Compound as well as preparation method and application thereof

Abstract

Provided herein are novel compounds, for example, compounds of Formula I, or pharmaceutically acceptable salts thereof. Also provided herein are methods of making the compounds and methods of using the compounds, for example, to inhibit PI3K in a cell and / or to treat various diseases, such as cancer.

Description

[0001] Cross Reference to Related Applications

[0002] This application claims priority to International Application No. PCT / CN2023 / 080246 filed March 8, 2023; International Application No. PCT / CN2023 / 098920 filed June 7, 2023; International Application No. PCT / CN2023 / 108770 filed July 22, 2023; and International Application No. PCT / CN2023 / 140932 filed December 22, 2023, the contents of each of which are incorporated herein by reference in their entirety. TECHNICAL FIELD

[0003] In various embodiments, the present disclosure relates generally to novel compounds, compositions comprising the compounds, methods of making the compounds, and methods of using the compounds, e.g., for inhibiting PI3K and / or for treating various diseases or conditions, such as cancer. BACKGROUND

[0004] Phosphoinositide 3-kinases (PI3Ks) are members of intracellular lipid kinases that phosphorylate the 3'-OH group on phosphatidylinositol or phosphoinositides. The PI3K family comprises a dozen kinases with distinct substrate specificities, expression patterns, and modes of regulation. PI3K-a (PI3Ka) is a heterodimeric protein complex composed of a catalytic subunit pl 10a (encoded by the PIK3CA gene) and a regulatory subunit p85a (encoded by the PIK3R1 gene) (Vasan N. et al., Annals of Oncology, 30(10):x3-x11 (2019)). pl 10a binds to p85a and catalyzes the phosphorylation of the lipid phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol-3,4,5-trisphosphate (PIP3).

[0005] The PI3K signaling pathway has been associated with a variety of diseases, particularly cancer. Genetic alterations in genes in PI3K signaling are believed to be involved in a range of diseases, including in cancers such as breast, endometrial, gastric, colorectal, ovarian, cervical, head and neck, liver, lung, and prostate cancers. A number of cancer-associated PIK3CA mutations have been identified. These mutations can lead to activation of the PI3K pathway, resulting in increased cell growth and tumorigenesis. SUMMARY

[0006] The present disclosure is based, in part, on the Applicants’ discovery of compounds that can act as inhibitors of PI3K, particularly inhibitors of PI3K-a (“PI3Ka”). In various embodiments, the present disclosure provides novel compounds, pharmaceutical compositions, methods of making and using them. The compounds and compositions herein can be useful in the treatment of various diseases or disorders, such as the cancers described herein.

[0007] In various embodiments, the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof:

[0008]

[0009] wherein the variables are defined herein. In some embodiments, the compound of Formula I can have a subformula of Formula I-1, I-1-A, I-1-B, I-1-C, I-1-D, I-2, I-2-A, I-2-B, I-2-C, I-2-D, I-3, I-3-A, I-3-B, I-3-C, I-4, I-4-A, I-4-B, or I-4-C, as defined herein. In some embodiments, the compound of Formula I can have a subformula according to Formula X-1, X-1a, X-1b, X-1c, X-2, X-3, X-3a, X-3b, X-4a, X-4a-1, X-4a-2, X-4b, X-4b-1, X-4b-2, X-4c, X-4c-1, or X-4c-2, as defined herein. In some embodiments, the compound of Formula I can be any one of the compounds as defined in enumerated embodiments 1-88. In some embodiments, the compound of Formula I can be any one of the compounds as defined in claims 1-65 herein. In some embodiments, the present disclosure provides a compound selected from those as shown in Table A, or a pharmaceutically acceptable salt thereof.

[0010] Certain embodiments of the present disclosure relate to pharmaceutical compositions comprising one or more of the compounds of the present disclosure (e.g., a compound of Formula I (e.g., Formula I-1, I-1-A, I-1-B, I-1-C, I-1-D, I-2, I-2-A, I-2-B, I-2-C, I-2-D, I-3, I-3-A, I-3-B, I-3-C, I-4, I-4-A, I-4-B, or I-4-C, or Formula X-1, X-1a, X-1b, X-1c, X-2, X-3, X-3a, X-3b, X-4a, X-4a-1, X-4a-2, X-4b, X-4b-1, X-4b-2, X-4c, X-4c-1, or X-4c-2), any of the compounds selected from the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof) and optionally a pharmaceutically acceptable excipient. The pharmaceutical compositions described herein can be formulated for various routes of administration, such as oral administration, parenteral administration, or inhalation, etc.

[0011] Certain embodiments relate to methods of treating a disease or disorder associated with the activity of PI3K. In some embodiments, the methods comprise administering to a subject in need thereof a therapeutically effective amount of a compound of the disclosure (e.g., a compound of Formula I (e.g., Formula I-1, I-1-A, I-1-B, I-1-C, I-1-D, I-2, I-2-A, I-2-B, I-2-C, I-2-D, I-3, I-3-A, I-3-B, I-3-C, I-4, I-4-A, I-4-B, or I-4-C, or Formula X-1, X-la, X-lb, X-lc, X-2, X-3, X-3a, X-3b, X-4a, X-4a-l, X-4a-2, X-4b, X-4b-l, X-4b-2, X-4c, X-4c-l, or X-4c-2), 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 PI3K suitable for treatment with this method include any cancer described herein. In some embodiments, diseases or disorders associated with PI3K suitable for treatment with this method include CLOVES syndrome (congenital lipomatous overgrowth, vascular malformation, epidermal nevus, scoliosis / skeletal and spinal syndrome) or PIK3CA-related overgrowth syndrome (PROS).

[0012] In some embodiments, a method of treating a 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 disclosure (e.g., a compound of Formula I (e.g., Formula I-1, I-1-A, I-1-B, I-1-C, I-1-D, I-2, I-2-A, I-2-B, I-2-C, I-2-D, I-3, I-3-A, I-3-B, I-3-C, I-4, I-4-A, I-4-B, or I-4-C, or Formula X-1, X-la, X-lb, X-lc, X-2, X-3, X-3a, X-3b, X-4a, X-4a-l, X-4a-2, X-4b, X-4b-l, X-4b-2, X-4c, X-4c-l, or X-4c-2), 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 endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer.

[0013] Administration in the methods herein is not limited to any particular route of administration. For example, in some embodiments, the administration can be oral, nasal, transdermal, pulmonary, inhalation, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal, or parenteral.

[0014] The compounds of the present disclosure can be used as monotherapy or in combination therapy. In some embodiments, the combination therapy comprises treating a subject with a targeted therapeutic agent, a chemotherapeutic agent, a therapeutic antibody, radiation, cell therapy, and / or immunotherapy.

[0015] It is to be understood that the foregoing summary of the invention and the following detailed description are merely exemplary and illustrative of the application herein and are not limiting thereof. BRIEF DESCRIPTION OF DRAWINGS

[0016] Figure 1 Exemplary compound 114 tested for inhibition of tumor growth in human lung cancer tumor xenograft model NCI-H1048 is shown. DETAILED DESCRIPTION

[0017] In a broad aspect, the present disclosure provides compounds and compositions useful for inhibiting PI3K, such as PI3Ka, and / or treating or preventing various diseases or disorders described herein (e.g., cancer).

[0018] Compounds

[0019] In some embodiments, the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof:

[0020]

[0021] wherein:

[0022] X is -C(=Z)-, -S(O)-, -S(O)(=NH)-, or -S(O)2-, wherein Z is O, CHR 5 or NR 5 ;

[0023] Y is N or CR 6 ;

[0024] R 1 is optionally substituted C 1-6 alkyl, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 2-6 alkenyl, or optionally substituted C 2-6 alkynyl;

[0025] R 2The substituted 5-14 membered heterocyclic group or the substituted 5-14 membered heteroaryl group is selected;

[0026] R 3 and R 4 Together with the C and C atoms in between, they connect to form optional substituted C atoms. 5-10 Carbocyclic base ring, optionally substituted 5-10 membered heterocyclic base ring, optionally substituted C 6-10 Aryl ring or optionally substituted 5-10 membered heteroaryl ring;

[0027] R 5 H, OH, or optionally substituted C 1-4 Alkyl groups, optionally substituted C 1-4 Halogenated alkyl groups, optionally substituted C 1-4 Heteroalkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 2-6 alkenyl or optionally substituted C 2-6 alkynyl group; or

[0028] R 3 R 4 and R 5 Together with the C, C, C and (N or CH) atoms, they connect to form optionally substituted C atoms. 10-14 Carbocyclic ring, optionally substituted C 10-14 aryl ring, optionally substituted 10-14 membered heterocyclic ring, or optionally substituted 10-14 membered heteroaryl ring; and

[0029] R 6 H, halogen, OH, NH2, CN, or optionally substituted C 1-4 Alkyl groups, optionally substituted C 1-4 Halogenated alkyl groups, optionally substituted C 1-4 Heteroalkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 2-6 alkenyl or optionally substituted C 2-6 Alkyne group.

[0030] It will be apparent to those skilled in the art that, in certain circumstances, compounds of Formula I can exist as mixtures of tautomers. This disclosure is not limited to any particular tautomer. Rather, this disclosure covers any and all such tautomers, whether or not explicitly drawn or mentioned.

[0031] In some embodiments, compounds of Formula I (including any of the applicable subformulae as described herein) can exist as isotopically-labeled compounds (in particular, deuterated analogs), wherein one or more hydrogen atoms of the compound of Formula I are substituted with deuterium atoms having an abundance greater than the natural abundance of deuterium, such as CD3 analogs when the compound has a CH3 group. Without wishing to be bound by theory, it is believed that in some cases, deuterated analogs can have a better or more desirable pharmacokinetic profile when compared to their non-deuterated counterparts.

[0032] In some embodiments, compounds of Formula I can be characterized as having Formula I-1, I-2, I-3, or I-4:

[0033]

[0034] wherein X a is N or CR a , X b is N or CR b , and X c is N or CR c ,

[0035] wherein R a , R b , R c , and R e are each independently hydrogen, halogen, OH, NH2, CN, -C(O)-NH2, G, -(C 1-4 alkylene)-G, O-G, NH-G, O-(C 1-4 alkylene)-G, NH-(C 1-4 alkylene)-G, -C(O)-NH-G, -C(O)-NGG, SG, S(O)-G, or S(O)2-G, wherein G is independently at each occurrence optionally substituted C 1-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-10 carbocyclyl ring, optionally substituted 4-10 membered heterocyclyl ring, optionally substituted C 6-10 aryl, or optionally substituted 5-10 membered heteroaryl; preferably, R a , R b , R c , and R e are each independently hydrogen, halogen, OH, NH2, CN, -C(O)-NH2, -C(O)-NH(C 1-4 alkyl), -C(O)-N(C 1-4 alkyl)2, optionally substituted C 1-6alkyl, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-10 carbocyclyl ring, optionally substituted 4-10 membered heterocyclyl ring, optionally substituted C 6-10 aryl or optionally substituted 5-10 membered heteroaryl; or

[0036] R a and R b , or R b and R c , together with the C and C atoms therebetween, join to form an optionally substituted C 5-10 carbocyclyl ring, optionally substituted 5-10 membered heterocyclyl ring, optionally substituted C 6-10 aryl ring or optionally substituted 5-10 membered heteroaryl ring;

[0037] R d is H, halogen, OR 7 , or NR 7 R 8 , wherein R 7 and R 8 are each independently H, optionally substituted C 1-4 alkyl or optionally substituted C 1-4 haloalkyl;

[0038] R f is hydrogen, halogen (e.g., F or CI), G A , -(C 1-4 alkylene)-G A , OH, CN, OG A , O-(C 1-4 alkylene)-G A , SG A , S(O)-G A , or S(O)2-G A , wherein G A is optionally substituted C 1-6 alkyl, optionally substituted C 1-4 heteroalkyl, optionally substituted C 3-6 cycloalkyl or optionally substituted 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O, and S. In some preferred embodiments, G A is C 1-4 alkyl (e.g., methyl) and OH. In some preferred embodiments, G 3-6cycloalkyl. In some preferred embodiments, G A is unsubstituted or substituted with one or more (e.g., 1, 2, 3, or 4) substituents independently selected from F, oxo, C 1-4 alkyl (e.g., methyl), and OH.

[0039] In some embodiments, the compound of Formula I can be characterized as having Formula I-1, I-2, I-3, or I-4:

[0040]

[0041] wherein X a is N or CR a , X b is N or CR b , and X c is N or CR c ,

[0042] wherein R a , R b , R c , and R e are each independently hydrogen, F, Cl, CN, OH, NH2, CH3, CH2CH3, CHF2, CF3, OCH3, OCH2CH3, OCH(CH3)2, OCHF2, OCF3, SCF3, or cyclopropyl; preferably, H, F, Cl, CH3, CH2CH3, CF3, or OCF3; or

[0043] R a and R b , or R b and R c , together with the C and C atoms therebetween, join to form an optionally substituted C 5-10 carbocyclyl ring, an optionally substituted 5-10 membered heterocyclyl ring, an optionally substituted C 6-10 aryl ring, or an optionally substituted 5-10 membered heteroaryl ring;

[0044] R d is H, halogen, OR 7 , or NR 7 R 8 , wherein R 7 and R 8 are each independently H, optionally substituted C 1-4 alkyl, or optionally substituted C 1-4 haloalkyl;

[0045] R f is hydrogen, halogen (e.g., F or Cl), GA , -(C 1-4 alkylene)-G A , OH, CN, OG A , O-(C 1-4 alkylene)-G A , SG A , S(O)-G A , or S(O)2-G A , wherein G A is optionally substituted C 1-6 alkyl, optionally substituted C 1-4 heteroalkyl, optionally substituted C 3-6 cycloalkyl, or optionally substituted 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O, and S. In some preferred embodiments, G A is unsubstituted or substituted with one or more (e.g., 1, 2, 3, or 4) substituents independently selected from F, oxo, C 1-4 alkyl (e.g., methyl), and OH. In some preferred embodiments, G 3-6 is unsubstituted C A cycloalkyl or 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O, and S, which is unsubstituted or substituted with one or more (e.g., 1, 2, 3, or 4) substituents independently selected from F, oxo, C 1-4 alkyl (e.g., methyl), and OH. In some preferred embodiments, G

[0046] In some embodiments, the compound of Formula I can be characterized as having Formula I-1-A, I-1-B, I-1-C, or I-1-D:

[0047]

[0048] wherein Y, R 1 , R 2 , R a , R b , R c , and R d are defined herein.

