was added dropwise BBr₃ (5.7 g, 22.8 mmol). After the addition was completed, the mixture was stirred at room temperature for 16 h. Ice water was added to the reaction mixture and the precipitate was collected by filtration, washed with H₂O and dried to afford 32-8.

Step 8: To a mixture of 32-8 (300 mg, 0.71 mmol) in DMF (10 mL) were added Cs₂CO3 (690 mg, 2.12 mmol) and 3-bromooxolane (213.2 mg, 1.41 mmol). Then the mixture was stirred at 85° C. for 1 h. The solvent was removed under vacuum. The residue was purified by reverse phase HPLC (acetonitrile/H₂O: 5%-42%) to afford 32-9.

Step 9: 32-9 (100 mg) was purified by SFC (column: DAICELCHIRALPAK®IC, ETOH (+0.10% 7.0 mol/1 Ammonia in methanol) to afford 32 (14.80 mg) and 33 (15.23 mg) respectively. 32: SFC analysis: 100% ee; retention time: 9.164 min; column: DAICELCHIRALPAK®IC, ETOH (+0.1% 7.0 mol/l Ammonia in methanol) in CO₂, 40% to 60%; pressure: 100 bar; flow rate: 1.0 mL/min; LCMS (ESI, m/z): [M+H]⁺=495.4; ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 7.79 (s, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.50 (s, 1H), 7.20-7.16 (d, J=8.0 Hz, 1H), 6.91 (s, 1H), 5.44-5.42 (m, 1H), 4.22-4.15 (m, 2H), 4.05-3.95 (m, 1H), 3.95-3.78 (m, 3H), 3.51-3.49 (m, 3H), 3.49-3.38 (m, 2H), 2.41 (s, 3H), 2.39-2.30 (m, 2H), 2.22-2.18 (m, 2H), 2.09-1.94 (m, 3H). 33: SFC analysis: 98.89% cc; retention time: 10.858 min; column: DAICELCHIRALPAK®IC, ETOH (+0.1% 7.0 mol/l Ammonia in methanol) in CO₂, 40% to 60%; pressure: 100 bar; flow rate: 1.0 mL/min; LCMS (ESI, m/z): [M+H]⁺=495.4; ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 7.79 (s, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.50 (s, 1H), 7.20-7.16 (d, J=8.0 Hz, 1H), 6.91 (s, 1H), 5.44-5.41 (m, 1H), 4.23-4.15 (m, 2H), 4.01-3.95 (m, 1H), 3.91-3.86 (m, 2H), 3.83-3.78 (m, 1H), 3.51-3.49 (m, 3H), 3.41-3.95 (m, 2H), 2.41 (s, 3H), 2.39-2.30 (m, 2H), 2.22-2.18 (m, 2H), 2.07-1.96 (m, 3H).

Example 14 Synthesis of Compounds 34 and 35

Step 1: Compound 34-2 was prepared from compound 34-1 following the procedure for the synthesis of compound 28-3 in example 11.

Step 2: A mixture of 34-2 (3.2 g, 14.3 mmol), 28-9 (4.0 g, 17.2 mmol), K₂CO₃ (5.9 g, 43.0 mmol), NaI (0.2 g, 1.4 mmol) and TBAI (0.5 g, 1.4 mmol) in acetonitrile (80 mL) was stirred at 90 for 66 h. The reaction mixture was filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=3/1) to afford 34-3.

Step 3: To a stirred solution of 34-3 (450 mg, 1.1 mmol) in isopropanol (10 mL) was added Pd/C (10%, 45 mg) at 25. The mixture was degassed several times with H₂, then the mixture was stirred at 25 under H₂ for 21 h. The reaction mixture was filtered and the filtrate was concentrated to afford 34-4.

Step 4: To a mixture of 5-2 (1.0 g, 6.54 mmol) and K₂CO₃ (2.7 g, 19.54 mmol) in DMSO (10 mL) was added H₂O₂ (2.2 g, 19.54 mmol) at 0 slowly. Then the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=10/1 to 2/1) to afford 34-5.

Step 5: To a solution of 34-5 (5.0 g, 29.2 mmol) in NMP (100 mL) were added Zn (0.4 g, 5.84 mmol), Zn(CN)₂ (6.9 g, 58.4 mmol), dppf (1.0 g, 1.75 mmol) and Pd₂(dba)₃ (2.7 g, 2.92 mmol) under N₂. The reaction mixture was stirred at 120 for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=10/1 to 0/1) to afford 34-6.

Step 6: To a solution of 34-6 (0.5 g, 3.08 mmol) in dioxane (20 mL) was added triphosgene (457.5 mg, 1.54 mmol) under N₂. The reaction mixture was stirred at 100 for 3 h. The resulting mixture was cooled to room temperature, filtered and dried to afford 34-7.

Step 7: To a solution of 34-7 (255 mg, 1.36 mmol) in toluene (10 mL) were added POCl₃ (1.26 mL, 13.6 mmol) and DIPEA (0.67 mL, 4.06 mmol). The reaction mixture was stirred at 100 for 16 h. The reaction mixture was concentrated to afford 34-8 which was used for the next step directly without further purification.

Step 8: To a solution of 34-8 (300 mg, crude) in THF (10 mL) were added DIPEA (2.2 mL, 13.3 mmol) and 34-4 (437.8 mg, 1.33 mmol). The reaction mixture was stirred at 50 for 4 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=10/1 to 0/1) to afford 34-9.

Step 9: To a solution of 34-9 (240 mg, 0.46 mmol) in dioxane (15 mL) were added (tert-butoxy)carbohydrazide (184 mg, 1.39 mmol), Cs₂CO₃ (453.8 mg, 1.39 mmol), tBubrettphos (22.5 mg, 0.046 mmol) and Pd₂(dba)₃ (42.5 mg, 0.046 mmol). The reaction mixture was stirred at 80 for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=10/1 to 0/1) to afford 34-10.

Step 10: To a solution of 34-10 (240 mg, 0.39 mmol) in dichloromethane (6 mL) was added TFA (3 mL). The reaction mixture was stirred at 25 for 1 h. The mixture was concentrated to afford 34-11 which was used in the next step directly without further purification.

Step 11: A mixture of 34-11 (180 mg, crude) and CH(OCH₃)₃ (5 mL) was stirred at 80 for 1 h. The mixture was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=2/1 to 0/1) to afford 34-12.

Step 12: 34-12 (90 mg) was purified by SFC (column: DAICELCHIRALCEL®AD, EtOH (+0.10% 7.0 mol/l Ammonia in EtOH)/Supercritical CO₂=40/60) to afford 34 (31.64 mg) and 35 (8.09 mg) respectively. 34: SFC analysis: 100% de; retention time: 4.35 min; column: DAICELCHIRALPAK®AD, EtOH (0.1% DEA) in CO₂, 5% to 40%; pressure: 1800 psi; flow rate: 1.5 mL/min. LCMS (ESI, m/z): [M+H]⁺=523.5. ¹H NMR (400 MHz, methanol-d₄, ppm): δ 9.32 (s, 1H), 8.77-8.75 (m, 1H), 8.31-8.29 (m, 1H), 7.69-7.67 (m, 2H), 7.67-7.55 (m, 2H), 5.96-5.53 (m, 1H), 3.68-3.65 (m, 1H), 3.48-3.39 (m, 2H), 3.12-3.05 (m, 1H), 2.96-2.92 (m, 1H), 2.46 (s, 1H), 2.23 (s, 1H), 2.06-2.00 (m, 2H), 1.73-1.65 (m, 1H), 1.58-1.53 (m, 2H), 1.09-1.06 (m, 3H), 0.78-0.69 (m, 6H). ¹⁹F NMR (376 MHz, methanol-d₄, ppm): δ −63.83 (3F). 35: SFC analysis: 97.18% de; retention time: 4.94 min; column: DAICELCHIRALPAK®AD, EtOH (0.1% DEA) in CO₂, 5% to 40%; pressure: 1800 psi; flow rate: 1.5 mL/min. LCMS (ESI, m/z): [M+H]⁺=523.5. ¹H NMR (400 MHz, methanol-d₄, ppm): δ 9.32 (s, 1H), 8.77-8.75 (m, 1H), 8.30-8.28 (m, 1H), 7.65-7.63 (m, 2H), 7.60-7.58 (m, 2H), 5.32 (s, 1H), 3.66-3.47 (m, 3H), 2.70-2.66 (m, 1H), 2.37-2.33 (m, 1H), 2.20-2.16 (m, 1H), 2.07-1.90 (m, 3H), 1.70-1.56 (m, 3H), 1.13-1.03 (m, 3H1), 0.71-0.65 (m, 6H1). ¹⁹F NMR (376 MHz, methanol-d₄, ppm): δ −63.82 (3F).

Example 15 Synthesis of Compounds 36 and 37

Step 1: A mixture of LiAlH₄ (0.30 g, 8.2 mmol) in THF (20 mL) was stirred at 0 under N₂ for 0.5 h. Then 36-1 (1 g, 4.1 mmol) was added and the mixture was stirred at 25 for 16 h. The mixture was diluted with THF, quenched with saturated Na₂SO₄ (1.5 mL) and filtered. The filtrate was concentrated to afford 36-2 which was used for the next step directly without further purification.

Step 2: A solution of 36-2 (700 mg, crude), 4-(trifluoromethoxy)benzoic acid (626.5 mg, 3.04 mmol), HATU (1733.5 mg, 4.56 mmol) and DIPEA(0.75 mL, 4.56 mmol) in DMF (12 mL) was stirred at 25 for 3 h. The mixture was diluted with H₂O and extracted with ethyl acetate. The organic phase was washed with H₂O and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 2/1) to afford 36-3.

Step 3: To a solution of 36-3 (580 mg, 1.39 mmol) in dichloromethane (8 mL) was added DAST (0.28 mL, 2.08 mmol) at 0. Then the mixture was stirred at 20 for 1 h. The mixture was quenched with NaHCO₃ aqueous, extracted with dichloromethane. The organic phase was concentrated, the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 3/1) to afford 36-4.

Step 4: To a solution of 36-4 (588 mg, 1.47 mmol) in dichloromethane (6 mL) was added HCl in ethyl acetate (4M, 2.5 mL) at 20. The mixture was stirred at 20 for 1.5 h. The mixture was concentrated under reduced pressure to afford 36-5.

Step 5: A solution of 5-7 (250 mg, 0.87 mmol), 36-5 (208.9 mg, 0.67 mmol) and DIPEA (1.50 mL, 9.1 mmol) in acetonitrile (10 mL) was stirred at 85 for 3 h under N₂. The mixture was concentrated. The residue was dissolved in ethyl acetate and washed with H₂O. The organic phase was concentrated. The residue was purified by reverse phase HPLC (acetonitrile/H₂O: 5%-80%) to afford 37. LCMS (ESI, m/z): [M+H]⁺=494.2. ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 8.28-8.23 (m, 1H), 8.09-7.92 (m, 3H), 7.55-7.42 (m, 2H), 4.75-3.90 (m, 6H), 3.46 (s, 3H), 1.98-1.78 (m, 4H). ¹⁹F NMR (376 MHz, DMSO-d₆, ppm): δ −56.68 (3F).

Step 6: A solution of 37 (100 mg, 0.20 mmol), dppf (22.5 mg, 0.040 mmol), Zn (13.2 mg, 0.20 mmol), Zn(CN)₂ (47.6 mg, 0.41 mmol) and Pd₂(dba)₃ (18.5 mg, 0.02 mmol) in NMP (8 mL) was stirred at 90 for 16 h under N₂. The mixture was diluted with H₂O and extracted with ethyl acetate. The organic phase was washed with H₂O and concentrated. The residue was purified by reverse phase HPLC (acetonitrile/H₂O: 5%-80%) to afford 36. LCMS (ESI, m/z): [M+H]⁺=485.2. ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 8.13-7.89 (m, 3H), 7.85-7.78 (m, 1H), 7.54-7.43 (m, 2H), 4.80-3.90 (m, 6H), 3.45 (s, 3H), 1.94-1.75 (m, 4H). ¹⁹F NMR (376 MHz, DMSO-d₆, ppm): δ −56.68 (3F).

Example 16 Synthesis of Compounds 39 and 42

Step 1: To a stirred solution of 39-1 (1 g, 4.71 mmol) in NMP (10 mL) were added ZnBr₂ (10.6 g, 47.15 mmol), Pd(dppf)Cl₂ (0.3 g, 0.47 mmol), DIPEA (15.59 mL, 94.3 mmol) and ethynylcyclopropane (3.12 g, 47.15 mmol) under N₂. The reaction mixture was stirred at 120° C. for 2 h. The reaction mixture was quenched with H₂O and extracted with ethyl acetate. The combined organic layer was washed with brine. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 20/1) to afford 39-2.

Step 2: To a solution of 5-7 (583 mg, 2.53 mmol) in acetonitrile (5 mL) were added 39-2 (500 mg, 2.53 mmol) and DIPEA (983 mg, 7.6 mmol). The reaction was stirred at room temperature for 3 h under N₂. The reaction mixture was concentrated, the residue was purified by reverse phase HPLC (acetonitrile/H₂O, 5%-50%) to afford 39. LCMS (ESI, m/z): [M+H]+=391.2; ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 7.98 (d, J=8.0 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.14-7.10 (m, 1H), 6.97-6.90 (m, 2H), 4.06-4.02 (m, 2H), 3.50 (s, 3H), 2.84-2.80 (m, 2H), 1.99-1.93 (m, 2H), 1.63-1.56 (m, 1H), 0.96-0.94 (m, 2H), 0.93-0.91 (m, 2H).

Step 3: To a solution of 39 (140 mg, 0.36 mmol) in DMF (1.5 mL) were added Zn(CN)₂ (420 mg, 3.58 mmol) and Pd(PPh₃)₄ (206.8 mg, 0.18 mmol). Then the reaction mixture was stirred at 110° C. for 1 h under N₂. The reaction mixture was concentrated, the residue was purified by reverse phase HPLC (acetonitrile/H₂O: 5%˜50%) to afford 42. LCMS (ESI, m/z): [M+H]⁺=382.2; ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 8.19 (d, J=8.0 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.17-7.13 (m, 1H), 6.96-6.94 (m, 2H), 4.08-4.03 (m, 2H), 3.50 (s, 3H), 2.85-2.82 (m, 2H), 2.01-1.95 (m, 2H), 1.62-1.58 (m, 1H), 0.95-0.93 (m, 2H), 0.92-0.91 (m, 2H).

Example 17 Synthesis of Compounds 44 and 45

Step 1: To a solution of N₁,N₁,N₂,N₂-tetramethylethane-1,2-diamine (5.8 g, 56.28 mmol) in THF (80 mL) was added n-BuLi (40 mL, 64 mmol, 1.6 mol/L in THF) dropwise at −40 under N₂. The reaction was stirred at −40 for 40 minutes. Then 44-1 (7 g, 40.2 mmol) was added to the mixture over 5 minutes. The mixture was stirred at −40 for 30 minutes. The second batch of n-BuLi (25.328 mL, 40.525 mmol, 1.6 mol/L in THF) was added dropwise over 5 minutes, then the reaction mixture was stirred at −40 for 2 h. Remove the cold bath, CuBr (7.5 g, 52.26 mmol) was added to the mixture, and the reaction mixture was stirred at 25 for another 1 h. The reaction was cooled to −30 and a solution of 3-bromoprop-1-ene (9.73 g, 80.4 mmol) in THF (10 mL) was added dropwise over 5 minutes, then the reaction mixture was stirred at −40 for 2 h. The reaction was quenched by addition of methanol. The pH of the mixture was adjusted to 6 with HCl (6M). The reaction mixture was filtered and the filter cake was washed with ethyl acetate. The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine. The combine organic layer was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 3/1) to afford 44-2.

Step 2: To a solution of 44-2 (5 g, 23.34 mmol) in THF (50 mL) was added allylmagnesium bromide (25.68 mL, 25.68 mmol), and the reaction was stirred at −40 for 1 h. The reaction was quenched with saturated aqueous NH₄Cl. The reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 2/1) to afford 44-3.

Step 3: To a solution of 44-3 (2.0 g, 7.8 mmol) in dichloromethane (160 mL) was added Grubbs 2nd catalyst (331 mg, 0.39 mmol). The reaction was stirred at 20 for 18 h under N₂. The reaction mixture was diluted with water. The organic layer was separated, washed with brine and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 2/1) to afford 44-4.

Step 4: To a solution of 44-4 (1.36 g, 5.96 mmol) in EtOH (25 mL) was added 10% Pd/C (0.1 g). The suspension was degassed under vacuum and purged with H₂ 3 times, then the mixture was stirred at 25 for 1 h under H₂. The suspension was filtered, and the filter cake was washed with EtOH (20 mL). The combined filtrates were concentrated to afford 44-5.

Step 5: To a solution of 44-5 (1 g, 4.34 mmol) in dichloromethane (25 mL) was added SOCl₂ (0.47 mL, 6.51 mmol), and the reaction was stirred at 0 for 1.5 h. The reaction was quenched with water. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 10/1) to afford 44-6.

Step 6: To a solution of 28-14 (250 mg, 0.77 mmol) in acetonitrile (10 mL) were added DIPEA (0.25 mL, 1.53 mmol), NaI (344 mg, 2.3 mmol) and 44-6 (380 mg, 1.53 mmol). The reaction mixture was stirred at 80 for 24 h. Then another batch of 44-6 (190 mg, 0.76 mmol) was added to the reaction mixture, and reaction was stirred at 80 for another 24 h. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane/methanol=1/0 to 10/1) to afford 44-7.

Step 7: 44-7 (150 mg, 0.28 mmol) was purified by reverse phase HPLC (acetonitrile/0.1% TFA in water: 75%) to afford 44 (10.43 mg) and 45 (4.01 mg). 44: Analytical HPLC: retention time: 1.85 min; column: Waters ACQUITY BEH C18 2.1*50 mm, 1.7 um; Mobile phase A: H₂O (0.05% TFA); Mobile phase B: Acetonitrile (0.05% TFA); flow rate: 1.0 mL/min; Run time: 5 min; 95 to 5% A in 3 min, 5% A for 2 min. LCMS (ESI, m/z): [M+H]⁺=539.4; ¹H NMR (400 MHz, CDCl₃): δ 7.89-7.77 (m, 1H), 7.63-7.54 (m, 1H), 7.40-7.30 (m, 2H), 7.25-7.20 (m, 1H), 6.16-5.54 (m, 1H), 5.34-5.09 (m, 1H), 3.75-3.67 (m, 1H), 3.64-3.34 (m, 5H), 3.12-2.97 (m, 1H), 2.74-2.63 (m, 1H), 2.63-2.52 (m, 1H), 2.18-2.11 (m, 1H), 2.06-1.90 (m, 4H), 1.87-1.75 (m, 2H), 1.73-1.63 (m, 1H), 1.49-1.36 (m, 2H), 1.31-1.25 (m, 1H), 1.09-0.90 (m, 3H), 0.74-0.60 (m, 3H). ¹⁹F NMR (376 MHz, CDCl₃, ppm): δ −62.33 (3F). 45: Analytical HPLC: retention time: 1.85 min; column: Waters ACQUITY BEH C18 2.1*50 mm, 1.7 um; Mobile phase A: H₂O (0.05% TFA); Mobile phase B: Acetonitrile (0.05% TFA); flow rate: 1.0 mL/min; Run time: 5 min; 95 to 5% A in 3 min, 5% A for 2 min. LCMS (EST, m/z): [M+H]+=539.4; ¹H NMR (400 MHz, CDCl3): δ 7.89-7.77 (m, 1H), 7.64-7.54 (m, 1H), 7.46-7.29 (m, 2H), 7.24-7.16 (m, 1H), 6.03-4.80 (m, 2H), 3.77-3.07 (m, 6H), 2.95-2.80 (m, 1H), 2.78-2.53 (m, 2H), 2.30-2.10 (m, 4H), 2.08-1.90 (m, 2H), 1.74-1.67 (m, 2H), 1.41-1.29 (m, 3H), 1.05-0.96 (m, 3H), 0.69-0.37 (m, 3H). ¹⁹F NMR (376 MHz, CDCl₃, ppm): δ −62.34 (3F).

Example 18 Synthesis of Compound 50

Step 1: To a solution of methyltriphenylphosphonium bromide (4.4 g, 12.19 mmol) in THF (25 mL) was added potassium tert-butoxide (12.19 mL, 12.19 mmol) at 20 The mixture was stirred at 55 under N₂ for 2 h. Then 50-1 (1.3 g, 6.09 mmol) was added and the mixture was stirred at 55 for 16 h. The mixture was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 10/1) to afford 50-2.

Step 2: Compound 50 was prepared from 50-2 following the procedure for the synthesis of compound 30 in example 12. LCMS (ESI, m/z): [M+H]⁺=499.2; 1H NMR (400 MHz, DMSO-d₆, ppm): δ 8.30-8.23 (m, 1H), 8.06-7.98 (m, 1H), 7.88-7.72 (m, 2H), 7.53-7.42 (m, 2H), 5.60-5.35 (m, 1H), 5.25-4.80 (m, 1H), 3.70-3.60 (m, 1H), 3.46 (s, 3H), 3.42-3.35 (m, 1H), 3.34-3.30 (m, 1H), 2.24-2.10 (m, 1H), 2.07-1.79 (m, 3H), 1.56-1.36 (m, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆, ppm): δ −56.75 (3F).

Example 19 Synthesis of Compounds 57 and 58

Step 1: To a stirred solution of 57-1 (45 g, 276 mmol) in EtOH (450 mL) was added thiourea (22.06 g, 290 mmol) at room temperature. The resulting mixture was stirred at 80 for 15 h under N₂. The solvent was removed under reduced pressure. The residue was diluted with H₂O and neutralized with NaHCO₃ until the pH is 8-9, then dichloromethane was added to the mixture. The mixture was extracted with dichloromethane. The combined organic layers were washed with saturated NaHCO₃ and brine, dried over anhydrous Na₂SO₄ and concentrated to afford 57-2.

Step 2: To a stirred solution of 57-2 (6 g, 19.9 mmol) and CuBr (4.3 g, 29.9 mmol) in acetonitrile (80 mL) was added t-BuONO (3.59 mL, 29.9 mmol) at 0-5 . The resulting mixture was stirred at room temperature for 30 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 6/1) to afford 57-3.

Step 3: To a stirred solution of 57-3 (1.0 g, 4.9 mmol) in THF (20 mL) was added n-BuLi (2.55 mL, 6.37 mmol) below −60 under N₂. The resulting mixture was stirred at this temperature for 1 h. A solution of 4-((trifluoromethyl)thio)benzaldehyde (1313.4 mg, 6.37 mmol) in THF (20 mL) was added into the above reaction mixture below −60 . The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with saturated NH₄Cl and diluted with H₂O. The mixture was extracted with ethyl acetate. The organic layer was combined, washed with brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 5/1) to afford 57-4.

Step 4: To a stirred solution of 57-4 (450 mg, 1.36 mmol) in dichloromethane (6 mL) was added SOCl₂ (0.15 mL, 2.04 mmol) at 25. The resulting mixture was stirred at 25 for 15 h. The reaction mixture was concentrated to afford 57-5 which was used for the next step directly without further purification.

Step 5: To a stirred solution of 57-5 (1.15 g, 2.63 mmol) and 28-14 (0.86 g, 2.63 mmol) in acetonitrile (10 mL) was added DIPEA (1.83 mL, 10.52 mmol) at 25 . The resulting mixture was stirred at 90 for 15 h. The reaction mixture was concentrated. The residue was purified by reverse phase HPLC (acetonitrile/0.05% TFA in H₂O, 0-60%) to afford 57 (11.65 mg) and 58 (6.24 mg). 57: Analytical HPLC: retention time: 1.85 min; column: Waters ACQUITY BEH C18 2.1*50 mm, 1.7 um; Mobile phase A: H₂O (0.05% TFA); Mobile phase B: Acetonitrile (0.05% TFA); flow rate: 1.0 mL/min; Run time: 5 min; 95 to 5% A in 3 min, 5% A for 2 min. LCMS (ESI, m/z): [M+H]⁺=640.2; ¹H NMR (400 MHz, methanol-d₄, ppm): δ 8.09-8.03 (m, 1H), 8.02-7.95 (m, 1H), 7.75-7.66 (m, 4H), 7.06 (s, 1H), 6.19-5.51 (m, 1H), 5.22-5.12 (m, 1H), 3.68-3.33 (m, 1H), 3.56 (s, 3H), 2.93-2.82 (m, 1H), 2.76-2.64 (m, 2H), 2.46-2.31 (m, 1H), 2.12-1.97 (m, 3H), 1.55-1.40 (m, 2H), 0.98-0.84 (m, 6H), 0.80-0.73 (m, 2H), 0.69-0.65 (m, 1H), 0.58-0.54 (m, 1H). ¹⁹F NMR (376 MHz, methanol-d₄, ppm): δ −44.64 (3F). 58: Analytical HPLC: retention time: 1.85 min; column: Waters ACQUITY BEH C18 2.1*50 mm, 1.7 um; Mobile phase A: H₂O (0.05% TFA); Mobile phase B: Acetonitrile (0.05% TFA); flow rate: 1.0 mL/min; Run time: 5 min; 95 to 5% A in 3 min, 5% A for 2 min. LCMS (ESI, m/z): [M+H]⁺=640.2; ¹H NMR (400 MHz, CDCl₃, ppm): δ 7.86-7.81 (m, 1H), 7.65-7.57 (m, 5H), 6.85 (s, 1H), 6.07-5.62 (m, 1H), 5.68-5.56 (m, 1H), 3.73-3.41 (m, 1H), 3.58 (s, 3H), 2.76-2.55 (m, 2H), 2.52-2.42 (m, 1H), 2.16-1.93 (m, 4H), 1.50-1.39 (m, 2H), 0.93-0.90 (m, 2H), 0.86-0.81 (m, 6H), 0.78-0.67 (m, 2H). ¹⁹F NMR (376 MHz, CDCl₃, ppm): δ −42.58 (3F).

Example 20 Synthesis of Compound 59

Step 1: Compound 59-2 was prepared from 59-1 following the procedure for the synthesis of compound 30-5 in example 12.

Step 2: To a mixture of 59-3 (4.9 g, 25.4 mmol) and methyl 2-hydroxyacetate (2.74 g, 30.4 mmol) in DMF (50 mL) was added NaH (1.22 g, 60%, 30.5 mmol) at 0. Then the mixture was stirred at room temperature for 1 h. H₂O was added to the reaction mixture and the mixture was extracted with ethyl acetate. The combined organic layers were dried over Na₂SO₄, filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 2/1) to afford 59-4.

Step 3: To a solution of 59-4 (4.9 g, 19.87 mmol) in EtOH (50 mL) and HOAc (20 mL) was added Fe (5.6 g, 100 mmol) at room temperature. Then the mixture was stirred at 80 for 2 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (dichloromethane/methanol=1/0 to 20/1) to afford 59-5.

Step 4: To a solution of 59-5 (2.6 g, 14.09 mmol) in THF (20 mL) was added BH₃-THF (1M, 65 mL, 65 mmol) at room temperature. Then the mixture was stirred at 80 for 2 h. The mixture was quenched with methanol and stirred at 80 for 30 minutes. Then the mixture was concentrated to afford 59-6 which was used for the next step directly without further purification.

Step 5: To a solution of 59-6 (1.0 g, crude) and (Boc)₂O (4.04 mL, 17.59 mmol) in THF (15 mL) was added DMAP (1.43 g, 11.72 mmol) and triethylamine (0.82 mL, 5.86 mmol) at room temperature. Then the mixture was stirred at 80 for 12 h. The mixture was concentrated, the residue was purified by column chromatography on silica gel (dichloromethane/methanol=1/0 to 20/1) to afford 59-7.

Step 6: To a solution of 59-7 (1.5 g, 5.54 mmol) in CHCl₃ (20 mL) was added mCPBA (2.25 g, 11.08 mmol) at room temperature. Then the mixture was stirred at 80 for 12 h. This mixture was concentrated and the residue was purified by column chromatography on silica gel (dichloromethane/methanol=1/0 to 10/1) to afford 59-8.

Step 7: To a solution of 59-8 (1.2 g, 4.19 mmol) in acetonitrile (20 mL) were added TMSCN (1.25 g, 12.56 mmol) and triethylamine (1.75 mL, 12.56 mmol) at room temperature. Then the mixture was stirred at 80 for 12 h. The mixture was concentrated and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 4/1) to afford 59-9.

Step 8: To a solution of 59-9 (620 mg, 2.1 mmol) and K₂CO₃ (870 mg, 6.29 mmol) in DMSO (10 mL) was added H₂O₂ (30%, 713.0 mg, 6.29 mmol) at 0 . Then the mixture was stirred at room temperature for 1 h. The solid was collected by filtration and washed with dichloromethane. The solid was suspended in H₂O, then cone. HCl was added until the pH was 4-5. The solid was collected by filtration to afford 59-10.

Step 9: Compound 59 was prepared from 59-10 following the procedure for the synthesis of compound 5 in example 5. LCMS (ESI, m/z): [M+H]⁺=513.2; ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 7.89 (s, 1H), 7.84-7.76 (m, 2H), 7.53-7.44 (m, 2H), 5.06-4.58 (m, 1H), 4.55-4.46 (m, 2H), 4.48-4.06 (m, 2H), 4.05-3.68 (m, 3H), 3.35 (s, 2H), 2.06-1.82 (m, 4H). ¹⁹F NMR (376 MHz, DMSO-d₆, ppm): δ −56.75 (3F).

Example 21 Synthesis of Compound 64

Step 1: To a suspension of 64-1 (950 mg, 3.62 mmol) in CCl₄ (20 mL) was added NBS (709.4 mg, 3.99 mmol) and AIBN (89.2 mg, 0.54 mmol). Then the mixture was stirred at 85 for 3 h. The mixture was concentrated and the residue was purified by column chromatography on silica gel (dichloromethane/methanol=1/0 to 10/1) to afford 64-2.

Step 2: To a mixture of 64-2 (500 mg, 1.17 mmol) and 28-14 (421.05 mg, 1.29 mmol) in acetonitrile (15 mL) was added DIPEA (0.97 mL, 5.86 mmol) and NaI (351.6 mg, 2.35 mmol). Then the mixture was stirred at 85 for 3 h. The mixture was extracted with ethyl acetate. The organic layer was washed with H₂O and brine (20 mL), dried over Na₂SO₄, filtered and concentrated. The residue was purified by reverse phase HPLC (acetonitrile/0.05% TFA in water: 0-60%) to afford 64-3 and 64-4.

Step 3: To a mixture of 64-3 (75 mg, 0.13 mmol) and N-[azanylidene (cyclopropyl)methyl]hydroxylamine (14.08 mg, 0.14 mmol) in DMSO (2 mL) was added DIPEA (58.3 mg, 0.15 mmol) and HATU (58.3 mg, 0.15 mmol). The mixture was stirred at room temperature for 30 minutes, then the mixture was heated to 90 and stirred for 30 minutes. The mixture was cooled and extracted with ethyl acetate. The organic layer was washed with H₂O and brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by reverse phase HPLC (acetonitrile/0.05% TFA in water: 0-70%) to afford 64 as 3.3 eq of TFA salt. LCMS (ESI, m/z): [M+H]⁺=651.4; ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 8.24 (d, J=8.8 Hz, 1H), 8.02-7.98 (m, 3H), 7.88-7.81 (m, 2H), 6.00-5.37 (m, 2H), 4.98-4.91 (m, 1H), 3.65-3.56 (m, 0.5 H), 3.44 (s, 3H), 3.30-3.18 (m, 1H), 2.90-2.82 (m, 0.5 H), 2.2-2.57 (m, 1H), 2.40-2.21 (m, 2H), 2.17-2.12 (m, 1H), 2.04-1.78 (m, 2H), 1.63-1.39 (m, 2H), 1.11-1.04 (m, 2H), 0.90-0.69 (m, 7H). ¹⁹F NMR (376 MHz, DMSO-d₆, ppm): δ 87.41-86.60 (1F), 64.20-63.80 (4F), −73.59 (9.9F, TFA).

Example 22 Synthesis of Compound 67

Step 1: To a stirred solution of 67-1 (25 g, 150.4 mmol) in acetonitrile (250 mL) was added NBS (28.1 g, 158 mmol) in portions at 25-40. The reaction mixture was stirred at 25-40 for 2 h. The precipitate was filtered and the cake was washed with acetonitrile. The cake was collected and dried to afford 67-2.

Step 2: To a stirred solution of 67-2 (20 g, 81.6 mmol) in THF (100 mL) was added dropwise acetyl acetate (24.14 mL, 257.06 mmol) at 25. The reaction mixture was stirred at 75 for 19 h. The reaction mixture was concentrated. The residue was diluted with H₂O and extracted with ethyl acetate. The organic layer was combined, dried over anhydrous Na₂SO₄ and concentrated to afford 67-3.

Step 3: To a solution of 67-3 (20.9 g, 72.8 mmol) and Cs₂CO₃ (52.2 g, 160.15 mmol) in DMF (150 mL) was added dropwise CH₃I (7.7 mL, 123.7 mmol) at 5-15 . The reaction mixture was stirred at 25 for 67 h. The reaction mixture was diluted with H₂O and extracted with ethyl acetate. The organic layer was combined, washed with H₂O and brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 1/4) to afford 67-4.

Step 4: KHMDS in THF (1M, 54.6 mL, 54.6 mmol) was added to THF (200 mL) at −10 under N₂, then 67-4 (13.7 g, 45.5 mmol) in THF (400 mL) was added to the solution at −60° C. to −50 under N₂. Then the reaction mixture was stirred at 20 for 1.5 h. The reaction was quenched with H₂O, and the mixture was extracted with ethyl acetate. The aqueous layer was acidified with HCl (2 N) to change the pH to 3-4. The precipitate was filtered, washed with H₂O and dried to afford 67-5.

Step 5: To a stirred solution of 67-5 (2 g, 7.84 mmol) in AcOH (20 mL) was added HNO₃ (1.3 mL, 31.74 mmol) at 25 . The reaction mixture was stirred at 80 for 15 h. The reaction mixture was cooled to 25 and diluted with H₂O. The mixture was stirred for 10 minutes and the precipitation was filtered and dried to afford 67-6.

Step 6: To a stirred solution of 67-6 (1.4 g, 4.67 mmol) in toluene (28 mL) was added DIPEA (4.06 mL, 23.33 mmol) and POCl₃ (2.17 mL, 23.33 mmol) at 25 . The reaction mixture was stirred at 110 for 3 h under N₂. The reaction mixture was concentrated to afford 67-7 which was used for the next step directly without further purification.

Step 7: To a stirred solution of 67-8 (34.9 g, 292.99 mmol) in methanol (250 mL) was added triethylamine (42.76 mL, 307.63 mmol) and benzaldehyde (31.27 mL, 307.63 mmol) at 5-10 . The reaction mixture was stirred at this temperature for 3 h. Then the reaction mixture was cooled to 0° C. and NaBH₄ (22.2 g, 585.964 mmol) was added into the reaction mixture in portions. The reaction mixture was stirred at 0-20 for 2.5 h. The reaction mixture was quenched with HCl (3 N) and extracted with ethyl acetate. The organic layer was washed with HCl (3 N). The aqueous layer was combined and neutralized with NaHCO₃ powder. The aqueous layer was concentrated. The residue was dissolved in dichloromethane/methanol (10:1) and filtered. The organic layer was concentrated, the residue was purified by column chromatography on silica gel (dichloromethane/methanol=1/0 to 10/1) to afford 67-9.

Step 8: To a solution of 67-9 (32.86 g, 157.04 mmol) and (2R)-2-{[(tert-butoxy)carbonyl]amino}butanoic acid (31.92 g, 157.04 mmol) in DMF (350 mL) was added dropwise DIPEA (82.06 mL, 471.11 mmol) at 25 , then HATU (89.6 g, 235.56 mmol) was added to the solution at 5-15 . The reaction mixture was stirred at 25 for 48 h. The reaction mixture was diluted with H₂O and extracted with ethyl acetate. The organic layer was combined, washed with H₂O and brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 0/1) to afford 67-10.

Step 9: To a stirred solution of 67-10 (28.9 g, 73.26 mmol) in methanol (280 mL) was added HCl in ethyl acetate (4M, 50 mL) at 25-35 . The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated to afford 67-11.

Step 10: A solution of 67-11 (25.4 g, 69.14 mmol) in DIPEA (35 mL, 200.93 mmol) and methanol (300 mL) was stirred at 70 for 15 h. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (dichloromethane/methanol=1/0 to 10/1) to afford 67-12.

Step 11: To a stirred solution of 67-12 (21 g, 80.06 mmol) in THF (100 mL) was added BH₃-THF (1M in THF, 22.9 mL, 22.9 mmol) at 0 C under N₂. The reaction mixture was stirred at 70 for 18 h. The reaction mixture was cooled to 0-10 , then quenched with methanol and HCl (2 N). The resulting mixture was stirred at 70 for 2 h. The reaction mixture was concentrated. The residue was diluted with H₂O (100 mL) and basified with NaHCO₃ to pH=8-9. The mixture was concentrated to dryness. The residue was dissolved in a mixture of 10% methanol in dichloromethane and the suspension was filtered. The filtrate was concentrated to afford 67-13 which was used for the next step directly without further purification.

Step 12: To a stirred solution of 67-13 (27.7 g, crude), DMAP (0.9 g, 7.09 mmol) and triethylamine (19.72 mL, 141.85 mmol) in dichloromethane (280 mL) was added (Boc)₂O (14.66 mL, 63.83 mmol) at 0-10 . The reaction mixture was stirred at room temperature for 15 h. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 2/1) to afford 67-14.

Step 13: To a stirred solution of 67-14 (5 g, 14.95 mmol) in methanol (30 mL) was added HCl in ethyl acetate (4M, 30 mL) at 25 , the reaction mixture was stirred at 25 for 15 h. The reaction mixture was concentrated to afford 67-15 which was used for the next step directly without further purification.

Step 14: A mixture of 67-15 (4.5 g, 14.61 mmol), 34-2 (8.13 g, 36.53 mmol), DIPEA (10.18 mL, 58.44 mmol), K₂CO₃ (8.1 g, 58.44 mmol) and KI (4.9 g, 29.22 mmol) in CH₃CN (100 mL) was stirred at 90 for 48 h. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 2/3) to afford 67-16 and 67-17.

Step 15: To a stirred solution of 67-16 (1.93 g, 4.59 mmol) in isopropanol (60 mL) was added Pd/C (5%, 450 mg) at 25 . The reaction mixture was degassed with H₂ several times, then the mixture was stirred at 60 for 15 h under H₂. The reaction mixture was filtered and the filtrate was concentrated to afford 67-18.

Step 16: A solution of 67-18 (1.6 g, 4.84 mmol), 67-7 (1.46 g, crude) and DIPEA (8.44 mL, 48.43 mmol) in CH₃CN (30 mL) was stirred at 90 for 15 h. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 1/4) to afford 67-19.

Step 17: To a stirred solution of 67-19 (700 mg, 1.14 mmol), Zn(CN)₂ (268.5 mg, 2.29 mmol), Zn (15.0 mg, 0.23 mmol) and dppf (38.0 mg, 0.069 mmol) in NMP (7 mL) was added Pd₂(dba)₃ (104.7 mg, 0.114 mmol) at 25 . The reaction mixture was degassed through N₂ for a while and stirred at 90 for 15 h. The reaction mixture was diluted with H₂O and extracted with ethyl acetate. The organic layer was combined, washed with H₂O and brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 1/4) to afford 67-20.

Step 18: To a stirred solution of 67-20 (180 mg, 0.31 mmol) in DMF (1.8 mL) was added DBU (139.8 mg, 0.92 mmol) at 25 . The reaction mixture was stirred at 130 for 15 h. The reaction mixture was diluted with H₂O and extracted with ethyl acetate. The organic layer was combined, washed with brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 0/1) and then by reverse phase HPLC (MeCN/0.1% TFA in water: 0-60%) to afford 67. Analytical HPLC: retention time: 1.69 min; column: Waters ACQUITY BEH C18 2.1*50 mm, 1.7 um; Mobile phase A: H₂O (0.05% TFA); Mobile phase B: Acetonitrile (0.05% TFA); flow rate: 1.0 mL/min; Run time: 5 min; 95 to 5% A in 3 min, 5% A for 2 min. LCMS (ESI, m/z): [M+H]+=512.2; ¹H NMR (400 MHz, methanol-d₄, ppm): δ 8.06-7.99 (m, 1H), 7.89-7.85 (m, 1H), 7.68-7.62 (m, 2H), 7.59-7.53 (m, 2H), 5.13-5.08 (m, 1H), 4.41-4.35 (m, 1H), 4.08-4.04 (m, 1H), 3.82-3.74 (m, 1H), 3.71 (s, 3H), 3.63-3.52 (m, 1H), 3.16-3.09 (m, 1H), 3.09-3.02 (m, 1H), 2.74-2.65 (m, 1H), 2.52-2.43 (m, 1H), 2.12-2.01 (m, 1H), 1.81-1.59 (m, 3H), 0.81 (t, J=7.4 Hz, 3H), 0.69 (t, J=7.3 Hz, 3H). ¹⁹F NMR (376 MHz, methanol-d₄, ppm): δ −63.86 (3F).

Example 23 Synthesis of Compounds 72 and 73

Step 1: To a mixture of methyl 72-1 (500 mg, 2.31 mmol) in 2-methoxyethyl ether (10 mL) was added 2,2′-bipyridine (542 mg, 3.47 mmol), AgSCF₃ (725.4 mg, 3.47 mmol) and CuI (661 mg, 3.47 mmol). Then the mixture was stirred at 130° C. for 24 h under N₂. The mixture was quenched by addition of water, the aqueous layer was extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over anhydrous Na₂SO₄, the mixture was concentrated. The residue was purified by reverse phase HPLC (MeCN/H₂O (0.05% TFA), 5-95%) to afford 72-2.

Step 2: To a solution of 72-2 (2.2 g, 9.28 mmol) in MeOH (2 mL) was added NaBH₄ (0.7 g, 18.55 mmol) at 0° C. and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM and saturated NH₄Cl solution. The organic layer was separated and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=10/1) to afford 72-3.

Step 3: To a solution of 72-3 (1.12 g, 5.35 mmol) in DCM (15 mL) was added Dess-Martin periodinane (3.0 g, 6.96 mmol) at 0° C. and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=10/1) to afford 72-4.

Step 4: To a solution of 72-4 (460 mg, 2.21 mmol) in THF (10 mL) was added 4-fluorophenylmagnesium bromide (0.32 mL, 0.32 mmol) at −78° C., then the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate and saturated NH₄Cl solution. The organic layer was separated and washed with saturated NaCl solution, then organic layer was concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=4/1) to afford 72-5.

Step 5: To a solution of 72-5 (580 mg, 1.91 mmol) in DCM (12 mL) were added DMF (0.01 mL, 0.13 mmol) and SOCl₂ (378 mg, 3.82 mmol) at 0° C., then the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated in vacuo to afford 72-6 which was used for the next step directly without further purification.

Step 6: Compound 72 and 73 was prepared from compound 72-6 following the procedure for the synthesis of compound 28-15 in example 11. The product was obtained by reverse phase HPLC (MeCN/water (0.05% TFA), 0-80%). 72: 2.23 TFA salts, LCMS (EST, m/z): [M+H]+=598.4; ¹H NMR (400 MHz, Methanol-d4, ppm): δ 8.98 (s, 1H), 8.22 (dd, J=8.0, 2.0 Hz, 1H), 8.14-8.01 (m, 2H), 7.76-7.60 (m, 3H), 7.25 (t, J=8.4 Hz, 2H), 6.43-5.91 (m, 2H), 5.42-5.32 (m, 1H), 4.10-3.99 (m, 1H), 3.60 (s, 3H), 3.20-3.02 (m, 2H), 1.91-1.59 (m, 5H), 1.39-1.28 (m, 1H), 0.85 (t, J=7.2 Hz, 3H). ¹⁹F NMR (376 MHz, Methanol-d₄, ppm): δ −44.15 (3F), −77.27 (6.7F, TFA), −111.5 (1F). 73: 1.48 TFA salts, LCMS (ESI, m/z): [M+H]⁺=598.4; H NMR (400 MHz, Methanol-d₄, ppm): δ 8.93 (s, 1H), 8.21 (dd, J=8.0, 2.0 Hz, 1H), 8.10 (d, J=8.8 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.81-7.67 (m, 3H), 7.18 (t, J=8.4 Hz, 2H), 6.34-5.96 (m, 1H), 5.55-5.23 (m, 2H), 4.10-3.85 (m, 1H), 3.59 (s, 3H), 3.28-3.15 (m, 1H), 3.10-2.90 (m, 1H), 1.65-1.28 (m, 6H), 0.78-0.64 (m, 3H). ¹⁹F NMR (376 MHz, Methanol-d4, ppm): δ −4.24 (3F), −77.38 (4.45F, TFA), -111.5 (1F).

Example 24 Synthesis of Compounds 77 and 78

Step 1: To a mixture of 64-3 (80 mg, 0.14 mmol) in THF (10 mL) was added CDI (44.2 mg, 0.27 mmol). After stirred for 16 h at room temperature, NaBH₄ (5.2 mg, 0.14 mmol) was added to the mixture. Then the mixture was stirred at room temperature for 20 minutes. The mixture was quenched by addition of water, the aqueous layer was extracted with ethyl acetate. The organic layer was combined and washed with brine, dried over anhydrous Na₂SO₄. The solvent was concentrated. The residue was purified by column chromatography on silica gel (DCM/MeOH=10/1) to afford 77. LCMS (ESI, m/z): [M+H]⁺=573.3; ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 8.30-8.18 (m, 1H), 8.01-7.91 (m, 1H), 7.90-7.78 (m, 2H), 7.65-7.06 (m, 2H), 6.12-5.57 (m, 0.5H), 5.62-5.53 (m, 0.5H), 5.11-4.71 (m, 2H), 3.81-3.64 (m, 5H), 3.06-2.72 (m, 3H), 2.61-2.53 (m, 1H), 2.37-2.11 (m, 1H), 2.09-1.47 (m, 2H), 1.2-1.41 (m, 2H), 1.07-0.84 (m, 3H), 0.79-0.56 (m, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆, ppm): δ 88.41 (1F), 64.39 (4F).

Step 2: To a mixture of 77 (50 mg, 0.087 mmol) in THF (2 mL) was added NaH (7.0 mg, 0.17 mmol) and iodomethane (37.0 mg, 0.26 mmol). Then the mixture was stirred at 0° C. for 3 h. The reaction mixture was quenched by water, the aqueous layer was extracted with ethyl acetate. The organic layer was combined and washed with brine, dried over anhydrous Na₂SO₄. The solvent was concentrated. The residue was purified by reverse phase HPLC (MeCN/water from 1/0 to 2/3) to afford 78. LCMS (ESI, m/z): [M+H]⁺=587.3; ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 8.31-8.17 (m, 1H), 8.03-7.94 (m, 1H), 7.96-7.83 (m, 2H), 7.70-7.58 (m, 2H), 6.09-5.78 (m, 0.5H), 5.53-5.26 (m, 0.5H), 5.09-4.75 (m, 1H), 3.98-3.80 (m, 1H), 3.69-3.48 (m, 3H), 3.43 (s, 3H), 3.20 (d, J=5.2 Hz, 3H), 3.14-2.81 (m, 2H), 2.37-2.16 (m, 1H), 2.13-1.70 (m, 2H), 1.56-1.31 (m, 2H), 1.01-0.83 (m, 3H), 0.77-0.55 (m 3H). ¹⁹F NMR (376 MHz, DMSO-d₆, ppm): δ 88.66 (1F), 64.36 (4F).

Example 25 Synthesis of Compound 84

Step 1: To a solution of 34-8 (2.39 g, 10.62 mmol) in MeCN (50 mL) was added DIPEA (14.04 mL, 84.97 mmol) and 28-11 (2.57 g, 10.62 mmol) at room temperature. Then the mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 10/1) to afford 84-1.

Step 2: To a solution of 84-1 (3.66 g, 8.49 mmol) in THF (30 mL) was added N₂H₄·H₂O (5 mL), the mixture was stirred at 50° C. for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=10/0 to 0/1) to afford 84-2.

Step 3: 84-2 (3.6 g, 8.44 mmol) was dissolved in trimethoxymethane (30 mL), the mixture was stirred at 100° C. under N₂ for 16 h. The mixture concentrated under reduced pressure to afford product 84-3.

Step 4: To a solution of 84-3 (3.65 g, 8.36 mmol) in DCM (30 mL) was added TFA (10 mL) at room temperature and stirred for 5 h. The mixture was concentrated under reduced pressure, the residue was dissolved in DCM and washed with saturated NaHCO₃. The combined organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated to afford 84-4.

Step 5: To a solution of 4-(trifluoromethyl)benzoic acid (100 mg, 0.53 mmol) in DMF (5 mL) was added DIPEA (0.13 mL, 0.79 mmol) and HATU (240.0 mg, 0.63 mmol), the mixture was stirred at 0° C. for 10 minutes, then 84-4 (176.9 mg, 0.53 mmol) was added to the mixture. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was purified by reverse phase HPLC (MeCN/water from 0/1 to 1/1) to afford 84. LCMS (ESI, m/z): [M+H]⁺=509.2. ¹H NMR (400 MHz, DMSO-d₆, ppm) δ 9.55 (s, 1H), 9.02-8.88 (m, 1H), 8.67-8.50 (m, 1H), 7.93-7.81 (m, 2H), 7.74-7.59 (m, 2H), 5.87-4.23 (m, 3H), 3.78-3.42 (m, 2H), 3.38-3.12 (m, 1H), 2.03-1.54 (m, 4H), 1.11-0.88 (m, 3H), 0.77-0.50 (m, 3H). ¹⁹F NMR (377 MHz, DMSO-d₆, ppm) 6-61.21 (3F).

Example 26 Synthesis of Compounds 91 and 92

Step 1: To a solution of 91-1 (15 g, 99.25 mmol) in MeCN (100 mL) was added CH₃NH₂ (200 mL, 3.56 mmol, 40% in H₂O). Then the reaction mixture was stirred at 80° C. for 16 h. The reaction mixture was quenched with H₂O. The mixture was extracted with ethyl acetate. The combined organic layers were washed with H₂O. The organic layer was dried over Na₂SO₄, filtered and concentrated to afford 91-2.