[0049] In some embodiments, the compound of Formula I can be characterized as having Formula I-2-A, I-2-B, I-2-C, or I-2-D:

[0050]

[0051] wherein Y, R 1 , R 2 , R a , R b , R c , and Rd are defined herein.

[0052] In some embodiments, the compound of Formula I can be characterized as having Formula I-3-A, I-3-B, or I-3-C:

[0053]

[0054]

[0055] wherein Y, R 1 , R 2 , R b , R c , R d , R e , and R f are defined herein.

[0056] In some embodiments, the compound of Formula I can be characterized as having Formula I-4-A, I-4-B, or I-4-C:

[0057]

[0058] wherein Y, R 1 , R 2 , R b , R c , R d , R e , and R f are defined herein.

[0059] In some embodiments, X is -C(O)-, -C(=NR 5 )-, -C(=CHR 5 )-, -S(O)-, -S(O)(=NH)-, or -S(O)2-. In some preferred embodiments, X in Formula I is -C(O)-. In some preferred embodiments, X in Formula I is -S(O)2-. In some preferred embodiments, X in Formula I is -S(O)-. In some preferred embodiments, X in Formula I is -S(O)(=NH)-. In some preferred embodiments, X in Formula I is -C(=NR 5 )-. In some preferred embodiments, X in Formula I is -C(=CHR 5 )-. In some more preferred embodiments, X in Formula I is -C(=NR 5 )-, wherein R 3 , R 4 , and R 5, C, C, and the N atom together with the intervening C, C, C, and C atoms join to form an optionally substituted 10-14 membered heterocyclyl ring or an optionally substituted 10-14 membered heteroaryl ring. In some more preferred embodiments, X in Formula I is -C(=CHR 5 ), wherein R 3 , R 4 , and R 5 together with the intervening C, C, C, and C atoms join to form an optionally substituted C 10-14 carbocyclyl ring or an optionally substituted C 10-14 aryl ring.

[0060] Generally, Y is N in Formula I or any of its subformulae. In some embodiments, Y is N, or Y is CH. In some embodiments, Y is CR 6 , wherein R 6 is H, halogen (e.g., F, Cl), OH, NH2, CN, C 1-4 alkyl (e.g., methyl, ethyl, n-propyl, i-propyl), C 1-4 haloalkyl (e.g., C 1-4 alkyl substituted with F (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, etc.)), C 1-4 heteroalkyl (e.g., C 1-4 alkyl substituted with OH (e.g., hydroxymethyl, hydroxyethyl, etc.)), or C 1-4 alkoxy (e.g., methoxy, ethoxy, i-propoxy, etc.)), C 3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl), C 2-6 alkenyl (e.g., ethenyl, propenyl, butenyl), or C 2-6 alkynyl (e.g., ethynyl, propynyl). In some preferred embodiments, Y is CR 6 , wherein R 6 is F or Cl.

[0061] In some embodiments, R 1 is optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 2-6 alkenyl, or optionally substituted C 2-6 alkynyl. In some embodiments, R 1 is unsubstituted or substituted with one or more substituents independently selected from F, Cl, OH, CN, methyl, or methoxy. In some embodiments, R 1 is C 1-4 alkyl (e.g., methyl, ethyl, n-propyl, i-propyl), C 1-4 haloalkyl (e.g., C 1-4alkyl (e.g., methyl, ethyl, n-propyl, i-propyl), hydroxy-substituted C 1-4 heteroalkyl (e.g., hydroxy-substituted C 1-4 alkyl (e.g., hydroxymethyl, hydroxyethyl, etc.), or C 1-4 alkoxy (e.g., methoxy, ethoxy, propoxy, etc.), C 3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl), C 2-6 alkenyl (e.g., ethenyl, propenyl, butenyl), or C 2-6 alkynyl (e.g., ethynyl, propynyl). In some embodiments, R 1 is a fluorine-substituted C 1-2 alkyl. In some embodiments, R 1 is selected from CF3, ethynyl, i-propyl, cyclopropyl, 1-methylcyclopropyl, or t-butyl. In some embodiments, R 1 is CF3. In some embodiments, R 1 is i-propyl.

[0062] In some embodiments, R 2 is an optionally substituted 5-14 membered heteroaryl, preferably an optionally substituted 9-membered bicyclic heteroaryl containing one or two ring oxygen and / or nitrogen atoms. In some preferred embodiments, R 2 is selected from:

[0063] wherein R A , R B , R C , R D , and R E are each independently hydrogen, F, Cl, CN, C 1-4 alkyl (e.g., methyl, ethyl, n-propyl, i-propyl), hydroxy-substituted C 1-4 alkyl (e.g., hydroxymethyl, hydroxyethyl, etc.), fluorine-substituted C 1-4 alkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, etc.), OH, cyclopropyl, cyclobutyl, azetidinyl, C 1-4 alkoxy (e.g., methoxy, ethoxy, i-propoxy, etc.), fluorine-substituted C 1-4 alkoxy (e.g., CF3O-, CF3CH2O-, etc.), C 1-4 alkylthio (e.g., CH3S-), fluorine-substituted C 1-4 alkylthio (e.g., CF3S-), cyclopropoxy, or cyclobutoxy; preferably, H, F, Cl, OH, CN, methyl, ethyl, or cyclopropyl. In some preferred embodiments, R 2 is selected from:

[0064] wherein RA is hydrogen, C 1-4 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl), hydroxy-substituted C 1-4 alkyl (e.g., hydroxymethyl, hydroxyethyl, etc.), fluoro-substituted C 1-4 alkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyclopropyl, cyclobutyl, or azetidinyl; preferably, H, methyl, ethyl, or cyclopropyl;

[0065] R B , R C , R D , and R E are each independently hydrogen, F, Cl, CN, C 1-4 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl), hydroxy-substituted C 1-4 alkyl (e.g., hydroxymethyl, hydroxyethyl, etc.), fluoro-substituted C 1-4 alkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, etc.), OH, cyclopropyl, cyclobutyl, azetidinyl, C 1-4 alkoxy (e.g., methoxy, ethoxy, isopropoxy, etc.), fluoro-substituted C 1-4 alkoxy (e.g., CF3O-, CF3CH2O-, etc.), C 1-4 alkylthio (e.g., CH3S-), fluoro-substituted C 1-4 alkylthio (e.g., CF3S-), cyclopropoxy, or cyclobutoxy; preferably, H, F, Cl, OH, CN, methyl, ethyl, or cyclopropyl.

[0066] In some preferred embodiments where R 2 is an optionally substituted 9-membered bicyclic heteroaryl as depicted herein, when applicable, R A is methyl, or R A is ethyl. In some preferred embodiments where R 2 is an optionally substituted 9-membered bicyclic heteroaryl as depicted herein, when applicable, R B is H. In some preferred embodiments where R 2 is an optionally substituted 9-membered bicyclic heteroaryl as depicted herein, when applicable, R C is F, or R C is Cl. In some preferred embodiments where R 2 is an optionally substituted 9-membered bicyclic heteroaryl as depicted herein, when applicable, R D is H. In some preferred embodiments where R 2 is an optionally substituted 9-membered bicyclic heteroaryl as depicted herein, when applicable, R EH, F, Cl, CN, methyl or cyclopropyl.

[0067] In some embodiments, R 2 is an optionally substituted 5-14 membered heterocyclyl, preferably an optionally substituted 9-membered bicyclic heterocyclyl containing one or two ring oxygen and / or nitrogen atoms. In some preferred embodiments, R 2 is selected from: wherein R A , R B , R B’ , R C , R C’ , R D , R D’ , R E and R E’ are each independently hydrogen, F, Cl, CN, C 1-4 alkyl (e.g., methyl, ethyl, n-propyl, i-propyl), hydroxy-substituted C 1-4 alkyl (e.g., hydroxymethyl, hydroxyethyl, etc.), fluoro-substituted C 1-4 alkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, etc.), OH, cyclopropyl, cyclobutyl, azetidinyl, C 1-4 alkoxy (e.g., methoxy, ethoxy, i-propoxy, etc.), fluoro-substituted C 1-4 alkoxy (e.g., CF3O-, CF3CH2O-, etc.), C 1-4 alkylthio (e.g., CH3S-), fluoro-substituted C 1-4 alkylthio (e.g., CF3S-), cyclopropoxy or cyclobutoxy; preferably, H, F, Cl, OH, CN, methyl, ethyl or cyclopropyl; or

[0068] R B and R B’ , R C and R C’ , R D and R D’ , or R E and R E’ , together with the C atoms therebetween, join to form a C 3-6 carbocyclic ring (e.g., a C3, C4, C5 or C6 carbocyclic ring which is unsubstituted or substituted with one or more substituents independently selected from F, Cl, OH, CN, methyl or methoxy). In some preferred embodiments, R 2 is selected from: wherein R A , R B , R B’ , R C , R C’ , R E and R E’each independently hydrogen, F, Cl, CN, C 1-4 alkyl (e.g., methyl, ethyl, n-propyl, i-propyl), hydroxy-substituted C 1-4 alkyl (e.g., hydroxymethyl, hydroxyethyl, etc.), fluorine-substituted C 1-4 alkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, etc.), OH, cyclopropyl, cyclobutyl, azetidinyl, C 1-4 alkoxy (e.g., methoxy, ethoxy, i-propoxy, etc.), fluorine-substituted C 1-4 alkoxy (e.g., CF3O-, CF3CH2O-, etc.), C 1-4 alkylthio (e.g., CH3S-), fluorine-substituted C 1-4 alkylthio (e.g., CF3S-), cyclopropoxy, or cyclobutoxy; preferably, H, F, Cl, OH, CN, methyl, ethyl, or cyclopropyl; or

[0069] R B and R B’ , R C and R C’ , or R E and R E’ , together with the C atoms therebetween, join to form a C 3-6 carbocyclyl ring (e.g., a C3, C4, C5, or C6carbocyclyl ring that is unsubstituted or substituted with one or more substituents independently selected from F, Cl, OH, CN, methyl, or methoxy). In some preferred embodiments, R 2 is selected from: wherein R A , R B , R B’ , R C , R C’ , R E and R E’ each independently hydrogen, F, Cl, CN, C 1-4 alkyl (e.g., methyl, ethyl, n-propyl, i-propyl), hydroxy-substituted C 1-4 alkyl (e.g., hydroxymethyl, hydroxyethyl, etc.), fluorine-substituted C 1-4 alkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, etc.), OH, cyclopropyl, cyclobutyl, azetidinyl, C 1-4 alkoxy (e.g., methoxy, ethoxy, i-propoxy, etc.), fluorine-substituted C 1-4 alkoxy (e.g., CF3O-, CF3CH2O-, etc.), C 1-4 alkylthio (e.g., CH3S-), fluorine-substituted C 1-4 alkylthio (e.g., CF3S-), cyclopropoxy, or cyclobutoxy; preferably, H, F, Cl, CN, methyl, or cyclopropyl; or

[0070] R B and R B’ , R C and R C’ , or R E and R E’ , together with the C atoms between them, join to form a C 3-6 carbocyclyl ring (such as a C3, C4, C5, or C6 carbocyclyl ring that is unsubstituted or substituted with one or more substituents independently selected from F, Cl, OH, CN, methyl, or methoxy); R D is hydrogen, C 1-4 alkyl (e.g., methyl, ethyl, n-propyl, i-propyl), hydroxy-substituted C 1-4 alkyl (e.g., hydroxymethyl, hydroxyethyl, and the like), fluoro-substituted C 1-4 alkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, and the like), cyclopropyl, cyclobutyl, or azetidinyl; preferably, H, methyl, ethyl, or cyclopropyl. In some preferred embodiments, R 2 is selected from:

[0071] wherein R A , R B , R B’ , R D , R D’ , R E , and R E’ are each independently hydrogen, F, Cl, CN, C 1-4 alkyl (e.g., methyl, ethyl, n-propyl, i-propyl), hydroxy-substituted C 1-4 alkyl (e.g., hydroxymethyl, hydroxyethyl, and the like), fluoro-substituted C 1-4 alkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, and the like), OH, cyclopropyl, cyclobutyl, azetidinyl, C 1-4 alkoxy (e.g., methoxy, ethoxy, i-propoxy, and the like), fluoro-substituted C 1-4 alkoxy (e.g., CF3O-, CF3CH2O-, and the like), C 1-4 alkylthio (e.g., CH3S-), fluoro-substituted C 1-4 alkylthio (e.g., CF3S-), cyclopropoxy, or cyclobutoxy; preferably, H, F, Cl, CN, methyl, or cyclopropyl; or

[0072] R B and R B’ , R D and R D’ , or R E and R E’ , together with the C atoms between them, join to form a C 3-6carbocyclyl ring (such as a C3, C4, C5, or C6carbocyclyl ring that is unsubstituted or substituted with one or more substituents independently selected from F, Cl, OH, CN, methyl, or methoxy); R C is hydrogen, C 1-4 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl), hydroxy-substituted C 1-4 alkyl (e.g., hydroxymethyl, hydroxyethyl, and the like), fluoro-substituted C 1-4 alkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, and the like), cyclopropyl, cyclobutyl, or azetidinyl; preferably, H, methyl, ethyl, or cyclopropyl.

[0073] In some preferred embodiments where R 2 is an optionally substituted 9-membered bicyclic heterocyclyl group as depicted herein, when applicable, R A is methyl, or R A is ethyl. In some preferred embodiments where R 2 is an optionally substituted 9-membered bicyclic heterocyclyl group as depicted herein, when applicable, R B is H or methyl and R B’ is H. In some preferred embodiments where R 2 is an optionally substituted 9-membered bicyclic heterocyclyl group as depicted herein, when applicable, R C is H or methyl and R C’ is H, or R C and R C’ are both methyl, or R C and R C’ together with the C atoms therebetween join to form a C3carbocyclyl ring. In some preferred embodiments where R 2 is an optionally substituted 9-membered bicyclic heterocyclyl group as depicted herein, when applicable, R D and R D’ are both H. In some preferred embodiments where R 2 is an optionally substituted 9-membered bicyclic heterocyclyl group as depicted herein, when applicable, R E and R E’ are both H, or R E is methyl and R E’ is OH.

[0074] In some embodiments, R 2 is wherein R A is C 1-3 alkyl (such as methyl), R C is halogen (such as F or Cl) or C 1-3 alkyl (such as methyl), and R EH, halogen (e.g., F, CI, or Br), CN, C 1-4 alkyl (e.g., methyl), C 2-4 alkenyl, C 2-4 alkynyl, or C 3-4 cycloalkyl (e.g., cyclopropyl). In some embodiments, R 2 is wherein R A is C 1-3 alkyl, R C is halogen, and R E is selected from H, halogen, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 3-4 cycloalkyl. In some embodiments, R 2 is wherein R E is H, F, CI, Br, CN, methyl, or cyclopropyl.

[0075] In some preferred embodiments, R 2 is selected from:

[0076] In some preferred embodiments, R 2 is In some preferred embodiments, R 2 is In some preferred embodiments, R 2 is In some preferred embodiments, R 2 is In some preferred embodiments, R 2 is

[0077] In some preferred embodiments, R 2 is selected from:

[0078]

[0079] In some preferred embodiments, R 2 is selected from:

[0080]

[0081] In some embodiments, the carbon connecting R 1 and R 2 in the compound is a chiral carbon and has the following chirality: For the chiral carbon, the compound has an enantiomeric excess ("ee") of greater than 50% (e.g., 60% ee or greater, 80% ee or greater, 90% ee or greater, 95% ee or greater, 98% ee or greater, 99% ee or greater). In some preferred embodiments, the carbon to which R 1 and R 2 are attached has the following chirality: In some preferred embodiments, the carbon to which R 1 and R 2 are attached has the following chirality:

[0082] In some embodiments, in Formula I-1 (e.g., Formula I-1-A, I-1-C, or I-1-D) or I-2 (e.g., Formula I-2-A, I-2-C, or I-2-D), X a is CR a and R a is hydrogen, halogen, OH, NH2, CN, -C(O)-NH2, -C(O)-NH(C 1-4 alkyl), -C(O)-N(C 1-4 alkyl)2, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-10 carbocyclyl ring, optionally substituted 4-10 membered heterocyclyl ring, optionally substituted C 6-10 aryl, or optionally substituted 5-10 membered heteroaryl. In some preferred embodiments, X a is CR a and R a is H.

[0083] In some preferred embodiments, in Formula I-1 (e.g., Formula I-1-A, I-1-C, or I-1-D) or I-2 (e.g., Formula I-2-A, I-2-C, or I-2-D), X a is CR a and R a is H, halogen, CN, R ax , -COR ax , -NHCOR ax , -CONH2, -CONHR ax , -CON(R ax )2, -OR ax , -NHR ax , -N(R ax)2, -SR ax , -SO2R ax , or -NHSO2R ax , wherein R ax is independently at each occurrence C 1-6 alkyl, a 3-10 membered ring, or (C 1-4 alkylene)-(3-10 membered ring), wherein the 3-10 membered ring is selected from C 3-10 carbocyclyl ring, 4-10 membered heterocyclyl ring, C 6-10 aryl, and 5-10 membered heteroaryl, and wherein the C 1-6 alkyl, C 1-4 alkylene, or 3-10 membered ring is optionally substituted, for example, the C 1-6 alkyl, C 1-4 alkylene, or 3-10 membered ring can be unsubstituted or substituted with one or more substituents independently selected from M A , M B , OM B , NHM B , N(C 1-4 alkyl)M B , CO-M B , -S-M B , -S(O)2-M B , CO2-M B , CO-NHM B , CO-N(C 1-4 alkyl)M B , NH-CO-M B , -N(C 1-4 alkyl)-CO-M B , -S(O)2-NHM B , -S(O)2-N(C 1-4 alkyl)M B , NH-S(O)2-M B , -N(C 1-4 alkyl)-S(O)2-M B , C 1-6 heteroalkyl, or -(C 1-6 heteroalkylene)-M B , wherein M A is independently at each occurrence halogen, OH, NH2, CN, oxo (as appropriate), COOH, or -C(O)-NH2, and M B is independently at each occurrence C 1-6 alkyl or a 3-6 membered ring selected from C 3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, or 5 or 6-membered heteroaryl, wherein the C 1-6The alkyl group or 3-6 membered ring may optionally be substituted by one or more substituents independently selected from the following: M A C can be substituted by F, OH, NH2, NHCH3 or N(CH3)2. 1-4 Alkyl groups and C groups optionally substituted with F, OH, NH2, NHCH3 or N(CH3)2 1-4 Alkoxy groups, provided the valence allows. In some implementations, C 1-6 Heteroalkyl groups can be -OC 1-4 Alkylene -OH, -OC 2-4 Alkylene-OC 1-4 Alkyl, -OC 2-4 Alkylene -NH2, -OC 2-4 Alkylene-N(C) 1-4 Alkyl)2, -OC 2-4 Alkylene-NH-C 1-4 Alkyl, -NH-C 2-4 Alkyl-NH2, -NH-C 2-4 Alkylene-N(C) 1-4 alkyl)2 or -NH-C 2-4 Alkylene-NH-C 1-4 Alkyl groups, provided that the total number of carbons is between 1 and 6, and C 1-6 Heteroalkyl groups can be the C13 groups described. 1-6 A divalent group of a heteroalkyl group. In some preferred embodiments, X a For CR a And R a For F, Cl, CN, -C(O)-NH2, -C(O)-NH(C 1-4 Alkyl), -C(O)-N(C) 1-4 Alkyl)2, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C(C) 1-2 alkyl)2OH, -NH-S(O)2-C 1-4 Alkyl or -OC 2-3 Alkylene-N(CH3)2. In some preferred embodiments, X a For CR a And R a It can be F, Cl, CN, CH3, -O-CH3, -S-CH3, -S(O)2-CH3 or -NH-S(O)2-CH3, or R aCF3, -C(O)-NH2, or -O-(CH2)2-N(CH3)2. In some preferred embodiments, X a is CR a and R a is C 3-6 carbon ring, 4-8 membered heterocyclyl ring, phenyl, or 5-6 membered heteroaryl, wherein said carbon ring, heterocyclyl ring, phenyl, or heteroaryl is unsubstituted or substituted with one or more substituents independently selected from halo, OH, NH2, CN, oxo, -C(O)-NH2, -C(O)-NH(C 1-4 alkyl), -C(O)-N(C 1-4 alkyl)2, C 1-6 alkyl, C 1-6 haloalkyl, -O-C 1-4 alkyl, -S-C 1-4 alkyl, -S(O)2-C 1-4 alkyl, -NH-S(O)2-C 1-4 alkyl, or -O-C 2-3 alkylene-N(C 1-4 alkyl)2. Preferably, said carbon ring, heterocyclyl ring, phenyl, or heteroaryl is unsubstituted or substituted with one or two substituents independently selected from oxo, NH2, CN, CH3, -C(O)-NH2, -C(O)-NH(CH3), -S(O)2-CH3, or -O-CH3. In some preferred embodiments, X a is CR a and R a is 4-, 5-, or 6-membered heterocyclyl containing one or two ring heteroatoms independently selected from N, O, and S and unsubstituted or substituted with one or more substituents independently selected from oxo, CN, OH, NH2, C 1-4 alkyl, fluoro-substituted C 1-4 alkyl, -O-C 1-4 alkyl, -S(O)2-C 1-4 alkyl, and 6-membered heterocyclyl containing one oxygen ring atom. In some preferred embodiments, X a is CR a and R a is 4-, 5-, or 6-membered heterocyclyl containing one or two ring heteroatoms independently selected from N, O, and S and unsubstituted or substituted with one or more substituents independently selected from oxo, CN, OH, NH2, C 1-4 alkyl, fluoro-substituted C 1-4 alkyl, and -O-C 1-4 alkyl. In some preferred embodiments, X a is CR a and Ra is a 4-10 membered bicyclic ring, preferably a carbocyclic or heterocyclyl ring, such as a spiro, bridged or fused bicyclic carbocyclic or heterocyclyl ring, wherein the 4-10 membered bicyclic ring optionally contains one or two ring heteroatoms independently selected from N, O and S and is unsubstituted or substituted with one or more substituents independently selected from CN, OH, NH2, C 1-4 alkyl, -O-C 1-4 alkyl, -C(O)-O(C 1-4 alkyl) and -C(O)-NH(C 1-4 alkyl). In some preferred embodiments, X a is CR a and R a is unsubstituted or substituted with one or more substituents independently selected from halogen, CN, OH, NH2, -C(O)-NH2, C 1-4 alkyl, fluorine substituted C 1-4 alkyl, -O-C 1-4 alkyl and -S(O)2-C 1-4 alkyl. In some preferred embodiments, X a is CR a and R a is C 1-4 alkyl, fluorine substituted C 1-4 alkyl, -O-C 1-4 alkyl, -NH-C 1-4 alkyl, and -O-C 2-4 alkylene-N(C 1-2 alkyl)2. In some preferred embodiments, X a is CR a and R a is H, halogen, CN or -C(O)-NH2. In some preferred embodiments, X a is CR a and R a is selected from:

[0084]

[0085] In some preferred embodiments, X a is CR a and R a is selected from:

[0086]

[0087] In some preferred embodiments, X a is CR a and R a is selected from:

[0088]

[0089] In some preferred embodiments, X a is CR a and R a is selected from:

[0090]

[0091] In some preferred embodiments, X a is CR a and R a is selected from:

[0092] In some embodiments, X a is CR a and R a is -0-(C 4-5 cycloalkyl), -0-C 1-2 alkylene-(C 4-5 cycloalkyl), -0-(4-5 membered heterocyclyl), or -0-C 1-2 alkylene-(4-5 membered heterocyclyl), wherein the C 4-5 cycloalkyl (such as cyclobutyl or cyclopentyl) and 4-5 membered heterocyclyl (such as those containing one ring nitrogen atom, e.g., azetidinyl) is optionally substituted with one or more substituents each independently selected from halogen (such as F), CN, OH, NH2, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or C 3-4 cycloalkyl. In some preferred embodiments, X a is CR a and R a is selected from: In some preferred embodiments, X a is CR a and R a is selected from: In some embodiments, X a is CR a and R a is C 3-10 cycloalkyl, 4-10 membered monocyclic or bicyclic heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein the C 3-10 cycloalkyl, 4-10 membered monocyclic or bicyclic heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl is optionally substituted with one or more substituents independently selected from halogen, CN, OH, NH2, C(O)NH2, oxo, oxide, C1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 3-4 cycloalkyl, NH-C 1-4 alkyl, O-C 3-4 cycloalkyl, O-C 1-4 haloalkyl, C 1-2 alkylene-O-C 1-4 alkyl, O-C 1-2 alkylene-O-C 1-4 alkyl, O-C 1-2 alkylene-OH, O-C 2-4 alkylene-N(C 1-4 alkyl)(C 1-4 alkyl), C(O)N(C 1-4 alkyl)(C 1-4 alkyl) and S(O)2(C 1-4 alkyl). In some embodiments, X a is CR a and R a is C 3-4 cycloalkyl (such as cyclopropyl), 4-6 membered monocyclic heterocyclyl containing one or two ring heteroatoms independently selected from N and O (such as azetidinyl, pyrrolidinyl, or tetrahydropyranyl), 8-9 membered bicyclic heterocyclyl containing one, two, or three ring heteroatoms independently selected from N and O (such as diazaspirooctanyl), phenyl, 5-6 membered heteroaryl containing 1-4, such as one, two, or three, ring heteroatoms independently selected from N, O, and S (such as pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyridinone, pyridyl N-oxide, pyrazinyl, pyrimidinyl, or pyridazinyl), or 9-10 membered bicyclic heteroaryl containing 1-4, such as one, two, or three, ring heteroatoms independently selected from N, O, and S (such as triazolopyridinyl), wherein the C 3-4 cycloalkyl (such as cyclopropyl), 4-6 membered monocyclic heterocyclyl (such as azetidinyl, pyrrolidinyl, or tetrahydropyranyl), 8-9 membered bicyclic heterocyclyl (such as diazaspirooctanyl), phenyl, 5-6 membered heteroaryl (such as pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyridinone, pyridyl N-oxide, pyrazinyl, pyrimidinyl, or pyridazinyl), or 9-10 membered bicyclic heteroaryl (such as triazolopyridinyl) is optionally substituted with one or more, such as one, two, three, or four, substituents independently selected from halogen (such as F), CN, OH, NH2, C(O)NH2, oxo, oxide, C 1-4 alkyl (such as methyl or ethyl), C 1-4 haloalkyl (such as CF3), C 1-4 alkoxy (such as methoxy and ethoxy), C 3-4 cycloalkyl (such as cyclopropyl), NH-C1-4 alkyl (e.g., NHCH3), O-C 3-4 cycloalkyl (e.g., O-cyclopropyl), O-C 1-4 haloalkyl (e.g., OCHF2), C 1-2 alkylene-O-C 1-4 alkyl (e.g., CH2OCH3), O-C 1-2 alkylene-O-C 1-4 alkyl (e.g., OCH2OCH3), O-C 1-2 alkylene-OH (e.g., OCH2CH2OH), O-C 2-4 alkylene-N(C 1-4 alkyl)(C 1-4 alkyl) (e.g., OCH2CH2N(CH3)2), C(O)N(C 1-4 alkyl)(C 1-4 alkyl) (e.g., C(O)N(CH3)2) and S(O)2(C 1-4 alkyl) (e.g., S(O)2CH3). In some preferred embodiments, X a is CR a and R a is selected from: In some preferred embodiments, X a is CR a and R a is selected from:

[0093]

[0094]

[0095] In some preferred embodiments, X a is CR a and R a is selected from:

[0096]

[0097] In some preferred embodiments, X a is CR a and R a is selected from:

[0098]

[0099] In some embodiments, in Formula I-1 (e.g., Formula I-1-A, I-1-C, or I-1-D) or I-2 (e.g., Formula I-2-A, I-2-C, or I-2-D), X a is CR a and R ais H, F, CI, CH3, CH2CH3, CF3, or OCF3. In some preferred embodiments, X a is CR a and R a is H or F.