Step 2: To a solution of 91-2 (8.2 g, 50.56 mmol) in MeCN (150 mL) was added NCS (7.4 g, 55.61 mmol), then the reaction mixture was stirred at 60° C. for 70 minutes. The mixture was quenched by addition of water. The aqueous layer was extracted with ethyl acetate. The organic layer was combined, washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 5/1) to afford 91-3.

Step 3: Compound 91-4 and 91-5 was prepared from compound 91-3 following the procedure for the synthesis of compound 5-8 in example 5, the product was obtained by reverse phase HPLC (MeCN/water, 55%-65%).

Step 4:91-4 (1.2 g) was purified by SFC (column: REGIS (S,S)WHELK-01, 250×25 mm I.D., 10 μm, A for CO₂ and B for Ethanol) to afford 91-6 (200 mg) and 91-7 (250 mg) respectively. 91-6: SFC analysis: 100.00% ee; retention time: 5.932 min; column: ChiralPak AD, 250×30 mm I.D., 10 μm, A for CO₂ and B for Ethanol, 40%; pressure: 100 bar; flow rate: 70 mL/min. 91-7: SFC analysis: 98.76% cc; retention time: 7.760 min; column: ChiralPak AD, 250×30 mm I.D., 10 μm, A for CO₂ and B for Ethanol, 40%; pressure: 100 bar; flow rate: 70 mL/min.

Step 5: To a solution of 91-6 (180 mg, 0.39 mmol) in DCM (1 mL) under N₂ at −78° C. was added dropwise BBr₃ (3.86 mL, 3.86 mmol). After the addition was completed, the mixture was stirred at room temperature for 16 h. Ice water was added to the mixture to quench the reaction and the precipitation was collected by filtration, washed with H₂O and dried to afford 91-8.

Step 6: The mixture of 91-8 (160 mg, 0.35 mmol), 3-bromotetrahydrofuran (67.84 mg, 0.45 mmol) and Cs₂CO₃ (266.2 mg, 0.82 mmol) in DMF (5 mL) was stirred at 100° C. for 6 h. Then the mixture was washed with water and extracted with ethyl acetate. The organic layer was dried over Na₂SO₄, filtered and concentrated to afford 91-9.

Step 7: 91-9 (110 mg) was purified by SFC (column: ChiralPak AD, 250×30 mm I.D., 10 μm, A for CO2 and B for Ethanol) to afford 91 (26 mg) and 92 (15 mg) respectively. 91: SFC analysis: 100.00% ee; retention time: 2.519 min; column: ChiralPak AD, 250×30 mm I.D., 10 μm, A for CO2 and B for Ethanol, 35%; pressure: 100 bar; flow rate: 80 mL/min. LCMS (ESI, m/z): [M+H]⁺=523.4; ¹H NMR (400 MHz, DMSO-d(, ppm): δ 7.77 (s, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.52 (s, 1H), 7.19 (d, J=8.4 Hz, 1H), 6.91 (s, 1H), 5.45-5.40 (m, 1H), 4.18-4.12 (m, 1H), 3.99-3.93 (m, 1H), 3.89-3.85 (m, 3H), 3.82-3.71 (m, 2H), 3.48 (s, 3H), 3.45-3.40 (m, 2H), 2.38-2.32 (m, 2H), 2.30-2.26 (m, 2H), 2.21-2.17 (m, 1H), 2.15-1.97 (m, 3H), 1.58-1.52 (m, 1H), 1.45-1.33 (m, 1H), 0.71 (t, J=7.6 Hz, 3H). 92: SFC analysis: 100.00% ee; retention time: 2.012 min; column: ChiralPak AD, 250×30 mm I.D., 10 μm, A for CO2 and B for Ethanol, 35%; pressure: 100 bar; flow rate: 80 mL/min. LCMS (ESI, m/z): [M+H]⁺=523.4; ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 7.77 (s, 1H), 7.61-7.48 (m, 2H), 7.19 (d, J=8.0 Hz, 1H), 6.91 (s, 1H), 5.92-5.30 (m, 1H), 4.20-4.15 (m, 1H), 3.98-3.92 (m, 1H), 3.92-3.84 (m, 3H), 3.80-3.70 (m, 2H), 3.55-3.45 (m, 5H), 2.38-2.32 (m, 2H), 2.30-2.26 (m, 2H), 2.21-2.15 (m, 1H), 2.15-1.98 (m, 3H), 1.60-1.52 (m, 1H), 1.43-1.34 (m, 1H), 0.71 (t, J=7.0 Hz, 3H).

Example 27 Synthesis of Compound 95

Step 1: To a solution of 84-4 (179.8 mg, 0.53 mmol) in DCM (2 mL) was added dropwise a solution of 1-isocyanato-4-(trifluoromethyl)benzene (100 mg, 0.53 mmol) in DCM (2 mL). The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated, the residue was purified by column chromatography on silica gel (DCM/MeOH=10/1) to afford 95. LCMS (ESI, m/z): [M+H]⁺=524.2. ¹H NMR (400 MHz, DMSO-d₆, ppm) 8 9.55 (s, 1H), 8.98-8.91 (m, 2H), 8.63-8.55 (m, 1H), 7.75-7.66 (m, 2H), 7.64-7.57 (m, 2H), 5.51-4.83 (m, 2H), 4.41 (m, 1H), 4.20-4.07 (m, 1H), 3.58 (m, 1H), 3.33-3.13 (m, 1H), 1.86 1.63 (m, 4H), 0.97-0.85 (m, 6H). ¹⁹F NMR (377 MHz, DMSO-d₆, ppm) 6-59.99 (s, 3F).

Example 28 Synthesis of Compounds 98 and 99

Step 1: Compound 98-1 was prepared from compound 28-12 following the procedure for the synthesis of compound 28-14 in example 11.

Step 2: To a 0° C. solution of 98-2 (4 g, 17.08 mmol) in DCM (100 mL) were added triethylamine (5.18 g, 51.24 mmol), DMAP (357.2 mg, 1.71 mmol) and 4-methylbenzenesulfonyl chloride (4.88 g, 25.62 mmol). Then the reaction mixture was stirred at room temperature for 4 h. The reaction was quenched with H₂O, extracted with DCM. The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 5/1) to afford 98-3.

Step 3: To a solution of 98-3 (3.8 g, 9.78 mmol) in THF (100 mL) were added TBAF (1M in THF, 14.7 mL, 14.7 mmol) and TMSCN (1.16 g, 11.74 mmol). The reaction mixture was stirred at 60° C. for 1 h. Then the reaction was quenched with H₂O, extracted with ethyl acetate. The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 4/1) to afford 98-4.

Step 4: To a solution of 98-4 (1 g, 4.11 mmol) in acetone (20 mL) was added K₂CO₃ (1.14 g, 8.22 mmol) and H₂O₂ (4 mL). Then the mixture was stirred at 40° C. for 48 h. Then the reaction was quenched with H₂O, extracted with ethyl acetate. The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (DCM/MeOH=1/0 to 10/1) to afford 98-5.

Step 5: To a solution of 98-5 (670 mg, 2.56 mmol) in CCl₄ (10 mL) were added AIBN (42 mg, 0.26 mmol) and NBS (683.44 mg, 3.84 mmol). Then the reaction mixture was stirred at 90° C. for 16 h. Then the reaction was quenched with H₂O, extracted with ethyl acetate. The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (DCM/MeOH=1/0 to 10/1) to afford 98-6.

Step 6: To a solution of 98-6 (200 mg, 0.59 mmol) in MeCN (4 mL) were added 98-1 (265.5 mg, 0.59 mmol), DIPEA (380 mg, 2.94 mmol) and NaI (105.8 mg, 0.71 mmol). Then the reaction was stirred at 90° C. for 2 h. The solvent was removed under vacuum, and the residue was purified by reverse phase HPLC (MeCN/H₂O, 5-80%) to afford 98-7.

Step 7: To a solution of 98-7 (110 mg, 0.19 mmol) in THF (4 mL) was added Lawesson's reagent (74.83 mg, 0.19 mmol). Then the reaction mixture was stirred at 50° C. for 30 h. The solvent was removed under vacuum, and the residue was purified by reverse phase HPLC (MeCN/H₂O, 5-80%) to afford 98-8.

Step 8: To a solution of 98-8 (30 mg, 0.049 mmol) in EtOH (1 mL) was added 2-bromo-1-cyclopropylethan-1-one (16 mg, 0.098 mmol). Then the reaction mixture was stirred at 80° C. for 2 h. The solvent was removed under vacuum. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 2/3) to afford 98-9.

Step 9: To a mixture of 98-9 (20 mg, 0.03 mmol) in DMF (1 mL) was added Zn(CN)₂ (10.6 mg, 0.09 mmol) and Pd(PPh₃)₄ (3.5 mg, 0.003 mmol). Then the mixture was stirred at 130° C. for 2 h under microwave. The reaction mixture was purified by reverse phase HPLC (MeCN/H₂O (0.05% TFA), 5-80%) to afford 98 (5 mg) and 99 (7 mg). 98: LCMS (ESI, m/z): [M+H]⁺=666.4; ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 8.23 (d, J=8.8 Hz, 1H), 8.01-7.88 (m, 3H), 7.79-7.70 (m, 2H), 7.25 (s, 1H), 5.96-5.82 (m, 0.5H), 5.42-5.38 (m, 0.5H), 5.22 (s, 1H), 4.98-4.83 (m, 1H), 3.62-3.58 (m, 0.5H), 3.43 (s, 3H), 3.38-3.32 (m, 0.5H), 2.80-2.71 (m, 1H), 2.23-2.18 (m, 1H), 2.05-1.88 (m, 3H), 1.49-1.38 (m, 3H), 0.86-0.77 (m, 6H), 0.70-0.64 (m, 1H), 0.62-0.45 (m, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆, ppm): δ 87.47 (1F), 64.17 (4F). 99: LCMS (ESI, m/z): [M+H]⁺=666.4; ¹H NMR (400 MHz, DMSO-d(, ppm): δ 8.28-8.19 (m, 1H), 8.02-7.88 (m, 3H), 7.82-7.73 (m, 2H), 7.30 (s, 1H), 5.95-5.82 (m, 0.5H), 5.43-5.38 (m, 0.5H), 5.27 (s, 1H), 5.01-4.85 (m, 1H), 3.62-3.58 (m, 0.5H), 3.49-3.42 (m, 3.5H), 2.20-2.11 (m, 1H), 2.08-1.84 (m, 4H), 1.73-1.37 (m, 3H), 0.90-0.82 (m, 2H), 0.79-0.61 (m, 8H). ¹⁹F NMR (376 MHz, DMSO-dd, ppm): δ 87.33 (1F), 64.18 (4F).

Example 29 Synthesis of Compound 102

Step 1: To a mixture of 102-1 (400 mg, 2.48 mmol), tert-butyl 2-ethyl-4-oxopiperidine-1-carboxylate (564.3 mg, 2.48 mmol) in THF (10 mL) was added dropwise TiCl₄ (235.4 mg, 1.24 mmol) at room temperature. The mixture was stirred for another 30 minutes, then sodium triacetoxyborohydride (1052.3 mg, 4.97 mmol) was added and the mixture was stirred at room temperature for 12 h. The mixture was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 4/1) to afford 102-2.

Step 2: To a mixture of 102-2 (646 mg, 1.74 mmol), acetaldehyde (382.1 mg, 8.68 mmol) in THF (10 mL) was added dropwise TiCl₄ (164.5 mg, 0.87 mmol) at room temperature. The mixture was stirred for another 30 minutes, then and sodium triacetoxyborohydride (735.2 mg, 3.47 mmol) was added and the mixture was stirred at room temperature for 12 h. The reaction mixture concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=10/1 to 3/1) to afford 102-3.

Step 3: To a solution of 102-3 (345 mg, 0.86 mmol) in DCM (5 mL) was added ethyl acetate/HCl (0.43 mL) and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to dryness to afford 102-4 which was used for the next step directly without further purification.

Step 4: Compound 102 was prepared from compound 102-4 following the procedure for the synthesis of compound 84-3 in example 25. LCMS (ESI, m/z): [M+H]⁺=495.3; ¹H NMR (400 MHz, DMSO-d₆, ppm): δ9.52 (s, 1H), 8.95-8.93 (d, J=8.8 Hz, 1H), 8.58-8.56 (d, J=8.8 Hz, 1H), 7.39-7.37 (d, J=8.8 Hz, 2H), 6.83-6.81 (d, J=8.8 Hz, 2H), 4.75-4.69 (m, 2H), 4.05-4.03 (m, 1H), 3.72-3.71 (m, 1H), 3.45-3.34 (m, 2H), 2.34-2.33 (m, 1H), 2.14-1.75 (m, 5H), 1.17-0.98 (m, 6H). ¹⁹F NMR (376 MHz, DMSO-d₆, ppm): δ −58.90 (3F).

Example 30 Synthesis of Compound 103

Step 1: To a mixture of 103-1 (9.50 g, 26.79 mmol) and ethyl (2E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-enoate (7.87 g, 34.83 mmol) in dioxane (95 mL) and H₂O (9.5 mL) were added Pd(dppf)Cl₂ (2.0 g, 2.68 mmol) and Na₂CO₃ (5.7 g, 53.59 mmol) at room temperature. Then the mixture was heated at 100 for 12 h. The mixture was filtered and the filtrate was concentrated under vacuo. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 1/4) to afford 103-2.

Step 2: To a mixture of 103-2 (12 g, 25.71 mmol) and CoCl₂·6H₂O (0.6 g, 2.57 mmol) in MeOH (360 mL) and THF (180 mL) was added NaBH₄ (5.8 g, 154.23 mmol) in portions at 0. Then the mixture was stirred at room temperature for 1 h. H₂O was added to the reaction mixture. This mixture was extracted with ethyl acetate. The combined organic layers were dried over Na₂SO₄, filtered and the filtrate was concentrated under vacuo. The residue was purified by column chromatography on silica gel (DCM) to afford 103-3.

Step 3: 103-3 (7.6 g, 23.12 mmol) in HCl/ethyl acetate (100 mL) was stirred at room temperature for 1 h. The mixture was concentrated under vacuo to afford 103-4.

Step 4: Compound 103 was prepared from compound 103-4 following the procedure for the synthesis of compound 59 in example 20. LCMS (ESI, m/z): [M+H]⁺=511.2; ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 8.07 (s, 1H), 7.82-7.77 (m, 2H), 7.49-7.47 (m, 2H), 4.92-4.17 (m, 4H), 3.91-3.83 (m, 2H), 3.35 (s, 2H), 2.96-2.89 (m, 2H), 2.02-1.90 (m, 6H). ¹⁹F NMR (376 MHz, DMSO-d₆, ppm): δ −56.75 (3F).

Example 31 Synthesis of Compound 104

Step 1: The mixture of 104-1 (5.0 g, 44.59 mmol), 1-(pyridin-3-yl)propan-1-one (7.23 g, 53.51 mmol), AgNO₃ (2.27 g, 13.38 mmol), H₂SO₄ (9.75 g, 89.18 mmol) and ammonium persulfate (10.17 g, 44.59 mmol) in H₂O (70 mL) and DCM (70 mL) was flushed with N₂ for 0.5 min, then the mixture was stirred at 25° C. for 18 h. The mixture quenched by addition of saturated NaHCO₃ solution, the aqueous layer was extracted with DCM. The organic extracts were combined, washed with brine, dried over anhydrous Na₂SO₄. The solvent was concentrated and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=3/1) to afford 104-2.

Step 2: To a solution of 104-2 (560 mg, 2.78 mmol) in MeOH (10 mL) was added NaBH₄ (12.3 mg, 3.34 mmol) at 0° C., the reaction mixture was stirred at room temperature for 2 h. The mixture was quenched by addition of H₂O, and the aqueous layer was extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over anhydrous Na₂SO₄ and concentrated to afford 104-3.

Step 3: To a solution of 104-3 (580 mg, 2.85 mmol) in DCM (15 mL) were added DMF (21.0 mg, 0.29 mmol) and SOCl₂ (509 mg, 4.28 mmol) at 0° C., the reaction mixture was stirred at room temperature for 3 hr. The solvent was removed under reduced pressure to afford 104-4 which was used for next step directly without further purification.

Step 4: The mixture of 28-9 (100 mg, 0.43 mmol), 104-4 (239 mg, 1.08 mmol), DIPEA (0.29 mL, 1.72 mmol) and NaI (129 mg, 0.86 mmol) in MeCN (2 mL) was stirred at 85° C. for 18 h. The mixture was filtered and concentrated, the residue was purified by reverse phase HPLC (0.05% NH₄HCO₃ in water/MeCN, 5-95%) to afford 104-5.

Step 5: To a solution of 104-5 (80 mg, 0.19 mmol) in 1,2-dichloroethane (1 mL) was added 1-chloroethyl chloromethanoate (274.5 mg, 1.92 mmol), the reaction was stirred at 110° C. for 96 h. The mixture was concentrated in vacuo, the residue was diluted with THF and H₂O. Then the mixture was stirred at 70° C. for 3 h. The solvent was removed under reduced pressure to afford 104-6 which was used for next step directly without further purification.

Step 6: Compound 104 was prepared from compound 104-6 following the procedure for the synthesis of compound 84-3 in example 25. LCMS (ESI, m/z): [M+H]⁺=522.4. ¹H NMR (400 MHz, DMSO-d₆, ppm) δ 9.49-9.46 (m, 1H), 8.92-8.87 (m, 1H), 8.56-8.51 (m, 1H), 8.42-8.37 (m, 1H), 7.73-7.67 (m, 1H), 7.30-7.23 (m, 1H), 5.94-5.83 (m, 0.5H), 5.45-5.23 (m, 0.5H), 5.21-4.74 (m, 1H), 3.64-3.47 (m, 1H), 3.46-3.40 (m, 0.5H), 3.30-3.07 (m, 0.5H), 2.92-2.80 (m, 1H), 2.56-2.55 (m, 1H), 2.30-2.23 (m, 1H), 2.14-2.08 (m, 6H), 2.00-1.82 (m, 3H), 1.70-1.35 (m, 4H), 1.03-0.94 (m, 3H), 0.72-0.58 (m, 6H).

Example 32 Synthesis of Compounds 107 and 108

Step 1: To a stirred solution of 107-1 (500 g, 3.27 mol) in dry DCM (5000 mL) was added benzaldehyde (352 g, 3.32 mol), K₂CO₃ (494.9 g, 3.58 mol) and Na₂SO₄ (462 g, 3.25 mol). The reaction mixture was stirred at room temperature for 6 h. Then sodium triacetoxyborohydride (1030 g, 4.86 mol) was added in portion wise over 30 minutes to the mixture at ice-bath. The mixture was stirred at room temperature for 16 h. The solid was removed by filtration and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and HCl (1N). The mixture was extracted with ethyl acetate. The pH of the aqueous layer was adjusted to 8.0 with NaHCO₃(aq) and the milky aqueous layer was extracted immediately with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to afford 107-2.

Step 2: To a solution of 107-2 in DMF (3500 mL) were added DIPEA (885 mL, 5.08 mol) and HATU (966 g, 2.54 mol), the reaction mixture was stirred at 0° C. for 10 minutes, then methyl (2R)-2-(benzylamino)butanoate (351 g, 1.69 mol) was added to the reaction mixture. The result mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous Na₂SO₄, filtered and evaporated under reduced pressure to afford 107-3.

Step 3: Compound 107-4 was prepared from compound 107-3 following the procedure for the synthesis of compound 67-14 in example 22.

Step 4: To a stirred solution of 107-4 (4.8 g, 11.31 mmol) in isopropanol (150 mL) was added Pd/C (10%, 0.96 g, 9.02 mmol) at room temperature, the resulting mixture was stirred at 80 under H₂ balloon for 15 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated to afford 107-5.

Step 5: A mixture of 107-5 (1 g, 3.89 mmol), 34-2 (1.73 g, 7.78 mmol), NaI (1.2 g, 7.78 mmol), DIPEA (2.03 mL 11.66 mmol) and K₂CO₃ (6.1 g, 44.2 mmol) in CH₃CN (15 mL) was stirred at 85 for 15 h. Another portion of DIPEA (2.03 mL, 11.66 mmol), NaI (1.2 g, 7.78 mmol) and 34-2 (1.73 g, 7.78 mmol) was added into the reaction mixture at 20° C. The resulting mixture was stirred at 85 under N₂ for 15 h. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 2/3) to afford 107-6.

Step 6: To a stirred solution of 107-6 (4.57 g, 10.09 mmol) in MeOH (20 mL) was added dropwise HCl in ethyl acetate (4M, 9.1 mL) at room temperature, the resulting mixture was stirred at 2 for 15 h. The reaction mixture was concentrated under reduced pressure to afford 107-7.

Step 7: Compound 107-8 was prepared from compound 107-7 following the procedure for the synthesis of compound 67-20 in example 22.

Step 8: To a stirred solution of 107-8 (350 mg, 0.63 mmol) in DMF (10 mL) was added CsF (285.5 mg, 1.88 mmol) at 15° C., the resulting mixture was stirred at 110 for 15 h. The reaction mixture was diluted with H₂O and extracted with ethyl acetate. The organic layer was combined, washed with H₂O and brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 0/1) to afford 107 (60 mg) and 108 (crude, 110 mg), the crude 108 was purification again by reverse phase HPLC (MeCN/water (0.5% FA): 30/70) to afford pure 108 (44 mg) as 0.33 FA salt. 107: LCMS (ESI, m/z): [M+H]⁺=512.4. ¹H NMR (400 MHz, Methanol-d4, ppm) δ 8.04 (d, J=8.7 Hz, 1H), 7.89 (d, J=8.7 Hz, 1H), 7.69-7.62 (m, 2H), 7.61-7.54 (m, 2H), 4.36-4.25 (m, 1H), 4.09-4.03 (m, 1H), 4.02-3.92 (m, 1H), 3.87-3.78 (m, 1H), 3.79-3.70 (m, 4H), 3.10-2.97 (m, 2H), 2.96-2.85 (m, 1H), 2.50-2.40 (m, 1H), 2.20-2.05 (m, 1H), 1.98-1.85 (m, 1H), 1.80-1.65 (m, 2H), 1.22 (t, J=7.4 Hz, 3H), 0.72 (t, J=7.3 Hz, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆, ppm): δ −63.83 (3F). 108: LCMS (ESI, m/z): [M+H]⁺=512.4. ¹H NMR (400 MHz, Methanol-d₄, ppm) δ 8.01 (s, 0.33 H), 8.00-7.98 (m, 1H), 7.86-7.83 (m, 1H), 7.65-7.63 (m, 2H), 7.48-7.46 (m, 2H), 4.72-4.60 (m, 1H), 4.40-4.32 (m, 1H), 4.15-4.00 (m, 2H), 3.68 (s, 3H), 3.45-3.38 (m, 1H), 3.30-3.26 (m, 1H), 3.23-3.16 (m, 1H), 2.38-2.37 (m, 1H), 2.26-2.20 (m, 1H), 2.10-1.92 (m, 2H), 1.90-1.70 (m, 2H), 1.03 (t, J=7.4 Hz, 3H), 0.87 (t, J=7.3 Hz, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆, ppm): δ −63.91 (3F).

Example 33 Synthesis of Compounds 109 and 110

Step 1: A solution of 34-9 (845 mg, 1.63 mmol), tert-butyl carbamate (287.2 mg, 2.45 mmol), Cs₂CO₃ (1.06 g, 3.27 mmol) and XantPhos Pd G₂ (17.2 mg, 0.019 mmol) in dioxane (15 mL) was stirred at 100 under N₂ for 6 h. The mixture was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 3/1) to afford 109-1.

Step 2: To a solution of 109-1 (660 mg, 1.1 mmol) in DCM (8 mL) was added HCl/ethyl acetate (6 mL). The mixture was stirred at 30 for 12 h. The mixture was concentrated to afford 109-2.

Step 3: A solution of 109-2 (611 mg, 1.23 mmol), 2-chloroacetaldehyde (5 mL, 0.49 mmol) and AcOH (0.070 mL, 1.23 mmol) in EtOH (12 mL) was stirred at 80 for 16 h. The mixture was concentrated. The residue was purified by reverse phase HPLC (MeCN/water (0.5% FA): 5%-80%) to afford 109-3.

Step 4: 109-3 (80 mg) was purified by prep-SFC (column: ChiralPak AD, 250×30 mm I.D., 5 μm, Ethanol/CO2=40/60) to afford 109 (42 mg) and 110 (17 mg). 109: SFC analysis: 100% ee; retention time: 1.393 min; column: Chiralpak AD-3 150×4.6 mm I.D., 3 μm, 40% of Ethanol (0.05% of DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min; LCMS (ESI, m/z): [M+H]⁺=522.3; ¹H NMR (400 MHz, DMSO-d₆, ppm) δ 8.84-8.82 (d, J=8.8 Hz, 1H), 8.47-8.45 (d, J=8.8 Hz, 1H), 8.184-8.181 (d, J=1.2 Hz, 1H), 7.75-7.73 (d, J=8.0 Hz, 2H1), 7.59-7.57 (d, J=8.0 Hz, 2H), 7.328-7.325 (d, J=1.2 Hz, 1H), 5.45-4.80 (m, 2H), 3.73-3.54 (m, 1H), 3.35-3.26 (m, 1H), 3.01-2.91 (m, 1H), 2.88-2.80 (m, 1H), 2.36-2.31 (m, 1H), 2.12-1.88 (m, 3H), 1.67-1.39 (m, 3H), 1.03-0.86 (m, 3H), 0.71-0.52 (m, 6H). ¹⁹F NMR (377 MHz, DMSO-d₆, ppm) 6-60.66 (3F). 110: SFC analysis: 100% ee; retention time: 3.046 min; column: Chiralpak AD-3 150×4.6 mm I.D., 3 μm, 40% of Ethanol (0.05% of DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min; LCMS (ESI, m/z): [M+H]⁺=522.4; ¹H NMR (400 MHz, DMSO-d₆, ppm) δ 8.86-8.84 (d, J=8.8 Hz, 1H), 8.49-8.47 (d, J=8.8 Hz, 1H), 8.26-8.14 (m, 1H), 7.73-7.71 (d, J=8.0 Hz, 2H), 7.60-7.58 (d, J=8.0 Hz, 2H), 7.42-7.26 (m, 1H), 5.75-4.55 (m, 2H), 3.61-3.41 (m, 2H), 3.22-3.02 (m, 1H), 2.66-2.53 (m, 1H), 2.27-2.12 (m, 1H), 2.03-1.73 (m, 3H), 1.69-1.36 (m, 3H), 1.06-0.90 (m, 3H), 0.71-0.49 (m, 6H). ¹⁹F NMR (377 MHz, DMSO-d₆, ppm) 6-60.67 (3F).

Example 34 Synthesis of Compounds 113 and 114

Step 1: To a solution of 28-11 (3.0 g, 12.38 mmol) in DCM (30 mL) was added DIPEA (5.12 mL, 30.95 mmol) and benzyl carbonochloridate (3.49 mL, 24.76 mmol), then the reaction mixture was stirred at 20° C. for 18 h. The reaction was concentrated in vacuo. The residue was diluted with ethyl acetate and water. The mixture was extracted with ethyl acetate. The combined organic layer was washed with NaCl aqueous and dried by Na₂SO₄, the solvent was concentrated and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 3/1) to afford 113-1.

Step 2: To a solution of 113-1 (4.5 g, 11.98 mmol) in DCM (30 mL) was added TFA (6 mL, 11.98 mmol) and the reaction was stirred at 20° C. for 18 h. The reaction mixture was concentrated under vacuo, the residue was dilute with DCM and neutralized by NaHCO₃ aqueous. The mixture was extracted with DCM. The combined organic layer was concentrated to afford 113-2.

Step 3: To a solution of 113-2 (500 mg, 1.81 mmol) in MeCN (20 mL) was added DIPEA (0.6 mL, 3.62 mmol), NaI (543 mg, 3.62 mmol) and 44-6 (900 mg, 3.62 mmol), and the reaction mixture was stirred at 80° C. for 24 h. The reaction was concentrated in vacuo. The residue was diluted with ethyl acetate and water. The mixture was extracted with ethyl acetate. The combined organic layer was washed with NaCl aqueous and dried by Na₂SO₄, filtered and the solvent was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 1/1) to afford 113-3.

Step 4: To a solution of 113-4 (280 mg, 0.57 mmol) in MeOH (10 mL) was added Pd/C 10% (6.1 mg, 0.057 mmol) under N₂. The then the reaction was stirred at 25° C. for 18 h at H₂ atmosphere. The mixture was filtered and the filtrate was concentrated to afford 113-4.

Step 5: Compound 113-5 was prepared from compound 113-4 following the procedure for the synthesis of compound 84-3 in example 25.

Step 6: 113-5 (73 mg) was purified by prep-SFC (column: ChiralPak IG, 250×30 mm I.D., 10 μm, MeOH(0.1% NH₃H2O)/CO2=40/60) to afford 113 (34.8 mg) and 114 (7.68 mg). 113: SFC analysis: 95% ee; retention time: 5.52 min; column: ChiralPak IG, 100×4.6 mm I.D., 3 μm, MeOH (0.05% DEA) in CO2, 5% to 40%; pressure: 100 bar; flow rate: 2.5 mL/min. LCMS (ESI, m/z): [M+H]⁺=549.4. ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 9.50 (s, 1H), 8.93-8.91 (d, J=8.4 Hz, 1H), 8.56-8.54 (d, J=8.4 Hz, 1H), 7.53-7.40 (m, 3H), 6.18-4.42 (m, 2H), 3.86-3.77 (m, 1H), 3.69-3.40 (m, 2H), 3.04 (m, 1H), 2.83-2.71 (m, 1H), 2.62-2.53 (m, 1H), 2.15-1.90 (m, 5H), 1.87-1.71 (m, 2H), 1.65-1.48 (m, 3H), 1.39-1.27 (m, 1H), 1.06-0.97 (m, 3H), 0.68-0.51 (m, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆, ppm) 6-60.77 (3F). 114: SFC analysis: 100% ee; retention time: 5.82 min; column: ChiralPak IG, 100×4.6 mm I.D., 3 μm, MeOH (0.05% DEA) in CO2, 5% to 40%; pressure: 100 bar; flow rate: 2.5 mL/min. LCMS (ESI, m/z): [M+H]⁺=549.4. ¹H NMR (400 MHz, methanol-d4, ppm): δ 9.33 (s, 1H), 8.80-8.74 (m, 1H), 8.35-8.25 (m, 1H), 7.43-7.35 (m, 3H), 6.00-5.65 (m, 1H), 5.15-4.89 (m, 1H), 3.82-3.77 (m, 1H), 3.73-3.63 (m, 1H), 3.06-3.00 (m, 1H), 2.78-2.67 (m, 2H), 2.36-2.03 (m, 6H), 1.78-1.70 (m, 1H), 1.67-1.50 (m, 3H), 1.44-1.29 (m, 2H), 1.16-1.08 (m, 3H), 0.68-0.51 (m, 3H). ¹⁹F NMR (376 MHz, methanol-d4, ppm): δ −63.91 (3F).

Example 35 Synthesis of Compounds 119 and 120

Step 1: To a solution of 28-9 (3 g, 12.91 mmol) and methyl 2-bromobutanoate (7.01 g, 38.73 mmol) in MeCN (50 mL) were added DIPEA (6.40 mL, 38.73 mmol) and NaI (1.9 g, 12.91 mmol) at room temperature. Then the mixture was heated at 80 for 12 h. The mixture was concentrated under vacuo, the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 10/1) to afford 119-1.

Step 2: To a solution of 119-1 (3.4 g, 10.23 mmol) in propan-2-ol (80 mL) was added (Boc)₂O (3.05 mL, 13.29 mmol) and Pd/C (10%, 0.5 g, 4.67 mmol) at room temperature. Then the mixture was stirred at 30 under H₂ balloon for 12 h. The mixture was filtered and the filtrate was concentrated under vacuo. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 6/1) to afford 119-2.

Step 3: To a solution of 119-2 (3.0 g, 8.76 mmol) in THF (30 mL) and H₂O (20 mL) was added LiOH (0.6 g, 13.14 mmol) at room temperature. Then the mixture was stirred at 30 for 12 h. NaOH (1.1 g, 26.28 mmol) was added to the reaction mixture. The mixture was heated at 80 for 12 h. The solvent was removed under vacuo. The pH of the residue was adjusted to 3 with HCl(6N). The mixture was extracted with DCM. The combined organic layers were dried over Na₂SO₄, filtered and the filtrate was concentrated to afford 119-3.

Step 4: To a mixture of 119-3 (2.7 g, 8.22 mmol) and N-hydroxycyclopropanecarboximidamide (0.82 g, 8.22 mmol) in DMF (80 mL) was added BOP (10.9 g, 24.66 mmol) and triethylamine (3.43 mL, 24.66 mmol) at room temperature. Then the mixture was stirred at room temperature for 0.5 h and heated at 90 for 4 h. The mixture was concentrated under vacuo. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 1/1) to afford 119-4.

Step 5: To a solution of 119-4 (400 mg, 1.02 mmol) in DCM (4 mL) was added TFA (4 mL) at room temperature. Then the mixture was stirred at room temperature for 1 h. The mixture was concentrated under vacuo to afford 119-5 which was used for the next step directly without further purification.

Step 6: Compound 119-6 was prepared from compound 119-5 following the procedure for the synthesis of compound 84-3 in example 25.

Step 7: 119-6 (160 mg) was purified by SFC (column: ChiralCel OX, 250×30 mm I.D., 10 μm, methanol/CO₂=30/70) to afford 119 (97.92 mg) and 120 (12.41 mg) respectively. 119: SFC analysis: 99.54% ee; retention time: 7.29 min; column: ChiralCel OX, 100×4.6 mm T.D., 3 μm, 40% of methanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. LCMS (ESI, m/z): [M+H]⁺=487.4. ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 9.49 (s, 1H), 8.93-8.91 (d, J=8.2 Hz, 1H), 8.58-8.56 (d, J=8.4 Hz, 1H), 5.51-5.21 (m, 1H), 5.12-4.91 (m, 1H), 4.03 (m, 1H), 3.50-3.47 (m, 1H), 3.04-3.02 (m, 1H), 2.68 (m, 2H), 2.16 (s, 1H), 1.96-1.72 (m, 4H), 1.44-1.03 (m, 4H), 0.97-0.76 (m, 11H); 120: SFC analysis: 98.66% ee; retention time: 8.28 min; column: ChiralCel OX, 100×4.6 mm I.D., 3 μm, 40% of methanol (0.05% DEA) in CO₂; pressure: 100 bar; flow rate: 2.5 mL/min. LCMS (ESI, m/z): [M+H]⁺=487.4. ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 9.50 (s, 1H), 8.92-8.90 (d, J=8.7 Hz, 1H), 8.6-8.54 (d, J=8.6 Hz, 1H), 7.38-7.18 (m, 1H), 5.25-4.90 (m, 1H), 4.04-4.00 (m, 1H), 3.53-3.44 (m, 1H), 3.03-2.94 (m, 1H), 2.87-2.78 (m, 1H), 2.62-2.55 (m, 1H), 2.16-2.09 (m, 1H), 2.08-1.94 (m, 1H), 1.89-1.72 (m. 3H), 1.56-1.44 (m, 1H), 1.10-1.02 (m. 3H), 0.92-0.79 (m, 11H).

Example 36 Synthesis of Compounds 121 and 122

Step 1: A solution of 121-1 (4 g, 18.49 mmol), 34-2 (5.35 g, 24.04 mmol), NaI (0.6 g, 3.69 mmol) and DIPEA (7.64 mL, 46.24 mmol) in MeCN (30 mL) was stirred at 85 for 12 h. The mixture was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 1/1) to afford 121-2.

Step 2: To a solution of 121-2 (2 g, 4.97 mmol) in DCM (12 mL) was added HCl/ethyl acetate (6 mL) at 15 . The mixture was stirred at 15 for 2 h. The mixture was concentrated to afford 121-3.

Step 3: Compound 121-4 was prepared from compound 121-3 following the procedure for the synthesis of compound 67-20 in example 22.

Step 4: To a solution of 121-4 (225 mg, 0.42 mmol) in DMF (30 mL) was added NaH (50.9 mg, 2.12 mmol) at 15 . The mixture was stirred at 110 for 16 h. water was added to quench the reaction. The mixture was extracted with ethyl acetate. The organic phase was concentrated. The residue was purified by column chromatography on silica gel (DCM/MeOH=1/0 to 10/1) to afford 121-5.

Step 5: To a solution of 121-5 (130 mg, 0.26 mmol) in THF (6 mL) was added triethyl amine (0.072 mL, 0.52 mmol) and TFAA (0.14 mL, 1.04 mmol) at 0 . The mixture was stirred at 15 for 48 h. The mixture was diluted with H₂O, extracted with ethyl acetate. The organic phase was concentrated. The residue was purified by reverse phase HPLC (0.5% TFA in water/MeCN, 5-70%) to afford 121-6.

Step 6: 121-6 (70 mg) was purified by SFC (column: ChiralCel OD, 250×30 mm I.D., 5 μm, Ethanol/CO₂=30/70) to afford 121 (18 mg) and 122 (5 mg) respectively. 121: SFC analysis: 100% ee; retention time: 2.69 min; column: ChiralCel OD, 150×4.6 mm I.D., 3 μm, 40% of ethanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. LCMS (ESI, m/z): [M+H]⁺=484.4. ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 8.13-8.00 (m, 2H), 7.78-7.66 (m, 2H), 7.58-7.42 (m, 2H), 4.80-4.50 (m, 1H), 4.34-4.20 (m, 1H), 4.12-3.96 (m, 1H), 3.58 (s, 3H), 3.50-3.42 (m, 1H), 3.34-3.23 (m, 2H), 2.84-2.70 (m, 2H), 2.35-2.25 (m, 1H), 2.22-2.10 (m, 1H), 2.03-1.88 (m, 1H), 1.83-1.68 (m, 1H), 0.73 (t, J=7.0 Hz, 3H). 19F NMR (376 MHz, DMSO-d₆, ppm) 6-60.73 (3F); 122: SFC analysis: 99.34% ee; retention time: 3.16 min; column: ChiralCel OD, 150×4.6 mm I.D., 3 μm, 40% of ethanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. LCMS (ESI, m/z): [M+H]⁺=484.4. ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 8.11-7.97 (m, 2H), 7.78-7.66 (m, 2H), 7.56-7.42 (m, 2H), 4.65-4.35 (m, 1H), 4.32-4.20 (m, 1H), 4.16-4.02 (m, 1H), 3.58 (s, 3H), 3.51-3.40 (m, 1H), 3.33-3.25 (m, 2H), 2.92-2.76 (m, 1H), 2.70-2.57 (m, 1H), 2.34-2.20 (m, 2H), 2.02-1.89 (m, 1H), 1.80-1.66 (m, 1H), 0.74 (t, J=7.2 Hz, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆, ppm) δ −60.75 (3F).

Example 37 Synthesis of Compounds 123 and 124

Step 1: To a stirred solution of 67-14 (2 g, 5.98 mmol) in isopropanol (35 mL) was added Pd/C (10%, 0.5 g, 0.470 mmol) at 25, the resulting mixture was stirred at 50 under H₂ balloon for 15 h. The reaction mixture was filtered and the filtrate was concentrated to afford 123-1.

Step 2: Compound 123-2 was prepared from compound 123-1 following the procedure for the synthesis of compound 67-20 in example 22.

Step 3: To a stirred solution of 123-2 (140 mg, 0.3 mmol) in DMF (15 mL) was added potassium tert-butoxide (99.7 mg, 0.89 mmol) at 15, the resulting mixture was stirred at 110 for 20 h. The reaction mixture was concentrated, the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 0/1) to afford 123-3.

Step 4: Compound 123 and 124 was prepared from compound 123-3 following the procedure for the synthesis of compound 28-15 in example 11. The product was obtained by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 0/1). 123: LCMS (ESI, m/z): [M+H]⁺=544.4. ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 8.11-8.06 (m, 2H), 7.71-7.69 (d, J=7.8 Hz, 2H), 7.53-7.51 (d, J=7.8 Hz, 2H), 5.32-5.25 (m, 1H), 4.16-4.14 (m, 1H), 3.83-3.79 (m, 1H), 3.61-3.52 (m, 4H), 3.35-3.31 (m, 1H), 3.09-2.99 (m, 2H), 2.38-2.33 (m, 2H), 2.01-1.86 (m, 2H), 1.79-1.72 (m, 2H), 1.04-1.00 (m, 3H), 0.59-0.52 (m, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆, ppm) 6-42.17 (3F). 124: LCMS (ESI, m/z): [M+H]⁺=544.4. ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 8.05 (s, 2H), 7.72-7.70 (d, J=8.0 Hz, 2H), 7.50-7.48 (d, J=7.8 Hz, 2H), 4.72-4.68 (m, 1H), 4.38-4.35 (m, 1H), 4.04-3.99 (m, 1H), 3.75-3.71 (m, 1H), 3.59 (s, 3H), 3.42-3.39 (m, 1H), 3.11-3.08 (m, 1H), 2.92-2.89 (m, 1H), 2.67-2.59 (m, 1H), 2.36-2.34 (m, 1H), 2.00-1.94 (m, 1H), 1.68-1.66 (m, 3H), 0.75-0.61 (m, 6H). ¹⁹F NMR (376 MHz, DMSO-d₆, ppm) 6-42.31 (3F).

Example 38 Synthesis of Compound 145

Step 1: Compound 67 and 145 was prepared from compound 123-3 following the procedure for the synthesis of compound 28-15 in example 11. The product was obtained by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 0/1). 145: LCMS (ESI, m/z): [M+H]⁺=512.2; ¹H NMR (400 MHz, CD₃OD, ppm) δ 8.08-8.04 (m, 1H), 7.94-7.90 (m, 1H), 7.67-7.62 (m, 2H), 7.59-7.55 (m, 2H), 5.62-5.52 (m, 1H), 4.18-4.11 (m, 1H), 3.91-3.84 (m, 1H1), 3.71 (s, 3H1), 3.68-3.61 (m, 11H), 3.49-3.41 (m, 11H), 3.25-3.11 (m, 3H1), 2.45-2.41 (m, 1H), 2.05-1.92 (m, 1H), 1.91-1.81 (m, 1H), 1.68-1.53 (m, 2H), 1.11 (t, J=7.4 Hz, 3H), 0.65 (t, J=7.3 Hz, 3H). ¹⁹F NMR (376 MHz, CD₃OD, ppm) 6-63.86 (3F).

Example 39 Synthesis of Compound 154

Step 1: To a solution of 154-1 in acetone (200 mL) was added ethyl 4-bromobutanoate (10.63 g, 54.51 mmol), K₂CO₃ (9.4 g, 68.14 mmol), and NaI (1.0 g, 6.81 mmol), the reaction mixture was stirred at 70° C. for 18 h. The mixture was concentrated in vacuo. The residue was diluted with ethyl acetate and water. The organic layer was separated and washed with NaCl aqueous. The organic layer was dried by Na₂SO₄, filtered and concentrated, the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 4/1) to afford 154-2.

Step 2: To a solution of 154-2 (13.7 g, 40.98 mmol) in DMF (300 mL) was added C₂H5OH (2.5 mL, 42.82 mmol) and NaH (3.8 g, 94.26 mmol), the mixture was stirred at room temperature for 18 h. Then the reaction mixture was heated to 100° C. for 2 h. The reaction mixture was cooled to room temperature, quenched with HCl. The mixture was concentrated in vacuo. The residue was diluted with ethyl acetate and water. The organic layer was separated and washed with NaCl aqueous. The organic layer was dried by Na₂SO₄, filtered and concentrated, the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 1/1) to afford 154-3 and 154-4.

Step 3: To a mixture of 154-3 (3.3 g, 10.92 mmol) and 154-4 (3.3 g, 11.45 mmol) in dioxane (100 mL) was added HCl (25 mL, 10.92 mmol) and the reaction was stirred at 100° C. for 18 h. The mixture was concentrated in vacuo. The residue was diluted with ethyl acetate and neutralized with NaHCO₃ aqueous. The organic layer was separated and washed with NaCl aqueous. The organic layer was dried by Na₂SO₄, filtered and concentrated, the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 3/2) to afford 154-5.

Step 4: To a solution of 154-5 (4.5 g, 19.55 mmol) in CH₃OH (40 mL) was added NaBH₄ (813.5 mg, 21.5 mmol) and the reaction was stirred at 0° C. for 18 h. The reaction was quenched with NH₄Cl aqueous and concentrated in vacuo. The residue was diluted with ethyl acetate and water. The organic layer was separated and washed with NaCl aqueous. The organic layer was dried by Na₂SO₄, filtered and concentrated, the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 3/2) to afford 154-6.

Step 5: Compound 154 was prepared from compound 154-6 following the procedure for the synthesis of compound 44-7 in example 17. The product was obtained by reverse phase HPLC (acetonitrile/H₂O: 5%˜95%) to afford 154. LCMS (ESI, m/z): [M+H]⁺=541.3; ¹H NMR (400 MHz, CDCl₃, ppm) δ 7.88-7.77 (m, 1H), 7.62-7.54 (m, 1H), 7.43-7.33 (m, 1H), 7.30-7.26 (m, 2H), 6.23-5.74 (m, 1H), 5.63-5.32 (m, 1H), 5.32-5.03 (m, 1H), 4.45-3.93 (m, 2H), 3.88-3.67 (m, 2H), 3.60-3.53 (m, 3H), 3.40-2.91 (m, 1H), 2.86-2.76 (m, 1H), 2.70-2.31 (m, 2H), 2.24-2.13 (m, 2H), 2.02-1.87 (m, 2H), 1.45-1.37 (m, 2H), 1.08-0.91 (m, 3H), 0.83-0.47 (m, 3H). ¹⁹F NMR (376 MHz, CDCl3, ppm) 6-62.52 (3F).

Example 40 Synthesis of Compound 192

Step 1: A solution of 192-1 (6 g, 25.84 mmol), NBS (5.1 g, 28.42 mmol) and AIBN (0.4 g, 2.584 mmol) in CCl₄ (60 mL) was stirred at 80 under N₂ for 15 h. The reaction mixture was concentrated under vacuo. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 3/1) to afford 192-2.

Step 2: Compound 192-4 was prepared from compound 192-3 following the procedure for the synthesis of compound 67-14 in example 22.

Step 3: To a stirred solution of 192-4 (3.6 g, 10.76 mmol) in isopropanol (50 mL) was added Pd/C (10%, 0.72 g) at 25 T, the resulting mixture was stirred at 50 under H₂ balloon for 15 h. The reaction mixture was filtered and the filtrate was concentrated to afford 192-5.

Step 4: To a stirred solution of 192-2 (3.02 g, 9.72 mmol), 192-5 (2.5 g, 9.72 mmol) and NaI (0.15 g, 1.0 mmol) in CH₃CN (50 mL) was added DIPEA (8.47 mL, 48.60 mmol) at 25, the resulting mixture was stirred at 95 for 15 h. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 1/1) to afford 192-6.

Step 5: To a stirred solution of NaBH₄ (132.4 mg, 3.50 mmol) in THF (3 mL) was added a cooled solution of 192-6 (500 mg, 1.17 mmol) in THF (6 mL) and Boron trifluoride diethyl etherate (2.9 mL, 1.17 mmol) dropwisely at 0-10 under N₂. After addition, the reaction mixture was stirred at 90 for 4.5 h. A cooled solution of HCl was added to quench the reaction. The reaction mixture was diluted with H₂O and extracted with ethyl acetate. The organic layer was combined, washed with brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel (DCM/methanol=1/0 to 5/1) to afford 192-7.

Step 6: Compound 192 was prepared from compound 192-7 following the procedure for the synthesis of compound 84-3 in example 25. The product was obtained by reverse phase HPLC (0-60% acetonitrile in water) to afford 192 (77 mg). LCMS (ESI, m/z): [M+H]⁺=509.2; ¹H NMR (400 MHz, CD₃OD, ppm) δ 9.36 (s, 1H), 8.82-8.76 (m, 1H), 8.32-8.28 (m, 1H), 7.72-7.59 (m, 4H), 5.47 (s, 1H), 4.85-4.61 (m, 1H), 4.01-3.87 (m, 1H), 3.82-3.73 (m, 1H), 3.60-3.48 (m, 2H), 3.448-3.40 (m, 1H), 3.13 (s, 1H), 2.73 (t, J=10.0 Hz, 2H), 2.34-2.02 (m, 3H), 0.88 (t, J=7.5 Hz, 3H). ¹⁹F NMR (376 MHz, CD₃OD, ppm) δ −64.02 (3F).

Example 41 Synthesis of Compounds 198 and 199

Step 1: To a stirred solution of 123-1 (7.5 g, 30.7 mmol) in THF (50 mL) and H₂O (50 mL) were added NaHCO₃ (7.7 g, 92.09 mmol) and CbzOSu (8.4 g, 33.76 mmol). The reaction mixture was stirred at 25 for 3 h. The reaction mixture was diluted with ethyl acetate, washed

with brine and dried over anhydrous Na₂SO₄. Evaporation of the solvent under reduced pressure, the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 3/1) to afford 198-1.

Step 2: NaIO₄ (9.9 g, 46.3 mmol) was dissolved in water (50 mL) and CH₃CN/dimethyl carbonate (40 ml, 1:1), then Ruthenium(III) chloride trihydrate (60.5 mg, 0.23 mmol) was added to the mixture, followed by a solution of 198-1 (8.76 g, 23.15 mmol) in CH₃CN/dimethyl carbonate (60 ml, 1:1) at 0 over 1 minutes. The solution was stirred at 25 for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organics were washed with brine and dried over Na₂SO₄. The mixture was filtered and concentrated. The residue was partitioned between ethyl acetate and NaHCO₃ aqueous. The layers were separated and the aqueous layer was extracted with ethyl acetate. The aqueous layer was adjusted to pH=3 with 2M HCl and the aqueous layer was extracted immediately with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to afford 198-2.