[0100] In some embodiments, in Formula I-1 (e.g., Formula I-1-A, I-1-B, or I-1-D), Formula I-2 (e.g., Formula I-2-A, I-2-B, or I-2-D), Formula I-3 (e.g., Formula I-3-A or I-3-C), or Formula I-4 (e.g., Formula I-4-A or I-4-C), X b is CR b and R b is hydrogen, halogen, OH, NH2, CN, -C(O)-NH2, -C(O)-NH(C 1-4 alkyl), -C(O)-N(C 1-4 alkyl)2, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-10 carbocyclyl ring, optionally substituted 4-10 membered heterocyclyl ring, optionally substituted C 6-10 aryl, or optionally substituted 5-10 membered heteroaryl. In some preferred embodiments, X b is CR b and R b is H. In some preferred embodiments, X b is CR b and R b is H, halogen, CN, R bx , -COR bx , -NHCOR bx , -CONH2, -CONHR bx , -CON(R bx )2, -OR bx , -NHR bx , -N(R bx )2, -SR bx , -SO2R bx , or -NHSO2R bx , wherein R bx is, at each occurrence, independently C 1-6 alkyl which is unsubstituted or substituted with one or more substituents independently selected from halogen (preferably F), OH, or N(CH3)2. In some preferred embodiments, Xb CR b and R b is F, CI, CN, -C(O)-NH2, -C(O)-NH(C 1-4 alkyl), -C(O)-N(C 1-4 alkyl)2, C 1-6 alkyl, C 1-6 haloalkyl, -O-C 1-4 alkyl, -S-C 1-4 alkyl, -S(O)2-C 1-4 alkyl, -C(C 1-2 alkyl)2OH, -NH-S(O)2-C 1-4 alkyl, or -O-C 2-3 alkylene-N(CH3)2. In some preferred embodiments, X b CR b and R b is F, CI, CN, CH3, CF3, -O-CH3, -S-CH3, -S(O)2-CH3, -NH-S(O)2-CH3, -C(CH3)2OH, -C(O)-NH2, or -O-(CH2)2-N(CH3)2. In some preferred embodiments, X b CR b and R b is F, CN, -O-CH3, or -S-CH3, or R b is -S(O)2-CH3. In some preferred embodiments, X b CR b and R b is F, CN, -O-CH3, or -S-CH3, or R b is -C(CH3)2OH. In some preferred embodiments, X b CR b and R b is C 3-6 carbon ring, a 4-8 membered heterocyclyl ring, phenyl, or 5-6 membered heteroaryl, wherein the carbon ring, heterocyclyl ring, phenyl, or heteroaryl is unsubstituted or substituted with one or more substituents independently selected from halogen, OH, NH2, CN, oxo, -C(O)-NH2, -C(O)-NH(C 1-4 alkyl), -C(O)-N(C 1-4 alkyl)2, C 1-6 alkyl, C 1-6 haloalkyl, -O-C 1-4 alkyl, -S-C 1-4 alkyl, -S(O)2-C 1-4 alkyl, -NH-S(O)2-C 1-4alkyl or -O-C 2-3 alkylene-N(C 1-4 alkyl)2, preferably unsubstituted or substituted with one or two substituents independently selected from oxo, NH2, CN, CH3, -C(O)-NH2, -C(O)-NH(CH3), -S(O)2-CH3, -Boc, or -S-CH3. In some preferred embodiments, X b is CR b and R b is a 5- or 6-membered heteroaryl containing one or two ring heteroatoms independently selected from N, O, and S, and unsubstituted or substituted with one or more substituents independently selected from CN, OH, NH2, C 1-4 alkyl, and -O-C 1-4 alkyl. In some preferred embodiments, X b is CR b and R b is a 4-, 5-, or 6-membered heterocyclyl containing one or two ring heteroatoms independently selected from N, O, and S, and unsubstituted or substituted with one or more substituents independently selected from oxo, CN, OH, NH2, C 1-4 alkyl, -O-C 1-4 alkyl, and -C(O)-NH(C 1-4 alkyl). In some preferred embodiments, X b is CR b and R b is a spiro or fused ring, wherein the ring contains one or two ring heteroatoms independently selected from N, O, and S, and is unsubstituted or substituted with one or more substituents independently selected from CN, OH, NH2, C 1-4 alkyl, -O-C 1-4 alkyl, -C(O)-O(C 1-4 alkyl), and -C(O)-NH(C 1-4 alkyl). In some preferred embodiments, X b is CR b and R b is unsubstituted or substituted with one or more substituents independently selected from halogen, CN, OH, NH2, -C(O)-NH2, C 1-4 alkyl, fluorinated C 1-4 alkyl, -O-C 1-4 alkyl, and -S(O)2-C 1-4 alkyl. In some preferred embodiments, X b is CR b and R b is C 1-4 alkyl, fluorinated C1-4 alkyl, -O-C 1-4 alkyl, -NH-C 1-4 alkyl, -S-C 1-4 alkyl, -S(O)2-C 1-4 alkyl and -O-C 2-4 alkylene-N(C 1-2 alkyl)2. In some preferred embodiments, X b is CR b and R b is H, halogen, CN or -C(O)-NH2. In some preferred embodiments, X b is CR b and R b is selected from:

[0101]

[0102] In some preferred embodiments, X b is CR b and R b is selected from:

[0103]

[0104] In some preferred embodiments, X b is CR b and R b is selected from:

[0105]

[0106] In some preferred embodiments, X b is CR b and R b is selected from:

[0107]

[0108] In some preferred embodiments, X b is CR b and R b is selected from:

[0109] In some preferred embodiments, X b is CR b and R b is selected from:

[0110] In some preferred embodiments, X b is CR b and Rb selected from: In some embodiments, in Formula I-1 (e.g., Formula I-1-A, I-1-B, or I-1-D), Formula I-2 (e.g., Formula I-2-A, I-2-B, or I-2-D), Formula I-3 (e.g., Formula I-3-A or I-3-C), or Formula I-4 (e.g., Formula I-4-A or I-4-C), X b is CR b and R b may have any of the definitions of R a described herein.

[0111] In some embodiments, in Formula I-1 (e.g., Formula I-1-A, I-1-B, or I-1-D), Formula I-2 (e.g., Formula I-2-A, I-2-B, or I-2-D), Formula I-3 (e.g., Formula I-3-A or I-3-C), or Formula I-4 (e.g., Formula I-4-A or I-4-C), X b is CR b and R b is H, F, CI, CH3, CH2CH3, CF3, or OCF3. In some preferred embodiments, X b is CR b and R b is H, F, or NH2. In some preferred embodiments, X b is CR b and R b is Br.

[0112] In some embodiments, in Formula I-1 (e.g., Formula I-1-A, I-1-B, or I-1-C), I-2 (e.g., Formula I-2-A, I-2-B, or I-2-C), Formula I-3 (e.g., Formula I-3-A or I-3-B), or Formula I-4 (e.g., Formula I-4-A or I-4-B), X c is CR c and R c is hydrogen, halogen, OH, NH2, CN, -C(O)-NH2, -C(O)-NH(C 1-4 alkyl), -C(O)-N(C 1-4 alkyl)2, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-10 carbocyclyl ring, optionally substituted 4-10 membered heterocyclyl ring, optionally substituted C 6-10aryl or optionally substituted 5-10 membered heteroaryl. In some preferred embodiments, X c is CR c and R c is H. In some preferred embodiments, X c is CR c and R c is H, halo, CN, R cx , -COR cx , -NHCOR cx , -CONH2, -CONHR cx , -CON(R cx )2, -OR cx , -NHR cx , -N(R cx )2, -SR cx , -SO2R cx , or -NHSO2R cx , wherein R cx is, at each occurrence, independently C 1-6 alkyl unsubstituted or substituted with one or more substituents independently selected from halo (preferably F), OH, or N(CH3)2. In some preferred embodiments, X c is CR c and R c is F, Cl, CN, -C(O)-NH2, -C(O)-NH(C 1-4 alkyl), -C(O)-N(C 1-4 alkyl)2, C 1-6 alkyl, C 1-6 haloalkyl, -O-C 1-4 alkyl, -S-C 1-4 alkyl, -S(O)2-C 1-4 alkyl, -C(C 1-2 alkyl)2OH, -NH-S(O)2-C 1-4 alkyl, or -O-C 2-3 alkylene-N(CH3)2. In some preferred embodiments, X c is CR c and R c is F, Cl, CN, CH3, CF3, -O-CH3, -S-CH3, -S(O)2-CH3, -NH-S(O)2-CH3, -C(CH3)2OH, -C(O)-NH2, or -O-(CH2)2-N(CH3)2. In some preferred embodiments, X c is CR c and R c is F, Cl, CN, or -C(O)-NH2. In some preferred embodiments, Xc CR c and R c is C 3-6 carbon ring, 4-8 membered heterocyclyl ring, phenyl, or 5-6 membered heteroaryl, wherein the carbon ring, heterocyclyl ring, phenyl, or heteroaryl is unsubstituted or substituted with one or more substituents independently selected from F, Cl, OH, NH2, CN, oxo, -C(O)-NH2, -C(O)-NH(CH3), -S(O)2-CH3, -Boc, or -S-CH3. In some preferred embodiments, X 1-4 alkyl), -C(O)-N(C 1-4 alkyl)2, C 1-6 alkyl, C 1-6 haloalkyl, -O-C 1-4 alkyl, -S-C 1-4 alkyl, -S(O)2-C 1-4 alkyl, -NH-S(O)2-C 1-4 alkyl, or -O-C 2-3 alkylene-N(C 1-4 alkyl)2. In some preferred embodiments, X c CR c and R c is 6-membered heterocyclyl ring or 5-membered heteroaryl, wherein the heterocyclyl ring or heteroaryl is unsubstituted or substituted with C 1-4 alkyl. In some preferred embodiments, X c CR c and R c is selected from: In some embodiments, in Formula I-1 (e.g., Formula I-1-A, I-1-B, or I-1-D), Formula I-2 (e.g., Formula I-2-A, I-2-B, or I-2-D), Formula I-3 (e.g., Formula I-3-A or I-3-C), or Formula I-4 (e.g., Formula I-4-A or I-4-C), X c CR c and R c may have any one of the definitions of R a or R b described herein.

[0113] In some embodiments, in Formula I-1 (e.g., Formula I-1-A, I-1-B, or I-1-C), I-2 (e.g., Formula I-2-A, I-2-B, or I-2-C), Formula I-3 (e.g., Formula I-3-A or I-3-B), or Formula I-4 (e.g., Formula I-4-A or I-4-B), Xc CR c and R c is H, F, CI, CH3, CH2CH3, CF3, or OCF3. In some embodiments, X c CR c and R c is H or F.

[0114] In some embodiments, in Formula I-1 (e.g., Formula I-1-A or I-1-D) or I-2 (e.g., Formula I-2-A or I-2-D), when X a CR a and X b CR b R a and R b , together with the C and C atoms therebetween, join to form a 5-7 membered ring that is unsubstituted or substituted with C 1-4 alkyl. In some embodiments, when X a CR a and X b CR b R a and R b , together with the C and C atoms therebetween, join to form a 5-membered ring containing zero, one, or two ring heteroatoms independently selected from N, O, and S and unsubstituted or substituted with one or two substituents independently selected from oxo and C 1-4 alkyl. In some embodiments, when X a CR a and X b CR b R a and R b , together with the C and C atoms therebetween, join to form a 5-membered ring containing zero, one, or two ring heteroatoms independently selected from N, O, and S and unsubstituted or substituted with C 1-4 alkyl. In some preferred embodiments, when X a CR a and X b CR b R a and R b , together with the C and C atoms therebetween, join to form a 5-7 membered ring selected from:

[0115]

[0116] wherein the carbon labeled "a" is attached to R a and the carbon labeled "b" is attached to R b , wherein R g is H or C1-4 alkyl, preferably H or methyl. In some preferred embodiments, R a and R b , together with the intervening C and C atoms, join to form a ring selected from: where the carbon marked "a" is attached to R a and the carbon marked "b" is attached to R b . In some preferred embodiments, R a and R b , together with the intervening C and C atoms, join to form a ring selected from: where the carbon marked "a" is attached to R a and the carbon marked "b" is attached to R b .

[0117] In some embodiments, in Formula I-1 (e.g., Formula I-1-A or I-1-B) or I-2 (e.g., Formula I-2-A or I-2-B), when X b is CR b and X c is CR c , R b and R c , together with the intervening C and C atoms, join to form a 5-7 membered ring that is unsubstituted or substituted with C 1-4 alkyl. In some embodiments, when X b is CR b and X c is CR c , R b and R c , together with the intervening C and C atoms, join to form a 5-membered ring containing zero, one, or two ring heteroatoms independently selected from N, O, and S and unsubstituted or substituted with one or two substituents independently selected from oxo and C 1-4 alkyl. In some embodiments, when X b is CR b and X c is CR c , R b and R c , together with the intervening C and C atoms, join to form a 5-membered ring containing zero, one, or two ring heteroatoms independently selected from N, O, and S and unsubstituted or substituted with C 1-4 alkyl. In some preferred embodiments, when X b is CR b and X c is CR c , R b and R ctogether with the intervening C and C atoms, join to form a 5-7 membered ring selected from:

[0118] wherein the carbon marked "b" connects R b and the carbon marked "c" connects R c , wherein R g is H or C 1-4 alkyl, preferably H or methyl. In some preferred embodiments, R b and R c together with the intervening C and C atoms, join to form a ring selected from: wherein the carbon marked "b" connects R b and the carbon marked "c" connects R c . In some preferred embodiments, R b and R c together with the intervening C and C atoms, join to form wherein the carbon marked "b" connects R b and the carbon marked "c" connects R c .

[0119] In some embodiments, in Formula I-1 (e.g., Formula I-1-A, I-1-B, I-1-C, or I-1-D), Formula I-2 (e.g., Formula I-2-A, I-2-B, I-2-C, or I-2-D), Formula I-3 (e.g., Formula I-3-A, I-3-B, or I-3-C), or Formula I-4 (e.g., Formula I-4-A, I-4-B, or I-4-C), R d is H, F, Cl, OH, NH2, OCH3, NHCH3, or NHCH2CH3. In some preferred embodiments, R d is H, Cl, OH, NH2, NHCH3, or NHCH2CH3. In some more preferred embodiments, R d is OH, or R d is NH2. In some more preferred embodiments, R d is NH2. In some embodiments, in Formula I-1 (e.g., Formula I-1-A, I-1-B, I-1-C, or I-1-D), Formula I-2 (e.g., Formula I-2-A, I-2-B, I-2-C, or I-2-D), Formula I-3 (e.g., Formula I-3-A, I-3-B, or I-3-C), or Formula I-4 (e.g., Formula I-4-A, I-4-B, or I-4-C), R d is NO2.

[0120] In some embodiments, in Formula I-3 (e.g., Formula I-3-A, I-3-B, or I-3-C) or Formula I-4 (e.g., Formula I-4-A, I-4-B, or I-4-C), R e is H, F, Cl, CH3, CH2CH3, CF3, or OCF3. In some embodiments, R e is H.

[0121] In some embodiments, in Formula I-3 (e.g., Formula I-3-A, I-3-B, or I-3-C) or Formula I-4 (e.g., Formula I-4-A, I-4-B, or I-4-C), R f is selected from:

[0122]

[0123] In some preferred embodiments, R f is selected from: In some preferred embodiments, R f is In some preferred embodiments, R f is halogen, such as F, Cl, or Br.

[0124] In some embodiments, the present disclosure provides the following enumerated exemplary embodiments 1-88 of the compounds of the present disclosure:

[0125] Embodiment 1: A compound of Formula X-1, or a pharmaceutically acceptable salt thereof:

[0126]

[0127] wherein:

[0128] R 1 is optionally substituted C 1-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 2-6 alkenyl, or optionally substituted C 2-6 alkynyl;

[0129] R 2 is optionally substituted 5-14 membered heterocyclyl or optionally substituted 5-14 membered heteroaryl;

[0130] m1 is 0 or 1;

[0131] m2 is 0, 1, or 2;

[0132] wherein R 10 and R 11Each time it appears, it is independently selected from halogen, OH, NH2, CN, COOH, C(O)NH2, S(O)2NH2, G 1 C(O)G 1 OG 1 NHG 1 NG 1 G 1 SG 1 S(O)G 1 S(O)2G 1 P(O)G 1 G 1 C(O)NHG 1 S(O)2NHG 1 S(O)2NG 1 G 1 ,NHC(O)G 1 、NHS(O)2G 1 、N(G 1 )C(O)G 1 or N(G) 1 )S(O)2G 1 G 1 Each time it appears, it is independently replaced by the arbitrarily chosen C. 1-6 Alkyl groups, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-10 Carbocyclic base ring, optionally substituted 4-10 membered heterocyclic base ring, optionally substituted C 6-10 aryl or optionally substituted 5-10 heteroaryl groups; or

[0133] R 10 and adjacent R 11 or two adjacent R 11 Together with the atoms in between, they connect to form optionally substituted C atoms. 5-10 Carbocyclic base ring, optionally substituted 5-10 membered heterocyclic base ring, optionally substituted C 6-10 The aryl ring or optionally substituted 5-10 membered heteroaryl ring; and

[0134] R d For H, halogen, OR 7 or NR 7 R 8 , where R 7 and R 8 Each independently represents H or the C that can be arbitrarily substituted. 1-4 alkyl.

[0135] Implementation Scheme 2: The compound of Implementation Scheme 1 or a pharmaceutically acceptable salt thereof, wherein R 1C1-C6-alkyl or C 1-4 C1-C6-alkyl or C 3-4 C1-C6-alkyl or C

[0136] Embodiment 3: The compound of embodiment 1 or a pharmaceutically acceptable salt thereof, wherein R 1 C1-C6-alkyl or C 1-4 C1-C6-alkyl or C

[0137] Embodiment 4: The compound of any one of embodiments 1-3 or a pharmaceutically acceptable salt thereof, wherein R 2 6,5-fused bicyclic heteroaryl having 1 or 2 ring heteroatoms independently selected from O, N or S, wherein when substituted, the 6,5-fused bicyclic heteroaryl is preferably substituted with 1-3 substituents each independently selected from halogen, CN, OH, C1-C6-alkyl optionally substituted with 1-3 F, C1-C6-alkoxy optionally substituted with 1-3 F, C1-C6-alkenyl optionally substituted with 1-3 F, C1-C6-alkynyl or a 3-6 membered ring selected from carbocyclyl, heterocyclyl or heteroaryl optionally substituted with 1-3 substituents independently selected from F, methyl or OH. 1-4 C1-C6-alkyl or C 1-4 C1-C6-alkyl or C 2-4 C1-C6-alkyl or C 2-4 C1-C6-alkyl or C

[0138] Embodiment 5: The compound of embodiment 4 or a pharmaceutically acceptable salt thereof, wherein in the 6,5-fused bicyclic heteroaryl, the 6-membered ring is selected from benzene, pyridine, pyrimidine or pyrazine and the 5-membered ring is selected from furan, pyrrole, pyrazole, imidazole, thiophene, oxazole or thiazole.

[0139] Embodiment 6: The compound of embodiment 4 or a pharmaceutically acceptable salt thereof, wherein the 6,5-fused bicyclic heteroaryl is indole or benzofuran, preferably 2-indolyl or 2-benzofuranyl.

[0140] Embodiment 7: The compound of any one of embodiments 1-3 or a pharmaceutically acceptable salt thereof, wherein R 2 2-benzofuranyl optionally substituted, wherein when substituted, the 2-benzofuranyl is preferably substituted with 1-3 substituents each independently selected from halogen (preferably F or CI), CN, C1-C6-alkyl optionally substituted with 1-3 F, C1-C6-alkoxy optionally substituted with 1-3 F, C1-C6-alkenyl optionally substituted with 1-3 F, C1-C6-alkynyl or a 3-6 membered ring selected from carbocyclyl, heterocyclyl or heteroaryl optionally substituted with 1-3 substituents independently selected from F, methyl or OH. 1-4 C1-C6-alkyl or C 1-4 C1-C6-alkyl or C 2-4 C1-C6-alkyl or C 2-4alkynyl or C 3-4 cycloalkyl.

[0141] Embodiment 8: The compound of any one of embodiments 1-7, or a pharmaceutically acceptable salt thereof, wherein R d is NH2, NH(C 1-4 alkyl) or N(C 1-4 alkyl)(C 1-4 alkyl), preferably R d is NH2.

[0142] Embodiment 9: The compound of any one of embodiments 1-8, or a pharmaceutically acceptable salt thereof, wherein m1 is 1, and the compound is characterized as having Formula X-1a, X-1b or X-1c:

[0143]

[0144] Embodiment 10: The compound of embodiment 9, or a pharmaceutically acceptable salt thereof, wherein R 10 is halogen, CN, R ax , -COR ax , -NHCOR ax , -CONH2, -CONHR ax , -CON(R ax )2, -OR ax , -NHR ax , -N(R ax )2, -SR ax , -SO2R ax or -NHSO2R ax , wherein R ax is, at each occurrence, independently C 1-6 alkyl which is unsubstituted or substituted with one or more substituents independently selected from halogen (preferably F), OH or N(CH3)2, or R ax is, at each occurrence, independently C 1-6 alkyl, a 3-10 membered ring or (C 1-4 alkylene)-(3-10 membered ring), wherein the 3-10 membered ring is selected from the group consisting of C 3-10 carbocyclyl ring, 4-10 membered heterocyclyl ring, C 6-10 aryl and 5-10 membered heteroaryl, and wherein the C 1-6 alkyl, C 1-4 alkylene or 3-10 membered ring is optionally substituted, for example, the C 1-6 alkyl, C 1-4 alkylene or 3-10 membered ring can be unsubstituted or substituted with one or more substituents independently selected from MA , M B , OM B , NHM B , N(C 1-4 alkyl)M B , CO-M B , -S-M B , -S(O)2-M B , CO2-M B , CO-NHM B , CO-N(C 1-4 alkyl)M B , NH-CO-M B , -N(C 1-4 alkyl)-CO-M B , -S(O)2-NHM B , -S(O)2-N(C 1-4 alkyl)M B , NH-S(O)2-M B , -N(C 1-4 alkyl)-S(O)2-M B , C 1-6 heteroalkyl or -(C 1-6 heteroalkylene)-M B , wherein M A is independently at each occurrence halogen, OH, NH2, CN, oxo (as applicable), COOH, or -C(O)-NH2, and M B is independently at each occurrence C 1-6 alkyl or a 3-6 membered ring selected from C 3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, or 5 or 6-membered heteroaryl, wherein the C 1-6 alkyl or 3-6 membered ring is optionally substituted with one or more substituents independently selected from M A , C 1-4 alkyl optionally substituted with F, OH, NH2, NHCH3, or N(CH3)2, and C 1-4 alkoxy optionally substituted with F, OH, NH2, NHCH3, or N(CH3)2, as valency allows, preferably the C 1-6 heteroalkyl can be -O-C 1-4 alkylene-OH, -O-C 2-4 alkylene-O-C 1-4 alkyl, -O-C 2-4 alkylene-NH2, -O-C 2-4 alkylene-N(C 1-4 alkyl)2, -O-C 2-4 alkylene-NH-C 1-4 alkyl, -NH-C2-4 Alkyl-NH2, -NH-C 2-4 Alkylene-N(C) 1-4 alkyl)2 or -NH-C 2-4 Alkylene-NH-C 1-4 Alkyl groups, provided that the total number of carbons is between 1 and 6, and C 1-6 Heteroalkyl groups can be the C13 groups described. 1-6 Divalent groups of heteroalkyl groups.

[0145] Implementation Scheme 11: The compound of Implementation Scheme 9 or a pharmaceutically acceptable salt thereof, wherein R 10 The phenyl group is a 5-membered heteroaryl group having 1-4 cyclic heteroatoms independently selected from O, S, or N, or a 6-membered heteroaryl group having 1 or 2 cyclic nitrogen atoms, wherein the phenyl, 5-membered heteroaryl group, or 6-membered heteroaryl group is optionally selected by one or more of the following independently: halogen, CN, OH, NH2, C(O)NH2, S(O)2NH2, G... 2 C(O)G 2 OG 2 NHG 2 NG 2 G 2 SG 2 S(O)G 2 S(O)2G 2 P(O)G 2 G 2 -C(O)NHG 2 S(O)2NHG 2 or S(O)2NG 2 G 2 The substituents are replaced by G, where G is the substituent. 2 Each time it appears, it is independently assigned to (i) by 1-3 Gs. S1 The C that was replaced 1-4 Alkyl; (ii) optionally coated with 1-3 G S1 The C that was replaced 2-6 (iii) Alkenyl; (iii) optionally surrounded by 1-3 G atoms S1 The C that was replaced 2-6 (iv) optionally surrounded by 1-3 G groups S2 The C that was replaced 3-6 A carbocyclic group; or (v) a 4-7 membered heterocyclic group having 1-3 independently selected cyclic heteroatoms chosen from N, O or S, wherein S is optionally oxidized, and wherein the 4-7 membered heterocyclic group is optionally oxidized by 1-3 G atoms. S2 Replaced; of which G S1 Each time it appears, it is independently F, OH, CN, NH2, or C that is optionally replaced by F. 1-4 Heteroalkyl (e.g., C10) 1-4Alkoxy, NH(C) 1-4 alkyl) or N(C) 1-3 Alkyl)(C 1-3 Alkyl group or a 3-4 membered carbon ring or heterocyclic ring optionally substituted with F, methyl and / or OH (e.g., cyclopropyl, etc.); wherein G S2 Each time it appears, it is independently F, OH, CN, NH2, or C that is optionally replaced by F. 1-4 Alkyl groups, C groups optionally substituted with F 1-4 Heteroalkyl (e.g., C10) 1-4 Alkoxy, NH(C) 1-4 alkyl) or N(C) 1-3 Alkyl)(C 1-3 Alkyl groups or optional 3-4 membered carbon rings or heterocyclic rings substituted with F, methyl and / or OH (e.g., cyclopropyl, oxetyl, aziridine, etc.).

[0146] Implementation Scheme 12: The compound of Implementation Scheme 9 or a pharmaceutically acceptable salt thereof, wherein R 10 It is a 5-membered heteroaryl group having 1-2 independently selected cyclic heteroatoms chosen from O, S, or N, such as pyrazole, oxazole, thiazole, isoxazole, isothiazole, imidazole, etc., wherein the 5-membered heteroaryl group is optionally composed of 1-3 independently selected halogens, CN, OH, NH2, C(O)NH2, S(O)2NH2, G 3 OG 3 NHG 3 NG 3 G 3 S(O)2G 3 -C(O)NHG 3 S(O)2NHG 3 or S(O)2NG 3 G 3 The substituents are replaced by G, where G is the substituent. 3 Each time it appears, it is independently (i) a C that is optionally replaced by 1-3 substituents, each independently selected from F or OH. 1-4 Alkyl; or (ii) C substituted with 1-3 substituents, each independently selected from F, methyl or OH. 3-4 Carbon cyclic group.