Step 3: To a stirred solution of 198-2 (6.4 g, 16.31 mmol) in CH₃CN (120 mL) were added K₂CO₃ (3.4 g, 24.46 mmol) and CH₃I (3.5 g, 24.46 mmol). The reaction mixture was stirred at 60° C. for 2 h. The reaction mixture was partitioned between ethyl acetate and H₂O. The separated organic layer was washed with brine and dried over anhydrous Na₂SO₄, filtered and concentrated, the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 5/11) to afford 198-3.

Step 4: To a stirred solution of 198-3 (5.76 g, 14.17 mmol) in propan-2-ol (50 mL) was added Pd/C (10%, 0.8 g). The reaction mixture was stirred at 25° C. under H₂ for 18 h. The reaction mixture was filtered, washed with propan-2-ol, evaporated under reduced pressure to afford 198-4.

Step 5: The mixture of 67-7 (4.4 g, 13.81 mmol), 198-4 (3.76 g, 13.81 mmol) and DIEA (6.85 mL, 41.44 mmol) in CH₃CN (50 mL) was stirred at 85° C. for 3 h. The solvent was removed under reduced pressure, the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 3/1) to afford 198-5.

Step 6: To a stirred solution of 198-5 (6.9 g, 12.45 mmol) in AcOH (70 mL) at 25° C. was added Fe (2.4 g, 43.56 mmol). The resultant suspension was stirred at 80 for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was suspended in CH₂Cl₂ and aqueous NaHCO₃ was added until the solution was adjusted to pH=8. The mixture was filtered. The phases were separated and the aqueous was washed with CH₂Cl₂. The combined organic extracts were washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated, the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 1/1) to afford 198-6.

Step 7: The mixture of 198-6 (300 mg, 0.61 mmol), K₂CO₃ (168.4 mg, 1.22 mmol), and CH₃I (864.8 mg, 6.09 mmol) in CH₃CN (5 mL) was stirred at 70° C. for 18 h. The solvent was removed under reduced pressure, the residue was purified by C18 reverse phase column (CH₃CN/H₂O (0.05% TFA), 5-95%) to afford 198-7.

Step 8: Compound 198 and 199 was prepared from compound 198-7 following the procedure for the synthesis of compound 28 and 29 in example 11. The product was obtained by SFC (column: ChiralPak AD, 250><30 mm, 10 μm, Ethanol (0.1% NH₃H2O)/Supercritical CO₂=25/75) to afford 198 (9.5 mg) and 199 (11.5 mg). 198: LCMS (ESI, m/z): [M+H]⁺=539.4; SFC analysis: 100% ee; retention time: 1.341 min; column: ChiralPak AD, 150×4.6 mm, 3 μm, 40% EtOH (0.05% DEA) in CO₂; pressure: 100 bar; flow rate: 2.5 mL/min. ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 8.18-8.12 (m, 2H), 7.70 (d, J=8.1 Hz, 2H), 7.58 (d, J=8.1 Hz, 2H), 5.17-5.04 (m, 1H), 3.78-3.68 (m, 2H), 3.63 (s, 3H), 3.49-3.39 (m, 1H), 3.24 (s, 3H), 3.09-3.01 (m, 1H), 2.94-2.76 (m, 2H), 1.94-1.83 (m, 1H), 1.69-1.47 (m, 3H), 0.94 (t, J=7.3 Hz, 3H), 0.62 (t, J=7.2 Hz, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆, ppm): δ −60.69 (3F). 199: LCMS (ESI, m/z): [M+H]⁺=539.4; SFC analysis: 99.48% ee; retention time: 1.603 min; column: ChiralPak AD, 150×4.6 mm, 3 μm, 40% EtOH (0.05% DEA) in CO₂; pressure: 100 bar; flow rate: 2.5 mL/min. ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 8.18-8.06 (m, 2H), 7.72 (d, J=8.1 Hz, 2H), 7.55 (d, J=8.1 Hz, 2H), 4.03-3.93 (m, 1H), 3.90-3.83 (m, 1H), 3.75-3.65 (m, 2H), 3.63 (s, 3H), 3.42-3.35 (m, 1H), 3.33 (s, 3H), 2.70-2.62 (m, 1H), 2.61-2.53 (m, 1H), 2.10-2.00 (m, 1H), 1.77-1.61 (m, 2H), 1.51-1.43 (m, 1H), 0.85-0.75 (m, 6H); ¹⁹F NMR (376 MHz, DMSO-d₆, ppm): δ −60.77 (3F) Example 42 Synthesis of Compounds 210 and 211

Step 1: To a stirred solution of 210-1 (10 g, 66.16 mmol) in AcOH (60 mL) and H2O (120 mL) was added iodine (16.8 g, 66.16 mmol) over a period of 10 minutes. The reaction mixture was stirred at room temperature for 48 h. The reaction mixture was filtered and the solid was collected and dried under vacuum to afford 210-2.

Step 2: To a stirred solution of 210-2 (12.1 g, 43.67 mmol) in dioxane (120 mL) was added triphosgene (7.1 g, 24.02 mmol) at 25, the resulting mixture was stirred at 100 for 15 h. The reaction mixture was concentrated under reduced pressure to afford 210-3 which was used for the next step directly.

Step 3: NaH (1.8 g, 45.89 mmol) was added to a mixture of diethyl malonate (27.28 mL, 180.56 mmol) and DMF (240 mL) with stirring at room temperature. A mixture of 210-3 (12 g, 37.62 mmol) and DMF (240 mL) was added dropwise to this solution, the mixture was stirred at 120 for 4 h. The mixture was filtered and the solid was added to H₂O (1 L) and HCl (30%, 200 mL), the mixture was stirred and filtered. The solid was collected and dried to afford 210-4.

Step 4: A solution of ethyl 210-4 (12 g, 32.16 mmol) in TFA (95 mL) and HCl (95 mL) was stirred at 100 for 16 h. The reaction mixture was diluted with H₂O and filtered. The cake was washed with a large amount of H₂O and dried under reduced pressure to afford 210-5.

Step 5: To a stirred solution of 210-5 (3 g, 9.96 mmol) in AcOH (26 mL) was added HNO₃ (1.6 mL, 2.46 mmol) at 25, the resulting mixture was stirred at 80 for 1.5 h. The reaction mixture was cooled to 25 and diluted with H₂O, after stirred for 10 minutes, the resulting solid was filtered and dried to afford 210-6.

Step 6: To a stirred solution of 210-6 (2.7 g, 7.80 mmol) and Zn (CN)₂ (2.7 g, 23.41 mmol) in DMF (40 mL) was added Pd(PPh₃)₄ (0.9 g, 0.78 mmol) at room temperature, the resulting mixture was stirred at 110 for 36 h under N₂. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (0-20% CH₃CN in H₂O (0.5% FA)) to afford 210-7.

Step 7: To a stirred solution of 210-7 (700 mg, 2.86 mmol) in toluene (15 mL) were added DIPEA (2.98 mL, 17.13 mmol) and POCl₃ (1.33 mL, 14.28 mmol) at room temperature, the resulting mixture was stirred at 110 under N₂ for 1.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 0/1) to afford 210-8.

Step 8: To a stirred solution of 67-18 (680 mg, 1.76 mmol) in CH₃CN (20 mL) were added DIPEA (3.07 mL, 17.63 mmol) and 210-8 (820.4 mg, 2.65 mmol) at room temperature, the resulting mixture was stirred at 85 under N₂ for 5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 1/2) to afford 210-9.

Step 9: To a stirred solution of 210-9 (320 mg, 0.57 mmol) in NMP (9 mL) was added t-BuOK (193.2 mg, 1.72 mmol) in one portion at room temperature, the resulting mixture was stirred at 120 for 18 h. The reaction mixture was diluted with H₂O and extracted with ethyl acetate. The organic layer was combined, washed with brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 2/3) by column chromatography (eluting with 0-60% EtOAc in petroleum ether) to afford 210 (8.56 mg) and 211 (22.04 mg). 210: LCMS (ESI, m/z): [M+H]+=511.2. ¹H NMR (400 MHz, CDCl₃, ppm) δ 7.97 (s, 1H), 7.62-7.52 (m, 3H), 7.45-7.39 (m, 2H), 7.36-7.30 (m, 1H), 4.20 (t, J=10.2 Hz, 1H), 3.90-3.81 (m, 1H), 3.80-3.73 (m, 1H), 3.67 (s, 3H), 3.34-3.28 (m, 1H), 3.09-2.98 (m, 2H), 2.99-2.89 (m, 1H), 2.81-2.72 (m, 1H), 2.51-2.42 (dd, 1H), 1.87-1.71 (m, 2H), 1.68-1.54 (m, 2H), 0.90 (t, J=7.4 Hz, 3H), 0.82 (t, J=7.3 Hz, 3H). ¹⁹F NMR (376 MHz, CDCl₃, ppm) δ −62.39 (3F). 211: LCMS (ESI, m/z): [M+H]⁺=511.2. ¹H NMR (400 MHz, CDCl₃, ppm) δ 7.95-7.86 (m, 1H), 7.62-7.53 (m, 3H), 7.32-7.27 (m, 3H), 4.55 (t, J=10.5 Hz, 1H), 4.25-4.18 (m, 1H), 3.97 (t, J=7.5 Hz, 1H), 3.71-3.64 (m, 3H), 3.27-3.21 (m, 1H), 3.16-3.04 (m, 1H), 3.01-2.92 (m, 1H), 2.77-2.64 (m, 1H), 2.57-2.42 (m, 2H), 1.96-1.82 (m, 1H), 1.80-1.64 (m, 3H), 0.93-0.77 (m, 6H). ¹⁹F NMR (376 MHz, CDCl₃, ppm) δ −62.46 (3F).

Example 43 Synthesis of Compound 219

Step 1: To a solution of propionaldehyde (4 g, 68.87 mmol) in THF (60 mL) was added (R)-(2-methylprop-2-yl)(oxo)-λ4-sulfanamine (10.0 g, 82.65 mmol) and Ti(OEt)₄ (47.1 g, 206.61 mmol) at room temperature. Then the mixture was heated at 60 for 2 h. The mixture was cooled to room temperature and quenched with H₂O. The mixture was filtered and the filtrate was concentrated under vacuo. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 5/1) to afford 219-2.

Step 2: A mixture of 219-3 (6.6 g, 36.83 mmol), Boc₂O (12.69 mL, 55.24 mmol) and triethylamine (15.36 mL, 110.48 mmol) in DCM (100 mL) was stirred at room temperature for 2 h. H₂O was added to the mixture, then the mixture was extracted with DCM. The combined organic layers were dried over Na₂SO₄, filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 1/1) to afford 219-4.

Step 3: To a solution of 219-4 (4 g, 14.32 mmol) in THF (60 mL) was added LiHMDS (1M, 14.32 mL) at −78 After the mixture was stirred at −78 for 30 minutes, 219-2 (2.31 g, 14.32 mmol) was added. Then the mixture was stirred at −78 for 30 minutes. The mixture was quenched with saturated NH₄Cl. The mixture was extracted with ethyl acetate. The combined organic layers were dried over Na₂SO₄, filtered and the filtrate was concentrated under vacuo. The reside was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 1/2) to afford 219-5.

Step 4: To a solution of 219-5 (6 g, 13.62 mmol) in THF (60 mL) was added LiAlH₄ (0.8 g, 20.43 mmol) at 0. Then the mixture was stirred at 0 for 0.5 h. The mixture was quenched with H₂O, NaOH (15%) and H₂O. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 1/2) to afford 219-6.

Step 5: To a solution of 219-6 (2.26 g, 5.48 mmol) in dioxane (10 mL) was added HCl/dioxane (40 mL) at room temperature. Then the mixture was stirred at room temperature for 1 h. This mixture was concentrated under vacuo to afford 219-7.

Step 6: To a mixture of 219-7 (1141 mg, crude) and ethyl 2-ethoxy-2-oxoacetate (1.6 g, 10.95 mmol) in DCM (6 mL) and methanol (24 mL) was added CH₃ONa (1183.6 mg, 21.91 mmol) at room temperature. Then the mixture was stirred at room temperature for 12 h and stirred at 60 for 2 h. The mixture was concentrated under vacuo, the residue was purified by column chromatography on silica gel (DCM/methanol=1/0 to 5/1) to afford 219-8.

Step 7: To a solution of 219-8 (1.0 g, 3.81 mmol) in THF (8 mL) was added borane tetrahydrofuran (22.87 mL, 22.87 mmol) at room temperature. Then the mixture was heated at 80 for 1 h. The mixture was quenched with methanol and HCl. This mixture was concentrated under vacuo to afford 219-9.

Step 8: To a solution of 219-9 (893 mg, crude) in THF (10 mL) and H₂O (10 mL) were added NaHCO₃ (3201.4 mg, 38.11 mmol) and (Boc)₂O (1.05 mL, 4.57 mmol) at room temperature. Then the mixture was stirred at room temperature for 30 minutes. H₂O was added to the mixture and the mixture was extracted with ethyl acetate. The combined organic layers were dried over Na₂SO₄, filtered and the filtrate was concentrated under vacuo. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 5/1) to afford 219-10.

Step 9: Compound 219-11 was prepared from compound 219-10 following the procedure for the synthesis of compound 192-7 in example 40.

Step 10: Compound 219 (26 mg) was prepared from compound 219-11 following the procedure for the synthesis of compound 5 in example 5. LCMS (ESI, m/z): [M+H]⁺=499.2; ¹H NMR (400 MHz, DMSO-d₆, ppm) δ 8.30-8.19 (m, 1H), 8.05-7.97 (m, 1H), 7.77-7.64 (m, 4H), 5.85-5.32 (m, 1H), 5.24-4.56 (m, 1H), 3.96-3.66 (m, 2H), 3.58-3.47 (m, 1H), 3.45 (s, 3H), 3.40-3.34 (m, 1H), 3.31-3.24 (m, 1H), 3.16-3.06 (m, 1H), 2.78-2.54 (m, 2H), 2.37-2.20 (m, 1H), 2.10-1.99 (m, 1H), 1.74-1.57 (m, 1H), 0.81 (t, J=7.4 Hz, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆, ppm): δ −60.88-60.90 (3F).

Example 44 Synthesis of Compounds 220 and 221

Step 1: The mixture of 67-7 (4 g, 12.56 mmol), 123-1 (3.07 g, 12.56 mmol) and DIPEA (4.9 g, 37.68 mmol) in MeCN (40 mL) was stirred at 85° C. for 3 h. The solvent was removed under reduced pressure, the residue was purified by column chromatography on silica gel (ethyl acetate/DCM=1/3) to afford 220-1.

Step 2: To a stirred solution of 220-1 (3.79 g, 7.2 mmol) in ethyl acetate (40 mL) was added 5% Pt/C (0.7 g, 3.6 mmol). The reaction mixture was stirred at 25° C. under H₂ for 18 h. The reaction mixture was filtered, washed with ethyl acetate, evaporated under reduced pressure to afford 220-2.

Step 3: To a solution of 220-2 (3.57 g, 7.19 mmol) and triethylamine (4 mL, 28.77 mmol) in CH₂Cl₂ (30 mL) was added MsCl (1.6 g, 14.38 mmol) at 0° C. Then the reaction mixture was stirred at 25° C. for 1 h, the solvent was removed under reduced pressure to afford 220-3 which was used for next step directly.

Step 4: To a solution of 220-3 (4.13 g, crude) in DMF (30 mL) was added DIPEA (1.9 g, 14.38 mmol). Then the reaction was stirred at 120° C. for 5 h. The reaction was purified by C18 reverse phase column (MeCN/H₂O(0.05% TFA), 5-95%) to afford 220-4.

Step 5: To a solution of 220-4 (1.0 g, 2.09 mmol) in anhydrous THF (10 mL) was added NaH (334.5 mg, 8.36 mmol) at 0° C., the mixture further stirred at 0° C. under N₂ for 30 mins. Then CH₃I (890.1 mg, 6.27 mmol) in THF (10 mL) was added dropwise and the mixture stirred at 25° C. for 1 h. The reaction was quenched with H₂O at 0° C. The mixture was partitioned between ethyl acetate and H₂O, the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine. The organic phase was separated, dried over Na₂SO₄, filtered and concentrated to afford 220-5.

Step 6: Compounds 220 and 221 were prepared from compound 220-5 following the procedure for the synthesis of compound 28-15 in example 11. The products, 220 (14 mg) and 221 (17 mg), were obtained by C18 reverse phase column (MeCN/H₂O (0.05% TFA), 5-95%) and column chromatography on silica gel (ethyl acetate/DCM=1/1). 220: LCMS (ESI, m/z): [M+H]+=525.3. ¹H NMR (400 MHz, methanol-d₄, ppm): δ 8.01 (d, J=8.7 Hz, 1H), 7.87 (d, J=8.7 Hz, 1H), 7.65 (d, J=8.1 Hz, 2H), 7.60 (d, J=8.1 Hz, 2H), 5.33-5.24 (m, 1H), 3.68 (s, 3H), 3.67-3.61 (m, 1H), 3.21-3.10 (m, 2H), 3.07-2.98 (m, 1H), 2.86-2.77 (m, 4H), 2.75-2.67 (m, 1H), 2.42-2.36 (m, 2H), 2.13-1.98 (m, 2H), 1.72-1.60 (m, 2H), 1.29-1.23 (m, 3H), 0.67 (t, J=7.3 Hz, 3H); ¹⁹F NMR (376 MHz, methanol-d₄, ppm): δ −63.83 (3F). 221: LCMS (ESI, m/z): [M+H]⁺=525.3. ¹H NMR (400 MHz, methanol-d4, ppm): δ 7.97 (d, J=8.7 Hz, 1H), 7.81 (d, J=8.7 Hz, 1H), 7.66 (d, J=8.1 Hz, 2H), 7.57 (d, J=8.1 Hz, 2H), 4.84-4.79 (m, 1H), 3.82-3.74 (m, 1H), 3.68 (s, 3H), 3.29-3.24 (m, 1H), 3.09-2.96 (m, 3H), 2.94-2.86 (m, 4H), 2.66-2.57 (m, 1H), 2.52-2.45 (m, 1H), 2.13-1.93 (m, 2H), 1.72-1.63 (m, 2H), 0.92 (t, J=7.4 Hz, 3H), 0.71 (t, J=7.3 Hz, 3H); ¹⁹F NMR (376 MHz, methanol-d₄, ppm): δ −63.86 (3F).

Example 45 Synthesis of Compound 227

Step 1: A mixture of 67-5 (50 g, 196.08 mmol), aniline (50 g, 537.63 mmol), and trimethyl orthoformate (56.3 g, 530.53 mmol.) in ethyleneglycol (400 mL) was heated to 70° C. under stirring. The temperature was increased to 170° C., then kept at 170° C. for 2 h. After cooling the solid was collected with filtration and washed with EtOH, dried at 55˜60° C. to afford 227-1.

Step 2: To a solution of 227-1 (63 g, 175.88 mmol) in anhydrous DMF (400 mL) was slowly added POCl₃ (42 g, 273.94 mmol) and the mixture was stirred at room temperature for 20 h. The mixture was poured into ice water (3.2 L), and the precipitate was collected with filtration and dried at 55-60° C. to afford 227-2.

Step 3: To a solution of 67-18 (150 mg, 0.45 mmol) in DCM (10 mL) were added 1H-imidazole (494.5 mg, 7.26 mmol), DMAP (5.5 mg, 0.045 mmol) and TBSCl (136.9 mg, 0.91 mmol). The reaction mixture was stirred at 25° C. for 4 h under N₂. The reaction was partitioned between DCM and H₂O. The separated organic layer was washed with brine and dried over anhydrous Na₂SO₄. Evaporation of the solvent under reduced pressure afford 227-3.

Step 4: The mixture of 227-2 (140 mg, 0.46 mmol), 227-3 (206.5 mg, crude), and Na₂CO₃ (98.4 mg, 0.93 mmol) in THF (4 mL) was stirred at 75° C. for 3 h. The solvent was removed under reduced pressure, the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 1/1) to afford 227-4.

Step 5: To a solution of 227-4 (200 mg, 0.28 mmol) and TMSOTf (62.6 mg, 0.28 mmol) in DCM (25 mL) was added Et₃SiH (65.5 mg, 0.56 mmol) at −78. The mixture was stirred at 25 for 3 h. The reaction was quenched by addition of H₂O, and the aqueous layer was extracted with DCM. The organic extracts were combined, washed with brine, dried over anhydrous Na₂SO₄ and concentrated to afford 227-5.

Step 6: To a solution of 227-5 (250 mg, 0.43 mmol) in DMF (5 mL) were added Zn(CN)₂ (152.0 mg, 1.29 mmol), Zn (8.5 mg, 0.13 mmol) and palladium(0)bis[tris(2-methylprop-2-yl)phosphane](22.0 mg, 0.043 mmol). The reaction mixture was stirred at 85° C. for 3 h under N₂. The reaction was concentrated to give a residue. The residue was purified by C18 reverse phase column (MeCN/H₂O (0.05% NH₃·H₂O), 5-95%) to afford 227 (53 mg). LCMS (ESI, m/z): [M+H]⁺=526.2. ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 8.11-8.00 (m, 2H), 7.73 (d, J=8.1 Hz, 2H), 7.48 (d, J=8.1 Hz, 2H), 4.81-4.72 (m, 1H), 4.68-4.55 (m, 2H), 4.43-4.32 (m, 1H), 4.20-4.10 (m, 1H), 4.05-3.94 (m, 1H), 3.87-3.78 (m, 1H), 3.53 (s, 3H), 2.98-2.84 (m, 2H), 2.44-2.35 (m, 1H), 2.13-1.98 (m, 2H), 1.97-1.85 (m, 1H), 1.77-1.64 (m, 1H), 1.58-1.40 (m, 1H), 0.96 (t, J=7.2 Hz, 3H), 0.87 (t, J=7.2 Hz, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆, ppm): δ −60.79 (3F).

Example 46 Synthesis of Compound 235

Step 1: To a solution of 235-1 (5 g, 24.49 mmol) in CCl₄ (50 mL) was added NBS (4.8 g, 26.94 mmol) and AIBN (0.4 g, 2.45 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction was diluted with ethyl acetate and water. The organic layer was separated, washed with saturated NaCl and concentrated in vacuo. The residue was purified by C18 column and was eluted with (Acetonitrile in water (0.1% FA), 0-70%, keep in 50% 25 min) to afford 235-2.

Step 2: To a solution of 235-2 (500 mg, 1.77 mmol) in MeOH (10 mL) was added H₂SO₄ (0.1 mL). This reaction mixture stirred at 85° C. for 18 h. The reaction mixture was diluted with ethyl acetate and saturated NaHCO₃. The organic layer was separated, washed with saturated NaCl and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 1/2) to afford 235-3.

Step 3: Compound 235-4 was prepared from compound 235-3 and 123-3 following the procedure for the synthesis of compound 28-15 in example 11.

Step 4: To a solution of 235-4 (300 mg, 0.55 mmol) in THF (3 mL) and water (0.5 mL) was added LiOH (232.5 mg, 5.54 mmol) The reaction mixture was stirred at 0° C. at N₂ overnight. The crude product was purified by reverse HPLC (0.1% TFA in water/MeCN, 0-70%) to afford 235-5.

Step 5: 235-5 (37 mg) was purified by SFC (column: ChiralCel OD, 250×30 mm I.D., 10 μm, Methanol/Supercritical CO₂=50/50) to afford 235-6 (15 mg) and 235-7 (8 mg). 235-6: SFC analysis: 100% ee; retention time: 6.129 min; column: ChiralCel OD, 100×4.6 mm I.D., 3 μm, 40% of Ethanol (0.05% DEA) in CO₂; pressure: 100 bar; flow rate: 2.5 mL/min. 235-7: SFC analysis: 100% ee; retention time: 8.821 min; column: ChiralCel OD, 100×4.6 mm I.D., 3 μm, 40% of Ethanol (0.05% DEA) in CO₂; pressure: 100 bar; flow rate: 2.5 mL/min.

Step 6: To a solution of 235-6 (20 mg, 0.038 mmol) in THF (2 mL) was added CDI (15.4 mg, 0.095 mmol), the reaction mixture stirred at 60° C. for 18 h. NaBH₄ (3.6 mg, 0.095 mmol) was added in and stirred at room temperature for 2 h. This reaction mixture was diluted with ethyl acetate and saturated NaCl. The organic layer was separated, washed with saturated NaCl and concentrated in vacuo. The residue was purified by reverse HPLC (MeCN in water (0.1% NH₄HCO₃), keep in 50%) to afford 235 (3 mg). LCMS (ESI, m/z): [M+H]⁺=514.2. ¹H NMR (400 MHz, methanol-d₄, ppm) δ 8.05 (d, J=8.8 Hz, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.67-7.52 (m, 4H), 5.46 (d, J=15.2 Hz, 1H), 4.17 (d, J=11.0 Hz, 1H), 3.93-3.81 (m, 4H), 3.71 (s, 3H), 3.57-3.46 (m, 1H), 3.29-3.19 (m, 1H), 3.15-3.05 (m, 1H), 2.59-2.48 (m, 2H), 1.95-1.82 (m, 1H), 1.75-1.63 (m, 1H), 1.10 (t, J=7.4 Hz, 3H). ¹⁹F NMR (376 MHz, methanol-d₄, ppm) 8-63.88 (3F).

Example 47 Synthesis of Compounds 241 and 242

Step 1: To a solution of 241-1 (10 g, 49.98 mmol) in DCM (100 mL) was added acetic anhydride (5.63 mL, 59.97 mmol) and triethylamine (13.89 mL, 99.96 mmol), then the reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with H₂O. The mixture was extracted with ethyl acetate. Combined the organic layer and washed with NaHCO₃. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 1/1) to afford 241-2.

Step 2: To a stirred solution of 241-2 (9.4 g, 38.82 mmol) in DCM (100 mL) was added oxalyl Chloride (3.94 mL, 46.59 mmol). The mixture was warmed up to room temperature and stirred for 1 h, then FeCl₃ (12.6 g, 77.65 mmol) was added, and stirred at room temperature for 24 h. The reaction was quenched with 1M HCl. The mixture was extracted with DCM. The organic layers were combined and dried over Na₂SO₄, filtered and concentrated to afford 241-3 which was used for the next step directly.

Step 3: To a solution of 241-3 (10 g, crude) in MeOH (100 mL) was added H₂SO₄ (25 mL). The reaction mixture was stirred at 65° C. for 4 h. After cooling to room temperature, the reaction mixture was quenched with NH₃·H₂O. The mixture was extracted with DCM. The organic layers were dried over Na₂SO₄, filtered and concentrated to afford 241-4 which was used for the next step directly.

Step 4: To a solution of 241-4 (5.5 g, crude) in EtOH (20 mL) was in portions added NaBH₄ (0.84 g, 22.10 mmol). After stirred at 0 for 2 h, HCl (15 mL, 5M) was added and the mixture was stirred at room temperature for 16 h. The solvent was removed and EtOH was added to the residue, followed by NH₃H₂O at 0° C. to quench the reaction. The mixture was extracted with DCM. The organic layers were dried over Na₂SO₄, filtered and concentrated to afford 241-5 which was used for the next step directly.

Step 5: To a stirred solution of 241-5 (5 g, crude) in DCM (10 mL) were added TEA (9.22 mL, 66.33 mmol) and (BOC)₂O (4.32 mL, 18.8 mmol) at 0° C. the reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with H₂O, extracted with ethyl acetate. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 4/1) to afford 241-6.

Step 6: To a solution of 241-6 (2 g, 6.13 mmol) in DMF (4 mL) and H₂O (1 mL) were added K₂CO₃ (3.4 g, 24.52 mmol) and Pd(PPh₃)₂Cl₂ (0.5 g, 0.61 mmol). Then the reaction mixture was stirred at 80° C. for 24 h. After cooling to room temperature, the reaction was quenched with H₂O. The mixture was extracted with DCM. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 2/1) to afford 241-7.

Step 7: To a solution of 241-7 (2.6 g, 6.64 mmol) in DCM (21 mL) was added TFA (7 mL). Then the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated to afford 241-8 which was used for the next step directly.

Step 8: Compound 241-9 was prepared from compound 241-8 following the procedure for the synthesis of compound 5 in example 5.

Step 9: 241-9 (100 mg) was purified by SFC (column: ChiralPak AD, 250×30 mm, 10 μm, Ethanol/Supercritical CO₂=35/65) to afford 241 (25 mg) and 242 (28 mg) respectively. 241: SFC analysis: 100% ee; retention time: 1.637 min; column: Chiralpak AD 150×4.6 mm I.D., 3 μm, 40% EtOH (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. LCMS (ESI, m/z): [M+H]⁺=476.4. ¹H NMR (400 MHz, methanol-d4, ppm): δ 8.13-8.03 (m, 1H), 8.01-7.90 (m, 1H), 7.80-7.70 (m, 2H), 7.59-7.49 (m, 2H), 7.42-7.20 (m, 2H), 7.15-7.05 (m, 1H), 6.78-6.65 (m, 0.5H), 6.21-6.11 (m, 0.5H), 5.61-5.50 (m, 0.5H), 4.86-4.75 (m, 0.5H), 3.82-3.71 (m, 0.5H), 3.58 (s, 3H), 3.51-3.40 (m, 0.5H), 3.22-3.02 (m, 1H), 2.78-2.55 (m, 1H), 1.91-1.60 (m, 3H); ¹⁹F NMR (376 MHz, methanol-d₄, ppm): δ −60.87 (3F). 242: SFC analysis: 99.56% ee; retention time: 2.105 min; Column: Chiralpak AD 150×4.6 mm I.D., 3 μm, 40% EtOH (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. LCMS (ESI, m/z): [M+H]⁺=476.4. ¹H NMR (400 MHz, methanol-d₄, ppm): δ 8.13-8.03 (m, 1H), 8.01-7.90 (m, 1H), 7.79-7.69 (m, 2H), 7.53-7.42 (m, 2H), 7.45-7.20 (m, 2H), 7.15-7.05 (m, 1H1), 6.76-6.65 (m, 0.5H1), 6.21-6.09 (m, 0.5H), 5.60-5.50 (m, 0.5H), 4.86-4.76 (m, 0.5H), 3.82-3.75 (m, 0.5H), 3.58 (s, 3H), 3.50-3.39 (m, 0.5H), 3.22-3.02 (m, 1H), 2.78-2.54 (m, 1H), 1.93-1.60 (m, 3H); ¹⁹F NMR (376 MHz, methanol-d₄, ppm): δ −60.87 (3F).

Example 48 Synthesis of Compound 252

Step 1: Compound 252-1 was prepared from compound 67-3 following the procedure for the synthesis of compound 67-7 in example 22.

Step 2: Compound 252-2 was prepared from compound 252-1 following the procedure for the synthesis of compound 67 in example 22.

Step 3: To a stirred solution of 252-2 (5 mg, 0.008 mmol) in TFA (1.5 mL) was stirred at 70° C. under N₂ for 18 h. The reaction mixture was concentrated. The residue was purified by C18 reverse phase column (MeCN/H₂O(0.05% NH₃·H₂O), 5-95%) to afford 252 (3 mg). LCMS (ESI, m/z): [M+H]⁺=498.2. ¹H NMR (400 MHz, methanol-d4, ppm): δ 7.91 (d, J=8.5 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.66 (d, J=8.1 Hz, 2H), 7.56 (d, J=8.1 Hz, 2H), 5.30-5.20 (m, 1H), 4.48-4.35 (m, 1H), 4.12-4.03 (m, 1H), 3.81-3.72 (m, 1H), 3.68-3.57 (m, 1H), 3.19-3.12 (m, 1H), 3.10-3.03 (m, 1H), 2.75-2.65 (m, 1H), 2.55-2.45 (m, 1H), 2.11-2.02 (m, 1H), 1.79-1.60 (m, 3H), 0.81 (t, J=7.4 Hz, 3H), 0.70 (t, J=7.3 Hz, 3H); ¹⁹F NMR (376 MHz, methanol-d4, ppm): δ −63.87 (3F).

Example 49 Synthesis of Compounds 261 and 262

Step 1: To a solution of 261-1 (2 g, 9.38 mmol) in EtOH (20 mL) was added TMSCN (1.76 mL, 14.07 mmol) and (NH₄)₂CO₃ (4.5 g, 46.89 mmol) at room temperature. Then the mixture was stirred at 60° C. for 6 h. This mixture was concentrated under vacuo. The residue was purified by column chromatography on silica gel (DCM/MeOH=1/0 to 6/1) to afford 261-2.

Step 2: To a solution of 261-2 (1.7 g, 6.0 mmol) in THF (30 mL) was added Boc₂O (5.51 mL, 24.0 mmol), DMAP (0.1 g, 1.20 mmol) and triethylamine (2.50 mL, 18.0 mmol) at room temperature. Then the mixture was stirred at room temperature for 2h. This mixture was washed with H₂O, extracted with ethyl acetate, dried and concentrated to afford 261-3 which was used for the next step directly.

Step 3: To a solution of 261-3 (2.8 g, crude) in THF (30 mL) and H₂O (10 mL) was added KOH (9.7 g, 172.88 mmol). Then the mixture was stirred at room temperature for 3 h. The mixture was concentrated under vacuo. The residue was purified by reverse-HPLC (57% MeCN in H₂O) to afford 261-4.

Step 4: A solution of LiAlH₄ (161.6 mg, 4.26 mmol) in THF (15 mL) was stirred at 0° C. under N₂ for 0.5 h. Then 261-4 (550 mg, 2.13 mmol) was added and stirred at 25° C. for 16 h. The mixture was diluted with THF, quenched with saturated Na₂SO₄, filtered and the filtrate was concentrated to afford 261-5 which was used for the next step directly.

Step 5: Compound 261 and 262 was prepared from compound 261-5 following the procedure for the synthesis of compound 36 in example 15. The product was purified by reverse-HPLC (80% ACN in H₂O) and SFC (Column: ChiralPak IG, 250×30 mm I.D., 10 μm; 30% Ethanol in CO₂, Flow rate: 150 mL/min, Back pressure: 100 bar) to afford 261 (8 mg) and 262 (8 mg). 261: SFC analysis: 100% ee; retention time: 2.666 min; column: ChiralPak IG, 100×4.6 mm I.D., 3 μm, 40% EtOH (0.05% DEA) in CO2, pressure: 100 bar; flow rate: 2.5 mL/min. LCMS (ESI, m/z): [M+H]⁺=499.2; ¹H NMR (400 MHz, methanol-d₄, ppm) δ 8.06 (d, J=8.8 Hz, 1H), 7.99 (d, J=8.7 Hz, 3H), 7.35 (d, J=8.2 Hz, 2H), 4.66-4.40 (m, 2H), 4.36-4.23 (m, 2H), 4.23-3.93 (m, 2H), 3.59 (s, 3H), 2.38-2.12 (m, 3H), 2.07-1.80 (m, 3H). ¹⁹F NMR (376 MHz, methanol-d₄, ppm) δ −59.37 (3F). 262: SFC analysis: 98.98% ee; retention time: 3.100 min; column: ChiralPak IG, 100×4.6 mm I.D., 3 μm, 40% EtOH (0.05% DEA) in CO2, pressure: 100 bar; flow rate: 2.5 mL/min. LCMS (ESI, m/z): [M+H]⁺=499.2; ¹H NMR (400 MHz, methanol-d₄, ppm) δ 8.11-8.03 (m, 1H), 7.99 (d, J=8.7 Hz, 3H), 7.35 (d, J=8.2 Hz, 2H), 4.64-4.39 (m, 2H), 4.35-4.24 (m, 2H), 4.24-3.92 (m, 2H), 3.59 (s, 3H), 2.39-2.11 (m, 3H), 2.07-1.79 (m, 3H). ¹⁹F NMR (376 MHz, methanol-d₄, ppm) δ −59.37 (3F).

Example 50 Synthesis of Compound 264

Step 1: A solution of 264-1 (3 g, 17.09 mmol) and cyclopropanamine (7.5 mL, 108.23 mmol) in dioxane (9 mL) was stirred at 85 for 10 h in a sealed tube. The mixture was concentrated. The residue was dissolved in ethyl acetate and H₂O. The mixture was adjusted pH to 5 by 2M HCl, the mixture was extracted with ethyl acetate. The organic phases were dried over Na₂SO₄, filtered and concentrated to afford 264-2.

Step 2: To a solution of 264-2 (3.62 g, crude) in EtOH (30 mL) was added SOCl₂ (6.18 mL, 85.12 mmol) at 0. The mixture was stirred at 20 for 12 h. The mixture was concentrated. The residue was dissolved in ethyl acetate and H₂O, the mixture was extracted with ethyl acetate. The organic phase was washed with H₂O, dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 4/1) to afford 264-3.

Step 3: To a solution of 264-3 (1.38 g, 5.73 mmol) in DCE (10 mL) was added acetyl chloride (1.63 mL, 22.93 mmol) at 0. The mixture was stirred at 60 for 4 h. The mixture was quenched with H₂O, extracted with ethyl acetate. The combined organic phases were washed with H₂O and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 1/20) to afford 264-4.

Step 4: Compound 264-5 was prepared from compound 264-4 following the procedure for the synthesis of compound 67-7 in example 22.

Step 5: Compound 264 (29 mg) was prepared from compound 264-5 following the procedure for the synthesis of compound 67 in example 22. LCMS: m/z 538.2 [M+H]f. ¹H NMR (400 MHz, DMSO-d₆, ppm) δ 8.28 (d, J=8.6 Hz, 1H), 8.03 (d, J=8.6 Hz, 1H), 7.72 (d, J=8.0 Hz, 2H), 7.56 (d, J=8.0 Hz, 2H), 4.74-4.62 (m, 1H), 4.42-4.34 (m, 1H), 4.00-3.90 (m, 1H), 3.81-3.73 (m, 1H), 3.41-3.36 (m, 1H), 3.06-2.87 (m, 3H), 2.63-2.54 (m, 1H), 2.40-2.32 (m, 1H), 2.04-1.91 (m, 1H), 1.76-1.66 (m, 1H), 1.65-1.51 (m, 2H), 1.32-1.17 (m, 2H), 0.85-0.74 (m, 4H), 0.72-0.60 (m, 4H). ¹⁹F NMR (376 MHz, DMSO-d₆, ppm) δ −60.73 (3F).

Example 51 Synthesis of Compounds 272 and 273

Step 1: To a solution of 4-(trifluoromethyl)benzoic acid (1 g, 5.26 mmol) in DMF (6 mL) were added 67-15 (1.3 g, 5.55 mmol), DIPEA (1.38 mL, 8.32 mmol) and HATU (3.2 g, 8.32 mmol), the reaction was stirred at 0° C. for 3 h. The mixture was diluted with ethyl acetate and water. The organic layer was separated and washed with brine. The organic layer was dried by Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 3/3) to afford 272-1.

Step 2: To a solution of 272-1 (1.2 g, 2.95 mmol) in DMF (5 mL) were added imidazole (0.3 g, 4.43 mmol) and TBSCl (0.5 g, 3.54 mmol), the mixture was stirred at 0° C. for 3 h. The mixture was diluted with ethyl acetate and water. The organic layer was separated and washed with brine. The organic layer was dried by Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 4/1) to afford 272-2.

Step 3: To a solution of 272-2 (450 mg, 0.86 mmol) in THF (4.5 mL) were added IrCl(CO)(PPh₃)₃ (67.4 mg, 0.086 mmol) at room temperature under N₂. Then the reaction mixture was cooled to −78° C., 1,1,3,3-Tetramethyldisiloxane(101.1 mg, 0.130 mmol) was added into the mixture, the mixture was stirred at −78° C. for 1.5 h, then bromo(prop-2-yl)magnesium (2.59 mL, 2.59 mmol) was added into the reaction, the mixture was stirred for another 18 h at room temperature under N₂. The reaction was quenched with saturated NH₄Cl aqueous and diluted with ethyl acetate and water. The organic layer was separated and washed with brine. The organic layer was dried by Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 4/1) afford 272-3.

Step 4: To a solution of 272-3 (410 mg, 0.75 mmol) in EtOH (10 mL) was added Pd/C (10%, 4.0 mg) under N₂. The suspension was degassed with H₂ for 4 times, and then the mixture was stirred at 25° C. for 2 h under H₂. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 1/1) to afford 272-4.

Step 5: Compound 272-5 was prepared from compound 272-4 following the procedure for the synthesis of compound 5 in example 5.

Step 6: To a solution of 272-5 (130 mg, 0.19 mmol) in DMF (5 mL) was added CsF (115.0 mg, 0.76 mmol) and the mixture was stirred at 110° C. for 36 h. The mixture was diluted with ethyl acetate and water. The organic layer was separated and washed with brine. The organic layer was dried by Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (DCM/MeOH=1/0 to 10/1) to afford 272-6.

Step 7: 272-6 (100 mg) was purified by SFC(column: ChiralPak AD, 250>30 mm I.D., 10 μm, Ethanol/Supercritical CO2=20/80) to afford 272 (48.85 mg) and 273 (5.2 mg) respectively. 272: SFC analysis: 100% ee; retention time: 2.185 min; column: ChiralPak AD, 150×4.6 mm I.D., 3 μm, 5-40% of ethanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. LCMS (ESI, m/z): [M+H]⁺=526.2. ¹H NMR (400 MHz, CDCl3, ppm) δ 7.75-7.65 (m, 2H), 7.61-7.51 (m, 2H), 7.48-7.40 (m, 2H1), 5.70-5.58 (m, 1H), 4.22-4.12 (m, 1H), 3.92-3.81 (m, 1H), 3.71 (s, 3H), 3.57-3.41 (m, 2H), 3.12-2.97 (m, 2H), 2.44-2.31 (m, 2H), 2.28-2.17 (m, 1H), 1.93-1.77 (m, 1H), 1.55-1.44 (m, 1H), 1.20-1.08 (m, 3H), 0.85-0.66 (m, 6H). ¹⁹F NMR (376 MHz, CDCl3, ppm) δ −62.26 (3F). 273: SFC analysis: 100% ee; retention time: 2.487 min; column: ChiralPak AD, 150×4.6 mm I.D., 3 μm, 5-40% of ethanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. LCMS (ESI, m/z): [M+H]⁺=526.2. ¹H NMR (400 MHz, CDCl3, ppm) δ 7.71-7.64 (m, 2H), 7.63-7.54 (m, 2H), 7.40-7.31 (m, 2H), 4.42-4.34 (m, 1H), 4.34-4.25 (m, 1H), 4.17-4.08 (m, 1H), 3.74-3.70 (m, 3H), 3.68-3.63 (m, 1H), 3.57-3.49 (m, 1H), 3.45-3.36 (m, 1H), 2.86-2.75 (m, 2H), 2.54-2.45 (m, 1H), 2.28 (dt, J=12.8, 6.4 Hz, 1H), 1.71-1.64 (m, 2H), 0.92-0.84 (m, 6H), 0.82-0.76 (m, 3H). ¹⁹F NMR (376 MHz, CDCl₃, ppm) δ −62.41 (3F).

Example 52 Synthesis of Compounds 278 and 279

Step 1: To a solution of 278-1 (2 g, 11.39 mmol) and DMF (0.088 mL, 1.14 mmol) in DCM (40 mL) was dropwise added oxalyl dichloride (1.45 mL, 17.09 mmol) at 0° C. and stirred for 12 h at room temperature. The reaction mixture was concentrated to dryness afford 278-2 which was used for next step directly.

Step 2: To a solution of 1H-1,2,4-triazol-5-amine (800 mg, 9.52 mmol) in DMF (30 mL) was added DIPEAe (7.86 mL, 47.57 mmol), then 278-2 (2214.9 mg, 11.42 mmol) in DMF (10 mL) was added to the mixture at 0° C. The resulting mixture was stirred at room temperature for 12 h. The reaction mixture used for the next step directly.

Step 3: K₂CO₃ (3.8 g, 27.32 mmol) was added to the reaction mixture from step 2, stirred at 100° C. under N₂ for 16 h. The reaction was quenched with HCl (2 N) until the pH to 4. The solid was collected with filtration to afford 278-4.

Step 4: Compound 272-5 was prepared from compound 272-4 following the procedure for the synthesis of compound 5 in example 5. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 1/4) to afford 278 (3 mg) and 279 (2 mg). 278: LCMS (ESI, m/z): [M+H]⁺=523.4. ¹H NMR (400 MHz, DMSO-d₆, ppm)_{8 8.76}-8.67 (m, 1H), 8.53-8.43 (m, 1H), 8.32 (s, 1H), 7.79-7.71 (m, 2H), 7.64-7.55 (m, 2H), 5.60-4.71 (m, 2H), 3.67 (s, 1H), 2.99-2.92 (m, 1H), 2.90-2.83 (m, 1H), 2.31-1.88 (m, 4H), 1.69-1.59 (m, 1H), 1.56-1.37 (m, 3H), 1.05-0.95 (m, 3H), 0.75-0.59 (m, 6H). ¹⁹F NMR (376 MHz, DMSO-d₆, ppm) δ −60.67 (3F). 279: LCMS (ESI, m/z): [M+H]⁺=523.4. ¹H NMR (400 MHz, DMSO-d₆, ppm) 68.78-8.64 (m, 1H), 8.52-8.42 (m, 1H), 8.33 (s, 1H), 7.78-7.69 (m, 2H), 7.65-7.56 (m, 2H), 6.21-4.53 (m, 2H), 3.53 (s, 1H), 2.62-2.58 (m, 1H), 2.26 (s, 1H), 2.07-1.94 (m, 2H), 1.85 (s, 2H), 1.66-1.54 (m, 2H), 1.46 (s, 2H), 1.08-0.99 (m, 3H), 0.67-0.57 (m, 6H). ¹⁹F NMR (376 MHz, DMSO-d₆, ppm) δ −60.67 (3F) Example 53 Synthesis of Compounds 282 and 283

Step 1: To a solution of 235-5 (153 mg, 0.29 mmol) in THF (5 mL) was added CDI (70.5 mg, 0.44 mmol) and the reaction was stirred at room temperature overnight. NaBH₄ (11.0 mg, 0.29 mmol) was added to this mixture and stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine and concentrated in vacuo. The residue was by reverse HPLC (MeCN in water (0.1% FA), 0-70%) to afford 282-1.

Step 2: To a solution of 282-1 (72 mg, 0.14 mmol) in THF (3 mL) was added NaH (6.2 mg, 0.15 mmol) at 0° C., the mixture was stirred at 0° C. for 2 h, then CH₃I (29.9 mg, 0.21 mmol) was added to the mixture. The reaction mixture was stirred at 30° C. for 2 h. The mixture was diluted with ethyl acetate and saturated NaCl aqueous. The organic layer was separated, washed with brine, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (DCM/ethyl acetate=1/0 to 1/3) to afford 282 (10 mg) and 283 (18 mg). 282: LCMS (ESI, m/z): [M+H]⁺=528.2. ¹H NMR (400 MHz, methanol-d₄, ppm) δ 8.05 (d, J=8.8 Hz, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.63 (s, 4H), 5.42-5.31 (m, 1H), 4.19-4.09 (m, 1H), 4.09-3.99 (m, 1H), 3.95-3.85 (m, 1H), 3.76-3.66 (m, 4H), 3.65-3.55 (m, 1H), 3.55-3.45 (m, 2H), 3.28 (s, 3H), 3.09-2.99 (m, 1H), 2.62-2.47 (m, 2H), 1.92-1.80 (m, 1H), 1.75-1.63 (m, 1H), 1.07 (t, J=7.4 Hz, 3H). ¹⁹F NMR (376 MHz, methanol-d₄, ppm): δ −63.89 (3F). 283: LCMS (ESI, m/z): [M+H]⁺=528.2. ¹H NMR (400 MHz, methanol-d₄, ppm) δ 8.04 (d, J=8.8 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 7.68-7.57 (m, 4H), 5.27-5.17 (m, 1H), 4.41-4.31 (m, 1H), 4.11-4.00 (m, 2H), 3.78-3.73 (m, 1H), 3.71 (s, 3H), 3.66-3.57 (m, 2H), 3.29 (s, 3H), 3.14-3.00 (m, 2H), 2.83-2.72 (m, 1H), 2.54-2.44 (m, 1H), 1.87-1.72 (m, 1H), 1.69-1.56 (m, 1H), 0.85 (t, J=7.4 Hz, 3H). ¹⁹F NMR (376 MHz, methanol-d₄, ppm): δ −63.91 (3F).

Example 54 Synthesis of Compounds 300 and 301

Step 1: To a solution of 220-1 (10 g, 19.0 mmol) in DMF (100 mL) was added Zn(CN)₂ (6.69 g, 57 mmol), Zn (372.6 mg, 5.7 mmol) and palladium(0) bis[tris(2-methylprop-2-yl)phosphane](970.9 mg, 1.90 mmol). The reaction mixture was stirred at 85° C. for 3 h under N₂. The reaction mixture was diluted with ethyl acetate, washed with brine and dried over anhydrous Na₂SO₄. Evaporation of the solvent under reduced pressure, the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 1/3) to afford 300-1.

Step 2: To a stirred solution of 300-1 (5.5 g, 11.64 mmol) in EtOH (60 mL) and H₂O (15 mL) at room temperature was added Fe (3.2 g, 58.20 mmol) and NH₄Cl (6.2 g, 116.40 mmol). The reaction mixture was stirred at 80 for 1 h. The hot reaction mixture was filtered and the filter cake was washed with EtOH. The filtrate was concentrated to dryness. The residue was purified by C18 reverse phase HPLC (MeCN/H₂O(0.05% TFA), 5-95%, 50 min) to afford 300-2.

Step 3: Compound 300-3 was prepared from compound 300-2 following the procedure for the synthesis of compound 220-4 in example 44.

Step 4: Compound 300-4 was prepared from compound 300-3 following the procedure for the synthesis of compound 28-15 in example 11.