[0147] Implementation Scheme 13: The compound of Implementation Scheme 9 or a pharmaceutically acceptable salt thereof, wherein R 10 The halogen is selected independently from 1-3 halogens, CN, OH, NH2, C(O)NH2, S(O)2NH2, G 3 OG 3 NHG 3 NG 3 G 3S(O)2G 3 -C(O)NHG 3 S(O)2NHG 3 or S(O)2NG 3 G 3 The phenyl group substituted by the substituent, wherein G 3 Each time it appears, it is independently (i) a C that is optionally replaced by 1-3 substituents, each independently selected from F or OH. 1-4 Alkyl; or (ii) C substituted with 1-3 substituents, each independently selected from F, methyl or OH. 3-4 Carbon cyclic group.

[0148] Implementation Scheme 14: The compound of Implementation Scheme 9 or a pharmaceutically acceptable salt thereof, wherein R 10 It is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, each of which is optionally selected independently by 1 to 3 halogens, CN, OH, NH2, C(O)NH2, S(O)2NH2, G 3 OG 3 NHG 3 NG 3 G 3 S(O)2G 3 -C(O)NHG 3 S(O)2NHG 3 or S(O)2NG 3 G 3 The substituents are replaced by G, where G is the substituent. 3 Each time it appears, it is independently (i) a C that is optionally replaced by 1-3 substituents, each independently selected from F or OH. 1-4 Alkyl; or (ii) C substituted with 1-3 substituents, each independently selected from F, methyl or OH. 3-4 Carbon cyclic group.

[0149] Implementation Scheme 15: The compound of Implementation Scheme 9 or a pharmaceutically acceptable salt thereof, wherein R 10 Selected from:

[0150]

[0151] in:

[0152] p is 0, 1, or 2, preferably 0 or 1, and

[0153] R a2 Each time it appears, it is independently selected from halogens, OH, NH2, C(O)NH2, S(O)2NH2, G 3 OG 3 NHG 3 NG 3G 3 , S(O)2G 3 , -C(O)NHG 3 , S(O)2NHG 3 , or S(O)2NG 3 G 3 , wherein G 3 is, at each occurrence, independently (i) C 1-4 alkyl optionally substituted with 1-3 substituents each independently selected from F or OH; or (ii) C 3-4 carbocyclyl optionally substituted with 1-3 substituents each independently selected from F, methyl or OH.

[0154] Preferably, p is 0, or when p is 1, R a2 is halogen, OH, NH2, C 1-4 alkyl optionally substituted with 1-3 F, or C 1-4 alkoxy optionally substituted with 1-3 F.

[0155] Embodiment 16: A compound of Embodiment 9, or a pharmaceutically acceptable salt thereof, wherein R 10 is a 4-10 membered heterocyclyl having 1-3 ring heteroatoms independently selected from O, S or N, wherein S is optionally oxidized, wherein the 4-10 membered heterocyclyl is optionally substituted with one or more substituents each independently selected from halogen, CN, oxo, OH, NH2, C(O)NH2, S(O)2NH2, G 2 , C(O)G 2 , OG 2 , NHG 2 , NG 2 G 2 , SG 2 , S(O)G 2 , S(O)2G 2 , P(O)G 2 G 2 , -C(O)NHG 2 , S(O)2NHG 2 , or S(O)2NG 2 G 2 , wherein G 2 is, at each occurrence, independently (i) C S1 alkyl optionally substituted with 1-3 G 1-4 ; (ii) C S1 alkenyl optionally substituted with 1-3 G 2-6 ; (iii) C S1 alkynyl optionally substituted with 1-3 G 2-6 ; (iv) C S2 alkoxy optionally substituted with 1-3 G3-6 carbocyclyl; or (v) 4-7 membered heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, or S, wherein S is optionally oxidized, wherein said 4-7 membered heterocyclyl is optionally substituted with 1-3 G S2 substituents; wherein G S1 is, at each occurrence, independently F, OH, CN, NH2, C 1-4 heteroalkyl (e.g., C 1-4 alkoxy, NH(C 1-4 alkyl), or N(C 1-3 alkyl)(C 1-3 alkyl)) or a 3-4 membered carbocyclyl or heterocyclyl ring optionally substituted with F, methyl, and / or OH (e.g., cyclopropyl, oxetanyl, azetidinyl, etc.). S2 is, at each occurrence, independently F, OH, CN, NH2, C 1-4 alkyl, C 1-4 heteroalkyl (e.g., C 1-4 alkoxy, NH(C 1-4 alkyl), or N(C 1-3 alkyl)(C 1-3 alkyl)) or a 3-4 membered carbocyclyl or heterocyclyl ring optionally substituted with F, methyl, and / or OH (e.g., cyclopropyl, oxetanyl, azetidinyl, etc.).

[0156] substituents; wherein G 3 is, at each occurrence, independently (i) C 3 heteroalkyl (e.g., C 3 alkoxy, NH(C 3 alkyl), or N(C 3 alkyl)(C 3 alkyl)) or a 3-4 membered carbocyclyl or heterocyclyl ring optionally substituted with F, methyl, and / or OH (e.g., cyclopropyl, oxetanyl, azetidinyl, etc.). 3 3 substituents; wherein G 3 is, at each occurrence, independently (i) C 3 heteroalkyl (e.g., C 3 alkoxy, NH(C 1-4 alkyl), or N(C 3-4 alkyl)(C

[0157] ​Embodiment 18: The compound of Embodiment 16, or a pharmaceutically acceptable salt thereof, wherein the 4-10 membered heterocyclyl is a spiro bicyclic heterocyclyl having 1 or 2 ring heteroatoms independently selected from N or O, optionally substituted with 1-3 substituents each independently selected from halogen, CN, OH, NH2, C(O)NH2, S(O)2NH2, G 3 3 3 3 3 3 3 3 3 3 3 1-4 3-4

[0158] Embodiment 19: The compound of Embodiment 16, or a pharmaceutically acceptable salt thereof, wherein the 4-10 membered heterocyclyl is selected from:

[0159]

[0160] wherein:

[0161] q is 0, 1, 2, or 3, preferably q is 0 or 1, and

[0162] R a3 is, at each occurrence, independently CN, halogen, OH, NH2, C(O)NH2, S(O)2NH2, G 3 3 3 3 3 3 3 3 3 3 3 1-4 3-4 ​​​​​​​​​​​​​​​​​​​​​​​​​​

[0163] Preferably, R a3 Each time it appears, it is independently CN, F, OH, NH2, or C that is optionally replaced by 1-3 F. 1-4 Alkyl groups or C groups optionally substituted with 1-3 F atoms 1-4 Alkyl group.

[0164] Implementation Scheme 20: The compound of Implementation Scheme 9 or a pharmaceutically acceptable salt thereof, wherein R 10 C 3-8 Carbocyclic ring, preferably, C 3-6 cycloalkyl, wherein the C 3-8 The carbocyclic group is optionally composed of one or more elements independently selected from halogens, CN, oxo, OH, NH2, C(O)NH2, S(O)2NH2, G 2 C(O)G 2 OG 2 NHG 2 NG 2 G 2 SG 2 S(O)G 2 S(O)2G 2 P(O)G 2 G 2 -C(O)NHG 2 S(O)2NHG 2 or S(O)2NG 2 G 2 The substituents are replaced by G, where G is the substituent. 2 Each time it appears, it is independently assigned to (i) by 1-3 Gs. S1 The C that was replaced 1-4 Alkyl; (ii) optionally coated with 1-3 G S1 The C that was replaced 2-6 (iii) Alkenyl; (iii) optionally surrounded by 1-3 G atoms S1 The C that was replaced 2-6 (iv) optionally surrounded by 1-3 G groups S2 The C that was replaced 3-6 A carbocyclic group; or (v) a 4-7 membered heterocyclic group having 1-3 independently selected cyclic heteroatoms chosen from N, O or S, wherein S is optionally oxidized, and wherein the 4-7 membered heterocyclic group is optionally oxidized by 1-3 G atoms. S2 Replaced; of which G S1 Each time it appears, it is independently F, OH, CN, NH2, or C that is optionally replaced by F. 1-4 Heteroalkyl (e.g., C10) 1-4 Alkoxy, NH(C) 1-4 alkyl) or N(C) 1-3 Alkyl)(C 1-3Alkyl group or a 3-4 membered carbon ring or heterocyclic ring optionally substituted with F, methyl and / or OH (e.g., cyclopropyl, etc.); wherein G S2 Each time it appears, it is independently F, OH, CN, NH2, or C that is optionally replaced by F. 1-4 Alkyl groups, C groups optionally substituted with F 1-4 Heteroalkyl (e.g., C10) 1-4 Alkoxy, NH(C) 1-4 alkyl) or N(C) 1-3 Alkyl)(C 1-3 Alkyl groups or optional 3-4 membered carbon rings or heterocyclic rings substituted with F, methyl and / or OH (e.g., cyclopropyl, oxetyl, aziridine, etc.).

[0165] Implementation Scheme 21: The compound of Implementation Scheme 9 or a pharmaceutically acceptable salt thereof, wherein R 10 The corresponding R selected from any of the compounds shown in Table A of this document 10 Group, or R 10 Having the R described in this article a R b or R c Any of the ones defined, but not hydrogen.

[0166] Implementation Scheme 22: The compound of any one of Implementation Schemes 1-21 or a pharmaceutically acceptable salt thereof, wherein m2 is 0.

[0167] Implementation Scheme 23: A compound or a pharmaceutically acceptable salt thereof from any of Implementation Schemes 1-21, wherein m2 is 1.

[0168] Implementation Scheme 24: The compound of Implementation Scheme 23 or a pharmaceutically acceptable salt thereof, wherein R 11 Halogen, CN, R bx -COR bx -NHCOR bx -CONH2, -CONHR bx -CON(R) bx )2、-OR bx -NHR bx -N(R) bx )2、-SR bx -SO2R bx or -NHSO2R bx , where R bx Each time it appears, it is independently an unsubstituted C or a C substituted by one or more substituents independently selected from halogens (preferably F), OH or N(CH3)2. 1-6 alkyl.

[0169] Embodiment 25: The compound of Embodiment 23 or a pharmaceutically acceptable salt thereof, wherein R 11 is F, CI, CN, -C(O)-NH2, -C(O)-NH(C 1-4 alkyl), -C(O)-N(C 1-4 alkyl)2, C 1-6 alkyl, C 1-6 haloalkyl, -O-C 1-4 alkyl, -S-C 1-4 alkyl, -S(O)2-C 1-4 alkyl, -C(C 1-2 alkyl)2OH, -NH-S(O)2-C 1-4 alkyl, or -O-C 2-3 alkylene-N(CH3)2.

[0170] Embodiment 26: A compound of Formula X-2:

[0171]

[0172] wherein:

[0173] R 1 is optionally substituted C 1-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 2-6 alkenyl, or optionally substituted C 2-6 alkynyl;

[0174] R A is C 1-3 alkyl optionally substituted with F and / or OH;

[0175] R C is halogen or C 1-3 alkyl,

[0176] R E is selected from H, halogen, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 3-4 cycloalkyl, wherein each of said C 1-4 alkyl, C 2-4 alkenyl, and C 2-4 alkynyl is optionally substituted with one or more substituents independently selected from F and OH, and said C 3-4 cycloalkyl is optionally substituted with one or more substituents independently selected from F, methyl, and OH;

[0177] m1 is 0 or 1;

[0178] m2 is 0, 1, or 2;

[0179] Where R 10 and R 11 Each time it appears, it is independently selected from halogen, OH, NH2, CN, COOH, C(O)NH2, S(O)2NH2, G 1 C(O)G 1 OG 1 NHG 1 NG 1 G 1 SG 1 S(O)G 1 S(O)2G 1 P(O)G 1 G 1 C(O)NHG 1 S(O)2NHG 1 S(O)2NG 1 G 1 ,NHC(O)G 1 、NHS(O)2G 1 、N(G 1 )C(O)G 1 or N(G) 1 )S(O)2G 1 G 1 Each time it appears, it is independently replaced by the arbitrarily chosen C. 1-6 Alkyl groups, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-10 Carbocyclic base ring, optionally substituted 4-10 membered heterocyclic base ring, optionally substituted C 6-10 aryl or optionally substituted 5-10 heteroaryl groups; or

[0180] R 10 and adjacent R 11 or two adjacent R 11 Together with the atoms in between, they connect to form optionally substituted C atoms. 5-10 Carbocyclic base ring, optionally substituted 5-10 membered heterocyclic base ring, optionally substituted C 6-10 The aryl ring or optionally substituted 5-10 membered heteroaryl ring.

[0181] Implementation Scheme 27: The compound of Implementation Scheme 26 or a pharmaceutically acceptable salt thereof, wherein m1 is 1.

[0182] Implementation Scheme 28: The compound of Implementation Scheme 26 or 27 or a pharmaceutically acceptable salt thereof, wherein R 10is as defined in embodiment 10.

[0183] Embodiment 29: The compound of embodiments 26 or 27, or a pharmaceutically acceptable salt thereof, wherein R 10 is as defined in embodiment 11.

[0184] Embodiment 30: The compound of embodiments 26 or 27, or a pharmaceutically acceptable salt thereof, wherein R 10 is as defined in embodiment 12.

[0185] Embodiment 31: The compound of embodiments 26 or 27, or a pharmaceutically acceptable salt thereof, wherein R 10 is as defined in embodiment 13.

[0186] Embodiment 32: The compound of embodiments 26 or 27, or a pharmaceutically acceptable salt thereof, wherein R 10 is as defined in embodiment 14.