Step 5: 300-4 (167 mg) was purified by SFC (column: ChiralCel OJ, 250×30 mm I.D., 10 μm, A for CO₂ and B for Ethanol (0.10% NH₃H₂O) to afford 300 (25 mg) and 301 (15 mg) respectively. 300: SFC analysis: 100.0% ee; retention time: 3.542 min; column: ChiralCel OJ, 150×4.6 mm I.D., 3 μm, A for CO₂ and B for Ethanol (0.05% DEA), 5-40%; pressure: 100 bar; flow rate: 2.5 mL/min. LCMS (ESI, m/z): [M+H]⁺=511.4; ¹H NMR (400 MHz, DMSO-d₆, ppm) δ 7.96 (d, J=8.8 Hz, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.71 (d, J=8.0 Hz, 2H), 7.58 (d, J=8.0 Hz, 2H), 6.09-5.99 (m, 1H), 4.49-4.39 (m, 1H), 3.74-3.64 (m, 1H), 3.64 (s, 3H), 3.28-3.18 (m, 1H), 3.04-2.90 (m, 4H), 2.57-2.47 (m, 1H), 2.41-2.31 (m, 1H), 1.95-1.82 (m, 1H), 1.78-1.46 (m, 3H), 1.01 (t, J=7.2 Hz, 3H), 0.66 (t, J=7.2 Hz, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆, ppm): δ −60.65 (3F). 301: SFC analysis: 98.18% ee; retention time: 3.740 min; column: ChiralCel OJ, 150×4.6 mm I.D., 3 μm, A for CO₂ and B for Ethanol (0.05% DEA), 5-40%; pressure: 100 bar; flow rate: 2.5 mL/min. LCMS (ESI, m/z): [M+H]⁺=511.4; ¹H NMR (400 MHz, DMSO-d₆, ppm) δ 7.92 (d, J=8.8 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.73 (d, J=8.0 Hz, 2H), 7.52 (d, J=8.0 Hz, 2H), 6.48-6.38 (m, 1H), 4.01-3.92 (m, 1H), 3.65 (s, 3H), 3.54-3.40 (m, 2H), 3.35-3.25 (m, 2H), 3.01-2.91 (m, 2H), 2.59-2.49 (m, 1H), 2.36-2.26 (m, 1H), 2.10-1.95 (m, 1H), 1.80-1.56 (m, 3H), 0.89-0.71 (m, 6H). ¹⁹F NMR (376 MHz, DMSO-d₆, ppm): δ −60.76 (3F1).

Example 55 Synthesis of Compound 302

Step 1: To a solution of 192-4 (3.6 g, 10.76 mmol) in DMF (40 mL) was added 1H-imidazole (1.8 g, 26.91 mmol) and TBSCl (2.4 g, 16.15 mmol), and the mixture was stirred at 0° C. for 3 h. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine and dried by Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 3/1) to afford 302-1.

Step 2: To a solution of 302-1 (4.06 g, 9.05 mmol) in propan-2-ol (50 mL) was added Pd/C (10%, 1.0 g) at room temperature. Then the mixture was stirred at room temperature under H₂ for 12 h. The mixture was filtered and the filtrate was concentrated under vacuo to afford 302-2.

Step 3: A mixture of 302-2 (3.12 g, 8.70 mmol), 192-2 (4.06 g, 13.05 mmol), DIPEA (4.31 mL, 26.10 mmol) and NaI (2.6 g, 17.40 mmol) in MeCN (70 mL) was heated at 80 for 16 h. The mixture was concentrated under vacuo and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 1/1) to afford 302-3.

Step 4: To a solution of 302-3 (4.5 g, 7.64 mmol) in THF (50 mL) was added LiAlH₄ (0.4 g, 11.46 mmol) at 0. Then the mixture was stirred at 0 for 0.5 h. The reaction was quenched with H₂O. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 4/1) to afford 302-4 and 302-5.

Step 5: To a solution of 302-4 (1.77 g, 3.24 mmol) in THF (40 mL) was added TBAF (9.71 mL, 9.71 mmol) and the reaction mixture was stirred at 30° C. for 1 h. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine and dried by Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 3/1) to afford 302-6.

Step 6: To a solution of 302-6 (300 mg, 0.69 mmol) in THF (5 mL) was added NaH (83.2 mg, 2.08 mmol). The mixture was stirred at room temperature for 30 minutes, then the mixture was cooled to 0. A solution of 4-methylbenzenesulfonyl chloride (132.2 mg, 0.69 mmol) in THF (0.5 mL) was slowly added to the mixture. The reaction mixture was stirred at room temperature for 12 h. The resulting mixture was quenched by saturated NH₄Cl aqueous. The mixture was concentrated, then ethyl acetate and water were added to the residue. The organic layer was separated and washed with brine, dried by Na₂SO₄. The organic solvent was removed in vacuo, the residue was purified by reverse HPLC (MeCN/H₂O(0.05% TFA), 5-95%) to afford 302-7.

Step 7: Compound 302 (21 mg) was prepared from compound 302-7 following the procedure for the synthesis of compound 30 in example 12. LCMS (EST, m/z): [M+H]⁺ =499.2; ¹H NMR (400 MHz, DMSO-d(, ppm) δ 8.26-8.15 (m, 1H), 8.00-7.90 (m, 1H), 7.85-7.76 (m, 2H), 7.73-7.64 (m, 2H), 5.51-5.26 (m, 1H), 5.04-4.59 (m, 1H), 4.18-3.87 (m, 3H), 3.85 (s, 1H), 3.47-3.41 (m, 1H), 3.40 (s, 3H), 2.89-2.60 (m, 3H), 2.20-1.83 (m, 3H), 1.01-0.79 (m, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆, ppm) δ −60.92 (3F).

Example 56 Synthesis of Compound 325

Step 1: To a stirred solution of 325-1 (10 g, 41.11 mmol) in DMF (10 mL) was added Cs₂CO3 (6.7 g, 20.55 mmol) and iodomethane (7.0 g, 49.33 mmol) at 0° C. The reaction mixture was stirred at room temperature for 4 h. The solvent was removed under vacuum, the residue was purified by reverse HPLC (MeCN/0.05% FA in water: 5%˜60%) to afford 325-2.

Step 2: To a stirred solution of 325-2 (0.3 g, 1.17 mmol) in MeOH (3 mL) was added NaBH₄ (88.22 mg, 2.33 mmol) in portions at 0° C. The mixture was stirred at room temperature for 1 h. The reaction was quenched with NH₄Cl solution. The mixture was extracted with EtOAc and washed with H₂O. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 1/1) to afford 325-3.

Step 3: Compound 325-4 was prepared from compound 325-3 following the procedure for the synthesis of compound 2-2 in example 2.

Step 4: To a stirred solution of 325-4 (900 mg, 2.23 mmol) in THF (9 mL) was added dropwise LiAlH₄ (4.46 mL, 4.46 mmol) at −78° C. The mixture was stirred at −78° C. for 1 h under N₂. The reaction was quenched with H₂O. The mixture was extracted with EtOAc and washed with H₂O. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 2/1) to afford 325-5.

Step 5: Compound 325 was prepared from compound 325-5 following the procedure for the synthesis of compound 107 in example 32. LCMS (ESI, m/z): [M+H]⁺=457.2; ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 8.15-8.05 (m, 2H), 7.66-7.64 (m, 2H), 7.22-7.20 (m, 2H), 5.20-5.09 (m, 1H), 4.87-4.75 (m, 1H), 4.35-4.24 (m, 1H), 4.11-4.01 (m, 1H), 3.66-3.54 (m, 4H), 3.14-3.02 (m, 1H), 2.30-2.20 (m, 1H), 2.19-2.09 (m, 1H), 1.70-1.50 (m, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆, ppm): δ −59.78 (3F).

Example 57 Synthesis of Compound 330 and 331

Step 1: To a solution of 330-1 (4 g, 14.04 mmol) in toluene (30 mL) was added n-BuLi (5.89 mL, 14.74 mmol) at −78 under N₂, the mixture was stirred at −78 for 0.5 h. propanal

(1.11 mL, 15.45 mmol) was added to the mixture and stirred at −78 C for 0.5 h. Then the mixture was warmed to 20 for 1 h. The reaction was quenched with H₂O and extracted with EtOAc. The combined organic layer was washed with H₂O and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 4/1) to afford 330-2.

Step 2: To a solution of 330-2 (983 mg, 4.53 mmol) in DCM (20 mL) were added PPh₃ (1.78 g, 6.79 mmol) and CBr₄ (2.25 g, 6.79 mmol) at 0 . The mixture was stirred at 20 for 5 h. The mixture was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 6/1) to afford 330-3.

Step 3: Compound 330-4 was prepared from compound 123-4 following the procedure for the synthesis of compound 28-15 in example 11.

Step 4: A solution of 330-4 (90 mg, 0.17 mmol), methyl methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (164.85 mg, 0.86 mmol) and CuI (6.5 mg, 0.034 mmol) in DMF (3 mL) was stirred at 100 for 16 h in a sealed tube. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 0/1) to afford 330 and 331. 330: LCMS (ESI, m/z): [M+H]⁺=514.2. ¹H NMR (400 MHz, CDCl₃, ppm): δ 8.93 (s, 2H), 7.66-7.59 (m, 2H), 5.05-4.95 (m, 1H), 4.30-4.12 (m, 1H), 4.08-3.90 (m, 1H), 3.92-3.80 (m, 1H), 3.64 (s, 3H), 3.55-3.10 (m, 3H), 2.85-2.70 (m, 1H), 2.60-2.50 (m, 1H), 2.10-1.90 (m, 2H), 1.85-1.65 (m, 1H), 1.50-1.35 (m, 1H), 1.10-0.95 (m, 3H), 0.70-0.62 (m, 3H). ¹⁹F NMR (376 MHz, CDCl₃, ppm): δ −62.30 (3F). 331: LCMS (ESI, m/z): [M+H]⁺=514.2. ¹H NMR (400 MHz, CDCl₃, ppm): δ 8.91 (s, 2H), 7.63-7.58 (m, 2H), 4.39-4.18 (m, 2H), 4.20-4.16 (m, 1H), 3.86-3.75 (m, 1H), 3.66 (s, 3H), 3.45-3.35 (m, 1H), 3.33-3.12 (m, 1H), 3.14-3.02 (m, 1H), 2.99-2.85 (m, 1H), 2.59-2.52 (m, 1H), 2.00-1.72 (m, 2H), 1.72-1.66 (m, 2H), 0.90-0.70 (m, 6H). ¹⁹F NMR (376 MHz, CDCl3, ppm): δ −62.34 (3F).

Example 58 Synthesis of Compound 332 and 333

Step 1: To a solution of ethyl 3-chloro-3-oxopropanoate (7.37 g, 48.96 mmol) and 1-5 (10 g, 40.80 mmol) in DCM (100 mL) was added DIPEA (20.23 mL, 122.41 mmol) at 0° C. The mixture was stirred at room temperature for 16 h. Then the solvent was removed and the residue was dissolved in EtOH (100 mL), followed by the addition of sodium ethoxide (11.1 g, 163.21 mmol). The resulting mixture was stirred at room temperature for 4 h. The reaction was quenched by the addition of water. The reaction mixture was acidified to pH=4 by the addition of HCl (1N). The resulting mixture was filtered, the filter cake was dried to afford 332-1.

Step 2: To a solution of 332-1 (5 g, 15.97 mmol) in DMF (50 mL) was added Sodium hydride (1.6 g, 39.92 mmol) at 0° C. The mixture was stirred at room temperature for 1 h. CH₃I (2.3 g, 15.97 mmol) was added to the mixture and the resulting mixture was stirred at room temperature for 16 h. The reaction was quenched by the addition of water. The reaction mixture was acidified to pH=3 by the addition of HCl (1N). The mixture was extracted with EtOAc and the organic layers were combined, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by reverse HPLC (0-100% of MeCN in water) to afford 332-2.

Step 3: To an ice-cold solution of 1H-imidazole (1.2 g, 17.94 mmol) and Ph₃P (4.7 g, 17.94 mmol) in DCM (30 mL) was added I2 (4.6 g, 17.94 mmol). The mixture was stirred at room temperature for 15 minutes, then 67-14 (3 g, 8.97 mmol) was added to the mixture. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water and extracted with DCM, the combined organic layer was dried and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 1/1) to afford 332-3.

Step 4: To a solution of 332-3 (2.8 g, 6.30 mmol) and TMSCN (0.8 g, 7.56 mmol) in THF (50 mL) was added TBAF (7.56 mL, 7.56 mmol). The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched with water and extracted with DCM. The combined organic layer was dried and concentrated, the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 1/1) to afford 332-4.

Step 5: A mixture of 332-4 (1.7 g, 4.95 mmol) in HCl (4M in MeOH, 10.92 mL) was stirred at 70° C. for 16 h. The solvent was removed under vacuum to afford 332-5.

Step 6: Compound 332-6 was prepared from compound 332-5 following the procedure for the synthesis of compound 67-18 in example 22.

Step 7: To a solution of N-Phenyl-bis(trifluoromethanesulfonimide) (1.9 g, 5.37 mmol) and 332-2 (1.58 g, 4.83 mmol) in MeCN (10 mL) was added K₂CO₃ (3.7 g, 26.85 mmol). The mixture was stirred at room temperature for 4 h, then 332-6 (1 g, 2.69 mmol) was added to the mixture. The resulting mixture was stirred at room temperature for another 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was dried and concentrated, the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 1/1) to afford 332-7.

Step 8: To a solution of Sodium ethoxide (249.6 mg, 3.67 mmol) in EtOH (10 mL) was added 332-7 (500 mg, 0.73 mmol). The resulting mixture was stirred at 50° C. for 4 h. The reaction was quenched with water and extracted with EtOAc. The combined organic layer was dried and concentrated to afford 332-8 which was used for the next step directly without further purification.

Step 9: To a solution of 332-8 (500 mg, crude) in MeOH (20 mL) was added HCl (6 N, 20 mL). The resulting mixture was stirred at 80° C. for 16 h. The reaction was quenched by the addition of water. The reaction mixture was adjusted the pH to 10 by the addition of NaOH (4 N). The mixture was extracted with EtOAc, the organic layers were combined, dried and concentrated to afford 332-9 which was used for the next step directly without further purification.

Step 10: To an ice-cold solution of 332-9 (350 mg, crude) in MeOH (20 mL) was added NaBH₄ (27.5 mg, 0.73 mmol). The resulting mixture was stirred at 0° C. for 1h. The mixture was diluted with water and extracted with EtOAc. The combined organic layer was dried and concentrated, the residue was purified by preparative TLC (MeOH/DCM=20:1) to afford 332-10.

Step 11: To solution of 332-10 (100 mg, 0.17 mmol) in triethylsilane (5 mL) and 1,2-dichloroethane (5 mL) was added TFA (196.8 mg, 1.73 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was diluted with DCM, then the solvent was removed under vacuum to afford 332-11 which was used for the next step directly without further purification.

Step 12: A mixture of 332-11 (100 mg, crude), Bis(tri-tert-butylphosphine)palladium (18.1 mg, 0.035 mmol), zinc (34.8 mg, 0.53 mmol) and Zn(CN)₂ (125.0 mg, 1.07 mmol) in DMF (0.5 mL) was stirred at 100° C. for 2 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layer was dried and concentrated. The residue was purified by preparative TLC (100% of ethyl acetate) and reverse HPLC (MeCN/H₂O (0.05% NH₄HCO₃), 0-100%) to afford 332 and 333. 332: LCMS (ESI, m/z): [M+H]⁺=510.2; ¹H NMR (400 MHz, CDCl₃, ppm): δ 7.72-7.63 (m, 2H), 7.59-7.57 (m, 2H), 7.44-7.42 (m, 2H), 5.09-5.05 (m, 1H), 3.67-3.63 (m, 4H), 3.37-3.25 (m, 1H), 3.01-2.98 (m, 2H), 2.88-2.83 (m, 1H), 2.69-2.59 (m, 2H), 2.45-2.43 (m, 1H), 2.01-2.94 (m, 2H), 1.79-1.73 (m, 2H), 1.56-1.50 (m, 2H), 0.85-0.81 (m, 3H), 0.68-0.64 (m, 3H). ¹⁹F NMR (376 MHz, CDCl₃, ppm): δ −62.30 (3F). 333: LCMS (ESI, m/z): [M+H]⁺=510.2; ¹H NMR (400 MHz, CD₃OD, ppm): δ 8.06-8.04 (m, 1H), 7.96-7.94 (m, 1H), 7.64-7.57 (m, 4H), 5.49-5.47 (m, 1H), 3.66-3.58 (m, 4H), 3.21-3.12 (m, 3H), 2.72-2.67 (m, 1H), 2.55-2.46 (m, 3H), 2.05-1.95 (m, 2H), 1.78-1.75 (m, 1H), 1.64-1.54 (m, 3H), 1.20-1.15 (m, 3H), 0.66-0.63 (m, 3H). ¹⁹F NMR (376 MHz, CD₃OD, ppm): δ −63.84 (3F).

Example 59 Synthesis of Compound 334

Step 1: To a mixture of 252 (140 mg, 0.28 mmol) in toluene (5 mL) was added DIPEA (145.5 mg, 1.13 mmol) and POCl₃ (172.6 mg, 1.13 mmol). Then the mixture was stirred at 1 10° C. for 3 h. The mixture was concentrated. The residue was purified by reverse HPLC (MeCN/H₂O (0.05% NH₃·H₂O), 5-95%) to afford 334-1.

Step 2: To a stirred solution of 334-1 (80 mg, 0.16 mmol) in THF (5 mL) was added hydrazine hydrate (0.009 mL, 0.16 mmol). The reaction mixture was stirred at 50° C. for 1.5 h. The mixture was diluted with EtOAc and washed with water, brine and dried over anhydrous Na₂SO₄, filtered and concentrated to afford 334-2 which was used for the next step directly without further purification.

Step 3: To a solution of 334-2 (70 mg, 0.14 mmol) in trimethoxymethane (5 mL) was stirred at 100° C. for 18 h. The mixture was concentrated in vacuo, the residue was purified by reverse HPLC (MeCN/H₂O(0.05% TFA), 5-80%) to afford 334 as 1.5 TFA salt. LCMS (ESI, m/z): [M+H]⁺=522.2. ¹H NMR (400 MHz, DMSO-d₆, ppm) δ 9.80 (s, 1H), 8.90-8.88 (m, 1H), 8.13-8.11 (m, 1H), 8.10-7.88 (m, 2H), 7.81-7.71 (m, 2H), 6.05-5.15 (m, 1H), 4.80-4.55 (m, 2H), 4.40-4.20 (m, 1H), 4.15-3.75 (m, 2H), 3.65-3.32 (m, 2H), 3.23-3.03 (m, 1H), 2.67-2.44 (m, 1H), 2.35-2.15 (m, 1H), 2.15-1.79 (m, 2H), 1.15-0.85 (m, 3H), 0.78 (m, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆, ppm): δ −64.39 (3F), −77.23 (4.5F).

Example 60 Synthesis of Compound 335

Step 1: To a solution of 335-1 (10 g, 83.26 mmol) in DCM (40 mL) was added NBS (17.8 g, 99.91 mmol) at 0. The mixture was stirred at 20 for 4.5 h. The mixture was diluted with H₂O and extracted with DCM. The combined organic phases were washed with H₂O, dried over Na₂SO₄, filtered and concentrated to afford 335-2 which was used for the next step directly without further purification.

Step 2: A solution of 335-2 (15.87 g, 47.85 mmol), (bromomethyl)benzene (6.82 mL, 57.42 mmol) and K₂CO₃ (9.9 g, 71.77 mmol) in CH₃CN (80 mL) was stirred at 75 for 2 h. The mixture was concentrated. The residue was diluted with H₂O and extracted with EtOAc. The combined organic phases were washed with H₂O and concentrated. The solid was filtered and the cake was washed with petroleum ether, dried under vacuum to afford 335-3.

Step 3: To a solution of 335-3 (4.72 g, 16.33 mmol) in THF (30 mL) was added Methylmagnesium bromide (16.33 mL, 48.98 mmol) at 0. The mixture was stirred at 20 for 3 h. Then the mixture was added to H₂O (60 mL) and stirred at 0 for 0.5 h. The mixture was diluted with H₂O and extracted with EtOAc. The combined organic phases were washed with H₂O and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 3/1) to afford 335-4.

Step 4: 335-4 (3.75 g, 12.25 mmol) in TFA (10 mL) was stirred at 80 for 2 h. The mixture was concentrated and the residue was diluted with NaHCO₃ solution, extracted with EtOAc. The combined organic phases were was washed with H₂O and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 4/1) to afford 335-5.

Step 5: To a solution of 335-5 (2.61 g, 12.08 mmol) in DMF (20 mL) was added NaH (2.4 g, 60.41 mmol) at 0. The mixture was stirred at 0 for 0.5 h. Then ethyl ethoxymethanoate (2.20 mL, 18.12 mmol) was added and the mixture was stirred at 80 for 0.5 h. The reaction was quenched with H₂O, the mixture was adjusted the pH to 4 by HCl (2N) and extracted with EtOAc. The combined organic phases were washed with H₂O and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 4/1) to afford 335-6.

Step 6: A solution of 335-6 (1.56 g, 5.42 mmol) and p-Toluenesulfonic acid (0.7 g, 4.33 mmol) in toluene (12 mL) was stirred at 90C for 10 h. The mixture was concentrated. The residue was purified by column chromatography on silica gel (DCM/MeOH=1/0 to 10/1) to afford 335-7.

Step 7: To a solution of 335-7 (400 mg, 1.65 mmol) in toluene (10 mL) was added DIPEA (1.37 mL, 8.26 mmol) and POCl₃ (0.46 mL, 4.96 mmol) at 20. The mixture was stirred at 90 for 2 h. The mixture was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 1/4) to afford 335-8.

Step 8: Compound 335-9 was prepared from compound 335-8 following the procedure for the synthesis of compound 67-20 in example 22.

Step 9: To a solution of 335-9 (127 mg, 0.25 mmol) in DCM (10 mL) was added Br₂ (0.25 mL, 0.25 mmol) at 0. The mixture was stirred at 0 for 40 minutes. Then triethylamine (0.053 mL, 0.38 mmol) was added and the mixture was stirred at 20 for 0.5 h. The mixture was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 1/1) to afford 335-10.

Step 10: A solution of 335-10 (77 mg, 0.13 mmol) and Cs₂CO₃ (86.6 mg, 0.27 mmol) in DMF (6 mL) was stirred at 90 for 1.5 h. The mixture was diluted with H₂O and extracted with EtOAc. The organic phases were concentrated. The residue was purified by reverse HPLC (MeCN/water (0.05% FA): 5%-60%) to afford 335 as 0.5 FA salt. LCMS (ESI, m/z): [M+H]⁺=499.2; ¹H NMR (400 MHz, DMSO-do, ppm): δ 8.46 (s, 0.5H), 8.37 (d, J=8.72 Hz, 1H), 8.20 (d, J=8.72 Hz, 1H), 7.78-7.68 (m, 2H), 7.62-7.53 (m, 2H), 5.20-5.10 (m, 1H), 4.63-4.52 (m, 1H), 4.46-4.34 (m, 1H), 3.80-3.72 (m, 11H), 3.70-3.60 (m, 1H), 3.19-3.13 (m, 1H), 3.11-3.04 (m, 1H), 2.65-2.55 (m, 1H), 2.49-2.44 (m, 1H), 2.06-1.90 (m, 1H), 1.71-1.46 (m, 3H), 0.84-0.71 (m, 3H), 0.67-0.57 (m, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆, ppm): δ −60.72 (3F).

Example 61 Synthesis of Compound 346 and 347

Step 1: To a solution of 272-2 (1.1 g, 2.11 mmol) in MeOH (15 mL) was added Pd/C (10%, 22.5 mg) under N₂. The suspension was degassed under vacuum and purged with H₂ for 4 times, then the mixture was stirred at 25° C. for 3 h under H₂. The mixture was filtered and concentrated, the residue was purified by column chromatography on silica gel (DCM/MeOH=1/0 to 5/1) to afford 346-1.

Step 2: To a solution of 346-1 (900 mg, 2.09 mmol) in DCM (15 mL) was added triethylamine (0.29 mL, 2.09 mmol), (Boc)₂O (0.53 mL, 2.3 mmol) and DMAP (12.8 mg, 0.11 mmol). The reaction mixture was stirred at room temperature for 18 h. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/0 to 5/1) to afford 346-2.

Step 3: Compound 346-3 was prepared from compound 346-2 following the procedure for the synthesis of compound 272-3 in example 51.

Step 4: To a solution of 346-3 (580 mg, 1.04 mmol) in DCM (8 mL) was added TFA (2 mL, 1.04 mmol), the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo. The residue was diluted with EtOAc and NaHCO₃ solution. The organic layer was separated and washed with brine. The organic layer was separated and dried over Na₂SO₄, filtered and concentrated under vacuum to afford 346-4 which was used for the next step directly without further purification.

Step 5: Compound 346 and 347 was prepared from compound 346-4 following the procedure for the synthesis of compound 272-6 in example 51. The pure product 346 and 347 was obtained by reverse HPLC (MeCN/water: 5%-95%). 346: LCMS (ESI, m/z): [M+H]+=524.2; ¹H NMR (400 MHz, CDCl3, ppm): δ 7.72-7.63 (m, 2H), 7.58-7.56 (m, 2H), 7.47-7.45 (m, 2H), 5.31-5.24 (m, 1H), 4.15-4.09 (m, 1H), 3.94-3.87 (m, 1H), 3.68 (s, 3H), 3.47-3.40 (m, 2H), 3.27-3.21 (m, 1H), 2.96-2.94 (m, 1H), 2.47-2.46 (m, 2H), 1.85-1.74 (m, 1H), 1.53-1.48 (m, 1H), 1.12-1.05 (m, 3H), 1.00-0.90 (m, 1H), 0.83-0.73 (m, 1H), 0.52-0.43 (m, 1H), 0.41-0.32 (m, 1H), 0.02-−0.02 (m, 1H). ¹⁹F NMR (376 MHz, CDCl3, ppm): δ −62.27 (3F). 347: LCMS (ESI, m/z): [M+H]⁺=524.2; ¹H NMR (400 MHz, CDCl₃, ppm): δ 7.66-7.60 (m, 2H), 7.56-7.54 (m, 2H), 7.42-7.40 (m, 2H), 5.23-5.17 (m, 1H), 4.38-4.32 (m, 1H), 4.07-4.00 (m, 1H), 3.67 (s, 3H), 3.65-3.57 (m, 1H), 3.42-3.35 (m, 1H), 2.97-2.91 (m, 1H), 2.77-2.71 (m, 1H), 2.64-2.55 (m, 1H), 2.50-2.43 (m, 1H), 1.69-1.59 (m, 1H), 1.45-1.35 (m, 1H), 0.97-0.88 (m, 1H), 0.82-0.75 (m, 4H), 0.43-0.28 (m, 2H), 0.02-−0.02 (m, 1H). ¹⁹F NMR (376 MHz, CDCl₃, ppm) δ −62.31 (3F).

Compounds of the present disclosure can be synthesized by those having ordinary skill in the art in view of the present disclosure. Representative further compounds synthesized by following similar procedures/methods described herein in the Examples section. The structures and representative analytical data are shown in Table 1 below.

TABLE 1
Characterization of exemplary compounds of the present disclosure
Compound
No.	Structure	[M + H]+	1H-NMR
6		527.2	0.33 TFA salt, 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.21-8.18 (m, 1H), 8.11-8.09 (m, 1H), 7.68 (s, 1H), 7.52 (s, 1H), 7.16-7.14 (m, 2H), 6.59-6.57 (m, 2H), 3.57 (s, 7H), 3.39-3.34 (m, 2H), 3.21 (s, 2H), 1.96 (t, J = 6.9 Hz, 2H), 1.78 (s, 4H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −57.36 (3F), −74.30 (1F, TFA).
7		439.4	1H NMR (400 MHz, DMSO-d6, ppm) δ 8.29-8.27 (m, 1H), 8.17-8.15 (m, 1H), 7.63-7.55 (m, 2H), 7.23-7.16 (m, 1H), 4.15-4.05 (m, 2H), 3.73-3.62 (m, 2H), 3.53 (s, 3H), 2.55-2.52 (m, 1H), 2.50-2.47 (m, 1H), 2.42 (s, 3H), 2.07-1.98 (m, 2H), 1.50 (s, 3H).
8		485.4	0.45 TFA salt, 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.25 (d, J = 8.8 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 8.4 Hz, 2H), 6.56 (d, J = 8.0 Hz, 2H), 3.58-3.48(m, 4H) 3.44 (s, 3H), 3.34 (t, J = 6.8 Hz, 2H), 3.22 (s, 2H), 1.96 (t, J = 6.8 Hz, 2H), 1.77-1.65 (m, 4H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −57.37 (3F), −74.44 (1.36 F, TFA).
9		443.4	1H NMR (400 MHz, DMSO-d6, ppm) δ 8.20 (d, J = 8.8 Hz, 1H), 8.11 (d, J = 8.8 Hz, 1H), 7.70 (s, 1H), 7.59-7.53 (m, 3H), 7.20-7.17 (dd, J = 8.0, 1.2 Hz, 1H), 3.82-3.79 (m, 2H), 3.57 (s, 3H), 3.38-3.25 (m, 3H), 2.42 (s, 3H), 2.22-2.19 (m, 2H), 2.15-2.06 (m, 2H).
10		457.4	1H NMR (400 MHz, DMSO-d6, ppm) δ 8.26- 8.24 (m, 1H), 7.99-7.96 (m, 1H), 7.18-7.15 (m, 2H), 6.51-6.49 (m, 2H), 4.44 (s, 1H), 4.30 (t, J = 6.8 Hz, 1H), 3.90-3.73 (m, 6H), 3.45 (s, 3H), 2.32 (t, J = 6.8 Hz, 1H), 2.17 (t, J = 6.8 Hz, 1H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −57.32 (3F).
11		457.4	1H NMR (400 MHz, DMSO-d6, ppm) δ 8.20- 8.19 (m, 1H), 8.09-8.10 (m, 1H), 7.64-7.45 (m, 4H), 7.18-7.20 (m, 1H), 3.63-3.66 (m, 2H), 3.56 (s, 3H), 3.19-3.24 (m, 2H), 2 .40-2.49 (m, 5H), 1.95-2.00 (m, 2H), 1.45 (s, 3H).
13		450.4	1H NMR (400 MHz, CDCl3-d, ppm) δ 7.89- 7.87 (m, 1H), 7.76-7.74 (m, 1H), 7.66 (s, 1H), 7.49 (s, 1H), 7.33-7.30 (m, 4H), 4.47- 4.44 (m, 2H), 3.72-3.62 (m, 5H), 3.07-3.01 (m, 1H), 2.28-2.25 (m, 5H), 2.10-2.00 (m, 2H).
14		468.4	1H NMR (400 MHz, CDCl3-d, ppm) δ 8.14 (s,1H), 7.83-7.80 (m, 1H), 7.72-7.70 (m, 1H), 7.63 (s, 1H), 7.44 (s, 1H), 7.30-7.27 (m, 4H), 6.15 (s, 1H), 4.03-4.00 (m, 2H), 3.64 (s, 3H), 3.44-3.38 (m, 2H), 3.04-2.99 (m, 1H), 2.24 (s, 3H), 2.14-2.12 (m, 2H), 2.03-2.00 (m, 2H).
15		499.4	0.48 TFA salt, 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.18 (d, J = 8.8 Hz, 1H), 8.04 (d, J = 8.9 Hz, 1H), 7.86 (s, 1H), 7.35 (s, 1H), 7.17- 7.15 (m, 2H), 6.49-6.51 (m, 2H), 4.11 (s, 2H), 3.97-4.00 (m, 2H), 3.81 (s, 4H), 3.53 (s, 3H), 2.15-2.18 (m, 2H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −57.33 (3F), −74.28 (1.43F, TFA).
18		474.2	SFC analysis: 99.04 % ee; retention time: 2.76 min; column: DAICELCHIRALPAK®WHELK, methanol (0.1% DEA) in CO2, 40%; pressure: 1800 psi; flow rate: 3.0 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.26-8.19 (m, 1H), 8.02-7.94 (m, 1H), 7.32-7.19 (m, 2H), 7.11-7.01 (m, 2H), 4.96-4.78 (m, 1H), 3.42 (s, 3H), 3.34- 3.30 (m, 3H), 2.22-2.09 (m, 2H), 2.02-1.82 (m, 2H), 1.75-1.62 (m, 1H), 1.60-1.44 (m, 1H), 1.00-0.80 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −57.25 (3F).
19		474.2	SFC analysis: 99.4 % ee; retention time: 4.47 min; column: DAICELCHIRALPAK®WHELK, methanol (0.1% DEA) in CO2, 40%; pressure: 1800 psi; flow rate: 3.0 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.29-8.22 (m, 1H), 8.05-7.98 (m, 1H), 7.36-7.25 (m, 2H), 7.14-7.03 (m, 2H), 4.95-4.82 (m, 1H), 3.46 (s, 3H), 3.38- 3.34 (m, 3H), 2.30-2.10 (m, 2H), 2.02-1.88 (m, 2H), 1.78-1.66 (m, 1H), 1.62-1.47 (m, 1H), 1.02-0.82 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −57.25 (3F).
20		401.4	1H-NMR (400 MHz, CDCl3-d, ppm) δ 7.80-7.77 (m, 1H), 7.56-7.50 (m, 1H), 7.40 (s, 1H), 7.33- 7.26 (m, 1H), 7.07-7.05 (m, 1H), 5.60-5.50 (m, 1H), 5.10-4.90(m,1H), 3.90-3.70 (m, 1H), 3.52 (s, 3H), 3.50-3.25 (m, 2H) 2.39 (s, 3H), 2.35- 2.25 (m, 2H), 2.20-2.05 (m, 2H).
22		416.2	1H NMR (400 MHz, DMSO-d6, ppm) δ 9.52-9.43 (m, 1H), 8.28-8.23 (m, 1H), 7.80-7.75 (m, 1H), 7.62-7.43 (m, 2H), 7.26-7.09 (m, 1H), 3.79-3.71 (m, 2H), 3.63-3.57 (m, 5H), 3.14-3.04 (m, 1H), 2.45-2.38 (m, 3H), 2.29-2.23 (m, 2H), 2.13-2.05 (m, 1H), 1.95-1.84 (m, 1H)
31		485.2	1H NMR (400 MHz, DMSO-d6, ppm): δ 8.30-8.24 (m, 1H), 8.06-8.00 (m, 1H), 7.86-7.72 (m, 2H), 7.55-7.40 (m, 2H), 4.80-3.85 (m, 4H), 3.47 (s, 3H), 3.37-3.34 (m, 2H), 2.05-1.89 (m, 4H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −56.74 (3F).
38		480.2	1H NMR (400 MHz, DMSO-d6, ppm): δ 8.32- 8.20 (m, 1H), 8.07-7.92 (m, 3H), 7.53-7.40 (m, 2H), 4.65-4.28 (m, 4H), 3.96-3.78 (m, 2H), 3.50- 3.39 (m, 3H), 2.33-2.20 (m, 1H), 2.19-2.09 (m, 1H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −56.68 (3F).
40		471.2	1H NMR (400 MHz, DMSO-d6, ppm): δ 8.06- 7.96 (m, 2H), 7.95-7.86 (m, 1H), 7.84-7.74 (m, 1H), 7.47 (d, J = 8.2 Hz, 2H), 4.65-4.21 (m, 4H), 3.95-3.73 (m, 2H), 3.49-3.39 (m, 3H), 2.30-2.07 (m, 2H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −56.68 (3F).
41		392.2	1H NMR (400 MHz, DMSO-d6, ppm) δ 9.70 (s, 1H), 8.97-8.95 (m, 1H), 8.52-8.50 (m, 1H), 7.12- 7.10 (m, 1H), 6.98-6.92 (m, 2H), 4.08-4.05 (m, 2H), 2.89-2.86 (m, 2H), 2.03-2.00 (m, 2H), 1.62- 1.59 (m, 1H), 0.94-0.92 (m, 2H), 0.80-0.78 (m, 2H).
43		365.2	LCMS (ESI, m/z): 1H NMR (400 MHz, DMSO-d6, ppm) δ 7.88 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.32-7.10 (m, 4H), 3.49- 3.46 (m, 6H), 1.56-1.48 (m, 1H), 0.89-0.85 (m, 2H), 0.73-0.70 (m, 2H).
46		356.2	0.17 FA salt, 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.15 (s, 0.17H, FA), 8.07 (d, J = 12.0 Hz, 1H), 7.96 (d, J = 12.0 Hz, 1H), 7.34-7.20 (m, 4H), 3.50-3.48 (m, 6H), 1.54-1.49 (m, 1H), 0.88-0.84 (m, 2H), 0.74-0.71 (m, 2H).
47		469.2	1H NMR (400 MHz, DMSO-d6, ppm) δ 8.20 (d, J = 8.9 Hz, 1H), 7.97-7.93 (m, 2H), 7.90 (s, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.69-7.64 (m, 1H), 4.70-3.90 (m, 4H), 3.42 (s, 3H), 3.40 (s, 2H), 2.01-1.89 (m, 4H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −61.43 (3F).
48		469.2	1H NMR (400 MHz, DMSO-d6, ppm) δ 8.22 (d, J = 8.9 Hz, 1H), 7.97 (d, J = 9.0 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.78-7.74 (m, 1H), 7.69-7.64 (m, 2H), 4.65-3.95 (m, 4H), 3.43 (s, 3H), 3.28 (s, 2H), 2.02-1.94 (m, 4H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −57.42 (3F).
49		469.2	1H NMR (400 MHz, DMSO-d6, ppm): δ 8.31- 8.23 (m, 1H), 8.07-7.99 (m, 1H), 7.93-7.79 (m, 4H), 4.95-3.75 (m, 4H), 3.46 (s, 3H), 3.39 (s, 2H), 2.05-1.89 (m, 4H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −61.23 (3F).
51		541.4	Analytical HPLC*: retention time: 1.45 min; 1.0 FA salt, 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.50 (s, 1H), 8.92-8.90 (m, 1H), 8.56- 8.54 (m, 1H), 8.40 (s, 1H, FA), 7.73-7.68 (m, 2H), 7.58-7.54 (m, 2H), 5.34-5.01 (m, 2H), 3.86-3.81 (m, 1H), 2.99-2.91 (m, 1H), 2.80-2.77 (m, 1H), 2.36 (s, 1H), 2.16 (s, 1H), 1.97-1.90 (m, 2H), 1.51-1.45 (m, 2H), 1.32- 1.30 (m, 3H), 1.00-0.94 (m, 3H), 0.75-0.68 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −42.24 (3F).
52		541.4	Analytical HPLC*: retention time: 1.50 min; 1.0 FA salt, 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.49 (s, 1H), 8.92-8.90 (m, 1H), 8.55- 8.53 (m, 1H), 8.40(s, 1H, FA), 7.71-7.69 (m, 2H), 7.59-7.56 (m, 2H), 5.22-4.90 (m, 1H), 3.68-3.66 (m, 1H), 2.66-2.59 (m, 1H), 2.23- 2.20 (m, 1H), 2.07-1.99 (m, 2H), 1.74-1.80 (m, 1H), 1.62 (s, 1H), 1.47-1.45 (m, 2H), 1.33-1.24 (m, 4H), 1.00-1.00 (m, 3H), 0.61- 0.58 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −42.38 (3F).
53		479.2	1H NMR (400 MHz, DMSO-d6, ppm): δ 9.57 (s, 1H), 9.00-8.91 (m, 1H), 8.63-8.54 (m, 1H), 7.94-7.80 (m, 4H), 4.45-4.26 (m, 2H), 4.25- 4.04 (m, 2H), 3.41 (s, 2H), 2.12-1.94 (m, 4H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −61.22 (3F).
54		511.2	1H NMR (400 MHz, DMSO-d6, ppm): δ 9.56 (s, 1H), 8.98-8.92 (m, 1H), 8.61-8.55 (m, 1H), 7.88-7.75 (m, 4H), 4.45-4.26 (m, 2H), 4.25-4.08 (m, 2H), 3.39 (s, 2H), 2.11- 1.92 (m, 4H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −41.86 (3F).
55		571.5	Analytical HPLC*: retention time: 1.75 min; 2.0 TFA salt, 1H NMR (400 MHz, DMSO-d6, ppm) δ − 8.43-7.44 (m, 6H), 6.27-5.67 (m, 1H), 5.39-4.92 (m, 1H), 4.91-4.56 (m, 1H), 4.07-3.60 (m, 1H), 3.47 (s, 3H), 3.42-3.24 (m, 1H), 3.21-2.63 (m, 1H), 2.51-2.43 (m, 2H), 2.42-1.89 (m, 3H), 1.88-1.77 (m, 1H), 1.76-1.66 (m, 1H), 1.12-0.93 (m, 3H), 0.92- 0.26 (m, 6H); 19F NMR (376 MHz, DMSO- d6, ppm): δ 86.51 (1F), 63.98 (4F), −74.47 (6F, TFA).
56		571.5	Analytical HPLC*: retention time: 1.79 min; 2.0 TFA salt, 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.42-7.41 (m, 6H), 6.51-5.21 (m, 1H), 5.19-4.50 (m, 1H), 4.23-3.53 (m, 2H), 3.47 (s, 3H), 3.36-3.04 (m, 1H), 2.82-2.51 (m, 1H), 2.42-2.19 (m, 1H), 2.17-1.22 (m, 6H), 1.21- 0.76 (m, 3H), 0.75-0.38 (m, 6H); 19F NMR (376 MHz, DMSO-d6, ppm): δ 86.41 (1F), 64.84 (4F), −74.58 (6F, TFA).
60		557.4	SFC analysis: 100% de; retention time: 4.12 min; column: REGIS (S,S)WHELK-O1, MeOH (0.1% of DEA) in CO2, 5% to 40%; pressure: 100 bar; flow rate: 1.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.24 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H), 5.90-5.54 (m, 1H), 5.01-4.72 (m, 1H) 3.70-3.62 (m, 1H), 3.43 (s, 3H), 3.20-3.11 (m, 1H), 2.94-2.83 (m, 1H), 2.71-2.53 (m, 1H), 2.39-2.30 (m, 1H), 1.97-1.82 (m, 1H), 1.70- 1.58 (m, 1H), 1.51-1.40 (m, 2H), 1.49-1.23 (m, 3H), 0.76-0.60 (m, 6H); 19F NMR (376 MHz, DMSO-d6, ppm): δ 88.20 (1F), 64.42 (4F).
61		557.4	SFC analysis: 81.04% de; retention time: 4.92 min; column: REGIS (S,S)WHELK-O1, MeOH (0.1% of DEA) in CO2, 5% to 40%; pressure: 100 bar; flow rate: 1.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.28- 8.20 (m, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H), 6.03-5.49 (m, 1H), 5.04-4.85 (m, 1H) 3.69-3.52 (m, 1H), 3.43 (s, 3H), 3.30-3.25 (m, 1H), 3.19-3.14 (m, 1H), 2.62-2.58 (m, 1H), 2.19- 2.05 (m, 1H), 1.82-1.79 (m, 1H), 1.61-1.50 (m, 1H), 1.47-1.36 (m, 2H), 1.32-1.27 (m, 3H), 1.05-0.95 (m, 3H), 0.62-0.57 (m, 3H); 19F NMR (376 MHz, DMSO-d6, ppm): δ 88.20 (1F), 64.42 (4F).
62		557.4	Analytical HPLC*: retention time: 1.72 min; 2.57 TFA salt, 1H NMR (400 MHz, CDCl3-d, ppm): δ 7.93-7.69 (m, 6H), 6.36-6.01 (m, 1H), 5.54-5.42 (m, 1H), 4.26-4.13 (m, 1H), 3.62 (s, 3H), 3.36-3.31 (m, 1H), 3.19-3.08 (m, 2H), 2.18-2.01 (m, 2H), 1.91-1.68 (m, 6H), 0.91- 0.69 (m, 6H). 19F NMR (376 MHz, CDCl3-d, ppm): δ 82.75 (1F), 62.61 (4F), −75.98 (7.7F, TFA).
63		557.4	Analytical HPLC*: retention time: 1.75 min; 2.0 TFA salt, 1H NMR (400 MHz, CDCl3-d, ppm): δ 7.90-7.72 (m, 6H), 6.53-6.14 (m, 1H), 5.56-5.34 (m, 1H), 4.14-4.05 (m, 2H), 3.63 (s, 3H), 3.31-3.24 (m, 2H), 2.99-2.98 (m, 1H), 2.28-2.21 (m, 2H), 2.11-1.83 (m, 5H), 1.25- 1.21 (m, 3H), 0.75-0.72 (m, 3H). 19F NMR (376 MHz, CDCl3-d, ppm): δ 82.62 (1F), 62.61 (4F), −75.84 (6F, TFA).
65		637.4	1H NMR (400 MHz, Methanol-d4, ppm) δ 8.09-8.04 (m, 1H), 8.02-7.95 (m, 1H), 7.93- 7.84 (m, 2H), 7.80-7.76 (m, 2H), 6.33-5.78 (m, 1H), 5.33 (s, 1H), 5.28-5.03 (m, 1H), 3.78-3.64 (m, 1H), 3.57 (s, 3H), 3.10-2.79 (m, 1H), 2.71-2.52 (m, 1H), 2.44-2.30 (m, 1H), 2.20-2.06 (m, 1H), 1.73-1.52 (m, 3H), 1.15-1.05 (m, 2H), 1.05-0.96 (m, 2H), 0.95-0.87 (m, 3H), 0.86-0.78 (m, 2H). 19F NMR (376 MHz, Methanol-d4): δ 82.48 (1F), 61.33 (4F).
66		541.4	Analytical HPLC*: retention time: 1.55 min; 2.7 TFA salt, 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.65-9.62 (m, 1H), 9.00 (d, J = 8.4 Hz, 1H), 8.68-8.62 (m, 1H), 7.93-7.53 (m, 4H), 5.60-5.05 (m, 1H), 4.62-4.49 (m, 1H), 4.01- 3.90 (m, 1H), 3.68-3.57 (m, 1H), 3.47-3.40 (m, 1H), 3.02-2.98 (m, 1H), 2.45-2.34 (m, 1H), 2.02-1.90 (m, 1H), 1.77-1.53 (m, 3H), 1.44-1.25 (m, 3H), 0.90-0.43 (m, 6H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −41.82 (3F), −73.93 (8.1 F, TFA).
68		555.4	Chiral HPLC analysis: 97.47% de; retention time: 4.84 min; column: Daicel CHIRALPAK®IG, EtOH (0.2% of DEA)/ n-Hexane = 5/95, flow rate: 1.0 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.48 (s, 1H), 8.91-8.89 (m, 1H), 8.55-8.53 (m, 1H), 7.73-7.71 (m, 2H), 7.52-7.50 (m, 2H), 5.54- 4.71 (m, 1H), 2.97-2.91 (m, 1H), 2.85-2.79 (m, 1H), 2.37-2.33 (m, 1H), 2.09 (s, 1H), 1.98-1.88 (m, 2H), 1.67-1.56 (m, 2H), 1.48- 1.42 (m, 2H), 1.25 (s, 2H), 0.99-0.94 (m, 3H), 0.65-0.62 (m, 6H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −42.27 (3F).
69		555.4	Chiral HPLC analysis: 81.52% de; retention time: 5.87 min; column: Daicel CHIRALPAK®IG, EtOH (0.2% of DEA)/ n-Hexane = 5/95, flow rate: 1.0 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.49 (s, 1H), 8.91-8.89 (m, 1H), 8.55-8.53(m, 1H), 7.71-7.69 (m, 2H), 7.54-7.52 (m, 2H), 5.41- 4.65 (m, 1H), 3.51-3.45 (m, 1H), 3.16 (s, 1H), 2.25-2.14 (m, 1H), 2.07-1.97 (m, 1H), 1.91-1.83 (m, 1H), 1.78-1.71 (m, 1H), 1.65-1.49 (m, 2H), 1.49-1.41 (m, 1H), 1.27-1.19 (m, 3H), 1.06-0.98 (m, 3H), 0.63- 0.55 (m, 6H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −42.44 (3F).
70		625.4	1H NMR (400 MHz, DMSO-d6, ppm) δ 8.29- 8.17 (m, 1H), 8.04-7.94 (m, 1H), 7.84-7.70 (m, 4H), 6.03-5.27 (m, 2H), 5.03-4.75 (m, 1H), 3.68- 3.48 (m, 1H), 3.44 (s, 3H), 3.29-2.80 (m, 1H), 2.71-2.54 (m, 1H), 2.42-2.31 (m, 1H), 2.20-1.69 (m, 3H), 1.65-1.28 (m 2H), 1.14-1.02 (m, 2H), 0.96-0.54 (m, 8H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −41.97 (3F).
71		541.4	Analytical HPLC*: retention time: 1.52 min; 0.34 FA/0.56 TFA salt, 1H NMR (400 MHz, DMSO-d6, ppm): δ 9.51 (s, 1H), 8.91 (d, J = 8.6 Hz, 1H), 8.55 (d, J = 8.6 Hz, 1H), 8.14 (s, 0.34H, FA), 7.70 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.0 Hz, 2H), 5.62-5.41 (m, 1H), 5.02-4.82 (m, 1H), 3.61-3.52 (m, 2H), 3.20-3.10 (m, 1H), 2.70-2.62 (m, 1H), 2.16-2.13 (m, 1H), 1.89- 1.86 (m, 1H), 1.78-1.72 (m, 1H), 1.67-1.63 (m, 1H), 1.54-1.45 (m, 1H), 1.41-1.31 (m, 3H), 1.14-1.04 (m, 3H), 0.67-0.52 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −42.26 (3F), −73.46 (1.68F, TFA).
74		513.4	SFC analysis: 92.77% ee; retention time: 4.358 min; column: AICELCHIRALCEL®AS, MeOH (0.1% of DEA) in CO2, 5% to 40%; pressure: 100 bar; flow rate: 70 mL/min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.31- 8.20 (m, 1H), 8.08-7.95 (m, 1H), 7.89- 7.75 (m, 2H), 7.55-7.39 (m, 2H), 5.75-5.25 (m, 1H), 5.22-4.65 (m, 1H), 3.72-3.56 (m, 1H), 3.46 (s, 3H), 3.34-3.22 (m, 2H), 2.18-1.73 (m, 6H), 1.04-0.85 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −56.75 (3F)
75		513.4	SFC analysis: 93.15% ee; retention time: 4.424 min; column: DAICELCHIRALCEL®AS, MeOH (0.1% of DEA) in CO2, 5% to 40%; pressure: 100 bar; flow rate: 70 mL/min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.32-8.20 (m, 1H), 8.08-7.94 (m, 1H), 7.89-7.73 (m, 2H), 7.55-7.40 (m, 2H), 5.72-5.28 (m, 1H), 5.24-4.60 (m, 1H), 3.74-3.58 (m, 1H), 3.46 (s, 3H), 3.34- 3.24 (m, 2H), 2.19-1.75 (m, 6H), 1.05-0.85 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −56.75 (3F).
76		485.4	SFC analysis: 100% ee; retention time: 1.787 in; column: Chiralpak AS, 150 × 4.6 mm I.D., 3 μm, 40% of Methanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min.1H NMR (400 MHz, DMSO-d6, ppm): δ 9.49 (s, 1H), 8.90 (d, J = 8.6 Hz, 1H), 8.54 (d, J = 8.6 Hz, 1H), 7.30-7.18 (m, 2H), 6.91-6.80 (m, 2H), 6.13-4.32 (m, 2H), 3.74 (s, 3H), 3.62-3.40 (m, 1H), 3.35-3.25 (m, 1H), 3.22-3.05 (m, 1H), 2.60- 2.50 (m, 1H), 2.41-2.30 (m, 1H), 2.12-1.71 (m, 3H), 1.68-1.39 (m, 3H), 1.06-0.92 (m, 3H), 0.71-0.55 (m, 6H).
79		599.4	SFC analysis: 99.12% ee; retention time: 4.630 min; column: DAICELCHIRALPAK®IG, EtOH (0.1%DEA) in CO2, 5% to 40%; pressure: 100 bar; flow rate: 1.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm): δ 7.90-7.81 (m, 3H), 7.58 (d, J = 7.8 Hz, 2H), 6.25-5.37 (m, 1H), 5.16-4.66 (m, 1H), 4.62-4.36 (m, 2H), 4.12-3.85 (m, 2H), 3.65- 3.51 (m, 1H), 3.46-3.40 (m, 1H), 3.13-3.10 (m, 1H), 2.15-2.10 (m, 1H), 1.97-1.93 (m, 1H), 1.79- 1.73 (m, 2H), 1.65-1.48 (m, 2H), 1.40-1.33 (m, 2H), 0.97-0.90 (m, 3H), 0.60-0.54 (m, 6H). 19F NMR (376 MHz, DMSO-d6, ppm): δ 87.95 (1F), 64.30 (4F).
80		567.4	Analytical HPLC*: retention time: 1.61 min; 0.41 FA salt, 1H NMR (400 MHz, DMSO-d6, ppm): δ 9.49 (s, 1H), 8.90 (d, J = 12.0 Hz, 1H), 8.54 (d, J = 8.8 Hz, 1H), 8.44 (s, 0.41H, FA), 7.91 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 5.81-5.40 (m, 1H), 5.35-5.05 (m, 1H), 3.71-3.65 (m, 1H), 3.42-3.39 (m, 1H), 2.95-2.87 (m, 1H), 2.78- 2.70 (m, 1H), 2.39-2.32 (m, 1H), 1.92-1.83 (m, 1H), 1.65-1.45 (m, 1H), 1.52-1.38 (m, 5H), 0.78- 0.70 (m, 3H), 0.68-0.61 (m, 3H); 19F NMR (376 MHz, DMSO-d6, ppm): δ 88.01 (1F), 64.44 (4F).
81		509.4	SFC analysis: 100% ee; retention time: 1.835 min; column: Chiralpak AD-3 150 × 4.6 mm I.D., 3 μm, 40% of Ethanol (0.05% of DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.49 (s, 1H), ), 8.92-8.90 (d, J = 8.6 Hz, 1H), 8.56-8.54 (d, J = 8.6 Hz, 1H), 7.81-7.67 (m, 2H), 7.64-7.50 (m, 2H), 5.85-4.75 (m, 2H), 3.75- 3.60 (m, 1H), 3.48-3.36 (m, 1H), 3.00-2.86 (m, 1H), 2.82-2.68 (m, 1H), 2.43-2.31 (m, 1H), 2.00-1.80 (m, 1H), 1.71-1.57 (m, 1H), 1.56-1.39 (m, 5H), 0.80- 0.55 (m, 6H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −60.68 (3F)
82		509.4	SFC analysis: 100% ee; retention time: 2.269 min; column: Chiralpak AD-3 150 × 4.6 mm I.D., 3 μm, 40% of Ethanol (0.05% of DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.51 (s, 1H), 8.93-8.91 (d, J = 8.6 Hz, 1H), 8.57-8.55 (d, J = 8.6 Hz, 1H), 7.84-7.48 (m, 4H), 6.10-4.50 (m, 2H), 3.78-3.47 (m, 2H), 3.25- 3.04 (m, 1H), 2.78-2.60 (m, 1H), 2.24-2.06 (m, 1H), 1.97-1.79 (m, 1H), 1.77-1.43 (m, 3H), 1.40-1.26 (m, 3H), 1.16-0.95 (m, 3H), 0.73-0.48 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −60.64 (3F).
83		599.4	SFC analysis: 100.00% ee; retention time: 4.302 min; column: DAICELCHIRALPAK®IG, EtOH (0.1%DEA) in CO2, 5% to 40%; pressure: 100 bar; flow rate: 1.5 mL/min. 0.29 TFA salt, 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.01-7.74 (m, 3H), 7.60-7.51 (m, 2H), 6.08-5.52 (m, 1H), 5.08-4.81 (m, 1H), 4.43-4.42 (m, 2H), 4.02-3.95 (m, 2H), 3.67-3.60 (m, 1H), 3.10-3.08 (m, 1H), 2.84-2.68 (m, 2H), 2.13-2.10 (m, 1H), 1.89-1.84 (m, 2H), 1.61-1.58 (m, 1H), 1.48-1.44 (m, 1H), 1.27-1.22 (m, 2H), 0.95-0.92 (m, 3H), 0.66-0.61 (m, 6H). 19F NMR (376 MHz, DMSO-d6, ppm): δ 88.01 (1F), 64.44 (4F), −73.45 (0.86F, TFA).
85		523.4	1H NMR (400 MHz, DMSO-d6, ppm) δ 9.54 (s, 1H), 8.99-8.89 (m, 1H), 8.63-8.54 (m, 1H), 7.74- 7.65 (m, 2H), 7.57-7.47 (m, 2H), 5.87-4.35 (m, 3H), 4.20 (s, 0.5H), 4.11-4.01 (m, 0.5H), 3.98- 3.78 (m, 2H), 3.57-3.34 (m, 1.5H), 3.08-2.95 (m, 0.5H), 1.83-1.50 (m, 4H), 0.98-0.73 (m, 6H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −60.78 (3F).
86		581.3	SFC analysis: 100% ee; retention time: 1.497 min; column: ChiralPak AD, 250 × 30 mm I.D., 10 μm, 5% to 35%; pressure: 100 bar; flow rate: 80 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm): δ 9.49 (s, 1H), 8.91 (d, J = 8.4 Hz, 1H), 8.56 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 5.92-4.92 (m, 2H), 3.68-3.60 (m, 1H), 2.94-2.84 ( m, 2H), 2.10-1.90 (m, 4H), 1.65- 1.45 (m, 4H), 1.10-0.90 (m, 3H), 0.75-0.55 (m, 6H). 19F NMR (376 MHz, DMSO-d6, ppm): δ 88.41 (1F), 64.61 (4F).
87		581.3	SFC analysis: 98.16% ee; retention time: 2.193 min; column: ChiralPak AD, 250 × 30mm I.D., 10 μm, 5% to 35%; pressure: 100 bar; flow rate: 80 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm): δ 9.50 (s, 1H), 8.91 (d, J = 8.4 Hz, 1H), 8.55 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 5.92-4.60 (m, 2H), 3.54-3.53 (m, 2H), 3.18-3.09 (m, 1H), 2.20-1.97 (m, 4H), 1.85-1.45 (m, 4H), 1.10-0.90 (m, 3H), 0.75-0.55 (m, 6H). 19H NMR (376 MHz, DMSO-d6, ppm): δ 88.42 (1F), 64.57 (4F).
88		567.2	SFC analysis: 100% ee; retention time: 1.618 min; column: Chiralpak AD, 150 × 4.6 mm I.D., 3 μm, 40% of ethanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/ min. 1H NMR (400 MHz, DMSO-d6, ppm): δ 9.49(s, 1H), 8.91 (d, J = 8.8 Hz, 1H), 8.55 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 5.92-4.72 (m, 2H), 3.93-3.81 (m, 1H), 2.99-2.79 (m, 2H), 2.34- 2.12 (m, 2H), 1.98-1.87 (m, 2H), 1.58-1.40 (m, 2H), 1.30-1.25 (m, 3H), 0.97-0.90 (m, 3H) 0.72-0.64 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm): δ 88.42 (1F), 64.58 (4F).
89		567.2	SFC analysis: 99.08% ee; retention time: 2.515 min; column: Chiralpak AD, 150 × 4.6mm I.D., 3 μm, 40% of ethanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm): δ 9.50 (s, 1H), 8.91 (d, J = 8.8 Hz, 1H), 8.55 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 5.96-4.42 (m, 2H), 3.75-3.68 (m, 1H), 3.60-3.48 (m, 1H), 3.18-3.10 (m, 1H), 2.34-2.22 (m, 2H), 2.05-1.87 (m, 2H), 1.58-1.40 (m, 2H), 1.28-1.21 (m, 3H), 1.05- 0.98 (m, 3H), 0.68-0.56 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm): δ 88.45 (1F), 64.55 (4F).
90		567.4	Analytical HPLC*: retention time: 1.67 min; 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.12-8.89 (m, 2H), 8.47-8.32 (m, 1H), 8.19- 7.92 (m, 2H), 7.81-7.52 (m, 2H), 5.42-4.65 (m, 1H), 4.20-3.83 (m, 1H), 3.24-3.02 (m, 1H), 2.81-2.75 (m, 1H), 2.22-2.15 (m, 1H), 2.05-1.95 (m, 1H), 1.82-1.79 (m, 1H), 1.70- 1.67 (m, 1H), 1.48-1.41 (m, 1H), 1.38-1.30 (m, 4H), 1.29-1.18 (m, 3H), 1.12-1.06 (m, 1H), 0.71-0.61 (m, 3H). 19F NMR (376 MHz, Chloroform-d, ppm): δ 82.75 (1F), 64.43 (4F).
93		523.4	SFC analysis: 100.00% ee; retention time: 4.770 min; column: ChiralPak AD, 250 × 30 mm I.D., 10 μm, A for CO2 and B for Ethanol (0.1% NH3H2O), 50%; pressure: 100 bar; flow rate: 80 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm): δ 7.77 (s, 1H), 7.60-7.51(m, 2H), 7.19 (d, J = 8.4 Hz, 1H), 6.91 (s, 1H), 5.44-5.38 (m, 1H), 4.19-4.10 (m, 1H), 3.99-3.92 (m, 1H), 3.89-3.84 (m, 3H), 3.82-3.71 (m, 2H), 3.48 (s, 3H), 3.42-3.36 (m, 1H), 2.27 (s, 3H), 2.36-2.31 (m, 1H), 2.30-2.26 (m, 2H), 2.24-2.18 (m, 1H), 2.15-1.97 (m, 2H), 1.58- 1.50 (m, 1H), 1.45-1.33 (m, 1H), 0.71 (t, J = 7.6 Hz, 3H).
94		523.4	SFC analysis: 100.00% ee; retention time: 6.152 min; column: ChiralPak AD, 250 × 30 mm I.D., 10 μm, A for CO2 and B for Ethanol (0.1% NH3H2O), 50%; pressure: 100 bar; flow rate: 80 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm): δ 7.77 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.52 (s, 1H), 7.19 (d, J = 8.4 Hz, 1H), 6.91 (s, 1H), 5.44-5.38 (m, 1H), 4.19-4.10 (m, 1H), 3.99- 3.93 (m, 1H), 3.92-3.84 (m, 3H), 3.80-3.72 (m, 2H), 3.49 (s, 3H), 3.42-3.36 (m, 1H), 2.27 (s, 3H), 2.36-2.30 (m, 1H), 2.28- 2.24 (m, 2H), 2.21-2.15 (m, 1H), 2.08- 1.98 (m, 2H), 1.58-1.50 (m, 1H), 1.40- 1.33 (m, 1H), 0.71 (t, J = 6.8 Hz, 3H).
96		523.2	Analytical HPLC*: retention time: 1.961 min; 1H NMR (400 MHz, DMSO-d6, ppm): δ 7.73 (s, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.16 (d, J = 8.0 Hz, 1H), 6.90 (s, 1H), 5.42 (s, 1H), 4.60-4.50 (m, 1H), 4.20-4.09 (m, 1H), 4.08-3.97 (m, 1H), 3.96-3.85 (m, 2H), 3.85-3.70 (m, 1H), 3.65-3.52 (m, 2H), 3.47 (s, 3H), 2.40-2.10 (m, 4H), 2.09-1.95 (m, 4H), 1.85-1.70 (m, 3H), 0.92-0.80 (m, 3H).
97		523.2	Analytical HPLC*: retention time: 1.959 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 7.73 (s, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.16 (d, J = 8.0 Hz, 1H), 6.90 (s, 1H), 5.42 (s, 1H), 4.61-4.50 ( m, 1H), 4.18-4.06 (m, 1H), 4.05-3.94 (m, 1H), 3.93-3.82 (m, 2H), 3.81-3.70 (m, 1H), 3.65-3.55 (m, 2H), 3.47 (s, 3H), 2.40-2.33 (m, 3H), 2.20-2.00 (m, 6H), 1.90-1.75 (m, 2H), 0.95-0.80 (m, 3H).
100		539.3	SFC analysis: 100% ee; retention time: 1.502 min; column: ChiralPak AD, 150 × 4.6 mm I.D., 3 μm, 40% of ethanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, Methanol-d4, ppm) 9.33 (s, 1H), 8.79-8.77 (d, J = 8.7 Hz, 1H), 8.33-8.31 (d, J = 8.6 Hz, 1H), 7.49- 7.47 (d, J = 8.5 Hz, 2H), 7.31-7.29 (d, J = 8.1 Hz, 2H), 6.27-4.90 (m, 2H), 3.80- 3.59 (m, 1H), 3.56-3.34 (m, 1H), 3.20- 2.90 (m, 2H), 2.66-2.48 (m, 1H), 2.33- 1.95 (m, 3H), 1.79-1.46 (m, 3H), 1.15- 1.00 (m, 3H), 0.84-0.64 (m, 6H). 19F NMR (376 MHz, Methanol-d4, ppm) δ −59.49 (3F).
101		539.3	SFC analysis: 100% ee; retention time: 1.901 min; column: ChiralPak AD, 150 × 4.6 mm I.D., 3 μm, 40% of ethanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/ min. 1H NMR (400 MHz, Methanol-d4, ppm) δ 9.32 (s, 1H), 8.76 (d, J = 8.7 Hz, 1H), 8.30 (d, J = 7.4 Hz, 1H), 7.48 (d, J = 8.6 Hz, 2H), 7.25 (d, J = 8.1 Hz, 2H), 6.43-4.62 (m, 2H), 3.85-3.48 (m, 1H), 3.47-3.40 (m, 1H), 3.28- 3.18 (m, 1H), 2.70-2.60 (m, 1H), 2.42-2.31 (m, 1H), 2.22-1.78 (m, 3H), 1.76-1.50 (m, 3H), 1.18-1.04 (m, 3H), 0.72-0.63 (m, 6H). 19F NMR (376 MHz, Methanol-d4, ppm) δ −59.57 (3F).
105		523.4	SFC analysis: 100% ee; retention time: 1.328 min; column: Chiral-MIC, EtOH (0.05% of DEA) in CO2, 5% to 40%; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm): δ 9.49 (s, 1H), 8.91-8.89 (m, 1H), 8.56-8.53 (m, 1H), 7.69-7.60 (m, 4H), 5.60-4.80 (m, 2H), 3.70-3.66 (m, 1H), 3.31- 3.27 (m, 1H), 2.96-2.93 (m, 1H), 2.86-2.82 (m, 1H), 2.33-2.32 (m, 1H), 2.09-2.08 (m, 1H), 2.00-1.88 (m, 2H), 1.65-1.58 (m, 1H), 1.47-1.43 (m, 2H), 0.97 (t, J = 7.6 Hz, 3H), 0.66-0.62 (m, 6H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −60.88 (3F).
106		523.4	SFC analysis: 97.52% ee; retention time: 1.581 min; column: Chiral-MIC, EtOH (0.05% of DEA) in CO2, 5% to 40%; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm): δ 9.50 (s, 1H), 8.92-8.89 (m, 1H), 8.56-8.53 (m, 1H), 7.65-7.63 (m, 1H), 7.60-7.56 (m, 3H), 5.91-4.56 (m, 2H), 3.57- 3.54 (m, 2H), 3.20-3.11 (m, 1H), 2.67-2.56 (m, 1H), 2.33-2.32 (m, 1H), 2.23-2.20 (m, 1H), 1.89-1.73 (m, 2H), 1.63-1.45 (m, 3H), 1.03 (t, J= 7.2Hz, 3H), 0.62-0.57 (m, 6H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −61.0 (3F).
111		524.2	Analytical HPLC*: retention time: 1.468 min; 2.4 FA salt, 1H NMR (400 MHz, DMSO-d6, ppm): δ 9.48 (s, 1H), 8.91 (d, J = 8.4 Hz, 1H), 8.75 (s, 1H), 8.54 (d, J = 8.8 Hz, 1H), 8.46 (s, 2.4H,, FA), 8.08 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 5.95-4.84 (m, 2H), 3.82-3.72 (m, 1H), 2.94-2.82 (m, 2H), 2.04-1.89 (m, 4H), 1.73-1.62 (m, 2 H), 1.54-1.44 (m, 2H), 0.99-0.89 (m, 3H), 0.75-0.59 (m, 6H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −66.10 (3F).
112		524.2	Analytical HPLC*: retention time: 1.530 min; 3.5 FA salt, 1H NMR (400 MHz, DMSO-d6, ppm): δ 9.49 (s, 1H), 8.91 (d, J = 8.4 Hz, 1H), 8.75 (s, 1H), 8.54 (d, J = 8.4 Hz, 1H), 8.46 (s, 3.5H, FA), 8.08 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 5.92-4.33 (m, 2H), 3.75-3.66 (m, 1H), 2.26-2.18 (m 2H), 2.04-1.89 (m, 4H), 1.69-1.58 (m, 2H), 1.48-1.38 (m, 2H), 1.06- 0.95 (m, 3H), 0.69-0.58 (m, 6H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −66.11 (3F).
115		503.4	Analytical HPLC*: retention time: 1.342 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.48 (s, 1H), 8.90 (d, J = 8.8 Hz, 1H), 8.54 (d, J = 8.8 Hz, 1H), 7.38 (t, J = 8.4 Hz, 1H), 6.93-6.76 (m, 2H), 5.55-4.75 (m, 2H), 3.88-3.83 (m, 1H), 3.78 (s, 3H), 3.35-3.28 (s, 1H), 2.95-2.82 (m, 1H), 2.80-2.71 (m, 1H), 2.42-2.38 (m, 1H), 2.09-1.79 (m,3H), 1.67-1.53 (m, 1H), 1.50- 1.34 (m, 2H), 0.96 (t, J = 7.6 Hz, 3H), 0.72-0.62 (m, 6H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −116.84 (1F).
116		503.4	Analytical HPLC*: retention time: 1.377 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.49 (s, 1H), 8.90 (d, J = 8.4 Hz, 1H), 8.54 (d, J = 8.4 Hz, 1H), 7.43 (t, J = 8.4 Hz, 1H), 6.88- 6.72 (m, 2H), 5.91-5.62 (m, 1H), 4.98-4.40 (m, 1H), 3.82-3.66 (m, 4H), 3.58-3.42 (m, 1H), 3.20-3.11 (m, 1H), 2.63-2.54 (m, 1H), 2.42- 2.27 (m, 1H), 1.99-1.93 (m, 1H), 1.90-1.69 (m, 2H), 1.66-1.47 (m, 2H), 1.47-1.32 (m, 1H), 1.00 (t, J = 7.2 Hz, 3H), 0.66 (t, J = 7.2 Hz, 6H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −117.18 (1F).
117		583.4	SFC analysis: 100% ee; retention time: 1.120 min; column: Chiralpak AD, 150 × 4.6 mm I.D., 3 μm, 40% of ethanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.28- 8.19 (m, 1H), 7.99 (d, J = 9.0 Hz, 1H), 7.92- 7.85 (m, 2H), 7.66-7.58 (m, 2H), 5.83-5.71 (m, 0.5H), 5.63-5.51 (m, 0.5H), 5.09-5.00 (m, 0.5H), 4.92-4.80 (m, 0.5H), 3.52-3.40 (m, 4.5H), 3.15- 3.07 (m, 0.5H), 2.85-2.65 (m, 2H), 2.31-1.90 (m, 3H), 1.45-1.31 (m, 2H), 1.05-0.92 (m, 3H), 0.91- 0.83 (m, 1H), 0.82-0.74 (m, 1H), 0.73-0.51 (m, 3H), 0.48-0.23 (m, 2H), 0.08-0.00 (m, 1H); 19F NMR (376 MHz, DMSO-d6, ppm): δ −88.11 (1F), 64.46 (4F).
118		583.4	SFC analysis: 99.72% ee; retention time: 1.517 min; column: Chiralpak AD, 150 × 4.6 mm I.D., 3 μm, 40% of ethanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.30-8.17 (m, 1H), 8.05-7.93 (m, 1H), 7.91-7.83 (m, 2H), 7.64-7.55 (m, 2H), 6.14- 6.05 (m, 0.5H), 5.29-5.20 (m, 0.5H), 5.16- 5.07 (m, 0.5H), 4.80-4.71 (m, 0.5H), 3.71- 3.63 (m, 0.5H), 3.62-3.50 (m, 1H), 3.43(s, 3H), 3.39-3.35 (m, 0.5H), 2.92-2.84 (m, 1H), 2.70- 2.64 (m, 0.5H), 2.35-2.31 (m, 0.5H), 2.11-1.75 (m, 3H), 1.55-1.41 (m, 2H), 1.05-0.90 (m, 4H), 0.84-0.75 (m, 1H),0.65-0.55 (m, 3H), 0.51-0.22 (m, 2H), 0.06-( −0.06) (m, 1H); 19F NMR (376 MHz, DMSO-d6, ppm): δ 88.09 (1F), 64.40 (4F).
125		524.2	SFC analysis: 100% ee; retention time: 1.504 min; column: Chiralpak AD, 150 × 4.6 mm I.D., 3 μm, 40% of ethanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. 0.19 TFA salt, 1H NMR (400 MHz, DMSO-d6, ppm): δ 9.52 (s, 1H), 9.06-8.96 (m, 1H), 8.95- 8.85 (m, 1H), 8.61-8.50 (m, 1H), 8.31-8.20 (m, 1H), 7.80-7.65 (m, 1H), 5.00-4.60 (m, 2H), 4.00-3.81 (m, 1H), 3.59-3.38 (m, 2H), 3.12-2.75 (m, 2H), 2.05-1.81 (m, 4H), 1.59-1.35 (m, 2H), 1.00-0.89 (m, 3H), 0.80-0.58 (m, 6H). 19F NMR (376 MHz, DMSO-d6, ppm): 8-60.64 (3F), −73.48 (0.58F, TFA).
126		524.2	SFC analysis: 98.66% ee; retention time: 2.142 min; column: Chiralpak AD, 150 × 4.6 mm I.D., 3 μm, 40% of ethanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. 0.85 TFA salt, 1H NMR (400 MHz, DMSO-d6, ppm): δ 9.56 (s, 1H), 9.05-8.85 (m, 2H), 8.64-8.52 (m, 1H), 8.40-8.12 (m, 1H), 7.85-7.69 (m, 1H), 5.60- 4.05 (m, 2H), 3.89-3.61 (m, 2H), 3.25-2.72 (m, 3H), 2.05-1.85 (m, 4H), 1.68-1.51 (m, 2H), 1.07- 0.96 (m, 3H), 0.72-0.60 (m, 6H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −60.64 (3F), δ 73.47 (2.55F, TFA).
127		484.2	SFC analysis: 100% ee; retention time: 2.922 min; column: ChiralPak AD, 150 x 4.6 mm I.D., 3 μm, Methanol (0.05% DEA)/CO2-40/60; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm): δ 9.53 (s, 1H), 8.94-8.91 (d, J = 8.8 Hz, 1H), 8.57-8.55 (d, J = 8.8 Hz, 1H), 7.33-7.31 (m, 2H), 7.12- 7.09 (m, 2H), 5.14 (s, 1H), 4.85 (s, 1H), 4.77- 4.75 (m, 1H), 3.68-3.61 (m, 1H), 2.19-1.98 (m, 6H), 0.89-0.85 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −57.23 (3F).
128		484.2	SFC analysis: 100% ee; retention time: 4.037 min; column: ChiralPak AD, 150 × 4.6 mm I.D., 3 μm, Methanol (0.05% DEA)/CO2 = 40/60; pressure: 100 bar; flow rate: 2.5 mL/ min. 1H NMR (400 MHz, DMSO-d6, ppm): δ 9.53 (s, 1H), 8.94-8.91 (d, J = 8.8 Hz, 1H), 8.57-8.55 (d, J = 8.8 Hz, 1H), 7.33-7.31 (m, 2H), 7.12-7.09 (m, 2H), 5.14 (s, 1H), 4.85 (s, 1H), 4.76-4.74 (m, 1H), 3.68-3.62 (m, 1H), 2.21-1.98 (m, 6H), 0.89-0.85 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −57.24 (3F).
129		484.2	SFC analysis: 100% ee; retention time: 2.37 min; column: ChiralPak AD, 150 × 4.6 mm I.D., 3 μm, Ethanol (0.05% DEA)/CO2 = 40/60; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm): δ 9.55 (s, 1H), 8.94-8.92 (d, J = 8.8 Hz, 1H), 8.58- 8.55 (d, J = 8.8 Hz, 1H), 7.31-7.29 (m, 2H), 7.12-7.09 (m, 2H), 5.36 (s, 1H), 4.95-4.90 (m, 2H), 3.49-3.42 (m, 1H), 2.26-1.72 (m, 6H), 0.99-0.95 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −57.25 (3F)
130		484.2	SFC analysis: 100% ee; retention time: 3.168 min; column: ChiralPak AD, 150 × 4.6 mm I.D., 3 μm, Ethanol (0.05% DEA)/CO2 = 40/60; pressure: 100 bar; flow rate: 2.5 mL/ min. 1H NMR (400 MHz, DMSO-d6, ppm): δ 9.55 (s, 1H), 8.94-8.92 (d, J = 8.8 Hz, 1H), 8.58-8.55 (d, J = 8.8 Hz, 1H), 7.31-7.29 (m, 2H), 7.12-7.09 (m, 2H), 5.36 (s, 1H), 4.96-4.90 (m, 2H), 3.50-3.43 (m, 1H), 2.26- 1.71 (m, 6H), 0.99-0.91 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −57.25 (3F).
131		513.3	SFC analysis: 100% ee; retention time: 2.631 min; column: ChiralPak IC, 100 × 4.6 mm I.D., 3 μm, Methanol (0.05% DEA)/CO2 = 40/60; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm): δ 9.48 (s, 1H), 8.92-8.89 (d, J = 8.8 Hz, 1H), 8.56-8.54 (d, J = 8.8 Hz, 1H), 7.35-7.32 (m, 1H), 6.98- 6.87 (m, 2H), 5.45-4.75 (m, 2H), 3.88-3.84 (m, 1H), 3.33 (m, 1H), 2.91-2.79 (m, 2H), 2.50-2.40 (m, 1H), 1.97-1.84 (m, 4H), 1.63-1.59 (m, 1H), 1.43-1.39 (m, 2H), 1.0- 0.94 (m, 5H), 0.74-0.66 (m, 8H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −119.55 (1F).
132		513.4	SFC analysis: 100% ee; retention time: 3.185 min; column: ChiralPak IC, 100 × 4.6 mm I.D., 3 μm, Methanol (0.05% DEA)/CO2 = 40/60; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm): δ 9.49 (s, 1H), 8.92-8.90 (d, J = 8.8 Hz, 1H), 8.56-8.53 (d, J = 8.8 Hz, 1H), 7.41-7.37 (m, 1H), 6.98- 6.82 (m, 2H), 5.75-4.65 (m, 2H), 3.76-3.73 (m, 1H), 3.33 (m, 1H), 3.11-3.01 (m, 1H), 2.58-2.55 (m, 1H), 2.35-2.32 (m, 1H), 1.96-1.78 (m, 4H), 1.59-1.44 (m, 3H), 1.01- 0.95 (m, 5H), 0.71-0.63 (m, 8H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −119.81 (1F).
133		498.2	Analytical HPLC*: retention time: 1.504 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.08(s, 2H), 7.72-7.62 (m, 4H), 5.15-5.12 (m, 1H), 4.20-4.18 (m, 1H), 3.95-3.75 (m, 2H), 3.58 (s, 3H), 3.18-2.93 (m, 2H), 2.39-2.36 (m, 2H), 1.76-1.55 (m, 2H), 1.35-1.24 (m, 4H), 1.13-1.03 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −60.68 (3F).
134		498.2	Analytical HPLC*: retention time: 1.501 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.06 (s, 2H), 7.72-7.59 (m, 4H), 5.03-4.99 (m, 1H), 4.37-4.34 (m, 1H), 4.00-3.95 (m, 2H), 3.59 (s, 3H), 3.34 (m, 1H), 2.99-2.94 (m, 2H), 2.58- 2.55 (m, 1H), 2.41-2.39 (m, 1H), 1.70-1.56 (m, 2H), 1.32-1.30 (m, 3H), 0.78 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −60.73 (3F).
135		515.2	SFC analysis: 100% ee; retention time: 3.712 min; column: CHIRALCEL®OD, 150 × 4.6 mm, 3 μm, Methanol (0.1% DEA)/CO2 = 40/60; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm): δ 9.50 (s, 1H), 8.92 (d, J = 8.6 Hz, 1H), 8.57 (d, J = 8.6 Hz, 1H), 5.66-5.28 (m, 1H), 5.17-4.92 (m, 1H), 4.39-4.23 (m, 1H), 3.64-3.46 (m, 1H), 3.16-3.03 (m, 1H), 2.88-2.64 (m, 2H), 2.11- 1.89 (m, 2H), 1.84-1.68 (m, 2H), 1.51-1.35 (m, 1H), 1.27-1.21 (m, 1H), 0.98-0.88 (m, 6H), 0.87- 0.76 (m, 3H); 19F NMR (376 MHz, DMSO-d6, ppm): δ −65.15 (3F).
136		515.2	SFC analysis: 99.32% ee; retention time: 4.395 min; column: CHIRALCEL®OD, 150 × 4.6 mm, 3pm, Methanol (0.1% DEA)/CO2 = 40/60; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm): δ 9.51 (s, 1H), 8.92 (d, J = 8.6 Hz, 1H), 8.56 (d, J = 8.6 Hz, 1H), 5.87-4.62 (m, 2H), 4.37-4.27 (m, 1H), 3.70-3.39 (m, 1H), 3.13-2.98 (m, 1H), 2.95- 2.80 (m, 1H), 2.75-2.64 (m, 1H), 2.05-1.84 (m, 4H), 1.63-1.50 (m, 1H), 1.14-1.03 (m, 1H), 0.98- 0.84 (m, 9H); 19F NMR (376 MHz, DMSO-d6, ppm): δ −65.26 (3F).
137		537.3	SFC analysis: 100% ee; retention time: 1.314 min; column: ChiralPak AD, 150 × 4.6 mm I.D., 3 μm, Ethanol (0.05% DEA)/CO2 = 40/60; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.49 (s, 1H), 8.91 (d, J = 8.8 Hz, 1H), 8.55 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 6.4 Hz, 2H), 5.32-4.87 (m, 2H), 3.96-3.85 (m, 1H), 3.31-3.13 (m, 1H), 3.03 (d, J = 11.8 Hz, 1H), 2.81 (d, J = 9.2 Hz, 1H), 2.45 (s, 3H), 2.40-2.27 (m, 1H), 2.21-2.11 (m, 1H), 2.00-1.82 (m, 2H), 1.67 (dd, J = 14.4, 6.8 Hz, 1H), 1.58-1.36 (m, 2H), 0.96 (t, J = 7.6 Hz, 3H), 0.64 (t, J = 7.2 Hz, 6H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −60.73 (3F).
138		537.3	SFC analysis: 100% ee; retention time: 2.001 min; column: ChiralPak AD, 150 × 4.6 mm I.D., 3 μm, Ethanol (0.05% DEA)/CO2 = 40/60; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.50 (s, 1H), 8.91 (d, J = 8.8 Hz, 1H), 8.55 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.59-7.45 (m, 2H), 5.50-5.15 (m, 2H), 3.82 (d, J = 6.4 Hz, 1H), 3.60-3.48 (m, 1H), 3.25-3.09 (m, 1H), 2.62 (dd, J = 12.0, 3.2 Hz, 1H), 2.41 (s, 3H), 2.15 (d, J = 11.6 Hz, 1H), 2.03-1.71 (m, 3H), 1.69-1.43 (m, 3H), 1.03 (t, J = 7.2 Hz, 3H), 0.68-0.50 (m, 6H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −60.74 (3F)
139		499.2	SFC analysis: 100% ee; retention time: 3.534 min; column: ChiralPak AD, 150 × 4.6 mm I.D., 3 μm, Ethanol (0.05% DEA)/CO2 = 40/60; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.26-8.24 (d, J = 8.9 Hz, 1H), 8.00-7.98 (d, J = 9.0 Hz, 1H), 7.79-7.76 (m, 2H), 7.46-7.44 (d, J = 8.2 Hz, 2H), 4.40-4.18 (m, 2H), 4.02-3.77 (m, 2H), 3.46 (s, 3H), 3.32-3.20 (m, 2H), 2.28-2.06 (m, 3H), 2.02-1.78 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −56.75 (3F).
140		499.2	SFC analysis: 100% ee; retention time: 5.021 min; column: ChiralPak AD, 150 x 4.6 mm I.D., 3 μm, Ethanol (0.05% DEA)/CO2 = 40/60; pressure: 100 bar; flow rate: 2.5 mL/ min. 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.26-8.24 (d, J = 8.9 Hz, 1H), 8.00-7.98 (d, J = 9.0 Hz, 1H), 7.79-7.76 (m, 2H), 7.46- 7.44 (d, J = 8.3 Hz, 2H), 4.42-4.19 (m, 2H), 4.01-3.75 (m, 2H), 3.46 (s, 3H), 3.33-3.20 (m, 2H), 2.29-2.06 (m, 3H), 2.02-1.78 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −56.76 (3F).
141		462.2	Analytical HPLC*: retention time: 1.405 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.10- 8.05 (m, 2H), 7.38-7.34 (m, 2H), 7.16 (t, J = 8.8 Hz, 2H), 5.26 (d, J = 9.9 Hz, 1H), 4.17-4.14 (m, 1H), 3.80 (dd, J = 10.9, 7.7 Hz, 1H), 3.58 (s, 3H), 3.53-3.49 (m, 1H), 3.30-3.26 (m, 1H), 3.06-3.00 (m, 2H), 2.41-2.29 (m, 2H), 1.88-1.70 (m, 2H), 1.56-1.40 (m, 2H), 1.02 (t, J = 7.3 Hz, 3H), 0.57 (t, J = 7.2 Hz, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −115.99 (1F).
142		462.2	Analytical HPLC*: retention time: 1.479 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.04 (s, 2H), 7.34 (dd, J = 8.5, 5.8 Hz, 2H), 7.17 (t, J = 8.8 Hz, 2H), 4.66 (dd, J = 12.1, 4.0 Hz, 1H), 4.34 (dd, J = 10.8, 2.8 Hz, 1H), 4.00 (dd, J = 10.7, 8.1 Hz, 1H), 3.65 (dd, J = 8.7, 4.8 Hz, 1H), 3.58 (s, 3H), 3.33-3.19 (m, 1H), 3.14-3.05 (m, 1H), 2.89 (dd, J = 11.8, 3.0 Hz, 1H), 2.60 (dd, J = 11.6, 9.3 Hz, 1H), 2.36 (d, J = 5.8 Hz, 1H), 2.02-1.88 (m, 1H), 1.68-1.45 (m, 3H), 0.73 (t, J = 7.3 Hz, 3H), 0.64 (t, J = 7.3 Hz, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −115.81 (1F).
143		530.2	Analytical HPLC*: retention time: 1.702 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.13- 8.03 (m, 2H), 7.79 (t, J = 7.3 Hz, 1H), 7.64 (t, J = 9.2 Hz, 2H), 5.31 (d, J = 10.4 Hz, 1H), 4.20 (dd, J = 11.0, 2.8 Hz, 1H), 3.99 (dd, J = 9.2, 3.6 Hz, 1H), 3.81 (dd, J = 10.9, 7.8 Hz, 1H), 3.59 (s, 3H), 3.03 (dd, J = 20.3, 11.0 Hz, 2H), 2.45-2.32 (m, 2H), 1.93-1.70 (m, 2H), 1.69-1.40 (m, 3H), 1.02 (t, J = 7.3 Hz, 3H), 0.63 (t, J = 7.2 Hz, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −60.90 (3F), −116.42 (1F).
144		530.2	Analytical HPLC*: retention time: 1.711 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ −8.04 (s, 2H), 7.78-7.56 (m, 3H), 4.87-4.76 (m, 1H), 4.36 (d, J = 8.6 Hz, 1H), 4.13-3.94 (m, 2H), 3.58 (s, 3H), 3.45 3.37 (m, 2H), 3.05 (d, J = 11.3 Hz, 1H), 2.94 (d, J = 9.9 Hz, 1H), 2.70-2.59 (m, 1H), 2.38 (d, J = 7.6 Hz, 1H), 2.08-1.90 (m, 1H), 1.73-1.45 (m, 2H), 0.77 (t, J = 7.2 Hz, 3H), 0.68 (t, J = 7.1 Hz, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −60.99 (3F), −115.89 (1F)
146		498.2	Analytical HPLC*: retention time: 1.369 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.08-8.01 (m, 2H), 7.16 (t, J = 9.3 Hz, 2H), 5.13 (dd, J = 12.1, 2.4 Hz, 1H), 4.23 (dd, J = 10.9, 2.9 Hz, 1H), 4.01-3.92 (m, 1H), 3.87-3.77 (m, 1H), 3.57 (s, 3H), 3.32-3.23 (m, 1H), 3.04-2.90 (m, 2H), 2.61- 2.53 (m, 1H), 2.44 (d, J = 11.1 Hz, 1H), 1.98-1.89 (m, 1H), 1.85-1.61 (m, 2H), 1.46-1.34 (m, 1H), 0.97 (t, J = 7.3 Hz, 3H), 0.69 (t, J = 7.3 Hz, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −108.16 (2F), −109.69 (1F).
147		498.2	Analytical HPLC*: retention time: 1.352 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ −8.04 (s, 2H), 7.19 (t, J = 9.4 Hz, 2H), 4.81 (dd, J = 12.2, 3.6 Hz, 1H), 4.37 (dd, J = 10.8, 2.8 Hz, 1H), 4.03- 3.92 (m, 2H), 3.58 (s, 3H), 3.42-3.35 (m, 1H), 3.07 (d, J = 10.0 Hz, 1H), 2.98-2.89 (m, 1H), 2.67-2.54 (m, 1H), 2.40 (d, J = 8.1 Hz, 1H), 2.08-1.96 (m, 1H), 1.83-1.58 (m, 2H), 1.52-1.37 (m, 1H), 0.82-0.64 (m, 6H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −107.98 (2F), −109.40 (1F).