[0187] Embodiment 33: The compound of embodiments 26 or 27, or a pharmaceutically acceptable salt thereof, wherein R 10 is as defined in embodiment 15.

[0188] Embodiment 34: The compound of embodiments 26 or 27, or a pharmaceutically acceptable salt thereof, wherein R 10 is as defined in embodiment 16.

[0189] Embodiment 35: The compound of embodiments 26 or 27, or a pharmaceutically acceptable salt thereof, wherein R 10 is as defined in embodiment 17.

[0190] Embodiment 36: The compound of embodiments 26 or 27, or a pharmaceutically acceptable salt thereof, wherein R 10 is as defined in embodiment 18.

[0191] Embodiment 37: The compound of embodiments 26 or 27, or a pharmaceutically acceptable salt thereof, wherein R 10 is as defined in embodiment 19.

[0192] Embodiment 38: The compound of embodiments 26 or 27, or a pharmaceutically acceptable salt thereof, wherein R 10 is as defined in embodiment 20.

[0193] Embodiment 39: The compound of embodiments 26 or 27, or a pharmaceutically acceptable salt thereof, wherein R 10 is as defined in embodiment 21.

[0194] Embodiment 40: The compound of any one of embodiments 26-39, or a pharmaceutically acceptable salt thereof, wherein m2 is 0.

[0195] Embodiment 41: The compound of any one of embodiments 26-39, or a pharmaceutically acceptable salt thereof, wherein m2 is 1.

[0196] Embodiment 42: The compound of embodiment 41, or a pharmaceutically acceptable salt thereof, wherein R 11 is halogen, CN, R bx , -COR bx , -NHCOR bx , -CONH2, -CONHR bx , -CON(R bx )2, -OR bx , -NHR bx , -N(R bx )2, -SR bx , -SO2R bx , or -NHSO2R bx , wherein R bx is, at each occurrence, independently C 1-6 alkyl unsubstituted or substituted with one or more substituents independently selected from halogen (preferably F), OH, or N(CH3)2.

[0197] Embodiment 43: The compound of embodiment 41, or a pharmaceutically acceptable salt thereof, wherein R 11 is F, Cl, CN, -C(O)-NH2, -C(O)-NH(C 1-4 alkyl), -C(O)-N(C 1-4 alkyl)2, C 1-6 alkyl, C 1-6 haloalkyl, -O-C 1-4 alkyl, -S-C 1-4 alkyl, -S(O)2-C 1-4 alkyl, -C(C 1-2 alkyl)2OH, -NH-S(O)2-C 1-4 alkyl, or -O-C 2-3 alkylene-N(CH3)2.

[0198] Embodiment 44: The compound of any one of embodiments 26-43, or a pharmaceutically acceptable salt thereof, wherein R A is C 1-3 alkyl, R C is halogen, and R E is selected from H, halogen, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C3-4 Cycloalkyl.

[0199] Implementation Scheme 45: A compound or a pharmaceutically acceptable salt thereof from any one of Implementation Schemes 26-43, wherein R A For methyl, R C Let F be the integer part of the integer part, and R be the integer part of the integer part. E Selected from H, halogens, CN, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group and C 3-4 Cycloalkyl.

[0200] Implementation Scheme 46: A compound or a pharmaceutically acceptable salt thereof from any one of Implementation Schemes 26-43, wherein R A For methyl, R C Let F be the integer part of the integer part, and R be the integer part of the integer part. E It can be hydrogen, F, Cl, Br, CN, methyl or cyclopropyl.

[0201] Implementation Scheme 47: A compound or a pharmaceutically acceptable salt thereof from any one of Implementation Schemes 26-43, wherein R A For methyl, R C Let F be the integer part of the integer part, and R be the integer part of the integer part. E It can be hydrogen or F.

[0202] Implementation Scheme 48: A compound or a pharmaceutically acceptable salt thereof from any of Implementation Schemes 26-47, wherein R 1 C can be arbitrarily replaced by 1-3 Fs. 1-4 Alkyl groups or C groups optionally substituted with 1-3 F atoms 3-4 Cycloalkyl.

[0203] Implementation Scheme 49: A compound or a pharmaceutically acceptable salt thereof from any one of Implementation Schemes 26-48, wherein R 1 C can be arbitrarily replaced by 1-3 Fs. 1-4 Alkyl, preferably methyl, CHF2 or CF3.

[0204] Implementation Scheme 50: A compound of formula X-3 or a pharmaceutically acceptable salt thereof:

[0205]

[0206] in:

[0207] R 1 C is arbitrarily replaced 1-6 Alkyl groups, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 2-6 alkenyl or optionally substituted C 2-6alkynyl;

[0208] R A is C 1-3 alkyl;

[0209] R C is halogen or C 1-3 alkyl,

[0210] R E is selected from H, halogen, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl and C 3-4 cycloalkyl, wherein the C 1-4 alkyl, C 2-4 alkenyl and C 2-4 alkynyl are each optionally substituted with one or more substituents independently selected from F and OH, and the C 3-4 cycloalkyl is optionally substituted with one or more substituents independently selected from F, methyl and OH;

[0211] m2 is 0 or 1 ;

[0212] wherein R 10 and R 11 are at each occurrence independently selected from halogen, OH, NH2, CN, COOH, C(O)NH2, S(O)2NH2, G 1 , C(O)G 1 , OG 1 , NHG 1 , NG 1 G 1 , SG 1 , S(O)G 1 , S(O)2G 1 , P(O)G 1 G 1 , C(O)NHG 1 , S(O)2NHG 1 , S(O)2NG 1 G 1 , NHC(O)G 1 , NHS(O)2G 1 , N(G 1 )C(O)G 1 or N(G 1 )S(O)2G 1 , wherein G 1 is at each occurrence independently optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C3-10 carbocyclyl ring, optionally substituted 4-10 membered heterocyclyl ring, optionally substituted C 6-10 aryl or optionally substituted 5-10 membered heteroaryl; or

[0213] R 10 and R 11 , when adjacent to one another, together with the atoms interposed therebetween, form an optionally substituted C 5-10 carbocyclyl ring, optionally substituted 4-10 membered heterocyclyl ring, optionally substituted C 6-10 aryl ring or optionally substituted 5-10 membered heteroaryl ring.

[0214] Embodiment 51 : The compound of Embodiment 50, or a pharmaceutically acceptable salt thereof, characterized by having the formula according to X-3a:

[0215]

[0216] Embodiment 52: The compound of Embodiment 50, or a pharmaceutically acceptable salt thereof, characterized by having the formula according to X-3b:

[0217]

[0218] Embodiment 53: The compound of Embodiment 50, or a pharmaceutically acceptable salt thereof, wherein m2 is 0.

[0219] Embodiment 54: The compound of any one of Embodiments 50-53, or a pharmaceutically acceptable salt thereof, wherein R 10 is as defined in Embodiment 10.

[0220] Embodiment 55: The compound of any one of Embodiments 50-53, or a pharmaceutically acceptable salt thereof, wherein R 10 is as defined in Embodiment 11.

[0221] Embodiment 56: The compound of any one of Embodiments 50-53, or a pharmaceutically acceptable salt thereof, wherein R 10 is as defined in Embodiment 12.

[0222] Embodiment 57: The compound of any one of Embodiments 50-53, or a pharmaceutically acceptable salt thereof, wherein R 10 is as defined in Embodiment 13.

[0223] Embodiment 58: The compound of any one of Embodiments 50-53, or a pharmaceutically acceptable salt thereof, wherein R 10 is as defined in Embodiment 14.

[0224] Embodiment 59: The compound of any one of embodiments 50-53, or a pharmaceutically acceptable salt thereof, wherein R 10 is as defined in embodiment 15.

[0225] Embodiment 60: The compound of any one of embodiments 50-53, or a pharmaceutically acceptable salt thereof, wherein R 10 is as defined in embodiment 16.

[0226] Embodiment 61: The compound of any one of embodiments 50-53, or a pharmaceutically acceptable salt thereof, wherein R 10 is as defined in embodiment 17.

[0227] Embodiment 62: The compound of any one of embodiments 50-53, or a pharmaceutically acceptable salt thereof, wherein R 10 is as defined in embodiment 18.

[0228] Embodiment 63: The compound of any one of embodiments 50-53, or a pharmaceutically acceptable salt thereof, wherein R 10 is as defined in embodiment 19.

[0229] Embodiment 64: The compound of any one of embodiments 50-53, or a pharmaceutically acceptable salt thereof, wherein R 10 is as defined in embodiment 20.

[0230] Embodiment 65: The compound of any one of embodiments 50-53, or a pharmaceutically acceptable salt thereof, wherein R 10 is as defined in embodiment 21.

[0231] Embodiment 66: The compound of any one of embodiments 50-52 and 54-65, or a pharmaceutically acceptable salt thereof, wherein m2 is 1.

[0232] Embodiment 67: The compound of embodiment 66, or a pharmaceutically acceptable salt thereof, wherein R 11 is halogen, CN, R bx , -COR bx , -NHCOR bx , -CONH2, -CONHR bx , -CON(R bx )2, -OR bx , -NHR bx , -N(R bx )2, -SR bx , -SO2R bx , or -NHSO2R bx , wherein R bxis independently at each occurrence unsubstituted or substituted with one or more substituents independently selected from halogen (preferably F), OH, or N(CH3)2 1-6 alkyl.

[0233] Embodiment 68: The compound of Embodiment 66, or a pharmaceutically acceptable salt thereof, wherein R 11 F, Cl, CN, -C(O)-NH2, -C(O)-NH(C 1-4 alkyl), -C(O)-N(C 1-4 alkyl)2, C 1-6 alkyl, C 1-6 haloalkyl, -O-C 1-4 alkyl, -S-C 1-4 alkyl, -S(O)2-C 1-4 alkyl, -C(C 1-2 alkyl)2OH, -NH-S(O)2-C 1-4 alkyl, or -O-C 2-3 alkylene-N(CH3)2.

[0234] Embodiment 69: The compound of any one of Embodiments 50-68, or a pharmaceutically acceptable salt thereof, wherein R A is C 1-3 alkyl, R C is halogen, and R E is selected from H, halogen, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 3-4 cycloalkyl.

[0235] Embodiment 70: The compound of any one of Embodiments 50-68, or a pharmaceutically acceptable salt thereof, wherein R A is methyl, R C is F, and R E is selected from H, halogen, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 3-4 cycloalkyl.

[0236] Embodiment 71: The compound of any one of Embodiments 50-68, or a pharmaceutically acceptable salt thereof, wherein R A is methyl, R C is F, and R E is hydrogen, F, Cl, Br, CN, methyl, or cyclopropyl.

[0237] Embodiment 72: The compound of any one of Embodiments 50-68, or a pharmaceutically acceptable salt thereof, wherein RA is methyl, R C is F, and R E is hydrogen or F.

[0238] Embodiment 73: The compound of any one of embodiments 50-72, or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1-4 alkyl or C 3-4 cycloalkyl optionally substituted with 1-3 F.

[0239] Embodiment 74: The compound of any one of embodiments 50-72, or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1-4 alkyl optionally substituted with 1-3 F, preferably methyl, CHF2, or CF3.

[0240] Embodiment 75: A compound of Formula X-4a, X-4b, or X-4c, or a pharmaceutically acceptable salt thereof:

[0241]

[0242] wherein:

[0243] R 1 is optionally substituted C 1-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 2-6 alkenyl, or optionally substituted C 2-6 alkynyl;

[0244] R 2 is optionally substituted 5-14 membered heterocyclyl or optionally substituted 5-14 membered heteroaryl;

[0245] m1 is 0 or 1;

[0246] m2 is 0 or 1;

[0247] wherein R 10 and R 11 are independently at each occurrence selected from halogen, OH, NH2, CN, COOH, C(O)NH2, S(O)2NH2, G 1 , C(O)G 1 , OG 1 , NHG 1 , NG 1 G 1 , SG 1 , S(O)G 1 , S(O)2G 1 , P(O)G1 G 1 C(O)NHG 1 S(O)2NHG 1 S(O)2NG 1 G 1 ,NHC(O)G 1 、NHS(O)2G 1 、N(G 1 )C(O)G 1 or N(G) 1 )S(O)2G 1 G 1 Each time it appears, it is independently replaced by the arbitrarily chosen C. 1-6 Alkyl groups, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-10 Carbocyclic base ring, optionally substituted 4-10 membered heterocyclic base ring, optionally substituted C 6-10 aryl or optionally substituted 5-10 heteroaryl groups; or

[0248] R 10 and R 11 When adjacent to each other, they connect with the atoms between them to form optionally substituted C atoms. 5-10 Carbocyclic base ring, optionally substituted 5-10 membered heterocyclic base ring, optionally substituted C 6-10 The aryl ring or optionally substituted 5-10 membered heteroaryl ring; and

[0249] R d For H, halogen, OR 7 or NR 7 R 8 , where R 7 and R 8 Each independently represents H or the C that can be arbitrarily substituted. 1-4 alkyl.

[0250] Implementation Scheme 76: The compound of Implementation Scheme 75 or a pharmaceutically acceptable salt thereof, wherein R 1 C can be arbitrarily replaced by 1-3 Fs. 1-4 Alkyl groups or C groups optionally substituted with 1-3 F atoms 3-4 Cycloalkyl.

[0251] Implementation Scheme 77: The compound of Implementation Scheme 75 or a pharmaceutically acceptable salt thereof, wherein R 1 C can be arbitrarily replaced by 1-3 Fs. 1-4 Alkyl group, preferably methyl, CHF2 or CF3.