148		512.2	Analytical HPLC*: retention time: 1.530 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.03 (d, J = 8.7 Hz, 2H), 7.71-7.52 (m, 4H), 5.22 (d, J = 11.9 Hz, 1H), 4.26-4.08 (m, 1H), 3.87- 3.73 (m, 1H), 3.66 (d, J = 6.0 Hz, 1H), 3.57 (s, 3H), 3.32-3.22 (m, 1H), 3.16-2.93 (m, 2H), 2.43-2.26 (m, 2H), 1.94-1.67 (m, 2H), 1.61- 1.40 (m, 2H), 1.01 (t, J = 7.2 Hz, 3H), 0.57 (t, J = 7.1 Hz, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −60.87 (3F).
149		512.2	Analytical HPLC*: retention time: 1.651 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.09- 8.01 (m, 2H), 7.69-7.54 (m, 4H), 4.72 (dd, J = 12.1, 3.8 Hz, 1H), 4.36 (dd, J = 10.8, 2.8 Hz, 1H), 4.08-3.96 (m, 1H), 3.85-3.76 (m, 1H), 3.59 (s, 3H), 3.48-3.36 (m, 1H), 3.08 (dd, J = 12.0, 2.2 Hz, 1H), 2.91 (dd, J = 11.6, 2.9 Hz, 1H), 2.72-2.57 (m, 1H), 2.32 (d, J = 5.8 Hz, 1H), 2.08-1.91 (m, 1H), 1.73 1.52 (m, 3H), 0.73 (t, J = 7.3 Hz, 3H), 0.65 (t, J = 7.3 Hz, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −60.90 (3F).
150		570.2	Analytical HPLC*: retention time: 1.770 min; 1H NMR (400 MHz, CDCl3, ppm) δ 7.80-7.62 (m, 4H), 7.43 (d, J = 8.1 Hz, 2H), 5.43 (d, J = 10.6 Hz, 1H), 4.16 (dd, J = 10.9, 2.5 Hz, 1H), 3.97-3.82 (m, 1H), 3.70 (s, 3H), 3.52 (d, J = 6.1 Hz, 1H), 3.42 (d, J = 9.1 Hz, 1H), 3.23-3.04 (m, 2H), 2.46-2.28 (m, 2H), 1.97- 1.74 (m, 2H), 1.38-1.22 (m, 2H), 1.13 (t, J = 7.2 Hz, 3H), 0.65 (t, J = 7.2 Hz, 3H). 19F NMR (376 MHz, CDCl3, ppm) δ 86.26- 84.03 (m, 1F), 63.57-62.82 (m, 4F)
151		570.2	Analytical HPLC*: retention time: 1.797 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.08- 7.99 (m, 2H), 7.87 (d, J = 8.6 Hz, 2H), 7.55 (d, J = 8.3 Hz, 2H), 4.71 (dd, J = 12.1, 3.5 Hz, 1H), 4.35 (dd, J = 10.7, 2.5 Hz, 1H), 4.07- 3.93 (m, 1H), 3.85-3.74 (m, 1H), 3.58 (s, 3H), 3.45-3.35 (m, 1H), 3.09 (d, J = 10.2 Hz, 1H), 2.94-2.82 (m, 1H), 2.70-2.54 (m, 1H), 2.35 (d, J = 6.2 Hz, 1H), 2.02-1.87 (m, 1H), 1.71-1.47 (m, 3H), 0.75 (t, J = 7.3 Hz, 3H), 0.64 (t, J = 7.2 Hz, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ 89.23-86.76 (m, 1F), 64.77-63.67 (m, 4F).
152		526.2	Analytical HPLC*: retention time: 1.782 min; 1H NMR (400 MHz, CDCl3, ppm) δ 7.75-7.65 (m, 2H), 7.62-7.56 (m, 2H), 7.49-7.42 (m, 2H), 5.44-5.35 (m, 1H), 4.18-4.09 (m, 1H), 3.94- 3.84 (m, 1H), 3.71 (s, 3H), 3.64-3.55 (m, 1H), 3.44-3.34 (m, 1H), 3.22-3.07 (m, 2H), 2.45- 2.30 (m, 2H), 1.88-1.77 (m, 2H), 1.68-1.62 (m, 1H), 1.17-1.09 (m, 3H), 1.08-0.89 (m, 3H), 0.87-0.82 (m, 3H). 19F NMR (376 MHz, CDCl3, ppm) δ −-62.28 (3F).
153		526.2	Analytical HPLC*: retention time: 1.684 min; 1H NMR (400 MHz, CDCl3, ppm) 8 7.71-7.64 (m, 2H), 7.59 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 7.9 Hz, 2H), 4.77 (dd, J = 12.0, 3.9 Hz, 1H), 4.42-4.32 (m, 1H), 4.20-4.08 (m, 1H), 3.83- 3.75 (m, 1H), 3.71 (s, 3H), 3.57-3.47 (m, 1H), 3.26-3.15 (m, 1H), 3.01-2.88 (m, 1H), 2.77-2.64 (m, 1H), 2.54-2.44 (m, 1H), 1.95-1.80 (m, 1H), 1.77-1.65 (m, 1H), 1.65-1.61 (m, 1H), 1.21-0.90 (m, 3H), 0.89-0.82 (m, 6H). 19F NMR (376 MHz, CDCl3, ppm) δ −62.37 (3F).
155		527.2	Analytical HPLC*: retention time: 1.580 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.53- 8.47 (m, 1H), 8.06 (s, 2H), 7.80-7.72 (m, 1H), 7.64-7.54 (m, 3H), 7.41-7.34 (m, 2H), 7.27-7.21 (m, 1H), 5.25-5.14 (m, 1H), 5.01 (s, 1H), 4.29-4.16 (m, 1H), 3.92-3.80 (m, 1H), 3.58 (s, 3H), 3.53-3.51 (m, 1H), 3.15-3.03 (m, 1H), 2.58-2.52 (m, 2H), 2.01-1.99 (m, 1H), 1.80-1.57 (m, 2H), 0.73-0.60 (m, 3H).
156		527.2	Analytical HPLC*: retention time: 1.609 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.48- 8.42 (m, 1H), 8.06 (s, 2H), 7.84-7.77 (m, 1H), 7.76-7.70 (m, 1H), 7.56-7.50 (m, 2H), 7.41- 7.34 (m, 2H), 7.27-7.20 (m, 1H), 5.31-5.23 (m, 1H), 4.98 (s, 1H), 4.27-4.16 (m, 1H), 3.91-3.79 (m, 1H), 3.63-3.52 (m, 4H), 3.13- 3.01 (m, 1H), 2.58-2.51 (m, 3H), 1.82-1.67 (m, 1H), 1.65-1.51 (m, 1H), 0.77-0.67 (m, 3H).
157		512.2	Analytical HPLC*: retention time: 1.653 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.13-8.03 (m, 2H), 7.74-7.67 (m, 2H), 7.66-7.59 (m, 2H), 5.22-5.10 (m, 1H), 4.24-4.16 (m, 1H), 3.91-3.76 (m, 2H), 3.58 (s, 3H), 3.32-3.26 (m, 1H), 3.19-3.07 (m, 2H), 2.43-2.29 (m, 2H), 1.84-1.62 (m, 2H), 1.53-1.35 (m, 2H), 1.28-1.24 (m, 3H), 0.91 (t, J = 7.2 Hz, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −60.68 (3F).
158		512.2	Analytical HPLC*: retention time: 1.678 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.10-8.00 (m, 2H), 7.74-7.67 (m, 2H), 7.64- 7.56 (m, 2H), 5.10-4.96 (m, 1H), 4.43-4.33 (m, 1H), 4.06-3.86 (m, 2H), 3.59 (s, 3H), 3.54-3.44 (m, 1H), 3.02-2.89 (m, 2H), 2.57- 2.51 (m, 2H), 1.76-1.61 (m, 1H), 1.53-1.41 (m, 2H), 1.34-1.28 (m, 3H), 1.03-0.91 (m, 1H), 0.74 (t, J = 7.0 Hz, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −60.73 (3F).
159		542.1	SFC analysis: 100% ee; retention time: 4.822 min; column: ChiralCel OX, 100 × 4.6 mm I.D., 3 μm; Ethanol (0.05% DEA)/ CO2 = 40/60; pressure: 100 bar; flow rate: 2.5 mL/min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.07 (s, 2H), 7.66-7.58 (m, 2H), 7.29-7.20 (m, 2H), 5.47 (s, 1H), 4.89-4.81 (m, 1H), 4.25-4.16 (m, 1H), 3.95-3.87 (m, 1H), 3.59 (s, 3H), 3.45-3.35 (m, 1H), 3.29- 3.21 (m, 1H), 2.55-2.51 (m, 2H), 2.41-2.34 (m, 1H), 2.18-2.10 (m, 1H), 1.78-1.60 (m, 2H), 1.12-1.01 (m, 2H), 0.92-0.86 (m, 2H), 0.83 (t, J = 7.3 Hz, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −113.25 (1F).
160		542.1	SFC analysis: 98.92% ee; retention time: 7.450 min; column: ChiralCel OX, 100 × 4.6 mm I.D., 3 μm; Ethanol (0.05% DEA)/CO2 = 40/60; pressure: 100 bar; flow rate: 2.5 mL/min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.06 (s, 2H), 7.64-7.56 (m, 2H), 7.29-7.20 (m, 2H), 5.43 (s, 1H), 5.13-5.06 (m, 1H), 4.32- 4.24 (m, 1H), 3.95-3.87 (m, 1H), 3.59 (s, 3H), 3.53-3.45 (m, 1H), 3.15-3.07 (m, 1H), 2.71-2.62 (m, 1H), 2.49-2.42 (m, 2H), 2.16-2.08 (m, 1H), 1.72-1.59 (m, 1H), 1.52-1.38 (m, 1H), 1.09-1.03 (m, 2H), 0.92-0.85 (m, 2H), 0.73 (t, J = 7.3 Hz, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −113.07 (1F).
161		469.2	Analytical HPLC*: retention time: 1.301 min; 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.07-8.02 (m, 2H), 7.82 (d, J = 8.2 Hz, 2H), 7.54 (d, J = 8.2 Hz, 2H), 4.83-4.66 (m, 1H), 4.44-4.29 (m, 1H), 4.08-3.93 (m, 1H), 3.84-3.72 (m, 1H), 3.59 (s, 3H), 3.46-3.36 (m, 1H), 3.15-3.04 (m, 1H), 2.95-2.86 (m, 1H), 2.69-2.56 (m, 1H), 2.40- 2.31 (m, 1H), 2.03-1.87 (m, 1H), 1.72-1.49 (m, 3H), 0.75 (t, J = 7.3 Hz, 3H), 0.64 (t, J = 7.2 Hz, 3H).
162		469.2	Analytical HPLC*: retention time: 1.321 min; 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.12-8.03 (m, 2H), 7.82 (d, J = 8.2 Hz, 2H), 7.55 (d, J = 8.2 Hz, 2H), 5.35- 5.23 (m, 1H), 4.23-4.10 (m, 1H), 3.86-3.74 (m, 1H), 3.68-3.61 (m, 1H), 3.58 (s, 3H), 3.31-3.26 (m, 1H), 3.15-2.96 (m, 2H), 2.40- 2.30 (m, 2H), 1.94-1.69 (m, 2H), 1.61-1.41 (m, 2H), 1.02 (t, J = 7.3 Hz, 3H), 0.57 (t, J = 7.2 Hz, 3H)
163		532.4	Analytical HPLC*: retention time: 1.757 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.15- 7.99 (m, 2H), 7.47-7.35 (m, 1H), 6.85-6.68 (m, 2H), 5.32-5.17 (m, 1H), 4.24-4.15 (m, 1H), 4.02-3.91 (m, 1H), 3.86-3.76 (m, 3H), 3.58 (s, 3H), 3.32-3.25 (m, 1H), 3.14-2.97 (m, 2H), 2.47-2.38 (m, 1H), 2.37-2.28 (m, 1H), 1.84- 1.62 (m, 2H), 1.47-1.31 (m, 2H), 1.28-1.18 (m, 4H), 0.97-0.83 (m, 3H), 0.64-0.48 (m, 2H), 0.37-0.24 (m, 2H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −118.18 (1F)
164		532.4	Analytical HPLC*: retention time: 1.766 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.12- 8.00 (m, 2H), 7.40-7.30 (m, 1H), 6.87-6.62 (m, 2H), 5.08-4.95 (m, 1H), 4.44-4.33 (m, 1H), 4.10-4.01 (m, 1H), 4.00-3.91 (m, 1H), 3.83- 3.77 (m, 2H), 3.58 (s, 3H), 3.48 -3.40 (m, 1H), 3.02-2.85 (m, 2H), 2.57-2.52 (m, 1H), 2.49-2.44 (m, 1H), 1.75-1.60 (m, 1H), 1.51-1.35 (m, 2H), 1.33-1.26 (m, 3H), 1.24-1.16 (m, 1H), 1.04- 0.87 (m, 1H), 0.80-0.70 (m, 3H), 0.61-0.47 (m, 2H), 0.36-0.26 (m, 2H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −117.70 (1F)
165		457.3	1H NMR (400 MHz, CDCl3, ppm) δ 7.79-7.67 (m, 2H), 7.20-7.12 (m, 2H), 6.85 (d, J = 7.4 Hz, 1H), 5.43 (dd, J = 13.0, 2.3 Hz, 1H), 4.45 (dd, J = 11.1, 3.0 Hz, 1H), 4.38-4.21 (m, 2H), 4.17- 4.08 (m, 1H), 3.72 (s, 3H), 3.70-3.64 (m, 1H), 3.44-3.27 (m, 2H), 2.39 (s, 3H), 1.89-1.78 (m, 2H), 1.07 (t, J = 7.4 Hz, 3H).
166		476.3	SFC analysis: 100% ee; retention time: 5.139 min; column: ChiralCel OJ, 150 x 4.6 mm I.D., 3 μm; Methanol (0.05% DEA)/CO2 = 40/60; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.09-8.02 (m, 2H), 4.40-4.34 (m, 1H), 4.24-4.11 (m, 2H), 3.88-3.81 (m, 1H), 3.61 (s, 3H), 3.17-3.10 (m, 1H), 3.09-3.02 (m, 1H), 2.64-2.57 (m, 1H), 2.56-2.52 (m, 1H), 2.19-2.11 (m, 1H), 1.94-1.84 (m, 2H), 1.69- 1.17 (m, 3H), 1.11-1.05 (m, 2H), 0.94-0.81 (m, 8H).
167		476.3	SFC analysis: 100% ee; retention time: 5.436 min; column: ChiralCel OJ, 150 x 4.6 mm I.D., 3 μm; Methanol (0.05% DEA)/CO2 = 40/60; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.10-8.03 (m, 2H), 4.88-4.80 (m, 1H), 4.32-4.25 (m, 1H), 4.11-4.03 (m, 1H), 3.96-3.89 (m, 1H), 3.59 (s, 3H), 3.19-3.10 (m, 1H), 2.97-2.87 (m, 1H), 2.82-2.72 (m, 1H), 2.67-2.58 (m, 1H), 2.15- 2.05 (m, 1H), 1.92-1.70 (m, 2H), 1.67-1.55 (m, 1H), 1.28-1.12 (m, 2H), 1.09-1.02 (m, 2H), 0.95-0.79 (m, 8H).
168		567.3	SFC analysis: 100% ee; retention time: 1.836 min; column: ChiralPak IG, 100 × 4.6 mm I.D., 3 μm; Methanol (0.05% DEA)/CO2 = 40/60; pressure: 100 bar; flow rate: 2.5 mL/ min. 1H NMR (400 MHz, CDCl3, ppm) δ 8.86 (s, 1H), 8.37-8.26 (m, 1H), 8.12-8.02 (m, 1H), 7.69-7.59 (m, 2H), 7.52-7.31 (m, 2H), 5.81-4.82 (m, 2H), 3.75-3.21 (m, 2H), 2.99-2.61 (m, 2H), 2.49-2.01 (m, 3H), 1.49- 1.37 (m, 2H), 1.04 (s, 3H), 0.97-0.89 (m, 1H), 0.87-0.81 (m, 1H), 0.78-0.59 (m, 3H), 0.48-0.33 (m, 2H), 0.08-0.02 (m, 1H). 19F NMR (376 MHz, CDCl3, ppm) δ −42.73 (3F).
169		567.3	SFC analysis: 100% ee; retention time: 2.655 min; column: ChiralPak IG, 100 × 4.6 mm I.D., 3 μm; Methanol (0.05% DEA)/CO2 = 40/60; pressure: 100 bar; flow rate: 2.5 mL/ min. 1H NMR (400 MHz, CDCl3, ppm) δ 8.85 (s, 1H), 8.38-8.26 (m, 1H), 8.11-7.99 (m, 1H), 7.68-7.56 (m, 2H), 7.49-7.31 (m, 2H), 6.14-4.79 (m, 2H), 4.03-3.31 (m, 2H), 2.90-2.71 (m, 1H), 2.68-2.14 (m, 2H), 2.13- 1.79 (m, 2H), 1.69-1.63 (m, 1H), 1.52-1.42 (m, 1H), 1.16-0.94 (m, 4H), 0.85-0.76 (m, 1H), 0.66 (s, 3H), 0.50-0.31 (m, 2H), 0.07- 0.00 (m, 1H). 19F NMR (376 MHz, CDCl3, ppm) δ −42.91 (3F).
170		498.3	Analytical HPLC*: retention time: 1.407 min; 1H NMR (400 MHz, methanol-d4, ppm) δ 8.07-8.00 (m, 1H), 7.92-7.86 (m, 1H), 7.32-7.21 (m, 1H), 7.02-6.94 (m, 1H), 5.19-5.08 (m, 1H), 4.43-4.36 (m, 1H), 4.17-4.10 (m, 1H), 4.08-4.02 (m, 1H), 3.70 (s, 3H), 3.53 (t, J = 8.7 Hz, 1H), 3.19-3.08 (m, 1H), 3.11-3.03 (m, 1H), 2.72 (t, J = 10.6 Hz, 1H), 2.58-2.49 (m, 1H), 2.16-2.03 (m, 1H), 1.95-1.81 (m, 1H), 1.82-1.68 (m, 1H), 1.62-1.48 (m, 1H), 0.90- 0.76 (dt, 6H). 19F NMR (376 MHz, methanol-d4, ppm) δ −117.87 (1F), −137.02 (1F), −144.36 (1F).
171		498.3	Analytical HPLC*: retention time: 1.437 min; 1H NMR (400 MHz, methanol-d4, ppm) δ 8.07-8.02 (m, 1H), 7.93-7.88 (m, 1H), 7.28-7.18 (m, 1H), 7.00-6.91 (m, 1H), 5.43-5.36 (m, 1H), 4.26-4.20 (m, 1H), 4.20-4.13 (m, 1H), 3.97-3.90 (m, 1H), 3.70 (s, 3H), 3.50-3.41 (m, 1H), 3.20-3.14 (m, 1H), 3.08-3.02 (m, 1H), 2.69-2.62 (m, 2H), 2.09-1.89 (m, 2H), 1.85-1.74 (m, 1H), 1.52-1.42 (m, 1H), 1.05 (t, J = 7.4 Hz, 3H), 0.79 (t, J = 7.4 Hz, 3H). 19F NMR (376 MHz, methanol-d4, ppm) δ −118.02 (1F), −137.08 (1F), −144.45 (1F).
172		469.2	SFC analysis: 100% ee; retention time: 3.229 min; column: Chiralcel OJ-3 150 × 4.6 mm I.D., 3 μm; Ethanol (0.05% DEA)/CO2 = 40/60; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.08-8.01 (m, 2H), 7.81-7.72 (m, 2H), 7.71-7.65 (m, 1H), 7.61-7.54 (m, 1H), 4.77-4.61 (m, 1H), 4.45-4.27 (m, 1H), 4.06-3.97 (m, 1H), 3.80- 3.71 (m, 1H), 3.65-3.55 (m, 3H), 3.17-3.07 (m, 1H), 2.94-2.85 (m, 1H), 2.73-2.60 (m, 1H), 2.41-2.29 (m, 1H), 2.05-1.91 (m, 1H), 1.71-1.51 (m, 3H), 0.81-0.71 (m, 3H), 0.70-0.56 (m, 3H).
173		469.2	SFC analysis: 100% ee; retention time: 4.974 min; column: Chiralcel OJ-3 150 × 4.6 mm I.D., 3μm; Ethanol (0.05% DEA)/CO2 = 40/60; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.11-8.04 (m, 2H), 7.80-7.72 (m, 2H), 7.72-7.67 (m, 1H), 7.60-7.54 (m, 1H), 5.33-5.20 (m, 1H), 4.23- 4.12 (m, 1H), 3.86-3.75 (m, 1H), 3.65-3.52 (m, 4H), 3.33-3.31 (m, 1H), 3.13-3.03 (m, 1H), 3.04-2.95 (m, 1H), 2.42-2.29 (m, 2H), 1.91- 1.81 (m, 1H), 1.81-1.69 (m, 1H), 1.60-1.40 (m, 2H), 1.09-0.95 (m, 3H), 0.63-0.50 (m, 3H).
174		480.2	Analytical HPLC*: retention time: 1.520 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.08- 7.99 (m, 2H), 7.56-7.43 (m, 1H), 7.27-7.17 (m, 1H), 7.16-7.06 (m, 1H), 4.84-4.70 (m, 1H), 4.43-4.30 (m, 1H), 4.05-3.91 (m, 2H), 3.61-3.53 (m, 3H), 3.20-3.01 (m, 2H), 2.99-2.89 (m, 1H), 2.70-2.55 (m, 1H), 2.43-2.33 (m, 1H), 2.05-1.88 (m, 1H), 1.73-1.40 (m, 3H), 0.83-0.72 (m, 3H), 0.72-0.63 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −112.22 (1F), −114.33 (1F)
175		480.2	Analytical HPLC*: retention time: 1.485 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.12- 8.00 (m, 2H), 7.61-7.49 (m, 1H), 7.26-7.05 (m, 2H), 5.33-5.20 (m, 1H), 4.29-4.13 (m, 1H), 3.92- 3.75 (m, 2H), 3.63-3.53 (m, 3H), 3.32-3.25 (m, 1H), 3.10-2.93 (m, 2H), 2.48-2.30 (m, 2H), 1.96- 1.83 (m, 1H), 1.82-1.68 (m, 1H), 1.61-1.43 (m, 2H), 1.08-0.95 (m, 3H), 0.68-0.56 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −112.51 (1F), −115.04 (1F)
176		474.4	Analytical HPLC*: retention time: 1.457 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.09- 7.99 (m, 2H), 7.27-7.15 (m, 2H), 6.99-6.84 (m, 2H), 4.68-4.51 (m, 1H), 4.40-4.26 (m, 1H), 4.07-3.94 (m, 1H), 3.75 (s, 3H), 3.59 (s, 3H), 3.58-3.51 (m, 1H), 3.35 (s, 1H), 3.19-3.09 (m, 1H), 2.92-2.82 (m, 1H), 2.65-2.55 (m, 1H), 2.39 (s, 1H), 2.02-1.86 (m, 1H), 1.67-1.42 (m, 3H), 0.79-0.70 (m, 3H), 0.69-0.60 (m, 3H).
177		474.4	Analytical HPLC*: retention time: 1.432 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.15- 7.98 (m, 2H), 7.30-7.16 (m, 2H), 6.98-6.78 (m, 2H), 5.37-5.14 (m, 1H), 4.23-4.07 (m, 1H), 3.85-3.77 (m, 1H), 3.75 (s, 3H), 3.58 (s, 3H), 3.46-3.39 (m, 1H), 3.29 (s, 1H), 3.09-2.96 (m, 2H), 2.47-2.39 (m, 1H), 2.35-2.25 (m, 1H), 1.84 (s, 1H), 1.78-1.66 (m, 1H), 1.55-1.40 (m, 2H), 1.09-0.96 (m, 3H), 0.62-0.48 (m, 3H)
178		498.3	SFC analysis: 100% ee; retention time: 4.816 min; column: ChiralCel OX, 100 × 4.6 mm I.D., 3 μm; 5-40% of Ethanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.8 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.11- 8.03 (m, 2H), 7.71 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 8.1 Hz, 2H), 5.03-4.87 (m, 1H), 4.21-4.03 (m, 1H), 3.94-3.80 (m, 1H), 3.58 (s, 3H), 3.55- 3.51 (m, 1H), 3.50-3.41 (m, 1H), 3.39-3.34 (m, 1H), 3.32-3.25 (m, 1H), 2.44-2.32 (m, 2H), 2.01- 1.85 (m, 1H), 1.67-1.51 (m, 1H), 1.09 (d, J = 6.4 Hz, 3H), 0.60 (t, J = 7.2 Hz, 3H); 19F NMR (376 MHz, DMSO-d6, ppm): δ −60.67 (3F).
179		498.3	SFC analysis: 100% ee; retention time: 6.006 min; column: ChiralCel OX, 100 × 4.6 mm I.D., 3 μm; 5-40% of Ethanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.8 mL/ min. 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.11-7.99 (m, 2H), 7.72 (d, J = 8.2 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 4.40-4.32 (m, 1H), 4.22-4.11 (m, 1H), 4.08-3.96 (m, 1H), 3.84- 3.73 (m, 1H), 3.59 (s, 3H), 3.47-3.40 (m, 1H), 3.37-3.34 (m, 1H), 2.86-2.56 (m, 3H), 2.04- 1.86 (m, 1H), 1.71-1.56 (m, 1H), 1.03 (d, J = 6.3 Hz, 3H), 0.72 (t, J = 7.2 Hz, 3H); 19F NMR (376 MHz, DMSO-d6, ppm): δ −60.77 (3F).
180		504.2	SFC analysis: 99.78% ee; retention time: 1.337 min; column: ChiralPak®AD, 150 × 4.6 mm, 3 μm; Methanol (0.05%DEA)/CO2-30/70; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.17- 7.98 (m, 2H), 4.78-4.56 (m, 1H), 4.43-4.33 (m, 1H), 4.32-4.24 (m, 1H), 4.00-3.87 (m, 1H), 3.59 (s, 3H), 3.38-3.33 (m, 1H), 3.32-3.25 (m, 2H), 3.10-2.98 (m, 1H), 2.93-2.86 (m, 1H), 2.74- 2.62 (m, 1H), 2.03-1.79 (m, 2H), 1.72-1.58 (m, 1H), 0.98-0.81 (m, 6H); 19F NMR (376 MHz, DMSO-d6, ppm): δ −65.20 (3F).
181		504.2	SFC analysis: 98.10% ee; retention time: 1.567 min; column: ChiralPak®AD, 150 × 4.6 mm, 3 μm; Methanol (0.05% DEA)/CO2 = 30/70; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.11- 8.00 (m, 2H), 4.51-4.43 (m, 1H), 4.42-4.35 (m, 1H), 4.28-4.15 (m, 1H), 4.08-3.89 (m, 1H), 3.62 (s, 3H), 3.28-3.07 (m, 3H), 2.81-2.58 (m, 2H), 2.11-1.92 (m, 2H), 1.74-1.49 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H), 0.88 (t, J = 7.3 Hz, 3H); 19F NMR (376 MHz, DMSO-d6, ppm): δ −65.14 (3F).
182		480.4	Analytical HPLC*: retention time: 1.517 min; 0.65FA salt; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.48 (s, 0.65H), 8.18-8.00 (m, 2H), 7.45-7.31 (m, 2H), 7.25-7.12 (m, 1H), 5.38- 5.21 (m, 1H), 4.25-4.13 (m, 1H), 3.88-3.73 (m, 1H), 3.58 (s, 3H), 3.55-3.45 (m, 1H), 3.31- 3.24 (m, 1H), 3.10-2.96 (m, 2H), 2.41-2.30 (m, 2H), 1.90-1.67 (m, 2H), 1.55-1.39 (m, 2H), 1.02 (t, J = 7.3 Hz, 3H), 0.59 (t, J = 7.2 Hz, 3H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −138.92 (1F),-141.15 (1F).
183		480.4	Analytical HPLC*: retention time: 1.470 min; 0.73 FA salt; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.48 (s, 0.73H), 8.12-7.98 (m, 2H), 7.46-7.30 (m, 2H), 7.26-7.12 (m, 1H), 4.79-4.62 (m, 1H), 4.42-4.27 (m, 1H), 4.07-3.93 (m, 1H), 3.75-3.68 (m, 1H), 3.59 (s, 3H), 3.46-3.36 (m, 1H), 3.18-3.06 (m, 1H), 2.94-2.84 (m, 1H), 2.72-2.58 (m, 1H), 2.43-2.33 (m, 1H), 2.03-1.86 (m, 1H), 1.68-1.48 (m, 3H), 0.77 (t, J = 7.3 Hz, 3H), 0.66 (t, J = 7.2 Hz, 3H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −138.99 (1F), −141.02 (1F).
184		522.4	Analytical HPLC*: retention time: 1.144 min; 0.78 FA salt; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.46 (s, 0.78H, FA), 8.10- 8.00 (m, 2H), 7.91 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 4.75-4.61 (m, 1H), 4.40- 4.20 (m, 1H), 4.10-3.95 (m, 1H), 3.87-3.75 (m, 1H), 3.59 (s, 3H), 3.46-3.36 (m, 1H), 3.22 (s, 3H), 3.15-3.05 (m, 1H), 2.95- 2.85 (m, 1H), 2.70-2.56 (m, 1H), 2.40-2.29 (m, 1H), 2.07-1.87 (m, 1H), 1.66-1.58 (m, 3H), 0.75 (t, J = 7.2 Hz, 3H), 0.66 (t, J = 7.2 Hz, 3H).
185		522.4	Analytical HPLC*: retention time: 1.187 min; 0.81 FA salt; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.46 (s, 0.81H, FA), 8.15-8.07 (m, 2H), 7.90 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.3 Hz, 2H), 5.35-5.25 (m, 1H), 4.25-4.10 (m, 1H), 3.90-3.75 (m, 1H), 3.70-3.62 (m, 1H), 3.59 (s, 3H), 3.40-3.30 (m, 1H), 3.23 (s, 3H), 3.15-3.05 (m, 2H), 2.45-2.35 (m, 2H), 2.06-1.70 (m, 2H), 1.65-1.52 (m, 2H), 1.02 (t, J = 7.2 Hz, 3H), 0.58 (t, J = 7.2 Hz, 3H).
186		513.3	Analytical HPLC*: retention time: 1.508 min; 1H NMR (400 MHz, CDCl3, ppm): δ 8.86 (s, 1H), 7.96-7.86 (m, 1H), 7.70-7.60 (m, 2H), 7.49-7.39 (m, 1H), 4.52-4.38 (m, 2H), 4.28- 4.18 (m, 1H), 4.05-3.95 (m, 1H), 3.73 (s, 3H), 3.55-3.34 (m, 2H), 3.02-2.82 (m, 2H), 2.62- 2.50 (m, 1H), 2.23-1.71 (m, 4H), 0.95-0.70 (m, 6H); 19F NMR (376 MHz, CDCl3, ppm): δ −62.12 (3F).
187		513.3	Analytical HPLC*: retention time: 1.433 min; 1H NMR (400 MHz, CDCl3, ppm): δ 8.76 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 4.0 Hz, 1H), 7.65 (d, J = 4.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 5.28-5.18 (m, 1H), 4.10-4.00 (m, 1H), 3.89-3.79 (m, 1H), 3.83-3.73 (m, 1H), 3.66 (s, 3H), 3.49-3.32 (m, 1H), 3.21-2.95 (m, 2H), 2.56-2.22 (m, 2H), 1.98-1.65 (m, 4H), 1.10-1.04 (m, 3H), 0.63-0.59 (m, 3H); 19F NMR (376 MHz, CDCl3, ppm): δ −62.21 (3F).
188		496.1	SFC analysis: 100% ee; retention time: 3.058 min; column: ChiralPak AD, 150 × 4.6 mm I.D., 3 μm, 40% of Ethanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/ min; 1H NMR (400 MHz, CDCl3, ppm): δ 8.91 (s, 1H), 8.30-8.45 (m, 2H), 8.10-8.00 (m, 1H), 7.79-7.52 (m, 1H), 7.20-7.09 (m, 1H), 5.46-5.05 (m, 1H), 3.56-3.11 (m, 2H), 2.81-2.62 (m, 1H), 2.39-2.18 (m, 2H), 2.11-1.94 (m, 4H), 1.76-1.42 (m, 4H), 1.13-0.94 (m, 7H), 0.88-0.70 (m, 6H).
189		496.1	SFC analysis: 98.60% ee; retention time: 3.461 min; column: ChiralPak AD, 150 x 4.6 mm I.D., 3 μm, A for CO2 and B for Ethanol (0.05% DEA, 40%); pressure: 100 bar; flow rate: 2.5 mL/min; 1H NMR (400 MHz, CDCl3, ppm): δ 8.84 (s, 1H), 8.36 (s, 1H), 8.29 (d, J = 8.0 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.72-7.49 (m, 1H), 7.19-7.08 (m, 1H), 5.71-5.22 (m, 1H), 3.73-3.12 (m, 2H), 3.05-2.79 (m, 2H), 2.57-2.38 (m, 1H), 2.21-1.85 (m, 4H), 1.79-1.59 (m, 2H), 1.57- 1.38 (m, 2H), 1.20-1.07 (m,4H), 1.05-0.90 (m, 3H), 0.83-0.65 (m, 6H).
190		579.3	SFC analysis: 100% ee; retention time: 4.803 min; column: Chiralcel OX, 100 × 4.6 mm I.D., 3 μm, 5-40% of Ethanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.85 (s, 1H), 8.28-8.18 (m, 1H), 8.10-8.00 (m, 3H), 7.63-7.53 (m, 2H), 7.20-7.08 (m, 2H), 5.40-5.25 (m, 1H), 5.08 (s, 1H), 4.29-4.18 (m, 1H), 3.88-3.78 (m, 1H), 3.58-3.32 (m, 4H), 3.15-3.02 (m, 1H), 2.67-2.54 (m, 3H), 1.81-1.70 (m, 1H), 1.65-1.54 (m, 1H), 0.71 (t, J = 6.8 Hz, 3H); 19F NMR (376 MHz, DMSO-d6, ppm): δ −60.72(3F), −114.53 (1F).
191		579.3	SFC analysis: 98.78% ee; retention time: 5.185 min; column: Chiralcel OX, 100 × 4.6 mm I.D., 3 μm, 5-40% of Ethanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.90 (s, 1H), 8.24-8.12 (m, 1H), 8.10-8.00 (m, 2H), 7.92-7.80 (m, 1H), 7.68-7.55 (m, 2H), 7.23- 7.11 (m, 2H), 5.29-5.16 (m, 2H), 4.28-4.15 (m, 1H), 3.89-3.78 (m, 1H), 3.62-3.48 (m, 4H), 3.20-3.08 (m, 1H), 2.62-2.51 (m, 2H), 2.09-1.90 (m,1H), 1.77-1.55(m, 2H), 0.86 (t, J = 6.8 Hz, 3H); 19F NMR (376 MHz, DMSO-d6, ppm): δ −60.78 (3F), −114.79 (1F).
193		499.2	1H NMR (400 MHz, DMSO-d6, ppm) δ 8.28-8.20 (m, 1H), 8.03-7.98 (m, 1H), 7.78-7.72 (m, 2H), 7.68-7.61 (m, 2H), 5.58-5.26 (m, 1H), 5.04-4.63 (m, 1H), 3.99-3.69 (m, 2H), 3.49-3.35 (m, 6H), 2.91 (t, J = 12.2 Hz, 1H), 2.62-2.51 (m, 2H), 2.24-2.10 (m, 1H), 2.09-1.81 (m, 2H), 0.72 (t, J = 7.2 Hz, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −60.88 (3F).
194		491.4	SFC analysis: 100% ee; retention time: 5.276 min; column: ChiralPak IG, 150 × 4.6 mm I.D., 3 μm, 5-40% of Methanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.48 (s, 1H), 8.91 (d, J = 8.7 Hz, 1H), 8.55 (d, J = 8.7 Hz, 1H), 7.55 (dd, J = 15.4, 8.2 Hz, 1H), 7.27-7.11 (m, 2H), 5.88-4.40 (m, 2H), 3.94-3.87 (m, 1H), 2.95-2.74 (m, 2H), 2.41-2.34 (m, 1H), 2.08-1.79 (m, 3H), 1.68- 1.53 (m, 1H), 1.50-1.35 (m, 2H), 1.29-1.08 (m, 1H), 0.99-0.92 (m, 3H), 0.76-0.64 (m, 6H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −112.24 (1F), −114.75 (1F)
195		491.4	SFC analysis: 100% ee; retention time: 5.816 min; column: ChiralPak IG, 150 × 4.6 mm I.D., 3 μm, 5-40% of Methanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.49 (s, 1H), 8.91 (d, J = 8.7 Hz, 1H), 8.54 (d, J = 8.6 Hz, 1H), 7.60 (dd, J = 15.4, 8.4 Hz, 1H), 7.23 7.09 (m, 2H), 6.12-4.38 (m, 2H), 3.80-3.74 (m, 1H), 3.62-3.39 (m, 1H), 3.16-3.06 (m, 1H), 2.63- 2.56 (m, 1H), 2.35-2.25 (m, 1H), 2.06-1.72 (m, 3H), 1.67-1.50 (m, 2H), 1.49-1.35 (m, 1H), 1.04-0.97 (m, 3H), 0.69-0.61 (m, 6H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −112.47 (1F), −115.06 (1F).
196		496.2	SFC analysis: 100% ee; retention time: 3.869 min; column: ChiralCel OD, 150 × 4.6 mm I.D., 3 μm, 40% of Ethanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. 0.8 TFA salt, LCMS (ESI, m/z): [M + H]+ = 496.2. 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.10- 8.00 (m, 2H), 7.58-7.47 (m, 1H), 7.40-7.28 (m, 2H), 5.91-5.81 (m, 1H), 5.32-5.20 (m, 1H), 4.28-4.18 (m, 1H), 3.85-3.75 (m, 1H), 3.59 (s, 3H), 3.55-3.45 (m, 1H), 3.08-2.90 (m, 2H), 2.40-2.29 (m, 2H), 1.90-1.69 (m, 2H), 1.58- 1.37 (m, 2H), 1.01 (t, J = 7.2 Hz, 3H), 0.58 (t, J = 7.0 Hz, 3H); 19F NMR (376 MHz, DMSO-d6, ppm): δ −73.43(2.4F, TFA), −118.92 (1F).
197		496.2	SFC analysis: 100% ee; retention time: 4.892 min; column: ChiralCel OD, 150 × 4.6 mm I.D., 3 μm, 40% of Ethanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. 2.09 TFA salts, LCMS (ESI, m/z): [M + H]+ = 496.2. 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.10- 8.00 (m, 2H), 7.55-7.45 (m, 1H), 7.40-7.30 (m, 2H), 4.74-4.63 (m, 1H), 4.36-4.25 (m, 1H), 4.07-3.96 (m, 1H), 3.73-3.63 (m, 1H), 3.61 (s, 3H), 3.48-3.36 (m, 1H), 3.15-3.05 (m, 1H), 2.96-2.87 (m, 1H), 2.72-2.60 (m, 1H), 2.42- 2.31 (m, 1H), 2.01-1.91 (m, 1H), 1.65-1.54 (m, 3H), 0.76-0.74 (m, 3H), 0.67-0.64 (m,3H); 19F NMR (376 MHz, DMSO-d6, ppm): δ −73.47 (6.27F, TFA), −118.74 (1F).
200		491.4	Analytical HPLC*: retention time: 1.451 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.48 (s, 1H), 8.91 (d, J = 8.8 Hz, 1H), 8.55 (d, J = 8.8 Hz, 1H), 7.50-7.39 (m, 2H), 7.19 (s, 1H), 5.80-4.50 (m, 2H), 3.62-3.51 (m, 1H), 3.40-3.30 (m, 1H), 2.92-2.80 (m, 2H), 2.42-2.32 (m, 1H), 2.20-2.01 (m, 1H), 1.95-1.85 (m, 2H), 1.60-1.50 (m, 1H), 1.49-1.35 (m, 2H), 0.97 (t, J = 7.6 Hz, 3H), 0.75-0.58 (m, 6H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −138.90 (1F), −141.04 (1F).
201		491.4	Analytical HPLC*: retention time: 1.589 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.49 (s, 1H), 8.91 (d, J = 8.8 Hz, 1H), 8.55 (d, J = 8.8 Hz, 1H), 7.49-7.36 (m, 2H), 7.20 (s, 1H), 6.01-4.55 (m, 2H), 3.67-3.38 (m, 2H), 3.19- 3.05 (m, 1H), 2.65-2.55 (m, 1H), 2.31-2.22 (m, 1H), 2.12-1.92 (m, 1H), 1.90-1.80 (m, 2H), 1.71-1.59 (m, 1H), 1.56-1.35 (m, 2H), 1.01 (t, J = 7.2 Hz, 3H), 0.75-0.54 (m, 6H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −139.21 (1F), −141.10 (1F).
202		509.4	SFC analysis: 100% ee; retention time: 2.258 min; column: ChiralPak AD, 150 x 4.6 mm I.D., 3 μm, 30% of Ethanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.49 (s, 1H), 8.91 (d, J = 8.7 Hz, 1H), 8.54 (d, J = 8.6 Hz, 1H), 7.19 (t, J = 9.4 Hz, 2H), 6.33-4.18 (m, 2H), 3.92-3.83 (m, 1H), 3.42 (s, 1H), 3.16- 3.04 (m, 1H), 2.76-2.67 (m, 1H), 2.42-2.34 (m, 1H), 2.03-1.80 (m, 3H), 1.78-1.68 (m, 1H), 1.67-1.53 (m, 1H), 1.44-1.31 (m, 1H), 1.04- 0.94 (m, 3H), 0.75-0.59 (m, 6H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −109.62 (3F)
203		509.4	SFC analysis: 100% ee; retention time: 2.691 min; column: ChiralPak AD, 150 × 4.6 mm I.D., 3 μm, 30% of Ethanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.48 (s, 1H), 8.91 (d, J = 8.6 Hz, 1H), 8.55 (d, J = 8.6 Hz, 1H), 7.22 (t, J = 9.3 Hz, 2H), 6.36-4.36 (m, 2H), 4.01-3.94 (m, 1H), 3.43-3.33 (m, 1H), 2.99-2.89 (m, 1H), 2.86-2.74 (m, 1H), 2.42-2.33 (m, 1H), 2.06-1.88 (m, 2H), 1.88-1.75 (m, 2H), 1.52-1.36 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H), 0.80-0.71 (m, 6H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −109.44 (3F).
204		537.3	SFC analysis: 98.52% ee; retention time: 4.932 min; column: ChiralCel OD, 150 × 4.6 mm I.D., 3 μm, 40% of Methanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.51-9.43 (m, 1H), 8.98-8.85 (m, 1H), 8.60-8.50 (m, 1H), 7.77-7.70 (m, 2H), 7.56-7.48 (m, 2H), 4.82-4.64 (m, 3H), 3.59-3.47 (m, 1H), 2.95 (dd, J = 11.9, 4.6 Hz, 1H), 2.77-2.61 (m, 1H), 2.43-2.33 (m, 2H), 1.92 (dd, J = 34.0, 26.4 Hz, 2H), 1.54-1.43 (m, 1H), 1.39-1.28 (m, 1H), 1.02-0.94 (m, 3H), 0.83-0.63 (m, 9H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −60.66 (3F).
205		541.5	Analytical HPLC*: retention time: 1.950 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.49 (s, 1H), 8.91 (d, J = 8.8 Hz, 1H), 8.55 (d, J = 8.6 Hz, 1H), 7.83-7.58 (m, 3H), 6.00-4.40 (m, 2H), 4.10-3.95 (m, 1H), 3.44-3.33 (m, 1H), 3.03-2.76 (m, 2H), 2.44-2.30 (m, 1H), 2.11-1.79 (m, 3H), 1.76-1.58 (m, 1H), 1.53- 1.34 (m, 2H), 1.02-0.90 (m, 3H), 0.80-0.62 (m, 6H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −60.93 (3F); −116.21 (1F).
206		546.4	Analytical HPLC*: retention time: 2.182 min; 1H NMR (400 MHz, methanol-d4, ppm) δ 8.10 (d, J = 8.8 Hz, 1H), 8.03-7.90 (m, 3H), 7.89-7.82 (m, 1H), 5.98-5.25 (m, 1H), 5.17- 4.94 (m, 1H), 4.36 (d, J = 8.9 Hz, 1H), 4.04- 3.92 (m, 1H), 3.85-3.61 (m, 5H), 3.60 3.41 (m, 1H), 3.28-2.89 (m, 2H), 2.49-2.05 (m, 2H), 2.08-1.71 (m, 2H), 1.39-1.05 (m, 3H), 0.74 (t, J = 7.3 Hz, 3H). 19F NMR (376 MHz, methanol-d4, ppm) δ −64.57 (3F).
207		546.4	Analytical HPLC*: retention time: 2.057 min; 1H NMR (400 MHz, methanol-d4, ppm) δ 8.09 (d, J = 8.8 Hz, 1H), 8.01-7.84 (m, 4H), 5.82- 5.60 (m, 1H), 5.07-4.90 (m, 1H), 4.52 (d, J = 9.0 Hz, 1H), 4.08 (t, J = 26.0, 15.2 Hz, 1H), 3.99-3.78 (m, 2H), 3.76 (s, 3H), 3.29-3.19 (m, 2H), 3.20-2.97 (m, 1H), 2.61-2.41 (m, 1H), 2.25- 1.66 (m, 3H), 1.03-0.58 (m, 6H). 19F NMR (376 MHz, methanol-d4, ppm) δ −64.57 (3F).
208		523.4	SFC analysis: 94.3% ee; retention time: 9.389 min; column: Whelk O1(S, S), 250 × 4.6 mm I.D., 5 μm, 50% of isopropanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.0 mL/ min. 1H NMR (400MHz, DMSO-d6, ppm) δ 9.49 (s, 1H), 8.98-8.84 (m, 1H), 8.58-8.49 (m, 1H), 7.57-7.44 (m, 2H), 7.38-7.28 (m, 1H), 4.44- 4.40 (m, 1H), 3.12-3.05 (m, 1H), 2.81-2.71 (m, 1H), 2.39-2.06 (m, 4H), 2.05-1.80 (m, 3H), 1.62- 1.40 (m, 3H), 1.01-0.95 (m, 3H), 0.72-0.62 (m, 6H).
209		523.4	SFC analysis: 97.36% ee; retention time: 10.051 min; column: Whelk O1(S, S), 250 × 4.6 mm I.D., 5um, 50% of isopropanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.0 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.49 (s, 1H), 8.96-8.87 (m, 1H), 8.59-8.47 (m, 1H), 7.52- 7.42 (m, 2H), 7.34-7.29 (m, 1H), 4.45-4.31 (m, 1H), 3.16-3.14 (m, 1H), 2.82-2.73 (m, 1H), 2.41- 2.20 (m, 2H), 2.18-2.09 (m, 1H), 2.07-1.96 (m, 1H), 1.86-1.83 (m, 1H), 1.72-1.68 (m, 2H), 1.44- 1.38 (m, 1H), 1.29-1.23 (m, 2H), 1.08-0.99 (m, 3H), 0.70-0.60 (m, 3H), 0.53-0.45 (m, 3H).
212		528.4	Analytical HPLC*: retention time: 1.408 min; 0.20 FA salt; 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.37(s, 0.2H, FA), 8.08-7.98 (m, 2H), 7.48-7.38 (m, 2H), 7.35-7.25 (m, 2H), 4.70- 4.60 (m, 1H), 4.38-4.28 (m, 1H), 4.05-3.92 (m, 1H), 3.70-3.60 (m, 1H), 3.69-3.58 (m, 4H), 3.15-3.05 (m, 1H), 2.90-2.80 (m, 1H), 2.65- 2.55 (m, 1H), 2.37-2.26 (m, 1H), 1.97-1.86 (m, 1H), 1.65-1.45 (m, 3H), 0.73 (t, J = 7.3 Hz, 3H), 0.65 (t, J = 7.2 Hz, 3H); 19F NMR (376 MHz, DMSO-d6, ppm): δ −56.77 (3F).
213		528.4	Analytical HPLC*: retention time: 1.510 min; 0.28 FA salt; 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.43(s, 0.28H, FA), 8.10-8.00 (m, 2H), 7.47-7.37 (m, 2H), 7.32-7.22 (m, 2H), 5.29-5.19 (m, 1H), 4.18-4.08 (m, 1H), 3.83- 3.71 (m, 1H), 3.58-3.48 (m, 4H), 3.30-3.20 (m, 1H), 3.10-2.90 (m, 2H), 2.39-2.29 (m, 2H), 1.85-1.60 (m, 2H), 1.59-1.40 (m, 2H), 1.02 (t, J = 7.3 Hz, 3H), 0.57 (t, J = 7.2 Hz, 3H); 19F NMR (376 MHz, DMSO-d6, ppm): δ −56.67 (3F).
214		496.2	Analytical HPLC*: retention time: 1.611 min; 0.19 FA salt; 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.40(s, 0.19H, FA), 8.10-8.00 (m, 2H), 7.66-7.54 (m, 1H), 7.44-7.34 (m, 1H), 7.29-7.19 (m, 1H), 5.18-5.08 (m, 1H), 4.41- 4.31 (m, 1H), 4.19-4.09 (m, 1H), 3.98-3.88 (m, 1H), 3.59 (s, 3H), 3.53-3.42 (m, 1H), 3.08-2.98 (m, 1H), 2.92-2.82 (m, 1H), 2.41- 2.31 (m, 2H), 2.03-1.90 (m, 1H), 1.70-1.43 (m, 3H), 0.77 (t, J = 6.0 Hz, 3H), 0.64 (t, J = 6.0 Hz, 3H); 19F NMR (376 MHz, DMSO-d6, ppm): δ −113.65 (1F).
215		496.2	Analytical HPLC*: retention time: 1.602 min; 0.29FA salt; 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.41(s, 0.29H, FA), 8.12- 8.02 (m, 2H), 7.64-7.54 (m, 1H), 7.44-7.34 (m, 1H), 7.33-7.23 (m, 1H), 5.34-5.24 (m, 1H), 4.22-4.06 (m, 2H), 3.86-3.76 (m, 1H), 3.58 (s, 3H), 3.43-3.33 (m, 1H), 3.08-2.94 (m, 2H), 2.43-2.30 (m, 2H), 1.94-1.72 (m, 2H), 1.62-1.44 (m, 2H), 1.02 (t, J = 8.0 Hz, 3H), 0.61 (t, J = 8.0 Hz, 3H); 19F NMR (376 MHz, DMSO-d6, ppm): δ −113.76 (1F).
216		507.4	SFC analysis: 100% ee; retention time: 2.373 min; column: ChiralCel OD, 100 × 4.6 mm I.D., 3 μm, 5-40% of Methanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm): δ 9.48 (s, 1H), 8.91 (d, J = 8.0 Hz, 1H), 8.54 (d, J = 6.0 Hz, 1H), 7.68-7.58 (m, 1H), 7.46-7.36 (m, 1H), 7.32- 7.22 (m, 1H), 5.91-4.66 (m, 2H), 4.13-4.03 (m, 1H), 3.42-4.32 (m, 1H), 3.01-2.81 (m, 2H), 2.41- 2.28 (m, 1H), 2.21-2.05 (m, 1H), 2.01-1.84 (m, 2H), 1.69-1.56 (m, 1H), 1.51-1.36 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H), 0.81-0.58 (m, 6H); 19F NMR (376 MHz, DMSO-d6, ppm): δ −113.63 (1F).
217		507.4	SFC analysis: 100% ee; retention time: 3.220 min; column: ChiralCel OD, 100 × 4.6 mm I.D., 3 μm, 5-40% of Methanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm): δ 9.50 (s, 1H), 8.91 (d, J = 8.0 Hz, 1H), 8.55 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 6.0 Hz, 1H), 7.43-7.33 (m, 1H), 7.32- 7.22 (m, 1H), 5.92-4.61 (m, 2H), 4.02-3.91 (m, 1H), 3.60-3.41 (m, 1H), 3.18-3.08 (m, 1H), 2.70-2.58 (m, 1H), 2.25-2.14 (m, 1H), 2.10-1.79 (m, 2H), 1.78-1.68 (m, 1H), 1.68-1.51 (m, 2H), 1.50-1.36 (m, 1H), 1.11-0.97 (m, 3H), 0.72-0.61 (m, 6H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −113.68 (1F).
218		537.3	SFC analysis: 99.68% ee; retention time: 5.565 min; column: ChiralCel OD, 150 × 4.6 mm I.D., 3 μm, 40% of Methanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.49 (s, 1H), 8.91 (d, J = 8.6 Hz, 1H), 8.55 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 5.36-4.89 (m, 1H), 4.87-4.58 (m, 2H), 3.57-3.54 (m, 1H), 3.05 (s, 1H), 2.62-2.53 (m, 1H), 2.31-2.17 (m, 2H), 2.15-2.02 (m, 1H), 1.95-1.84 (m, 1H), 1.67-1.52 (m, 1H), 1.48- 1.36 (m, 1H), 1.05-0.96 (m, 3H), 0.81-0.68 (m, 9H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −60.66 (3F).
222		484.4	SFC analysis: 100% ee; retention time: 1.592 min; column: Chiralcel OJ, 150 × 4.6 mm I.D., 3 μm, 40% of Methanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.10- 8.00 (m, 2H), 7.75-7.65 (m, 2H), 7.62-7.50 (m, 2H), 4.63-4.53 (m, 1H), 4.37-4.27 (m, 1H), 4.13-4.03 (m, 1H), 3.87-3.77 (m, 1H), 3.58 (s, 3H), 3.50-3.40 (m, 1H), 3.22-3.12 (m, 1H), 2.95-2.85 (m, 1H), 2.73-2.63 (m, 2H), 1.32 (d, J = 6.5 Hz, 3H), 0.98 (d, J = 6.4 Hz, 3H); 19F NMR (376 MHz, DMSO-d6, ppm): δ −60.77 (3F).
223		484.4	SFC analysis: 98.7% ee; retention time: 1.889 min; column: Chiralcel OJ, 150 × 4.6 mm I.D., 3 μm, 40% of Methanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.14- 8.04 (m, 2H), 7.75-7.65 (m, 2H), 7.63-7.53 (m, 2H), 4.63-4.53 (m, 1H), 4.15-4.05 (m, 1H), 3.97-3.87 (m, 1H), 3.82-3.72 (m, 1H), 3.59 (s, 3H), 3.49-3.38 (m, 2H), 3.35-3.25 (m, 1H), 2.47-2.36 (m, 2H), 1.29 (d, J = 6.5 Hz, 3H), 1.12 (d, J = 6.4 Hz, 3H); 19F NMR (376 MHz, DMSO-d6, ppm): δ −60.70 (3F).
224		540.2	1H NMR (400 MHz, methanol-d4, ppm) δ 8.21 (d, J = 9.0 Hz, 1H), 7.81 (d, J = 8.9 Hz, 1H), 7.64 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.1 Hz, 2H), 5.29 (s, 1H), 5.00 (dd, J = 12.2, 3.2 Hz, 1H), 4.59 (s, 1H), 4.38 (dd, J = 10.8, 2.9 Hz, 1H), 4.06-3.98 (m, 1H), 3.79-3.71 (m, 1H), 3.58-3.47 (m, 1H), 3.11-3.00 (m, 2H), 2.70- 2.60 (m, 1H), 2.46 (d, J = 7.5 Hz, 1H), 2.11- 1.98 (m, 1H), 1.85-1.72 (m, 1H), 1.70-1.64 (m, 1H), 1.60 (t, J = 7.4 Hz, 6H), 0.82 (t, J = 7.4 Hz, 3H), 0.68 (t, J = 7.3 Hz, 3H). 19F NMR (376 MHz, methanol-d4, ppm) δ −63.83 (3F).
225		493.2	SFC analysis: 100% ee; retention time: 11.822 min; column: Whelk O1(S, S), 250 × 4.6 mm I.D., 5 μm, 50% of Methanol (0.05% of DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/ min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.46 (s, 1H), 8.88-8.86 (m, 1H), 8.54-8.52 (m, 1H), 7.68-7.66 (m, 2H), 7.48-7.46 (m, 2H), 6.23- 5.89 (m, 1H), 5.26-4.92 (m, 1H), 3.40-3.39 (m, 1H), 3.00-2.98 (m, 1H), 2.69-2.67 (m, 1H), 2.44-1.74 (m, 7H), 1.73-1.56 (m, 1H), 0.80- 0.65 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −60.72 (3F)
226		493.2	SFC analysis: 100% ee; retention time: 12.599 min; column: Whelk O1(S, S), 250 × 4.6 mm I.D., 5 um, 50% of Methanol (0.05% of DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/ min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.46 (s, 1H), 8.89-8.87 (m, 1H), 8.54-8.52 (m, 1H), 7.67-7.65 (m, 2H), 7.48-7.46 (m, 2H), 6.23- 5.87 (m, 1H), 5.27-4.92 (m, 1H), 3.40-3.38 (m, 1H), 3.00-2.98 (m, 1H), 2.70-2.67 (m, 1H), 2.44-1.74 (m, 7H), 1.73-1.56 (m, 1H), 0.80-0.65 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −60.72 (3F)
228		526.5	1H NMR (400 MHz, CDCl3, ppm): δ 7.75- 7.65 (m, 2H), 7.62-7.52 (m, 2H). 7.47-7.36 (m, 2H), 4.77-4.67 (m, 1H), 4.38-4.28 (m, 3H), 4.17-4.07 (m, 1H), 3.74-3.64 (m, 1H), 3.52- 3.42 (m, 1H), 3.26-3.16 (m, 1H), 2.94-2.80 (m, 1H), 2.74-2.64 (m, 1H), 2.56-2.46 (m, 1H), 2.05-1.85 (m, 1H), 1.77-1.50 (m, 3H), 1.36- 1.29 (m, 3H), 0.86 (t, J = 8.0 Hz, 3H), 0.71 (t, J = 8.0 Hz, 3H). 19F NMR (376 MHz, CDCl3, ppm): δ −62.38 (3F).
229		493.2	SFC analysis: 100% ee; retention time: 2.836 min; column: Chiralpak IG-3 100 × 4.6 mm I.D., 3 μm, 40% of Methanol (0.05% of DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.52 (s, 1H), 8.91 (d, J = 8.6 Hz, 1H), 8.54 (d, J = 8.6 Hz, 1H), 7.77-7.70 (m, 2H), 7.68-7.60 (m, 2H), 4.95-4.52 (m, 2H), 3.69-3.54 (m, 2H), 3.52-3.44 (m, 1H), 3.42- 3.37 (m, 1H), 3.18-3.10 (m, 1H), 2.04-1.73 (m, 4H), 1.71-1.56 (m, 2H), 0.63 (t, J = 7.2 Hz, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −60.69 (3F).
230		493.2	SFC analysis: 99.56% ee; retention time: 4.430 min; column: Chiralpak IG-3 100 × 4.6 mm I.D., 3 μm, 40% of Methanol (0.05% of DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.52 (s, 1H), 8.91 (d, J = 8.6 Hz, 1H), 8.55 (d, J = 8.6 Hz, 1H), 7.77-7.70 (m, 2H), 7.68-7.60 (m, 2H), 4.97- 4.55 (m, 2H), 3.68-3.53 (m, 2H), 3.52-3.43 (m, 1H), 3.41-3.35 (m, 1H), 3.18-3.09 (m, 1H), 2.00-1.74 (m, 4H), 1.71-1.56 (m, 2H), 0.63 (t, J = 7.2 Hz, 3H). 19F NMR (377 MHz, DMSO-d6, ppm) δ −60.69 (3F).
231		492.4	SFC analysis: 100.00% ee; retention time: 4.311 min; column: ChiralCel OX, 100 × 4.6 mm I.D., 3 μm, 40% of Ethanol (0.05% of DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.13-7.99 (m, 2H), 7.39 (t, J = 8.8 Hz, 1H), 6.83-6.79 (m, 2H), 5.35- 5.20 (m, 1H), 4.25-4.10 (m, 1H), 3.87-3.78 (m, 2H), 3.77 (s, 3H), 3.58 (s, 3H), 3.31- 3.23 (m, 1H), 3.08-2.93 (m, 2H), 2.46-2.30 (m, 2H), 1.93-1.65 (m, 2H), 1.62-1.38 (m, 2H), 1.01 (t, J = 7.2 Hz, 3H), 0.63 (t, J = 7.2 Hz, 3H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −117.13 (1F).
232		492.4	SFC analysis: 99.6% ee; retention time: 5.780 min; column: ChiralCel OX, 100 × 4.6 mm I.D., 3 μm, 40% of Ethanol (0.05% of DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.10-8.00 (m, 2H), 7.33 (t, J = 8.8 Hz, 1H), 6.85-6.70 (m, 2H), 4.75-4.65 (m, 1H), 4.40-4.30 (m, 1H), 4.05-3.95 (m, 1H), 3.93-3.83 (m, 1H), 3.76 (s, 3H), 3.59 (s, 3H), 3.42-3.32 (m, 1H), 3.15-3.04 (m, 1H), 2.96-2.87 (m, 1H), 2.79-2.60 (m, 1H), 2.45- 2.30 (m, 1H), 2.10-1.96 (m, 1H), 1.64-1.49 (m, 3H), 0.76 (t, J = 7.3 Hz, 3H), 0.68 (t, J = 7.2 Hz, 3H) ;. 19F NMR (376 MHz, DMSO-d6, ppm): δ −116.31 (1F).
233		526.2	SFC analysis: 100.0% ee; retention time: 2.487 min; column: ChiralCel OD, 150 × 4.6mm I.D., 3 μm, 40% of Ethanol (0.05% of DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, methanol-d4, ppm) δ 8.05 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.56-7.40 (m, 2H), 5.50-5.32 (m, 1H), 4.20-4.10 (m, 1H), 4.09-3.97 (m, 1H) 3.91-3.80 (m, 1H), 3.71 (s, 3H), 3.65-3.42 (m, 1H), 3.35-3.25 (m, 1H), 3.21-3.11 (m, 1H), 2.60- 2.33 (m, 5H), 2.15-1.98 (m, 1H), 1.89-1.77 (m, 1H), 1.71-1.68 (m, 2H), 1.10 (t, J = 7.6 Hz, 3H), 0.67 (t, J = 7.6 Hz, 3H). 19F NMR (376 MHz, methanol-d4, ppm): δ −63.90 (3F).
234		526.2	SFC analysis: 100.0% ee; retention time: 3.403 min; column: ChiralCel OD, 150 × 4.6 mm I.D., 3 μm, 40% of Ethanol (0.05% of DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, methanol-d4, ppm) δ 8.03 (d, J = 8.8 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 6.4 Hz, 2H), 5.53-5.35 (m, 1H), 4.45- 4.30 (m, 1H), 4.15-4.01 (m, 2H), 3.70 (s, 3H), 3.65-3.52 (m, 1H), 3.12-3.02 (m, 1H), 3.00- 2.90 (m, 1H), 2.65-2.55 (m, 1H), 2.52-2.46 (m, 4H), 2.25-2.02 (m, 1H), 1.95-1.81 (m, 1H), 1.74- 1.62 (m, 1H), 1.60-1.51 (m, 1H), 0.80 (t, J = 7.2 Hz, 3H), 0.70 (t, J = 7.2 Hz, 3H). 19F NMR (376 MHz, methanol-d4, ppm): δ −63.89 (3F).
236		514.2	1H NMR (400 MHz, methanol-d4, ppm) δ 8.04 (d, J = 8.8 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.67-7.55 (m, 4H), 5.24-5.14 (m, 1H), 4.41- 4.33 (m, 1H), 4.13-4.03 (m, 1H), 3.98-3.88 (m, 1H), 3.92-3.79 (m, 2H), 3.71 (s, 3H), 3.66-3.58 (m, 1H), 3.18-3.03 (m, 2H), 2.83-2.73 (m, 1H), 2.55-2.47 (m, 1H), 1.87-1.74 (m, 1H), 1.68-1.56 (m, 1H), 0.83 (t, J = 7.4 Hz, 3H). 19F NMR (376 MHz, methanol-d4, ppm): δ −63.91 (3F).
237		482.2	SFC analysis: 100% ee; retention time: 3.500 min; column: ChiralCel OD, 150 × 4.6 mm I.D., 3 μm, 40% of Ethanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.13-8.03 (m, 2H), 7.55-7.44 (m, 1H), 7.42-7.32 (m, 2H), 4.95-4.85 (m, 1H), 4.18-4.08 (m, 1H), 3.93-3.82 (m, 1H), 3.58 (s, 3H), 3.46-3.38 (m, 2H), 3.25-3.12 (m, 2H), 2.41-2.31 (m, 2H), 1.97-1.87 (m, 1H), 1.58-1.48 (m, 1H), 1.07 (d, J = 8.0 Hz, 3H), 0.61 (t, J = 8.0 Hz, 3H); 19F NMR (376 MHz, DMSO-d6, ppm): δ −118.95 (1F).
238		482.2	SFC analysis: 99.72% ee; retention time: 4.484 min; column: ChiralCel OD, 150 × 4.6 mm I.D., 3 μm, 40% of Ethanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.10-8.00 (s, 2H), 7.58-7.48 (m, 1H), 7.44-7.30 (m, 2H), 4.39-4.29 (m, 1H), 4.21-4.11 (m, 1H), 3.96-3.86 (m, 1H), 3.75-3.65 (m, 1H), 3.60 (s, 3H), 3.49-3.39 (m, 1H), 3.30-3.20 (m, 1H), 2.85-2.60 (m, 3H), 1.96-1.88 (m, 1H), 1.62-1.52 (m, 1H), 1.03 (d, J = 8.0 Hz, 3H), 0.72(t, J = 8.0 Hz, 3H); 19F NMR (376 MHz, DMSO-d6, ppm): δ −118.79 (1F).
239		512.4	SFC analysis: 98.12% ee; retention time: 1.716 min; column: Chiralpak AD-3 150 × 4.6 mm I.D., 3 μm, 40% of Ethanol (0.05% of DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.15- 8.04 (m, 2H), 7.50-7.39 (m, 2H), 7.32-7.20 (m, 1H), 5.35-5.24 (m, 1H), 4.60-4.48 (m, 1H), 4.25- 4.14 (m, 1H), 3.85-3.75 (m, 1H), 3.58 (s, 3H), 3.30-3.15 (m, 1H), 3.12-3.02 (m, 1H), 2.95-2.85 (m, 1H), 2.60-2.50 (m, 1H), 2.41-2.29 (m, 1H), 2.26-2.14 (m, 1H), 1.98-1.87 (m, 1H), 1.70- 1.68 (m, 1H), 1.48-1.36 (m, 1H), 0.97 (t, J = 7.3 Hz, 3H), 0.62 (t, J = 7.2 Hz, 3H)
240		512.4	SFC analysis: 97.48% ee; retention time: 2.061 min; Column: Chiralpak AD-3 150 × 4.6 mm I.D., 3 μm, 40% of Ethanol (0.05% of DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.09- 7.99 (m, 2H), 7.49-7.39 (m, 2H), 7.32-7.22 (m, 1H), 5.28-5.18 (m, 1H), 4.51-4.41 (m, 1H), 4.39-4.29 (m, 1H), 3.96-3.85 (m, 1H), 3.58 (s, 3H), 3.49-3.39 (m, 1H), 3.11-3.01 (m, 1H), 2.87-2.76 (m, 1H), 2.59-2.49 (m, 1H), 2.26- 2.16 (m, 1H), 2.15-2.03 (m, 1H), 1.98-1.88 (m, 1H), 1.80-1.70 (m, 1H), 1.55-1.40 (m, 1H), 0.78 (t, J = 7.3 H, 3H), 0.67 (t, J = 7.2 Hz, 3H)
243		478.2	Analytical HPLC*: retention time: 1.553 min; 1H NMR (400 MHz, CDCl3, ppm) δ 7.74-7.64 (m, 2H), z 7.33-7.23 (m, 4H), 5.37 (dd, J = 12.0, 2.6 Hz, 1H), 4.13 (dd, J = 11.0, 3.0 Hz, 1H), 3.94-3.82 (m, 1H), 3.70 (s, 3H), 3.49-3.32 (m, 2H), 3.20-3.06 (m, 2H), 2.42-2.33 (m, 2H), 1.93-1.71 (m, 2H), 1.54-1.44 (m, 1H), 1.38-1.27 (m, 1H), 1.12 (t, J = 7.4 Hz, 3H), 0.64 (t, J = 7.3 Hz, 3H).
244		478.2	Analytical HPLC*: retention time: 1.548 min; 1H NMR (400 MHz, methanol-d4, ppm) δ 8.01 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.37-7.28 (m, 4H), 5.06 (dd, J = 12.3, 3.3 Hz, 1H), 4.36 (dd, J = 10.9, 3.0 Hz, 1H), 4.07-3.98 (m, 1H), 3.69 (s, 3H), 3.67-3.60 (m, 1H), 3.55-3.45 (m, 1H), 3.12-2.98 (m, 2H), 2.70-2.58 (m, 1H), 2.49 (d, J = 7.4 Hz, 1H), 2.08-1.96 (m, 1H), 1.79-1.66 (m, 1H), 1.66-1.52 (m, 2H), 0.80 (t, J = 7.4 Hz, 3H), 0.68 (t, J = 7.3 Hz, 3H).
245		546.2	Analytical HPLC*: retention time: 2.584 min; 1H NMR (400 MHz, CDCl3, ppm) δ 7.77-7.62 (m, 3H), 7.50 (s, 1H), 7.33 (d, J = 8.1 Hz, 1H), 5.42 (dd, J = 12.2, 2.6 Hz, 1H), 4.17 (dd, J = 11.0, 3.0 Hz, 1H), 3.97- 3.84 (m, 1H), 3.71 (s, 3H), 3.53-3.36 (m, 2H), 3.21-3.04 (m, 2H), 2.50-2.28 (m, 2H), 1.97-1.77 (m, 2H), 1.57-1.42 (m, 2H), 1.13 (t, J = 7.3 Hz, 3H), 0.66 (t, J = 7.3 Hz, 3H). 19F NMR (376 MHz, CDCl3, ppm) δ −62.27 (3F).
246		546.2	Analytical HPLC*: retention time: 2.493 min; 1H NMR (400 MHz, methanol-d4, ppm) δ 8.03 (d, J = 8.8 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.61 (s, 1H), 7.47 (d, J = 8.1 Hz, 1H), 5.11 (d, J = 9.0 Hz, 1H), 4.38 (dd, J = 10.9, 3.0 Hz, 1H), 4.12-4.00 (m, 1H), 3.84-3.76 (m, 1H), 3.70 (s, 3H), 3.62-3.52 (m, 1H), 3.12 (dd, J = 12.2, 1.9 Hz, 1H), 3.01 (dd, J = 11.8, 2.9 Hz, 1H), 2.73-2.64 (m, 1H), 2.55-2.42 (m, 1H), 2.11-1.97 (m, 1H), 1.82-1.71 (m, 1H), 1.69-1.56 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H), 0.71 (t, J = 7.3 Hz, 3H). 19F NMR (376 MHz, methanol-d4, ppm) δ −63.61 (3F).
247		482.2	Analytical HPLC*: retention time: 1.535 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.06 (s, 2H), 7.56 (d, J = 7.1 Hz, 1H), 7.39 (d, J = 7.8 Hz, 2H), 5.00 (d, J = 12.1 Hz, 1H), 4.38- 4.31 (m, 1H), 4.02-3.89 (m, 2H), 3.60 (s, 3H), 3.48 (s, 1H), 2.96 (dd, J = 32.3, 9.5 Hz, 2H), 2.44 (s, 1H), 2.01 (d, J = 7.8 Hz, 1H), 1.60 (d, J = 33.3 Hz, 2H), 1.30 (d, J = 6.4 Hz, 3H), 0.80 (t, J = 7.3 Hz, 3H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −119 (1F).
248		482.2	Analytical HPLC*: retention time: 1.480 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.11-8.05 (m, 2H), 7.57 (d, J = 7.3 Hz, 1H), 7.38 (dd, J = 11.2, 6.0 Hz, 2H), 5.08 (d, J = 9.5 Hz, 1H), 4.19 (d, J = 8.4 Hz, 1H), 3.92- 3.74 (m, 2H), 3.59 (s, 3H), 3.30-3.24 (m, 1H), 3.19 (d, J = 11.3 Hz, 1H), 2.99 (d, J = 10.7 Hz, 1H), 2.43-2.31 (m, 2H), 1.72 (s, 1H), 1.52 (s, 1H), 1.23 (d, J = 6.4 Hz, 4H), 1.01 (t, J = 7.2 Hz, 3H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −119.17 (1F).
249		512.2	Analytical HPLC*: retention time: 1.783 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.11-8.05 (m, 2H), 7.64-7.57 (m, 2H), 7.35 (d, J = 8.4 Hz, 1H), 5.30 (d, J = 12.8 Hz, 1H), 4.24-4.16 (m, 1H), 3.82 (dd, J = 10.7, 7.6 Hz, 1H), 3.59 (s, 3H), 3.55 (d, J = 5.8 Hz, 1H), 3.08-2.98 (m, 2H), 2.39 (d, J = 4.4 Hz, 1H), 1.81 (d, J = 38.1 Hz, 2H), 1.49 (dd, J = 14.1, 7.6 Hz, 2H), 1.24 (s, 2H), 1.02 (t, J = 7.3 Hz, 3H), 0.60 (t, J = 7.2 Hz, 3H).
250		512.2	Analytical HPLC*: retention time: 1.819 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.11- 8.05 (m, 2H), 7.64-7.57 (m, 2H), 7.35 (d, J = 8.4 Hz, 1H), 5.30 (d, J = 12.8 Hz, 1H), 4.24- 4.16 (m, 1H), 3.82 (dd, J = 10.7, 7.6 Hz, 1H), 3.59 (s, 3H), 3.55 (d, J = 5.8 Hz, 1H), 3.08- 2.98 (m, 2H), 2.39 (d, J = 4.4 Hz, 1H), 1.81 (d, J = 38.1 Hz, 2H), 1.49 (dd, J = 14.1, 7.6 Hz, 2H), 1.24 (s, 2H), 1.02 (t, J = 7.3 Hz, 3H), 0.60 (t, J = 7.2 Hz, 3H).
251		515.2	1H NMR (400 MHz, methanol-d4, ppm) δ 8.03 (d, J = 8.8 Hz, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 8.1 Hz, 2H), 5.13 (d, J = 11.2 Hz, 1H), 4.39 (dd, J = 10.9, 2.9 Hz, 1H), 4.10-4.02 (m, 1H), 3.85-3.75 (m, 1H), 3.62-3.52 (m, 1H), 3.16-3.04 (m, 2H), 2.77-2.65 (m, 1H), 2.57-2.45 (m, 1H), 2.14-2.03 (m, 1H), 1.84-1.58 (m, 3H), 0.81 (t, J = 7.4 Hz, 3H), 0.70 (t, J = 7.3 Hz, 3H). 19F NMR (376 MHz, methanol-d4, ppm): δ −63.89 (3F).
253		512.2	SFC analysis: 100% ee; retention time: 2.416 min; column: ChiralCel OD, 150 × 4.6 mm I.D., 3 μm, 40% of Methanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, methanol-d4, ppm) δ 8.05 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 8.2 Hz, 2H), 5.21-5.10 (m, 1H), 4.13-4.03 (m, 1H), 3.96-3.88 (m, 1H), 3.70 (s, 3H), 3.69-3.59 (m, 1H), 3.57-3.47 (m, 1H), 3.47-3.37 (m, 2H), 2.62- 2.35 (m, 2H), 2.03-1.90 (m, 1H), 1.78-1.55 (m, 1H), 1.20 (d, J = 6.5 Hz, 3H), 1.12-0.92 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H). 19F NMR (376 MHz, methanol-d4, ppm): δ −63.86 (3F).
254		512.2	SFC analysis: 100% ee; retention time: 3.227 min; column: ChiralCel OD, 150 × 4.6 mm I.D., 3 μm, 40% of Methanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, methanol-d4, ppm) δ 8.07 (d, J = 8.7 Hz, 1H), 7.88 (d, J = 8.7 Hz, 1H), 7.78- 7.52 (m, 4H), 4.49-4.36 (m, 1H), 4.27-4.17 (m, 1H), 4.13-3.86 (m, 1H), 3.73 (s, 3H), 3.65- 3.39 (m, 2H), 3.30-3.27 (m, 2H), 3.17-2.84 (m, 2H), 2.23-1.98 (m, 1H), 1.86-1.66 (m, 1H), 1.30-1.17 (m, 4H), 1.08-0.98 (m, 1H), 0.90 (t, J = 6.0Hz, 3H). 19F NMR (376 MHz, methanol-d4, ppm): δ −64.04 (3F).
255		524.4	Analytical HPLC*: retention time: 1.359 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.02 (s, 2H), 8.10-8.00 (m, 2H), 4.43-4.32 (m, 1H), 4.25-4.14 (m, 1H), 4.09-4.01 (m, 1H), 3.80- 3.72 (m, 1H), 3.61 (s, 3H), 3.43-3.35 (m, 1H), 3.14-3.02 (m, 2H), 2.78-2.71 (m, 1H), 2.56-2.52 (m, 1H), 1.98-1.87 (m, 2H), 1.82-1.60 (m, 2H), 0.88-0.79 (m, 6H).
256		524.4	Analytical HPLC*: retention time: 1.313 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.97 (s, 2H), 8.09-8.04 (m, 2H), 4.87-4.78 (m, 1H), 4.23-4.17 (m, 1H), 3.90-3.79 (m, 2H), 3.58 (s, 3H), 3.29-3.23 (m, 1H), 3.16-3.09 (m, 1H), 3.07-2.99 (m, 1H), 2.74-2.64 (m, 2H), 2.01-1.77 (m, 3H), 1.68-1.56 (m, 1H), 0.92 (t, J = 7.2 Hz, 3H), 0.71 (t, J = 7.2 Hz, 3H).
257		484.4	Analytical HPLC*: retention time: 1.398 min; 1H NMR (400 MHz, methanol-d4, ppm) δ 8.02 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 1.9 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.33 (dd, J = 8.3, 2.0 Hz, 1H), 4.91 (dd, J = 12.3, 3.4 Hz, 1H), 4.37 (dd, J = 11.0, 3.2 Hz, 1H), 4.12 (dd, J = 11.0, 7.4 Hz, 1H), 3.84- 3.75 (m, 1H), 3.70 (s, 3H), 3.64-3.54 (m, 1H), 3.26 (dd, J = 12.3, 2.8 Hz, 1H), 2.99 (dd, J = 11.6, 3.2 Hz, 1H), 2.91-2.78 (m, 1H), 2.77-2.65 (m, 1H), 1.34 (d, J = 6.6 Hz, 3H), 1.07 (d, J = 6.5 Hz, 3H).
258		484.4	Analytical HPLC*: retention time: 1.408 min; 1H NMR (400 MHz, methanol-d4, ppm) δ 8.02 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 1.8 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.34 (dd, J = 8.3, 1.9 Hz, 1H), 4.76 (dd, J = 12.1, 4.2 Hz, 1H), 4.11 (dd, J = 10.9, 3.1 Hz, 1H), 4.07-3.96 (m, 1H), 3.82-3.71 (m, 1H), 3.69 (s, 3H), 3.53 (dd, J = 12.1, 2.6 Hz, 1H), 3.49-3.40 (m, 1H), 3.40-3.32 (m, 1H), 2.58-2.41 (m, 2H), 1.33 (d, J = 6.6 Hz, 3H), 1.19 (d, J = 6.4 Hz, 3H).
259		468.2	Analytical HPLC*: retention time: 2.338 min; 1H NMR (400 MHz, methanol-d4, ppm) δ 8.04 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.53 (dd, J = 7.3, 2.0 Hz, 1H), 7.40-7.33 (m, 1H), 7.19 (t, J = 8.8 Hz, 1H), 4.81 (dd, J = 12.2, 4.1 Hz, 1H), 4.15-4.08 (m, 1H), 4.06-3.98 (m, 1H), 3.82-3.72 (m, 1H), 3.70 (s, 3H), 3.54 (dd, J = 12.1, 2.6 Hz, 1H), 3.51-3.43 (m, 1H), 3.43-3.33 (m, 1H), 2.56- 2.42 (m, 2H), 1.34 (d, J = 6.6 Hz, 3H), 1.20 (d, J = 6.4 Hz, 3H). 19F NMR (376 MHz, methanol-d4, ppm) δ −120.59 (1F)
260		468.2	Analytical HPLC*: retention time: 2.303 min; 1H NMR (400 MHz, methanol-d4, ppm) δ 8.02 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.51 (dd, J = 7.2, 2.1 Hz, 1H), 7.38-7.31 (m, 1H), 7.19 (t, J = 8.8 Hz, 1H), 4.92 (dd, J = 12.2, 3.5 Hz, 1H), 4.38 (dd, J = 11.0, 3.2 Hz, 1H), 4.19- 4.08 (m, 1H), 3.82-3.74 (m, 1H), 3.70 (s, 3H), 3.62-3.52 (m, 1H), 3.26 (dd, J = 12.3, 2.8 Hz, 1H), 3.00 (dd, J = 11.6, 3.2 Hz, 1H), 2.91-2.79 (m, 1H), 2.75-2.66 (m, 1H), 1.34 (d, J = 6.6 Hz, 3H), 1.07 (d, J = 6.5 Hz, 3H). 19F NMR (376 MHz, methanol-d4, ppm) δ −120.36 (1F)
263		552.2	1H NMR (400 MHz, CDCl3, ppm) δ 7.63 (dd, J = 12.8, 7.2 Hz, 4H), 7.45 (d, J = 7.9 Hz, 2H), 4.97- 4.77 (m, 2H), 4.37 (dd, J = 10.7, 2.4 Hz, 1H), 4.16-4.05 (m, 1H), 4.03-3.83 (m, 1H), 3.73 (dd, J = 8.7, 4.3 Hz, 1H), 3.53 (s, 1H), 3.10 (d, J = 11.0 Hz, 1H), 2.96 (d, J = 9.1 Hz, 1H), 2.83-2.73 (m, 1H), 2.70-2.47 (m, 5H), 2.08-1.73 (m, 5H), 0.91 (t, J = 7.3 Hz, 3H), 0.72 (t, J = 7.2 Hz, 3H). 19F NMR (376 MHz, CDCl3, ppm) δ −62.36 (3F).
265		484.2	1H NMR (400 MHz, DMSO-d6, ppm) δ 8.08 (s, 2H), 7.71 (d, J = 8.1 Hz, 2H), 7.60 (d, J = 8.0 Hz, 2H), 4.70 (dd, J = 12.2, 3.9 Hz, 1H), 4.27 (dd, J = 10.8, 2.7 Hz, 1H), 4.00 (dd, J = 10.7, 8.0 Hz, 1H), 3.85 (d, J = 14.3 Hz, 1H), 3.73 (d, J = 14.2 Hz, 1H), 3.61 (s, 3H), 3.44- 3.36 (m, 2H), 2.72-2.54 (m, 3H), 1.74-1.57 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −60.72 (3F).
266		484.2	1H NMR (400 MHz, DMSO-d6, ppm) δ 8.07 (s, 2H), 7.61 (dd, J = 4.9, 3.3 Hz, 2H), 7.37 (dd, J = 8.3, 1.7 Hz, 1H), 4.71 (dd, J = 12.1, 3.9 Hz, 1H), 4.27 (dd, J = 10.8, 2.7 Hz, 1H), 3.98 (dd, J = 10.7, 8.0 Hz, 1H), 3.74 (d, J = 14.2 Hz, 1H), 3.64 (d, J = 14.2 Hz, 1H), 3.60 (s, 3H), 3.42-3.37 (m, 1H), 3.32-3.28 (m, 1H), 2.70-2.54 (m, 3H), 1.73-1.53 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H).
267		484.2	Analytical HPLC*: retention time: 1.567 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.13- 8.03 (m, 2H), 7.70-7.68 (m, 1H), 7.59 (d, J = 2.1 Hz, 1H), 7.50-7.45 (m, 1H), 4.97-4.87 (m, 1H), 4.16-4.05 (m, 2H), 3.91-3.87 (m, 1H), 3.59 (s, 3H), 3.44-3.22 (m, 3H), 2.46- 2.34 (m, 2H), 1.25 (d, J = 6.4 Hz, 3H), 1.13 (d, J = 6.4 Hz, 3H).
268		484.2	Analytical HPLC*: retention time: 1.650 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.06 (d, J = 8.7 Hz, 2H), 7.64-7.58 (m, 2H), 7.46-7.44 (m, 1H), 5.01-4.97 (m, 1H), 4.37-4.34 (m, 1H), 4.13- 4.01 (m, 2H), 3.58 (s, 3H), 3.57-3.52 (m, 1H), 3.07- 3.04 (m, 2H), 2.82-2.80 (m, 1H), 2.60-2.50 (m, 1H), 1.23 (d, J = 6.4 Hz, 3H), 0.96 (d, J = 6.5 Hz, 3H).
269		562.4	1H NMR (400 MHz, DMSO-d6, ppm) δ 8.24 (d, J = 8.8 Hz, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 7.6 Hz, 2H), 7.56 (d, J = 7.4 Hz, 2H), 6.31 (t, J = 54.8 Hz, 1H), 4.93-4.65 (m, 3H), 4.38 (d, J = 9.7 Hz, 1H), 4.13-3.96 (m, 1H), 3.82-3.72 (m, 1H), 3.12 (d, J = 11.2 Hz, 1H), 2.93 (d, J = 11.0 Hz, 1H), 2.68-2.60 (m, 1H), 2.42-2.30 (m, 1H), 2.03-1.93 (m, 1H), 1.74-1.50 (m, 3H), 1.23 (s, 1H), 0.73 (t, J = 7.0 Hz, 3H), 0.64 (t, J = 7.1 Hz, 3H). 19F NMR (400 MHz, DMSO-d6, ppm) δ −60.73 (3F), −120.83 (2F).
270		450.2	Analytical HPLC*: retention time: 1.380 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.11- 8.04 (m, 2H), 7.46-7.37 (m, 4H), 4.65 7.45 (m, 1H), 4.20-4.05 (m, 1H), 4.02-3.90 (m, 1H), 3.80-3.68 (m, 1H), 3.59 (s, 3H), 3.50-3.42 (m, 1H), 3.42-3.36 (m, 1H), 3.31-3.22 (m, 1H), 2.48-2.41 (m, 1H), 2.40-2.31 (m, 1H), 1.26 (d, J = 6.4 Hz, 3H), 1.11 (d, J = 6.0 Hz, 3H).
271		450.2	Analytical HPLC*: retention time: 1.487 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.06- 8.03 (m, 2H), 7.46-7.35 (m, 4H), 4.58-4.53 (m, 1H), 4.37-4.34 (m, 1H), 4.11-4.07 (m, 1H), 3.80-3.75 (m, 1H), 3.59 (s, 3H), 3.51-3.42 (m, 1H), 3.25-3.15 (m, 1H), 2.95-2.85 (m, 1H), 2.77-2.61 (m, 2H), 1.29 (d, J = 6.4 Hz, 3H), 1.11 (d, J = 6.4 Hz, 3H).
274		468.2	Analytical HPLC*: retention time: 1.405 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.12- 8.04 (m, 2H), 7.59 (t, J = 8.2 Hz, 1H), 7.40 (dd, J = 10.2, 1.8 Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 4.88-4.76 (m, 1H), 4.14 (dd, J = 11.0, 2.8 Hz, 1H), 3.93 (ddd, J = 18.3, 12.0, 7.1 Hz, 2H), 3.59 (s, 3H), 3.47-3.38 (m, 1H), 3.34 (s, 1H), 3.33-3.29 (m, 1H), 2.46-2.32 (m, 2H), 1.29 (d, J = 6.5 Hz, 3H), 1.11 (d, J = 6.4 Hz, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −116.78 (1F).
275		468.2	Analytical HPLC*: retention time: 1.496 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.05 (s, 2H), 7.54 (t, J = 8.2 Hz, 1H), 7.41 (dd, J = 10.3, 2.0 Hz, 1H), 7.31 (dd, J = 8.4, 1.9 Hz, 1H), 4.62 (dd, J = 12.1, 3.7 Hz, 1H), 4.36 (dd, J = 10.9, 3.0 Hz, 1H), 4.14-4.06 (m, 2H), 3.59 (s, 3H), 3.46 (t, J = 8.1 Hz, 1H), 3.20 (dd, J = 12.1, 2.6 Hz, 1H), 2.92 (dd, J = 11.5, 3.1 Hz, 1H), 2.82-2.63 (m, 2H), 1.32 (d, J = 6.6 Hz, 3H), 0.99 (d, J = 6.4 Hz, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −116.07 (1F).
276		502.2	Analytical HPLC*: retention time: 1.510 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.14- 8.01 (m, 2H), 7.88-7.77 (m, 1H), 7.71-7.58 (m, 2H), 4.98-4.74 (m, 1H), 4.20-4.11 (m, 1H), 4.09-4.01 (m, 1H), 3.93-3.85 (m, 1H), 3.59 (s, 3H), 3.48-3.42 (m, 1H), 3.38 (s, 2H), 2.47-2.38 (m, 2H), 1.36-1.26 (m, 3H), 1.18-1.07 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −60.91 (3F),-117.13 (1F)
277		502.2	Analytical HPLC*: retention time: 1.577 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.06 (s, 2H), 7.82-7.73 (m, 1H), 7.70-7.57 (m, 2H), 4.75-4.63 (m, 1H), 4.43-4.29 (m, 1H), 4.24- 4.13 (m, 1H), 4.12-4.02 (m, 1H), 3.59 (s, 3H), 3.50 (s, 1H), 3.24-3.14 (m, 1H), 3.01-2.90 (m, 1H), 2.84-2.74 (m, 1H), 2.73-2.63 (m, 1H), 1.41-1.28 (m, 3H), 1.06-0.91 (m, 3H). 19F NMR (376 MHz, DMSO- d6, ppm) δ −60.99 (3F), −116.48 (1F)
280		482.2	SFC analysis: 100% ee; retention time: 3.672 min; column: ChiralCel OD, 150 × 4.6 mm I.D., 3 μm, 40% of Ethanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, methanol-d4, ppm): δ 8.04 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.47-7.39 (m, 1H), 7.32-7.25 (m, 1H), 7.21- 7.14 (m, 1H), 5.23-5.11 (m, 1H), 4.19-4.10 (m, 1H), 3.97-3.89 (m, 1H), 3.70 (s, 3H), 3.59-3.36 (m, 4H), 2.54-2.41 (m, 2H), 2.10-1.97 (m, 1H), 1.68-1.54 (m, 1H), 1.18 (d, J = 6.5 Hz, 3H), 0.69 (t, J = 7.4 Hz, 3H); 19F NMR (376 MHz, methanol-d4, ppm): δ −118.05 (1F).
281		482.2	SFC analysis: 99.90% ee; retention time: 4.868 min; column: ChiralCel OD, 150 × 4.6 mm I.D., 3 μm, 40% of Ethanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, methanol-d4, ppm): δ 8.02 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.48- 7.40 (m, 1H), 7.28-7.21 (m, 1H), 7.20-7.12 (m, 1H), 4.45-4.32 (m, 2H), 4.26-4.16 (m, 1H), 3.71 (s, 3H), 3.70-3.65 (m, 1H), 3.52-3.41 (m, 2H), 2.95-2.75 (m, 3H), 2.06-1.92 (m, 1H), 1.70-1.55 (m, 1H), 1.10 (d, J = 6.4 Hz, 3H), 0.76 (t, J = 7.3 Hz, 3H); 19F NMR (376 MHz, methanol-d4, ppm): δ −117.91 (1F).
284		502.2	Analytical HPLC*: retention time: 1.636 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.14- 8.03 (m, 2H), 7.81-7.73 (m, 1H), 7.56-7.42 (m, 2H), 4.65-4.53 (m, 1H), 4.19-4.12 (m, 1H), 4.02-3.95 (m, 1H), 3.88-3.80 (m, 1H), 3.60 (s, 3H), 3.49-3.43 (m, 1H), 3.40-3.37 (m, 1H), 3.33-3.28 (m, 1H), 2.49-2.36 (m, 2H), 1.29 (d, J = 6.6 Hz, 3H), 1.11 (d, J = 6.4 Hz, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −59.63 (3F); −115.96 (1F).
285		502.2	Analytical HPLC*: retention time: 1.690 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.10- 8.02 (m, 2H), 7.80-7.72 (m, 1H), 7.55-7.42 (m, 2H), 4.76-4.55 (m, 1H), 4.39-4.31 (m, 1H), 4.14-4.05 (m, 1H), 3.94-3.86 (m, 1H), 3.60 (s, 3H), 3.53-3.45 (m, 1H), 3.27-3.20 (m, 1H), 2.97-2.88 (m, 1H), 2.80-2.72 (m, 1H), 2.71- 2.64 (m, 1H), 1.32 (d, J = 6.6 Hz, 3H), 1.00 (d, J = 6.4 Hz, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −59.70 (3F); −115.94 (1F).
286		468.2	Analytical HPLC*: retention time: 1.468 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.15- 8.00 (m, 2H), 7.60-7.50 (m, 1H), 7.46-7.38 (m, 1H), 7.30-7.24 (m, 1H), 4.60-4.48 (m, 1H), 4.18-4.10 (m, 1H), 4.03-3.92 (m, 1H), 3.80- 3.71 (m, 1H), 3.60 (s, 3H), 3.49-3.42 (m, 1H), 3.39-3.34 (m, 1H), 3.31-3.23 (m, 1H), 2.50- 2.43 (m, 1H), 2.41-2.32 (m, 1H), 1.27 (d, J = 6.6 Hz, 3H), 1.10 (d, J = 6.4 Hz, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −116.49 (1F).
287		468.2	Analytical HPLC*: retention time: 1.538 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.10-8.00 (m, 2H), 7.60-7.51 (m, 1H), 7.46- 7.37 (m, 1H), 7.30-7.22 (m, 1H), 4.62-4.53 (m, 1H), 4.38-4.31 (m, 1H), 4.13-4.05 (m, 1H), 3.86-3.77 (m, 1H), 3.59 (s, 3H), 3.50-3.42 (m, 1H), 3.27-3.20 (m, 1H), 2.93-2.86 (m, 1H), 2.80-2.71 (m, 1H), 2.70-2.61 (m, 1H), 1.30 (d, J = 6.6 Hz, 3H), 0.99 (d, J = 6.4 Hz, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −116.47 (1F).
288		508.2	Analytical HPLC*: retention time: 1.688 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 7.98- 7.88 (m, 2H), 7.43-7.35 (m, 2H), 7.34-7.27 (m, 2H), 5.18-5.12 (m, 1H), 4.04-4.00 (m, 1H), 3.67-3.65 (m, 1H), 3.44 (s, 3H), 2.90-2.85 (m, 2H), 2.67 (s, 2H), 2.23 (s, 1H), 1.84 (s, 3H), 1.71 (s, 1H), 1.40-1.33 (m, 2H), 1.20 (s, 2H), 0.91-0.84 (m, 3H), 0.46-0.40 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −83.36 (2F).
289		508.2	Analytical HPLC*: retention time: 1.681 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.09 (s, 2H), 7.66-7.54 (m, 2H), 7.52-7.42 (m, 2H), 4.78-4.64 (m, 1H), 4.45-4.39 (m, 1H), 4.11- 4.01 (m, 1H), 3.81-3.73 (m, 1H), 3.64 (s, 3H), 3.54-3.46 (m, 1H), 3.46-3.41 (m, 1H), 3.23-3.13 (m, 1H), 3.01-2.90 (m, 1H), 2.74-2.64 (m, 1H), 2.48-2.38 (m, 1H), 2.06-1.97 (m, 3H), 1.76- 1.54 (m, 3H), 0.85-0.76 (m, 3H), 0.75-0.65 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −83.70 (2F).
290		494.2	Analytical HPLC*: retention time: 1.562 min; 1H NMR (400 MHz, CDCl3, ppm) δ 7.76-7.63 (m, 2H), 7.53-7.36 (m, 4H), 6.66 (t, J = 56.6 Hz, 1H), 5.39 (d, J = 9.9 Hz, 1H), 4.13 (dd, J = 10.9, 2.8 Hz, 1H), 3.95-3.83 (m, 1H), 3.70 (s, 3H), 3.51 (dd, J = 9.4, 3.2 Hz, 1H), 3.39 (d, J = 5.5 Hz, 1H), 3.26-3.00 (m, 2H), 2.43-2.31 (m, 2H), 2.03-1.76 (m, 2H), 1.59-1.47 (m, 2H), 1.13 (t, J = 7.3 Hz, 3H), 0.64 (t, J = 7.3 Hz, 3H). 19F NMR (376 MHz, CDCl3, ppm) δ −110.02 (2F)
291		494.2	Analytical HPLC*: retention time: 1.532 min; 1H NMR (400 MHz, CDCl3, ppm) δ 7.71-7.62 (m, 2H), 7.54-7.33 (m, 4H), 6.65 (t, J = 56.5 Hz, 1H), 4.86-4.66 (m, 1H), 4.36 (d, J = 9.6 Hz, 1H), 4.19-4.06 (m, 1H), 3.71 (s, 4H), 3.59-3.43 (m, 1H), 3.29-3.14 (m, 1H), 3.00- 2.84 (m, 1H), 2.77-2.64 (m, 1H), 2.62-2.45 (m, 1H), 2.04-1.88 (m, 1H), 1.82-1.61 (m, J = 8.0 Hz, 3H), 0.84 (t, 3H), 0.71 (t, J = 7.3 Hz, 3H). 19F NMR (376 MHz, CDCl3, ppm) δ −110.23 (2F).
292		502.2	SFC analysis: 100% ee; retention time: 5.522 min; column: ChiralCel OD, 150 × 4.6 mm I.D., 3 μm, 40% of Ethanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.12-8.04 (m, 2H), 6.84-6.75 (m, 3H), 5.28 (d, J = 10.5 Hz, 1H), 4.28-4.13 (m, 5H), 3.86-3.78 (m, 1H), 3.59 (s, 3H), 3.39- 3.35 (m, 1H), 3.31-3.26 (m, 1H), 3.07-2.96 (m, 2H), 2.49-2.42 (m, 1H), 2.35-2.26 (m, 1H), 1.87-1.65 (m, 2H), 1.53-1.36 (m, 2H), 1.02 (t, J = 7.3 Hz, 3H), 0.59 (t, J = 7.2 Hz, 3H).
293		502.2	SFC analysis: 100% ee; retention time: 7.099 min; column: ChiralCel OD, 150 × 4.6 mm I.D., 3 μm, 40% of Ethanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min. 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.10-8.97 (m, 2H), 6.84-6.72 (m, 3H), 4.60-4.53 (m, 1H), 4.37-4.31 (m, 1H), 4.24 (s, 4H), 4.06-3.99 (m, 1H), 3.60 (s, 3H), 3.56-3.49 (m, 1H), 3.19-3.13 (m, 1H), 2.88-2.82 (m, 1H), 2.68- 2.57 (m, 1H), 2.45-2.39 (m, 1H), 1.95-1.87 (m, 1H), 1.62-1.47 (m, 4H), 0.76 (t, J = 7.3 Hz, 3H), 0.68 (t, J = 7.2 Hz, 3H).
294		496.2	Analytical HPLC*: retention time: 1.690 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.13- 8.02 (m, 2H), 7.59-7.50 (m, 1H), 7.43-7.36 (m, 1H), 7.35-7.29 (m, 1H), 5.34-5.22 (m, 1H), 4.29-4.14 (m, 1H), 3.94-3.86 (m, 1H), 3.86- 3.76 (m, 1H), 3.59 (s, 3H), 3.30 (s, 1H), 3.08- 2.92 (m, 2H), 2.47-2.30 (m, 2H), 1.95-1.69 (m, 2H), 1.61-1.42 (m, 2H), 1.08-0.96 (m, 3H), 0.70-0.55 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −116.24 (1F).
295		496.2	Analytical HPLC*: retention time: 1.730 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.05 (s, 2H), 7.53-7.46 (m, 1H), 7.46-7.38 (m, 1H), 7.36-7.27 (m, 1H), 4.88-4.69 (m, 1H), 4.46-4.28 (m, 1H), 4.07-3.90 (m, 2H), 3.59 (s, 3H), 3.14-3.01 (m, 1H), 2.99-2.88 (m, 1H), 2.68-2.59 (m, 1H), 2.45-2.35 (m, 1H), 2.07-1.43 (m, 5H), 0.83-0.73 (m, 3H), 0.74-0.62 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −115.60 (1F).
296		496.2	Analytical HPLC*: retention time: 1.731 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.13- 8.03 (m, 2H), 7.59-7.53 (m, 1H), 7.41- 7.33 (m, 1H), 7.27-7.19 (m, 1H), 5.36-5.25 (m, 1H), 4.25-4.15 (m, 1H), 3.87-3.77 (m, 1H), 3.59 (s, 3H), 3.57-3.52 (m, 1H), 3.10- 2.98 (m, 2H), 2.45-2.30 (m, 3H), 1.92-1.69 (m, 2H), 1.48 (s, 2H), 1.08-0.98 (m, 3H), 0.60 (s, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −116.67 (1F)
297		496.2	Analytical HPLC*: retention time: 1.776 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.03 (s, 2H), 7.59-7.50 (m, 1H), 7.39-7.30 (m, 1H), 7.22- 7.13 (m, 1H), 4.74-4.60 (m, 1H), 4.39-4.25 (m, 1H), 4.05-3.92 (m, 1H), 3.76-3.64 (m, 1H), 3.57 (s, 3H), 3.37 (s, 1H), 3.13-3.06 (m, 1H), 2.90- 2.83 (m, 1H), 2.66-2.57 (m, 1H), 2.37 (s, 1H), 1.96-1.85 (m, 1H), 1.65-1.48 (m, 3H), 0.79-0.71 (m, 3H), 0.67-0.60 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −116.68 (1F)
298		518.2	Analytical HPLC*: retention time: 1.697 min; 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.10- 8.05 (m, 2H), 7.85 (d, J = 8.2 Hz, 1H), 7.72 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 4.99-4.55 (m, 1H), 4.16-4.01 (m, 1H), 3.99-3.96 (m, 1H), 3.86-3.82 (m, 1H), 3.60 (s, 3H), 3.48-3.46 (m, 1H), 3.38-3.33 (m, 1H), 3.31-3.28 (m, 1H), 2.51-2.37 (m, 2H), 1.29 (d, J = 6.4 Hz, 3H), 1.11 (d, J = 6.3 Hz, 3H). ; 19F NMR (376 MHz, DMSO-d6, ppm): δ 60.81 (3F).
299		518.2	Analytical HPLC*: retention time: 1.758 min; 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.05 (s, 2H), 7.83 (d, J = 8.1 Hz, 1H), 7.27 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 4.67-4.64 (m, 1H), 4.36-4.33(m, 1H), 4.11-4.07 (m, 1H), 3.91-3.89 (m, 1H), 3.51 (s, 3H), 3.50-3.47 (m, 1H), 3.24-3.20 (m, 1H), 2.94-2.90 (m, 1H), 2.76-2.70 (m, 2H), 1.31(d, J = 6.6 Hz, 3H), 0.99 (d, J = 6.4 Hz, 3H). ; 19F NMR (376 MHz, DMSO-d6, ppm): δ 60.88 (3F).
303		480.2	Analytical HPLC*: retention time: 1.518 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.12- 8.02 (m, 2H), 7.59-7.48 (m, 4H), 4.70-4.56 (m, 1H), 4.16-4.06 (m, 1H), 4.00-3.91 (m, 1H), 3.80-3.72 (m, 1H), 3.60 (s, 3H), 3.47-3.37 (m, 2H), 3.32-3.29 (m, 1H), 2.48-2.42 (m, 1H), 2.41-2.32 (m, 1H), 2.03-1.94 (m, 3H), 1.33- 1.23 (m, 3H), 1.16-1.06 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −83.60 (2F).
304		480.2	Analytical HPLC*: retention time: 1.601 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.09- 8.02 (m, 2H), 7.64-7.41 (m, 4H), 4.64-4.50 (m, 1H), 4.42-4.29 (m, 1H), 4.15-4.03 (m, 1H), 3.87-3.75 (m, 1H), 3.59 (s, 3H), 3.46-3.42 (m, 1H), 3.24-3.16 (m, 1H), 2.99-2.87 (m, 1H), 2.79-2.61 (m, 2H), 2.06-1.90 (m, 3H), 1.37-1.24 (m, 3H), 1.03-0.89 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −83.89 (2F).
305		516.4	Analytical HPLC*: retention time: 1.726 min; 1H NMR (400 MHz, CDCl3, ppm): δ 7.76-7.66 (m, 3H), 7.47-7.45 (m, 1H), 7.34-7.32 (m, 1H), 5.03-5.00 (m, 1H), 4.15-1.12 (m, 1H), 4.01- 3.94 (m, 2H), 3.72 (s, 3H), 3.52-3.50 (m, 1H), 3.46-3.41 (m, 2H), 2.57-2.51 (m, 1H), 2.46- 2.43 (m, 1H), 2.03-1.97 (m, 1H), 1.72-1.66 (m, 1H), 1.24-1.23 (m, 3H), 0.76-0.72 (m, 3H). 19F NMR (376 MHz, CDCl3, ppm): δ −63.56 (3F), −116.13 (1F).
306		516.2	Analytical HPLC*: retention time: 1.755 min; 1H NMR (400 MHz, CDCl3, ppm): δ 7.63- 7.58 (m, 2H), 7.48-7.45 (m, 1H), 7.36-7.34 (m, 1H), 7.28-7.26 (m, 1H), 4.32-4.29 (m, 1H), 4.25-4.20 (m, 1H), 4.09-4.01 (m, 2H), 3.65 (s, 3H), 3.48-3.44 (m, 1H), 3.40-3.38 (m, 1H), 2.80-2.76 (m, 3H), 1.91-1.88 (m, 1H), 1.62- 1.57 (m, 1H), 1.06-1.05 (m, 3H), 0.77-0.73 (m, 3H). 19F NMR (376 MHz, CDCl3, ppm): δ −63.68 (3F), −114.49 (1F).
307		482.2	SFC analysis: 100% ee; retention time: 2.150 min; column: ChiralCel OJ, 150 × 4.6 mm I.D., 3 μm; 5-40% of Ethanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min; 1H NMR (400 MHz, CDCl3, ppm): δ 7.67-7.57 (m, 2H), 7.39-7.33 (m, 1H), 7.11-7.07 (m, 1H), 7.02- 6.97 (m, 1H), 4.89-4.82 (m, 1H), 4.07-4.01 (m, 1H), 3.92-3.85 (m, 1H), 3.84-3.78 (m, 1H), 3.64 (s, 3H), 3.43-3.36 (m, 1H), 3.36-3.28 (m, 2H), 2.47-2.36 (m, 2H), 1.92-1.83 (m, 1H), 1.60- 1.53 (m, 1H), 1.14-1.12 (m, 3H), 0.67-0.60 (m, 3H). 19F NMR (376 MHz, CDCl3, ppm): δ −116.04 (1F).
308		482.2	SFC analysis: 100% ee; retention time: 2.507 min; column: ChiralCel OJ, 150 × 4.6 mm I.D., 3 μm; 5-40% of Ethanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min; 1H NMR (400 MHz, CDCl3, ppm) δ 7.63-7.56 (m, 2H), 7.27-7.19 (m, 1H), 7.09- 7.0 (m, 2H), 4.32-4.20 (m, 2H), 4.02-3.96 (m, 1H), 3.95-3.87 (m, 1H), 3.65 (s, 3H), 3.52-3.46 (m, 1H), 3.38-3.32 (m, 1H), 2.80-2.74 (m, 3H), 1.90-1.81 (m, 1H), 1.63-1.52 (m, 1H), 1.05- 1.03 (m, 3H), 0.76-0.72 (m, 3H). 19F NMR (376 MHz, CDCl3, ppm) δ −114.13 (1F).
309		518.2	Analytical HPLC*: retention time: 1.760 min; 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.09- 8.08 (m, 2H), 7.84 (s, 1H), 7.73-7.72 (m, 2H), 4.52-4.44 (m, 1H), 4.15-4.11 (m, 1H), 4.05-3.97 (m, 1H), 3.91-3.86 (m, 1H), 3.60 (s, 3H), 3.52-3.49 (m, 1H), 3.38-3.35 (m, 1H), 3.28-3.25 (m, 1H), 2.48-2.33 (m, 2H), 1.29- 1.21 (m, 3H), 1.12-1.09 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −61.04 (3F).
310		518.2	Analytical HPLC*: retention time: 1.825 min; 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.06 (s, 2H), 7.82 (s, 1H), 7.74-7.69 (m, 2H), 4.67-4.63 (m, 1H), 4.37-4.33 (m, 1H), 4.10- 4.01 (m, 1H), 3.94-3.89 (m, 1H), 3.60 (s, 3H), 3.51-3.47 (m, 1H), 3.21-3.19 (m, 1H), 2.95- 2.91 (m, 1H), 2.76-2.63 (m, 2H), 1.33-1.29 (m, 3H), 0.99-0.96 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −61.03(3F).
311		492.2	SFC analysis: 100% ee; retention time: 2.820 min; column: ChiralPak AD, 50 × 4.6 mm I.D., 3 μm; 5-40% of Ethanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/ min; 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.05 (s, 2H), 7.42-7.34 (m, 4H), 4.71-4.63 (m, 1H), 4.39-4.33 (m, 1H), 4.04-3.97 (m, 1H), 3.77-3.71 (m, 1H), 3.59 (s, 3H), 3.41-3.35 (m, 1H), 3.13-3.07 (m, 1H), 2.95-2.87 (m, 1H), 2.66-2.56 (m, 1H), 2.39-2.31 (m, 1H), 1.94- 1.83 (m, 1H), 1.66-1.47 (m, 3H), 1.15-0.89 (m, 2H), 0.85-0.81 (m, 3H), 0.77-0.73 (m, 3H).
312		492.2	SFC analysis: 98.58% ee; retention time: 3.031 min; column: ChiralPak AD, 50 × 4.6 mm I.D., 3 μm; 5-40% of Ethanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min; 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.17-8.10 (m, 2H), 7.47-7.39 (m, 4H), 5.35-5.29 (m, 1H), 4.25-4.19 (m, 1H), 3.90-3.83 (m, 1H), 3.68-3.60 (m, 4H), 3.36- 3.31 (m, 1H), 3.14-3.02 (m, 2H), 2.47-2.36 (m, 2H), 2.10-2.00 (m, 1H), 1.86-1.74 (m, 2H), 1.61-1.47 (m, 3H), 1.11-1.06 (m, 3H), 0.89- 0.84 (m, 3H).
313		466.2	Analytical HPLC*: retention time: 1.265 min; 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.12- 8.04 (m, 2H), 7.59-7.51 (m, 4H), 7.21-6.86 (m, 1H), 4.66-4.57 (m, 1H), 4.15-4.06 (m, 1H), 4.00-3.91 (m, 1H), 3.81-3.74 (m, 1H), 3.60 (s, 3H), 3.49-3.37 (m, 2H), 3.32-3.26 (m, 1H), 2.47-2.32 (m, 2H), 1.33-1.24 (m, 3H), 1.17- 1.07 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −108.86 (2F).
314		466.2	Analytical HPLC*: retention time: 1.311 min; 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.05 (s, 2H), 7.58-7.49 (m, 4H), 7.18-6.84 (m, 1H), 4.60-4.56 (m, 1H), 4.41-4.30 (m, 1H), 4.14-4.04 (m, 1H), 3.87-3.78 (m, 1H), 3.59 (s, 3H), 3.49-3.45 (m, 1H), 3.26-3.15 (m, 1H), 3.00-2.90 (m, 1H), 2.78-2.60 (m, 2H), 1.36-1.27 (m, 3H), 1.04-0.89 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −108.91 (2F).
315		495.4	SFC analysis: 100% ee; retention time: 1.712 min; column: ChiralPak IG, 100 × 4.6 mm I.D., 3 μm; 40% of Methanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/ min; 1H NMR (400 MHz, DMSO-d6, ppm): δ 9.56 (s, 1H), 8.98-8.96 (m, 1H), 8.62-8.60 (m, 1H), 7.82-7.68 (m, 4H), 3.85-3.80 (m, 1H), 3.55-3.49 (m, 1H), 3.08-3.05 (m, 1H), 2.93- 2.89 (m, 2H), 2.23-2.21 (m, 1H), 2.08-1.98 (m, 1H), 1.44-1.26 (m, 5H), 1.06-0.98 (m, 6H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −60.71 (3F).
316		495.4	SFC analysis: 99.10% ee; retention time: 2.065 min; column: ChiralPak IG, 100 × 4.6 mm I.D., 3 μm; 40% of Methanol (0.05% DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/ min; 1H NMR (400 MHz, DMSO-d6, ppm): δ 9.44 (s, 1H), 8.86-8.83 (m, 1H), 8.49-8.47 (m, 1H), 7.66-7.56 (m, 4H), 3.60-3.50 (m, 3H), 2.62-2.55 (m, 1H), 2.17-2.14 (m, 1H), 1.98- 1.72 (m, 2H), 1.30-1.14 (m, 5H), 1.04-0.99 (m, 3H), 0.61-0.55 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −60.70(3F).
317		532.2	Analytical HPLC*: retention time: 1.667 min; 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.09-7.97 (m, 2H), 7.78-7.60 (m, 3H), 4.41- 4.30 (m, 1H), 4.21-4.11 (m, 1H), 4.09-4.02 (m, 1H), 3.82-3.79 (m, 1H), 3.60 (s, 3H), 3.49- 3.39 (m, 2H), 2.85-2.70 (m, 2H), 2.65-2.55 (m, 1H), 2.02-1.87 (m, 1H), 1.70-1.56 (m, 1H), 1.05- 1.01 (m, 3H), 0.73-0.65 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −61.01 (3F).
318		532.2	Analytical HPLC*: retention time: 1.642 min; 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.14- 8.03 (m, 2H), 7.81-7.63 (m, 3H), 4.94- 4.87 (m, 1H), 4.18-4.10 (m, 1H), 3.92-3.84 (m, 1H), 3.64-3.55 (m, 4H), 3.47-3.44 (m, 1H), 3.30 (s, 1H), 2.40-2.30 (m, 2H), 2.08 (s, 1H), 2.01-1.88 (m, 1H), 1.64-1.52 (m, 1H), 1.10- 1.02 (m, 3H), 0.65-0.60 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −60.99 (3F).
319		530.2	Analytical HPLC*: retention time: 1.729 min; 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.12- 8.06 (m, 2H), 7.80-7.74 (m, 1H), 7.51-7.45 (m, 1H), 7.44-7.38 (m, 1H), 5.37-5.28 (m, 1H), 4.25- 4.18 (m, 1H), 3.86-3.78 (m, 1H), 3.71-3.63 (m, 1H), 3.59 (s, 3H), 3.39-3.35 (m 1H), 3.13-3.06 (m, 1H), 3.05-2.98 (m, 1H), 2.41-2.36 (m, 2H), 1.93-1.72 (m, 2H), 1.60-1.42 (m, 2H), 1.07-1.00 (m, 3H), 0.63-0.56 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −59.62 (3F), −116.20 (1F).
320		530.2	Analytical HPLC*: retention time: 1.725 min; 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.06 (s, 2H), 7.81-7.74 (m, 1H), 7.52-7.45 (m, 1H), 7.43-7.36 (m, 1H), 4.79-4.69 (m, 1H), 4.40-4.31 (m, 1H), 4.07-3.98 (m, 1H), 3.89- 3.80 (m, 1H), 3.60 (s, 3H), 3.46-3.39 (m, 1H), 3.17-3.09 (m, 1H), 2.95-2.86 (m, 1H), 2.72-2.61 (m, 1H), 2.41-2.37 (m, 1H), 2.04- 1.89 (m, 1H), 1.70-1.54 (m, 3H), 0.84-0.74 (m, 3H), 0.72-0.64 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −59.66 (3F), −116.22 (1F).
321		498.2	Analytical HPLC*: retention time: 1.895 min; 1H NMR (400 MHz, CDCl3, ppm): δ 7.75-7.64 (m, 2H), 7.47-7.37 (m, 2H), 7.21-7.13 (m, 1H), 4.97-4.84 (m, 1H), 4.17-4.08 (m, 1H), 4.00-3.90 (m, 1H), 3.70 (s, 3H), 3.52-3.31 (m, 4H), 2.47- 2.36 (m, 2H), 2.01-1.86 (m, 1H), 1.59-1.47 (m, 1H), 1.19-1.15 (m, 3H), 0.71-0.67 (m, 3H).
322		498.2	Analytical HPLC*: retention time: 1.650 min; 1H NMR (400 MHz, CDCl3, ppm): δ 7.64- 7.58 (m, 2H), 7.45-7.33 (m, 2H), 7.13-7.10 (m, 1H), 4.38-4.34 (m, 1H), 4.31-4.20 (m, 1H), 4.14-4.00 (m, 1H), 3.71 (s, 3H), 3.66-3.34 (m, 3H), 2.91-2.70 (m, 3H), 1.99-1.80 (m, 1H), 1.39-1.25 (m, 1H), 1.10-1.07 (m, 3H), 0.79- 0.75 (m, 3H).
323		532.2	Analytical HPLC*: retention time: 1.705 min; 1H NMR (400 MHz, CDCl3, ppm): δ 7.77-7.61 (m, 3H), 7.50 (s, 1H), 7.33-7.27 (m, 1H), 4.98-4.90 (m, 1H), 4.13-4.05 (m, 1H), 4.00- 3.87 (m, 1H), 3.64 (s, 3H), 3.56-3.32 (m, 4H), 2.53-2.28 (m, 2H), 2.06-1.89 (m, 1H), 1.81- 1.67 (m, 1H), 1.18-1.11 (m, 3H), 0.69-0.58 (m, 3H). 19F NMR (376 MHz, CDCl3, ppm): δ −62.28 (3F).
324		532.2	Analytical HPLC*: retention time: 1.750 min; 1H NMR (400 MHz, CDCl3, ppm): δ 7.75-7.56 (m, 3H), 7.41 (s, 1H), 7.23-7.19 (m, 1H), 4.41-4.30 (m, 1H), 4.30-4.18 (m, 1H), 4.19- 4.01 (m, 1H), 3.78-3.59 (m, 4H), 3.55-3.38 (m, 2H), 2.94-2.69 (m, 3H), 1.95-1.79 (m, 1H), 1.71-1.62 (m, 1H), 1.08-1.03 (m, 3H), 0.75- 0.70 (m, 3H). 19F NMR (376 MHz, CDCl3, ppm): δ −62.40 (3F).
326		546.2	Analytical HPLC*: retention time: 1.771 min; 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.05- 7.96 (m, 2H), 7.74-7.68 (m, 1H), 7.67-7.57 (m, 2H), 5.28-5.11 (m, 1H), 4.18-4.09 (m, 1H), 3.78-3.69 (m, 1H), 3.64-3.57 (m, 1H), 3.51 (s, 3H), 3.25-3.18 (m, 1H), 3.05-2.97 (m, 1H), 2.96-2.88 (m, 1H), 2.34-2.26 (m, 2H), 1.89-1.60 (m, 2H), 1.52-1.33 (m, 2H), 0.96-0.93 (m, 3H), 0.52-0.48 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −60.99 (3F).
327		546.2	Analytical HPLC*: retention time: 1.668 min; 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.04- 7.94 (m, 2H), 7.75-7.53 (m, 3H), 4.75-4.62 (m, 1H), 4.33-4.24 (m, 1H), 3.98-3.88 (m, 1H), 3.82-3.72 (m, 1H), 3.52 (s, 3H), 3.39-3.31 (m, 1H), 3.06-2.97 (m, 1H), 2.88-2.75 (m, 1H), 2.63-2.52 (m, 1H), 2.32-2.22 (m, 1H), 1.96-1.81 (m, 1H), 1.64-1.45 (m, 3H), 0.71-0.67 (m, 3H), 0.59-0.54 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm): δ −61.04 (3F).
328		516.2	Analytical HPLC*: retention time: 1.637 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.13- 8.03 (m, 2H), 7.79-7.75 (m, 1H), 7.49-7.40 (m, 2H), 4.98-4.95 (m, 1H), 4.16-4.13 (m, 1H), 3.90-3.86 (m, 1H), 3.59 (s, 3H), 3.58- 3.53 (m, 1H), 3.50-3.42 (m, 1H), 3.33-3.23 (m, 2H), 2.45-2.35 (m, 2H), 2.05-1.85 (m, 1H), 1.71-1.50 (m, 1H), 1.10-1.06 (m, 3H), 0.63-0.57 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −59.63 (3F), −116.18 (1F).
329		516.2	Analytical HPLC*: retention time: 1.668 min; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.04 (s, 2H), 7.79-7.75 (m, 1H), 7.48-7.45 (m, 1H), 7.39-7.37 (m, 1H), 4.36-4.34 (m, 1H), 4.21-4.11 (m, 1H), 4.08-3.95 (m, 1H), 3.83- 3.76 (m, 1H), 3.60 (s, 3H), 3.47-3.43 (m, 2H), 2.88-2.78 (m, 1H), 2.78-2.71 (m, 1H), 2.69-2.59 (m, 1H), 2.04-1.83 (m, 1H), 1.74- 1.53 (m, 1H), 1.05-1.03 (m, 3H), 0.75- 0.71 (m, 3H). 19F NMR (376 MHz, DMSO-d6, ppm) δ −59.73 (3F), −116.16 (1F).
336		476.2	Analytical HPLC*: retention time: 1.485 min; 1H NMR (400 MHz, CDCl3, ppm): 87.66-7.59 (m, 2H), 7.05-7.01 (m, 2H), 6.90-6.86 (m, 1H), 5.29-5.25 (m, 1H), 4.08-4.05 (m, 1H), 3.86- 3.81 (m, 1H), 3.63 (s, 3H), 3.33-3.29 (m, 2H), 3.10-3.02 (m, 2H), 2.36-2.26 (m, 2H), 2.21 (s, 3H), 1.79-1.71 (m, 2H), 1.49-1.44 (m, 2H), 1.07-1.03 (m, 3H), 0.59-0.55 (m, 3H). 19F NMR (376 MHz, CDCl3, ppm): δ −120.09 (1F).
337		476.2	Analytical HPLC*: retention time: 1.432 min; 1H NMR (400 MHz, CDCl3, ppm): δ 8 7.62- 7.57(m, 2H), 7.01-6.95 (m, 2H), 6.89-6.85 (m, 1H), 4.60-4.56 (m, 1H), 4.29-4.25 (m, 1H), 4.09-4.04 (m, 1H), 3.63 (s, 3H), 3.52- 3.49 (m, 1H), 3.42-3.41 (m, 1H), 3.21-3.18 (m, 1H), 2.85-2.81 (m, 1H), 2.63-2.58 (m, 1H), 2.48-2.47 (m, 1H), 2.20 (s, 3H), 1.85-1.83 (m, 1H), 1.59-1.50 (m, 3H), 0.78-0.75 (m, 3H), 0.65-0.61 (m, 3H). 19F NMR (376 MHz, CDCl3, ppm) δ −119.99 (1F).
338		476.0	Analytical HPLC*: retention time: 1.489 min; 1H NMR (400 MHz, CDCl3, ppm): δ 7.66-7.59 (m, 2H), 7.08-7.03 (m, 1H), 6.95-6.89 (m, 2H), 5.30-5.27 (m, 1H), 4.09-4.05 (m, 1H), 3.85-3.80 (m, 1H), 3.63 (s, 3H), 3.35-3.32 (m, 2H), 3.10-3.02 (m, 2H), 2.38-2.30 (m, 2H), 2.20 (s, 3H), 1.79-1.70 (m, 2H), 1.57-1.47 (m, 2H), 1.08-1.02 (m, 3H), 0.59-0.52 (m, 3H). 19F NMR (376 MHz, CDCl3, ppm) δ −117.80 (1F).
339		476.0	Analytical HPLC*: retention time: 1.441 min; 1H NMR (400 MHz, CDCl3, ppm): δ 7.63- 7.57(m, 2H), 7.07-7.03 (m, 1H), 6.89-6.85 (m, 2H), 4.62-4.58 (m, 1H), 4.29-4.26 (m, 1H), 4.10-4.05 (m, 1H), 3.64 (s, 3H), 3.56-3.52 (m, 1H), 3.44-3.40 (m, 1H), 3.21-3.18 (m, 1H), 2.85-2.82 (m, 1H), 2.65-2.60 (m, 1H), 2.51- 2.49 (m, 1H), 2.21 (s, 3H), 1.87-1.84 (m, 1H), 1.63-1.48 (m, 3H), 0.80-0.76 (m, 3H), 0.67- 0.63 (m, 3H). 19F NMR (376 MHz, CDCl3, ppm) δ −117.82 (1F).
340		492.0	Analytical HPLC*: retention time: 1.574 min; 1H NMR (400 MHz, CDCl3, ppm): δ 7.66- 7.59 (m, 2H), 7.23-7.20 (m, 1H), 7.09 (s, 1H), 7.02-7.01 (m, 1H), 5.31-5.28 (m, 1H), 4.09- 4.05 (m, 1H), 3.85-3.80 (m, 1H), 3.63 (s, 3H), 3.33-3.29 (m, 2H), 3.10-3.02 (m, 2H), 2.36- 2.26 (m, 5H), 1.93-1.72 (m, 2H), 1.59-1.44 (m, 2H), 1.07-1.03 (m, 3H), 0.59-0.56 (m, 3H).
341		492.0	Analytical HPLC*: retention time: 1.518 min; 1H NMR (400 MHz, CDCl3, ppm): δ 7.63- 7.57 (m, 2H), 7.22-7.20 (m, 1H), 7.06 (s, 1H), 6.99-6.96 (m, 1H), 4.64-4.60 (m, 1H), 4.29- 4.26 (m, 1H), 4.09-4.04 (m, 1H), 3.64 (s, 3H), 3.53-3.50 (m, 1H), 3.44-3.42 (m, 1H), 3.20- 3.17 (m, 1H), 2.85-2.82 (m, 1H), 2.64-2.59 (m, 1H), 2.49-2.48 (m, 1H), 2.31 (s, 3H), 1.86-1.84 (m, 1H), 1.61-1.45 (m, 3H), 0.80- 0.76 (m, 3H), 0.66-0.62 (m, 3H).
342		492.0	Analytical HPLC*: retention time: 1.568 min; 1H NMR (400 MHz, CDCl3, ppm): δ 7.75-7.61 (m, 2H), 7.28-7.22 (m, 1H), 7.12-7.09 (m, 1H), 7.07-7.01 (m, 1H), 5.29-5.26 (m, 1H), 4.09-4.05 (m, 1H), 3.85-3.80 (m, 1H), 3.63 (s, 3H), 3.39-3.30 (m, 2H), 3.11-3.01 (m, 2H), 2.48-2.24 (m, 5H), 1.92-1.66 (m, 2H), 1.58- 1.43 (m, 2H), 1.08-0.99 (m, 3H), 0.59-0.51 (m, 3H).
343		492.0	Analytical HPLC*: retention time: 1.516 min; 1H NMR (400 MHz, CDCl3, ppm): δ 7.74-7.65 (m, 2H), 7.28 (s, 1H), 7.21-7.19 (m, 1H), 7.08-7.06 (m, 1H), 4.68-4.66 (m, 1H), 4.39- 4.35 (m, 1H), 4.24-4.09 (m, 1H), 3.73 (s, 3H), 3.67-3.56 (m, 1H), 3.58-3.45 (m, 1H), 3.31- 3.29 (m, 1H), 2.94-2.91 (m, 1H), 2.80-2.66 (m, 1H), 2.59-2.57 (m, 1H), 2.38 (s, 3H), 2.02- 1.85 (m, 1H), 1.79-1.66 (m, 1H), 1.64-1.53 (m, 2H), 0.88-0.82 (m, 3H), 0.77-0.73 (m, 3H).
344		458.2	Analytical HPLC*: retention time: 1.483 min; 1H NMR (400 MHz, CDCl3, ppm): δ 7.66- 7.59 (m, 2H), 7.19-7.12 (m, 2H), 7.07-7.05 (m, 2H), 5.27-5.24 (m, 1H), 4.07-4.04 (m, 1H), 3.84-3.80 (m, 1H), 3.68 (s, 3H), 3.46-3.31 (m, 2H), 3.21-3.05 (m, 2H), 2.41-2.40 (m, 1H), 2.38-2.27 (m, 4H), 1.95-1.70 (m, 2H), 1.59- 1.52 (m, 2H), 1.07-1.03 (m, 3H), 0.60-0.57 (m, 3H).
345		458.2	Analytical HPLC*: retention time: 1.578 min; 1H NMR (400 MHz, CDCl3, ppm): δ 7.70- 7.61 (m, 2H), 7.19-7.04 (m, 4H), 4.62-4.58 (m, 1H), 4.38-4.35 (m, 1H), 4.21-4.08 (m, 1H), 3.70 (s, 3H), 3.64-3.53 (m, 1H), 3.51-3.39 (m, 1H), 3.34-3.31(m, 1H), 2.94-2.91 (m, 1H), 2.77-2.62 (m, 1H), 2.59-2.58 (m, 1H), 2.35 (s, 3H), 1.99-1.85 (m, 1H), 1.69-1.59 (m, 3H), 0.87-0.81 (m, 3H), 0.76-0.71 (m, 3H).
*: Analytical HPLC: column: Waters ACQUITY BEH C18 2.1 * 50 mm,1.7 μm; Mobile phase A: H2O (0.05% TFA); Mobile phase B: Acetonitrile (0.05% TFA); flow rate: 1.0 mL/min; Run time: 5 min; 95 to 5% A in 3 min, 5% A for 2 min.

Biological Assay Example A: DGK ADP-Glo Kinase Assay

The DGKa and DGKz kinase assays were performed using Promega ADP-Glo kit (Promega, Cat #V9102). One microliter test compound was added to a 384-well plate. Reactions were performed in a 5 uL volume by adding 2 uL mixture of DGK enzyme and ATP in assay buffer (50 mM MOPS pH 7.5, 100 mM NaCl, 10 mM MgCl₂, 1 mM CaCl₂, 0.0025% BSA, and 1 mM DTT). The final concentration of DGKa, DGKz and ATP were 10 nM, 5 nM and 15 uM, respectively. The enzyme solution was incubated with test compound at 25 for 20 min. For the preparation of the substrate of micelles, 1 volume of a 16.1 mM solution of 1,2-dioleoyl-sn-glycerol in chloroform was slowly evaporated using a nitrogen stream. Subsequently, 22.55 volumes of a 510 mM solution of octyl-b-D-glucopyranoside in 50 mM MOPS buffer (pH 7.5) were added, and the mixture was sonicated in an ultrasonic bath for 20s. Then 35 volumes of 50 mM MOPS buffer (pH7.5) were added to yield a solution of 0.28 mM 1,2 dioleoyl-sn-glycerol and 200 mM octyl-b-D-glucopyranoside, which was aliquoted, flash-frozen in liquid nitrogen, and stored at −80° C. until use. The reaction was initiated by the addition of 2 uL of substrate solution (7 uM 1.2-dioleoyl-sn-glycerol, 5 mM octyl-b-D-glucopyranoside) in the 5 uL assay volume. The resulting mixture was incubated at 25° C. for 40 minutes. Next, 5 uL of ADP-Glo-reagent was added to the plate and incubated for 40 minutes. Then 10 uL of kinase detection reagent was added and incubated for 30 minutes. Luminescence was recorded using an Tecan SPARK microplate reader. 1% DMSO vehicle was used as control and no enzyme well was used as blank well. The percent inhibition was calculated with the formula: % inhibition=100-100*(RLU_cmpd−RLU_blank)/(RLU_control−RLU_blank). Inhibition at 50% activity (IC50) was calculated with the equation of Y=Bottom+(Top−Bottom)/(1+10{circumflex over ( )}((Log IC50−X)*Hill Slope)).

TABLE 2
DGKa and DGKz IC50 values of representative compounds.
	DGKa	DGKz
	kinase	kinase
Compound #	IC50 (uM)	IC50 (uM)
5	0.427	0.126
6	0.212	0.775
7	0.104	0.645
8	0.579	0.547
9	0.096	>10
10	0.324	0.29
11	0.073	>10
12	6.6	>10
13	0.579	1.66
14	1.18	>10
15	0.019	>10
16	0.926	0.058
17	0.053	0.212
18	0.022	0.156
19	2.05	0.055
20	1.16	1.84
21	0.013	6.40
22	0.005	>10
23	0.004	2.12
24	0.022	>10
25	0.058	0.301
26	0.042	0.172
27	0.016	0.146
28	0.012	0.050
29	0.014	0.055
30	0.074	0.034
31	0.020	0.024
32	0.009	>10
33	0.002	0.06
34	0.016	0.042
35	0.016	0.224
36	0.077	0.3
37	0.017	0.475
38	0.056	0.54
39	0.001	2.05
40	0.026	0.181
41	0.003	0.466
42	0.003	0.311
43	0.003	0.213
44	0.04	0.315
45	0.245	0.045
46	0.005	0.324
47	0.012	0.036
48	0.015	0.105
49	0.02	0.032
50	0.022	1.08
51	0.058	0.05
52	0.005	0.499
53	0.085	0.185
54	0.029	0.248
55	0.076	0.012
56	0.415	0.131
57	0.024	0.607
58	0.009	0.367
59	0.028	0.162
60	0.083	0.028
61	0.128	0.18
62	0.035	0.132
63	0.016	0.639
64	0.01	0.055
65	0.014	0.059
66	0.004	0.053
67	0.004	0.016
68	0.005	0.103
69	0.01	0.346
70	0.003	0.053
71	0.021	0.236
72	0.013	0.033
73	0.015	0.058
74	0.01	1.57
75	0.253	0.66
77	0.032	0.081
78	0.019	0.041
79	0.111	0.333
80	0.012	0.027
81	0.006	0.016
82	0.002	0.454
83	0.023	0.124
84	0.009	1.16
85	0.018	0.77
86	0.009	0.096
87	0.002	0.093
88	0.018	0.038
89	0.01	0.116
90	0.01	0.404
91	0.029	6.06
92	0.227	0.006
93	0.012	0.13
94	0.14	1.30
95	0.058	0.303
96	0.004	2.82
97	0.005	0.006
98	0.01	0.04
99	0.004	0.022
100	0.001	0.03
101	0.011	0.235
102	0.039	1.69
103	0.035	0.356
104	0.018	0.041
105	0.004	0.029
106	0.024	0.555
107	0.009	0.136
108	0.026	0.242
109	0.006	0.071
110	0.006	0.117
111	0.007	0.018
112	0.011	0.183
113	0.044	0.161
114	0.03	0.004
115	0.003	0.008
116	0.014	0.347
117	0.018	0.2
118	0.022	0.61
119	0.003	0.021
120	0.01	0.352
121	0.039	1.94
122	0.018	0.016
123	0.078	0.798
124	0.006	0.114

Biological Assay Example B: Human PBMC IL-2 Assay

PBMC (frozen) obtained from health donor were thawed in RPMI-1640 medium with 10% FBS and incubated for 4 h at 37° C. In a 96-well plate, −200,000 PBMC cells in 160 uL were added to each assay well. Ten microliter compound solution (10 uM to 0.6 nM, 8 points with 4-fold dilution) were added to cells in each well and incubated for 60 minutes at 37° C. Then 30 uL anti-CD3/CD28 antibody (Catalog #10991, Stemcell) were added to cells and incubated overnight at 37° C. After the incubation, 16 uL supernatants were transferred into a new 384-well white assay plate for cytokine analysis. IL-2 level was quantified using Human IL-2 kit (Catalog #62HIL02PEG, Cisbio) as described in the manufacturer manual. Activation at 50% activity (EC₅₀) was calculated with the equation:

$Y=\mathrm{Bottom}+\left(\mathrm{Top}-\mathrm{Bottom}\right)/\left(1+10^\left(\left(\mathrm{Log}{\mathrm{EC}}_{50}-X\right)*\mathrm{HillSlope}\right)\right)$

X is log of compound concentration, Y is the IL-2 concentration, increasing as X increases.

TABLE 3
PBMC IL-2 EC50 values of representative compounds.
           PBMC IL-2 assay
Compound # EC50 (uM)
5          0.728
6          1.8
7          0.372
17         0.401
19         0.918
34         0.044
67         0.04
135        0.069
137        0.096
139        0.869
140        0.259
143        0.178
144        0.061
147        0.096
148        0.582
149        0.162
151        0.082
153        0.085
154        0.734
156        0.083
158        0.579
159        0.041
160        0.075
161        0.053
162        0.786
163        0.34
164        0.233
165        0.375
168        0.032
170        0.186
171        1.25
174        0.025
178        0.299
179        0.058
182        1.88
183        0.156
185        7.23
186        0.023
187        0.322
188        0.577
189        0.276
192        3.05
193        1.31
194        0.079
195        2.2
196        0.846
197        0.078
199        1.58
200        0.042
201        0.52
204        0.107
207        0.284
209        1.38
210        1.72
211        0.175
212        0.039
220        3.84
221        0.624
222        0.154
223        0.047
228        0.227
232        0.019
233        0.361
235        0.662
236        0.583
237        1.33
238        0.078
239        3.42
240        0.109
241        1.1
243        0.212
244        0.011
245        0.314
246        0.023
250        0.016
251        0.05
252        0.106
257        0.119
258        1.1
259        1.88
260        0.089
261        0.415
262        0.618
265        0.152
266        0.111
268        0.89
270        0.616
271        0.057
272        0.325
275        0.023
281        0.049
283        0.036
289        0.007
291        0.011
295        0.01
296        0.068
297        0.012
303        0.105
304        0.024
306        0.03
308        0.018
311        0.001
312        0.049
314        0.022
315        0.063
316        0.742
317        0.105
318        0.349
319        0.285
320        0.056
321        0.54
322        0.025
323        0.474
324        0.049
325        0.561
326        0.062
327        0.103
328        0.302
329        0.054
330        0.115
331        0.016
332        0.064
334        0.031
336        0.163
337        0.016
338        0.153
339        0.013
341        0.013
342        0.28
343        0.018
344        0.053
345        0.010
346        0.138
347        0.013

Biological Assay Example C: Jurkat IL-2 Assay

Jurkat cells (ATCC) were cultured in RPMI-1640 medium supplemented with 10% FBS. In a 96-well plate, −250,000 cells in 130 uL were added to each assay well. Ten microliter compound solution (5 uM to 2.3 nM, 8 points with 3-fold dilution) were added to cells in each well and incubated for 60 minutes at 37° C. Then 10 uL anti-CD3/CD28 antibody (Catalog #10991, Stemcell) were added and incubated overnight at 37° C. After the incubation, 16 uL supernatants were transferred into a new 384-well white assay plate for cytokine analysis. IL-2 was quantified using Human IL-2 kit (Catalog #62HIL02PEG, Cisbio) as described in the manufacturer manual.

Activation at 50% activity (EC₅₀) was calculated with the equation:

$Y=\mathrm{Bottom}+\left(\mathrm{Top}-\mathrm{Bottom}\right)/\left(1+10^\left(\left(\mathrm{Log}{\mathrm{EC}}_{50}-X\right)*\mathrm{HillSlope}\right)\right)$

X is log of compound concentration, Y is the IL-2 concentration, increasing as X increases.

TABLE 4
Jurkat IL-2 EC50 values of representative compounds.
           Jurkat IL-2 assay
Compound # EC50 (uM)
34         0.067
45         0.858
50         0.435
67         0.049
135        0.07
137        0.248
139        0.251
140        0.598
143        0.483
144        0.076
147        0.055
148        0.209
149        0.076
151        0.032
153        0.043
154        0.526
156        0.124
158        0.277
159        0.012
160        0.021
161        0.026
162        0.1
168        0.042
170        0.246
174        0.013
179        0.029
183        0.077
186        0.013
193        1.62
194        0.104
195        1.11
196        1.28
197        0.039
199        0.873
200        0.086
201        0.822
204        0.202
207        0.150
209        1.01
210        0.565
211        0.485
212        0.011
221        0.503
222        0.144
223        0.07
228        0.087
232        0.047
233        0.287
235        0.538
236        0.098
238        0.189
239        0.687
240        0.242
241        0.588
243        0.473
244        0.063
245        0.189
246        0.03
250        0.032
251        0.051
252        0.122
257        0.132
258        0.758
259        0.624
260        0.069
261        0.554
262        0.478
263        0.582
265        0.165
266        0.163
270        0.506
271        0.079
272        0.256
275        0.051
281        0.118
283        0.04
289        0.016
291        0.01
295        0.008
296        0.091
297        0.034
303        0.153
304        0.034
306        0.036
308        0.009
311        0.054
312        0.218
314        0.077
315        0.090
316        0.707
317        0.021
318        0.359
319        0.519
320        0.042
321        0.223
322        0.012
323        0.364
324        0.095
325        0.688
326        0.087
327        0.064
328        0.339
329        0.097
330        0.267
331        0.014
332        0.130
334        0.026
336        0.131
337        0.012
338        0.086
339        0.007
341        0.006
342        0.125
343        0.045
344        0.096
345        0.018
346        0.091
347        0.009

Biological Assay Example D: Human Microsomal Clearance Assay

This study aimed to assess the metabolic stability of a compound in human liver microsomes using a microsomal clearance assay.

A mixture containing 100 mM potassium phosphate, pH 7.4, 0.5 mg/mL liver microsomes, 2 mM NADPH, and 1 μM compound were prepared and added to 96-well plate. The plates were then incubated at 37 for different time points (0, 5, 15, 30, 45 minutes) and the reaction was stopped with acetonitrile solution containing an internal standard. The samples were then analyzed by LC/MS/MS to determine how much of the compound remained at each time point. The elimination rate constant and half-life were calculated from the data, and the in vitro intrinsic clearance (CLint) was determined as follows:

$\mathrm{Elimination}\mathrm{rate}\mathrm{constant}\left(k\right)=-\mathrm{slope};\mathrm{Half}-\mathrm{life}\left(t1/2\right)=0.693/k.$

The in vitro intrinsic clearance, CLint, was calculated from the t1/2 as follows: CL′int=(0.693/t1/2)×(1/(microsomal protein concentration (0.5 mg/mL))) X Physiological Scaling Factor.

TABLE 5
In vitro intrinsic clearance values of representative compounds.
	Clint
Compound #	(mL/min/kg)	T1/2 (min)
28	7.7	225
31	5.1	342
36	2.7	654
67	7.5	233
86	3.2	539
151	4.1	428
223	18.3	95
246	1.1	1544
250	12.3	142
251	8.6	203
322	12.4	141
332	6.9	254

Biological Assay Example E: Mouse Whole Blood IFN-Gamma Assay

The whole blood from male C57BL6 mice (6-8 weeks old, Beijing Vital River Laboratory Animal Technology Co., Ltd.) was collected, pooled and dispensed at 200 uL per well in a 96-well plate. The blood was treated with compounds for one hour at 37° C. in a humidified 5% CO₂ incubator. The blood was then stimulated with anti-mouse CD3 and anti-mouse CD28 antibody (BioLegend Cat #100340, #102116) at a final concentration of 0.6 ug/mL for 20 hours at 37° C. in a humidified 5% CO₂ incubator. The blood was spun down, IFN-gamma in the supernatants was measured using ELISA kit (Excellbio Cat #EM002-96, #EM007-96) according the manufacture's instruction.

TABLE 6
IFN-gamma EC50 values of representative compounds.
           Mouse Whole Blood
Compound # IFN-gamma EC50 (uM)
34         0.335
67         0.102
197        0.312
223        0.679
246        0.265
250        0.144
322        0.281
334        0.241

Biological Assay Example F: In Vivo Efficacy Studies in Syngeneic Mouse Tumor Model

Murine colon adenocarcinoma cells MC-38 were obtained from American Type Culture Collection (ATCC) and cultured in RPMI 1640 media containing 10% fetal bovine serum (FBS) at 37° C. in a humidified 5% CO₂ incubator. Female C57BL/6 mice (20 2 g, 6-8 weeks old) were purchased from SPF Biotechnology Co., Ltd. (Beijing, China). MC-38 cells were collected from flask and suspended in PBS. Suspension of 1×10⁶ cells in 0.1 mL culture media without FBS was injected subcutaneously into animal armpits. Once the tumor reached 100-150 mm³, the mice were randomized into different groups and treatment was initiated. Mice were treated orally once per day (PO, QD) with compound 67 (0.6 mg/kg) or vehicle control. Anti-PD-1 antibody (BioXcell, Cat #BE0273) was diluted with PBS for dosing at 2 mg/kg and was administrated via intraperitoneal injection, twice per week. Tumor volume and body weight of mice were recorded twice per week.

All animals were housed in a room maintained at 23±3° C., 65%-75% humidity, with a controlled 12 h light-dark cycle for 5-7 days before experiments. Water and commercial laboratory complete food for mice were provided in the cage.

Tumor volume was calculated by measuring two perpendicular diameters using the following formula: (L×W²)/2, in which L and W refer to the length and width tumor diameter, respectively. Tumor growth inhibition (TGI) was calculated according to the following equation: TGI (%)=(1−(TVTreatment/Dn−TVTreatment/D0)/(TVControl/Dn−TVControl/D0))×100%, where the Dn is the final tumor volume and DO is starting tumor volume prior to treatment. Combination with anti-PD-1 shows significantly better tumor inhibition activity than either of the single agents (compound 67 or anti-PD-1) (see FIG. 1).

Biological Assay Example G: In Vivo Efficacy Studies in Syngeneic Mouse Tumor Model

Murine colorectal adenocarcinoma cells CT26 (purchased from ATCC) were cultured in RPMI 1640 medium with 10% FBS. For tumor implantation, 6-8 weeks old BALB/c female mice (Beijing Vital River Laboratory Animal Technology Co., Ltd.) were given a subcutaneous injection of CT26 cell (1×10{circumflex over ( )}7 cells/mL) in 0.1 mL suspension into the right flank. Once tumors grew to a volume of 50-100 mm3, mice were randomized into different groups and treatment was initiated. Mice were treated orally once per day (PO, QD) with DGK inhibitors (3 mg/kg) or vehicle control. Anti-PD-1 antibody (BioXcell, Cat #BE0273), anti-CTLA4 antibody (BioXcell, Cat #BE0164) were diluted with PBS for dosing at 10 mg/kg or 5 mg/kg, respectively. Antibody was administrated via intraperitoneal injection, twice per week. Tumor volume and body weight of mice were recorded twice per week.

All animals were housed in a room maintained at 23:3° C., 65%-75% humidity, with a controlled 12 h light-dark cycle for 5-7 days before experiments. Water and commercial laboratory complete food for mice were provided in the cage.

Exemplary compounds including compound 250 have been tested in this model and were found to inhibit tumor growth.

The Summary and Abstract sections may set forth one or more but not all exemplary embodiments of the present invention as contemplated by the inventor(s), and thus, are not intended to limit the present invention and the appended claims in any way.

The present invention has been described above with the aid of functional building blocks illustrating the implementation of specified functions and relationships thereof. The boundaries of these functional building blocks have been arbitrarily defined herein for the convenience of the description. Alternate boundaries can be defined so long as the specified functions and relationships thereof are appropriately performed.

With respect to aspects of the invention described as a genus, all individual species are individually considered separate aspects of the invention. If aspects of the invention are described as “comprising” a feature, embodiments also are contemplated “consisting of” or “consisting essentially of” the feature.

The foregoing description of the specific embodiments will so fully reveal the general nature of the invention that others can, by applying knowledge within the ordinary skill of the art, readily modify and/or adapt for various applications such specific embodiments, without undue experimentation, without departing from the general concept of the present invention. Therefore, such adaptations and modifications are intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance presented herein. It is to be understood that the phraseology or terminology herein is for the purpose of description and not of limitation, such that the terminology or phraseology of the present specification is to be interpreted by the ordinarily skilled artisan in light of the teachings and guidance.

The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments.

All of the various aspects, embodiments, and options described herein can be combined in any and all variations.

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent that any meaning or definition of a term in this document conflicts with any meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to that term in this document shall govern.

Claims

1. A compound of Formula III-2, or a pharmaceutically acceptable salt thereof:

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is N.

3. The compound of any of claims 1-2, or a pharmaceutically acceptable salt thereof, wherein U is CR6.

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R6 is hydrogen.

5. The compound of any of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R1 is CN.

6. The compound of any of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein (i) R1 is halogen, e.g., F or Cl; (ii) R1 is

7. The compound of any of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen.

8. The compound of any of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein X is N.

9. The compound of any of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein L1

10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein R9A at each occurrence is independently CH3, CH2CH3, CH2CH2CH3, fluorine-substituted C1-3 alkyl (e.g., CF2H), cyclopropyl, cyclobutyl, CH2OH, CH2OCH3, CH2OCH2CH3, CH2NH2, CH2N3, or CH2NHC(O)OCH3.

11. The compound of any of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein L1 is selected from the following (the bottom attaching point, N or C, is attached to L2):

12. The compound of any of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein L1 is selected from the following (the bottom attaching point, N or C, is attached to L2)

13. The compound of any of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein L1 is an optionally substituted 7-12 membered heterocyclylene having two or more rings and 1-4 ring heteroatoms each independently O, N, or S, when substituted, the substituent(s) can be attached to any one or more of the two or more rings.

14. The compound of any of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein L1 is selected from the following bicyclic heterocyclylene (the bottom attaching point, N or C, is attached to L2):

15. The compound of any of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein L1 is selected from the following bicyclic heterocyclylene (the bottom attaching point, N or C, is attached to L2):

16. The compound of any of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein L2 is absent.

17. The compound of any of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein L2 is an optionally substituted C1-4 alkylene.

18. The compound of any of claims 1-15, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-2-E-1, III-2-E-2, or III-2-E-3:

19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a, or III-2-F-3b:

20. The compound of claim 18 or 19, or a pharmaceutically acceptable salt thereof, wherein R13 is hydrogen.

21. The compound of claim 18 or 19, or a pharmaceutically acceptable salt thereof, wherein R13 is C1-4 alkyl, e.g., methyl, isopropyl, etc.

22. The compound of claim 18 or 19, or a pharmaceutically acceptable salt thereof, wherein R13 is CN, OH, COOH, CONH2, methoxy, ethoxy, cyclopropyl, cyclobutyl, optionally substituted phenyl, or optionally substituted 5 or 6 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S, wherein, when substituted, the optionally substituted phenyl or 5 or 6 membered heteroaryl is substituted with 1-3 substituents independently selected from halogen (preferably F or Cl), OH, CN, C1-4 alkyl optionally substituted with 1-3 F, C1-4 heteroalkyl optionally substituted with 1-3 F, and 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and/or methyl, e.g., R13 is OH, methoxy, cyclopropyl, phenyl,

23. The compound of any of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein R30 is optionally substituted phenyl, such as a phenyl which is substituted with 1-3 (e.g., 1 or 2) R22, wherein R22 at each occurrence is independently halogen (e.g., F, Cl, or Br), CN, OH, NH2, RM, ORM, COOH, CONH2, COORM, CONH(RM), CON(RM)2, NHCO(RM), N(RM)CO(RM), SO2RM, SO2NH2, S(O)(NH)RM, S(O)(NRM)RM, SO2N(RM)2, NHSO2RM, N(RM)SO2RM, P(O)(RM)2, P(O)(ORM)2, NH(RM), N(RM)2, SRM, or SF5, wherein RM at each occurrence is independently an optionally substituted C1-4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, optionally substituted C3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl having 1-4 ring heteroatoms independently selected from O, S, and N, or optionally substituted 4-7 membered heterocyclyl.

24. The compound of any of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein R30 is a phenyl which is substituted with 1-3 (e.g., 1 or 2) R22, wherein R22 at each occurrence is independently halogen (e.g., F, Cl, or Br), CN, OH, RM1, ORM1, SO2RM1, P(O)(RM1)2, SRM1, or SF5, wherein RM1 at each occurrence is independently an optionally substituted C1-4 alkyl or an optionally substituted 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.), wherein when substituted, the optionally substituted C1-4 alkyl or 3-4 membered ring is substituted with 1-3 substituents independently selected from halogen (preferably F or Cl), OH, CN, C1-4 alkyl optionally substituted with 1-3 F, C1-4 heteroalkyl optionally substituted with 1-3 F, and 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and/or methyl, preferably, R22 at each occurrence is independently F, Cl, Br, CF3, OCF3, SCF3, SF5, OMe, CN, methyl, CHF2, CF2CH3, cyclopropyl, CH3SO2, and OCH2-(cyclopropyl).

25. The compound of any of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein R30 is a phenyl which is substituted with 1-3 (e.g., 1 or 2) R22, wherein R22 at each occurrence is independently F, Cl, CN, RM2, ORM2, SRM2, or SF5, wherein RM2 at each occurrence is independently a C1-4 alkyl optionally substituted with 1-3 F, such as CF3.

26. The compound of any of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein R30 is an optionally substituted 5 or 6-membered heteroaryl, such as a pyridyl

27. The compound of any of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein R30 is a 5-membered heteroaryl

28. The compound of any of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein R30 is a 5-membered heteroaryl

29. The compound of any of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein R30 has a structure according to S-1-A, S-1-B, S-1-C, or S-1-D:

30. The compound of any of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein R30 is selected from the following:

31. The compound of any of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein R30 is selected from the following:

32. The compound of any of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein L1, L2, and R30 together (i.e., L1-L2-R30) are selected from:

33. The compound of any of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein L1, L2, and R30 together are selected from:

34. A compound of Formula III-4, or a pharmaceutically acceptable salt thereof,

35. The compound of claim 34, or a pharmaceutically acceptable salt thereof, wherein Y is N.

36. The compound of any of claims 34-35, or a pharmaceutically acceptable salt thereof, wherein U is CR6.

37. The compound of claim 36, or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen.

38. The compound of any of claims 34-37, or a pharmaceutically acceptable salt thereof, wherein R1 is CN.

39. The compound of any of claims 34-37, or a pharmaceutically acceptable salt thereof, wherein (i) R1 is halogen, e.g., F or Cl; (ii) R1 is

40. The compound of any of claims 34-39, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen.

41. The compound of any of claims 34-40, or a pharmaceutically acceptable salt thereof, wherein Z is CO.

42. The compound of any of claims 34-41, or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen, an optionally substituted C1-4 alkyl, such as CH3, CD3, ethyl, isopropyl, CH2CHF2, etc. or an optionally substituted 3-4 membered ring, such as cyclopropyl or cyclobutyl, etc., preferably, R3 is methyl or CD3.

43. The compound of any of claims 34-42, or a pharmaceutically acceptable salt thereof, wherein n1 is 0 or 1.

44. The compound of any of claims 34-42, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-4-C:

45. The compound of any of claims 34-42, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-4-C-4

46. The compound of any of claims 34-45, or a pharmaceutically acceptable salt thereof, wherein R9 at each occurrence is independently CH3, CH2CH3, CH2CH2CH3, fluorine-substituted C1-3 alkyl (e.g., CF2H), cyclopropyl, cyclobutyl, CH2OH, CH2OCH3, CH2OCH2CH3, CH2NH2, CH2N3, or CH2NHC(O)OCH3, preferably, R9 at each occurrence is independently CH3, CH2CH3, or CH2CH2CH3, more preferably, R9 at each occurrence is CH2CH3.

47. The compound of any of claims 34-46, or a pharmaceutically acceptable salt thereof, wherein L2 is an optionally substituted C1-4 alkylene.

48. The compound of any of claims 34-46, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-4-C-4a, III-4-C-4b, III-4-C-4c, III-4-C-4d, III-4-C-4e, or III-4-C-4f:

49. The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein R13 is hydrogen.

50. The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein R13 is C1-4 alkyl, e.g., methyl, isopropyl, etc.

51. The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein R13 is CN, OH, COOH, CONH2, methoxy, ethoxy, cyclopropyl, cyclobutyl, an optionally substituted phenyl, or an optionally substituted 5 or 6 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S, wherein, when substituted, the optionally substituted phenyl or 5 or 6 membered heteroaryl is substituted with 1-3 substituents independently selected from halogen (preferably F or Cl), OH, CN, C1-4 alkyl optionally substituted with 1-3 F, C1-4 heteroalkyl optionally substituted with 1-3 F, and 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and/or methyl, e.g., R13 is OH, methoxy, cyclopropyl, phenyl,

52. The compound of any of claims 34-51, or a pharmaceutically acceptable salt thereof, wherein R30 is an optionally substituted phenyl, such as a phenyl which is substituted with 1-3 (e.g., 1 or 2) R22, wherein R22 at each occurrence is independently halogen (e.g., F, Cl, or Br), CN, OH, NH2, RM, ORM, COOH, CONH2, COORM, CONH(RM), CON(RM)2, NHCO(RM), N(RM)CO(RM), SO2RM, SO2NH2, S(O)(NH)RM, S(O)(NRM)RM, SO2N(RM)2, NHSO2RM, N(RM)SO2RM, P(O)(RM)2, P(O)(ORM)2, NH(RM), N(RM)2, SRM, or SF5, wherein RM at each occurrence is independently an optionally substituted C1-4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, optionally substituted C3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl having 1-4 ring heteroatoms independently selected from O, S, and N, or optionally substituted 4-7 membered heterocyclyl.

53. The compound of any of claims 34-51, or a pharmaceutically acceptable salt thereof, wherein R30 is a phenyl which is substituted with 1-3 (e.g., 1 or 2) R22, wherein R22 at each occurrence is independently halogen (e.g., F, Cl, or Br), CN, OH, RM1, ORM1, SO2RM1, P(O)(RM1)2, SRM1, or SF5, wherein RM1 at each occurrence is independently an optionally substituted C1-4 alkyl or an optionally substituted 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.), wherein when substituted, the optionally substituted C1-4 alkyl or 3-4 membered ring is substituted with 1-3 substituents independently selected from halogen (preferably F or Cl), OH, CN, C1-4 alkyl optionally substituted with 1-3 F, C1-4 heteroalkyl optionally substituted with 1-3 F, and 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and/or methyl, preferably, R22 at each occurrence is independently F, Cl, Br, CF3, OCF3, SCF3, SF5, OMe, CN, methyl, CHF2, CF2CH3, cyclopropyl, CH3SO2, and OCH2-(cyclopropyl).

54. The compound of any of claims 34-51, or a pharmaceutically acceptable salt thereof, wherein R30 is a phenyl which is substituted with 1-3 (e.g., 1 or 2) R22, wherein R22 at each occurrence is independently F, Cl, CN, RM2, ORM2, SRM2, or SF5, wherein RM2 at each occurrence is independently a C1-4 alkyl optionally substituted with 1-3 F, such as CF3.

55. The compound of any of claims 34-51, or a pharmaceutically acceptable salt thereof, wherein R30 is an optionally substituted 5 or 6-membered heteroaryl, such as a pyridyl

56. The compound of any of claims 34-51, or a pharmaceutically acceptable salt thereof, wherein R30 is a 5-membered heteroaryl

57. The compound of any of claims 34-51, or a pharmaceutically acceptable salt thereof, wherein R30 is a 5-membered heteroaryl

58. The compound of any of claims 34-51, or a pharmaceutically acceptable salt thereof, wherein R30 has a structure according to S-1-A, S-1-B, S-1-C, or S-1-D:

59. The compound of any of claims 34-51, or a pharmaceutically acceptable salt thereof, wherein R30 is selected from the following:

60. The compound of any of claims 34-51, or a pharmaceutically acceptable salt thereof, wherein R30 is selected from the following:

61. The compound of any of claims 34-51, or a pharmaceutically acceptable salt thereof, wherein R30 is selected from the following:

62. A compound of Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, as defined herein, or a pharmaceutically acceptable salt thereof, such as defined in enumerated Embodiments A1-A38 and B1-B45.

63. A compound selected from Compound Nos. 1-347 or any of the compounds disclosed in Table A, or a pharmaceutically acceptable salt thereof.

64. A pharmaceutical composition comprising the compound of any of claims 1-63 or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable excipient.

65. A method for treating a disease comprising administering to a subject in need thereof a therapeutically-effective amount of at least one compound according to any of claims 1 to 63 or a pharmaceutical composition according to claim 64, wherein said disease is cancer or a viral infection.

66. The method according to claim 65, wherein said cancer is selected from colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, cancer of the head and neck, lymphoma, leukemia and melanoma.

67. The method of claim 65 or 66, further comprising administering to the subject an immuno-oncology agent (e.g., described herein, such as an antagonist of a protein that inhibits T cell activation and/or an agonist of a protein that stimulates T cell activation), preferably, the immuno-oncology agent is one or more antibodies selected from anti-PD-1, anti-PD-L1, anti-CTLA-4, and combinations thereof.

68. A method of inhibiting activity of at least one of diacylglycerol kinase selected from diacylglycerol kinase alpha (DGKa) and diacylglycerol kinase zeta (DGKz) comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound according to any of claims 1 to 63 or a pharmaceutical composition according to claim 64.