[0252] Embodiment 78: The compound of any one of embodiments 75-77, or a pharmaceutically acceptable salt thereof, wherein R 2 is an optionally substituted 6,5-fused bicyclic heteroaryl having 1 or 2 ring heteroatoms independently selected from O, N, or S, wherein when substituted, the 6,5-fused bicyclic heteroaryl is preferably substituted with 1-3 substituents each independently selected from halogen, CN, OH, C 1-4 alkyl optionally substituted with 1-3 F, C 1-4 alkoxy optionally substituted with 1-3 F, C 2-4 alkenyl optionally substituted with 1-3 F, C 2-4 alkynyl, or a 3-6 membered ring selected from carbocyclyl, heterocyclyl, or heteroaryl, optionally substituted with 1-3 substituents independently selected from F, methyl, or OH.

[0253] Embodiment 79: The compound of embodiment 78, or a pharmaceutically acceptable salt thereof, wherein in the 6,5-fused bicyclic heteroaryl, the 6-membered ring is selected from benzene, pyridine, pyrimidine, or pyrazine, and the 5-membered ring is selected from furan, pyrrole, pyrazole, imidazole, thiophene, oxazole, or thiazole.

[0254] Embodiment 80: The compound of embodiment 78, or a pharmaceutically acceptable salt thereof, wherein the 6,5-fused bicyclic heteroaryl is indole or benzofuran, preferably 2-indolyl or 2-benzofuranyl.

[0255] Embodiment 81: The compound of any one of embodiments 75-77, or a pharmaceutically acceptable salt thereof, wherein R 2 is an optionally substituted 2-benzofuranyl, wherein when substituted, the 2-benzofuranyl is preferably substituted with 1-3 substituents each independently selected from halogen (preferably F or Cl), CN, C 1-4 alkyl optionally substituted with 1-3 F, C 1-4 alkoxy optionally substituted with 1-3 F, C 2-4 alkenyl optionally substituted with 1-3 F, C 2-4 alkynyl, or C 3-4 cycloalkyl, optionally substituted with 1-3 substituents independently selected from F, methyl, or OH.

[0256] Embodiment 82: The compound of any one of embodiments 75-81, or a pharmaceutically acceptable salt thereof, wherein R d is NH2, NH(C 1-4 alkyl), or N(C 1-4 alkyl)(C 1-4 alkyl), preferably R d is NH2.

[0257] Embodiment 83: The compound of any one of embodiments 75-82, or a pharmaceutically acceptable salt thereof, wherein m1 is 1, and the compound is characterized as having the formula X-4a-1, X-4a-2, X-4b-1, X-4b-2, X-4c-1, or X-4c-2:

[0258]

[0259]

[0260] Embodiment 84: The compound of any one of embodiments 75-83, or a pharmaceutically acceptable salt thereof, wherein R 10 is as defined in any one of embodiments 10-21.

[0261] Embodiment 85: The compound of any one of embodiments 75-84, or a pharmaceutically acceptable salt thereof, wherein m2 is 0.

[0262] Embodiment 86: The compound of any one of embodiments 75-84, or a pharmaceutically acceptable salt thereof, wherein m2 is 1.

[0263] Embodiment 87: The compound of embodiment 86, or a pharmaceutically acceptable salt thereof, wherein R 11 is halogen, CN, R bx , -COR bx , -NHCOR bx , -CONH2, -CONHR bx , -CON(R bx )2, -OR bx , -NHR bx , -N(R bx )2, -SR bx , -SO2R bx , or -NHSO2R bx , wherein R bx is, at each occurrence, independently C 1-6 alkyl unsubstituted or substituted with one or more substituents independently selected from halogen (preferably F), OH, or N(CH3)2.

[0264] Embodiment 88: The compound of embodiment 86, or a pharmaceutically acceptable salt thereof, wherein R 11 is F, Cl, CN, -C(O)-NH2, -C(O)-NH(C 1-4 alkyl), -C(O)-N(C 1-4 alkyl)2, C 1-6 alkyl, C 1-6 haloalkyl, -O-C1-4 alkyl, -S-C 1-4 alkyl, -S(O)2-C 1-4 alkyl, -C(C 1-2 alkyl)2OH, -NH-S(O)2-C 1-4 alkyl or -O-C 2-3 alkylene-N(CH3)2.

[0265] In some embodiments, the compounds of any one of embodiments 1-88 can exist as individual stereoisomers or as a mixture of stereoisomers in any ratio. For example, in some embodiments, the compounds of X-1, X-la, X-lb, X-lc, X-2, X-3, X-3a, X-3b, X-4a, X-4a-l, X-4a-2, X-4b, X-4b-l, X-4b-2, X-4c, X-4c-l, or X-4c-2 can have the following chirality: For example, for a chiral carbon, the compound can have an enantiomeric excess (“ee”) greater than 50% (e.g., 60% ee or greater, 80% ee or greater, 90% ee or greater, 95% ee or greater, 98% ee or greater, 99% ee or greater). In some embodiments, the compounds of X-1, X-la, X-lb, X-lc, X-2, X-3, X-3a, X-3b, X-4a, X-4a-l, X-4a-2, X-4b, X-4b-l, X-4b-2, X-4c, X-4c-l, or X-4c-2 can have the following chirality: For example, for a chiral carbon, the compound can have an enantiomeric excess (“ee”) greater than 50% (e.g., 60% ee or greater, 80% ee or greater, 90% ee or greater, 95% ee or greater, 98% ee or greater, 99% ee or greater). In some embodiments, the compounds of X-1, X-la, X-lb, X-lc, X-2, X-3, X-3a, X-3b, X-4a, X-4a-l, X-4a-2, X-4b, X-4b-l, X-4b-2, X-4c, X-4c-l, or X-4c-2 can exist as a racemic mixture.

[0266] The compounds of any one of embodiments 1-88 are exemplary embodiments of Formula I, and Formula X-1, X-la, X-lb, X-lc, X-2, X-3, X-3a, X-3b, X-4a, X-4a-l, X-4a-2, X-4b, X-4b-l, X-4b-2, X-4c, X-4c-l, or X-4c-2 are subformulae of Formula I. In some embodiments, R10 and R 11 The definition may have the characteristics of R in this paper. a R b and R c Any of those not defined as hydrogen, provided that they apply and do not contradict the context. Other variables of formulas X-1, X-2, X-3, X-4a, X-4b, or X-4c (or their sub-formulas) in any of embodiments 1-88 may also have the corresponding definitions as defined herein with respect to formula I or its sub-formulas, provided that they apply and do not contradict the context.

[0267] In some embodiments, this disclosure also provides compounds selected from those shown in Table A or pharmaceutically acceptable salts thereof.

[0268] Table A: Exemplary Compounds of this Disclosure

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276] In some embodiments, the compounds in Table A may be present as individual stereoisomers (e.g., individual enantiomers) or as a mixture of stereoisomers (e.g., two enantiomers) in any ratio.

[0277] The compounds disclosed herein can be readily synthesized by those skilled in the art based on this disclosure. Example synthesis is also shown in the Examples section.

[0278] As will be apparent to those skilled in the art, conventional protecting groups can be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for a variety of functional groups, as well as suitable conditions for protecting and deprotecting particular functional groups, are well known in the art. For example, many protecting groups are described in “Protective Groups in Organic Synthesis”, 4th ed., P. G. M. Wuts; T. W. Greene, John Wiley, 2007, and references cited therein. The reagents used in the reactions described herein are well known compounds or can be prepared by known procedures or by obvious modifications thereof. For example, many of the reagents can be obtained from commercial suppliers (e.g., Aldrich Chemical Co. (Milwaukee, WI, USA), Sigma (St. Louis, MO, USA)). Other reagents can be prepared by procedures described in standard reference texts or by obvious modifications thereof, such as Fieser and Fieser’s “Reagents for Organic Synthesis” Vols. 1-15 (John Wiley and Sons, 1991), Rodd’s “Chemistry of Carbon Compounds” Vols. 1-5 and Supplemental (Elsevier Science Publishers, 1989), “Organic Reactions” Vols. 1-40 (John Wiley and Sons, 1991), March’s “Advanced Organic Chemistry” (Wiley, 7th ed.), and Larock’s “Comprehensive Organic Transformations” (VCH Publishers, 1989) and any available updates as of the filing date of this application.

[0279] Pharmaceutical compositions

[0280] Certain embodiments relate to pharmaceutical compositions comprising one or more compounds of the present disclosure.

[0281] The pharmaceutical compositions 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 I (e.g., Formula I-1, I-1-A, I-1-B, I-1-C, I-1-D, I-2, I-2-A, I-2-B, I-2-C, I-2-D, I-3, I-3-A, I-3-B, I-3-C, I-4, I-4-A, I-4-B, or I-4-C, or Formula X-1, X-la, X-lb, X-lc, X-2, X-3, X-3a, X-3b, X-4a, X-4a-l, X-4a-2, X-4b, X-4b-l, X-4b-2, X-4c, X-4c-l, or X-4c-2), any compound selected from the compounds illustrated 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, buffering agents, carriers, coating agents, colorants, diluents, disintegrants, emulsifiers, extenders, fillers, flavorants, humectants, lubricants, perfumes, preservatives, propellants, release agents, sterilants, sweeteners, solubilizers, wetting agents, and mixtures thereof. See also, Remington’s “The Science and Practice of Pharmacy” 21stEd., A.R. Gennaro (Lippincott, Williams & Wilkins, Baltimore, Md., 2005; incorporated herein by reference), which discloses various excipients used in formulation of pharmaceutical compositions and known techniques for their preparation.

[0282] A pharmaceutical composition can comprise any one or more of the compounds of the disclosure. For example, in some embodiments, a pharmaceutical composition comprises a compound of Formula I (e.g., Formula I-1, I-1-A, I-1-B, I-1-C, I-1-D, I-2, I-2-A, I-2-B, I-2-C, I-2-D, I-3, I-3-A, I-3-B, I-3-C, I-4, I-4-A, I-4-B, or I-4-C, or Formula X-1, X-la, X-lb, X-lc, X-2, X-3, X-3a, X-3b, X-4a, X-4a-l, X-4a-2, X-4b, X-4b-l, X-4b-2, X-4c, X-4c-l, or X-4c-2), 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, a pharmaceutical composition can comprise a therapeutically effective amount of a compound selected from the compounds shown in the Examples section, or a pharmaceutically acceptable salt thereof. In any of the embodiments described herein, a 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. In some preferred embodiments, the compounds of the disclosure used in the pharmaceutical compositions herein are selected from those compounds having an IC50 value of less than 1 micromolar (preferably less than 100 nM, or less than 50 nM) when tested in the PI3Ka_E545K kinase assay.

[0283] A pharmaceutical composition can also be formulated to be delivered via any known delivery route, including but not limited to oral, parenteral, inhalation, and the like.

[0284] In some embodiments, the pharmaceutical composition can be formulated for oral administration. Oral formulations can be presented as 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 liquid emulsion. Excipients used in preparing 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-butanediol, carbomer, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, cross-linked polyplarone, diglyceride, ethanol, ethyl cellulose, ethyl laurate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerin, groundnut oil, hydroxypropyl methyl cellulose, isopropyl alcohol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglyceride, 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 acid, stearyl fumarate, sucrose, surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof.

[0285] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (e.g., intravenous injection or infusion, subcutaneous or intramuscular injection). The parenteral formulation can be, for example, an aqueous solution, suspension, or emulsion. Excipients used in preparing 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.

[0286] In some embodiments, the pharmaceutical composition is formulated for inhalation. Inhalable formulations can be, for example, formulated as nasal sprays, dry powders, or aerosols that can be administered by metered dose inhalers. Excipients used in preparing formulations for inhalation are known in the art. Non-limiting suitable excipients include, for example, lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powders, and mixtures of these substances. The spray can also contain a propellant, such as chlorofluorocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0287] Pharmaceutical compositions can comprise various amounts of a compound of the disclosure, depending on factors such as the intended use and potency and selectivity of the compound. In some embodiments, a pharmaceutical composition comprises a therapeutically effective amount of a compound of the disclosure (e.g., a compound of Formula I (e.g., Formula I-1, I-1-A, I-1-B, I-1-C, I-1-D, I-2, I-2-A, I-2-B, I-2-C, I-2-D, I-3, I-3-A, I-3-B, I-3-C, I-4, I-4-A, I-4-B, or I-4-C, or Formula X-1, X-la, X-lb, X-lc, X-2, X-3, X-3a, X-3b, X-4a, X-4a-l, X-4a-2, X-4b, X-4b-l, X-4b-2, X-4c, X-4c-l, or X-4c-2), any compound selected from the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof). In some embodiments, a pharmaceutical composition comprises a therapeutically effective amount of a compound of the disclosure and a pharmaceutically acceptable excipient. As used herein, a therapeutically effective amount of a compound of the disclosure is an amount effective for treating a disease or disorder as described herein (such as a cancer as described herein), which can depend on the recipient of the treatment, the disease or disorder being treated, and its severity, the composition containing the compound, the time of administration, the route of administration, the duration of the treatment, the potency of the compound (e.g., for inhibiting PI3K), its clearance rate, and whether another drug is co-administered.

[0288] For veterinary use, the compounds of the disclosure can be administered in an appropriate acceptable formulation in accordance with normal veterinary practice. The veterinarian can determine the dosage regimen and route of administration most appropriate for a particular animal.

[0289] In some embodiments, all of the necessary components for treating a PI3K-related disease or disorder using a compound of the disclosure, either alone or in combination with another agent or intervention traditionally used to treat such a disease, can be packaged into a kit. In particular, in some embodiments, the present application provides a kit for therapeutic intervention in a disease, comprising a packaged pharmaceutical set comprising a compound disclosed herein and buffers and other components for preparing deliverable forms of the drug, and / or a device for delivering such a drug, and / or any reagents for use in combination therapy with a compound of the disclosure, and / or instructions for treating a disease packaged with the drug. The instructions can be fixed in any tangible medium of expression, e.g., printed paper, or a computer-readable medium, or instructions referenced from remote computer data sources, e.g., web pages accessible via the Internet.

[0290] Methods of treatment

[0291] The compounds of the present disclosure are useful as therapeutically active substances for the treatment and / or prophylaxis of diseases or conditions associated with the activity of phosphoinositide 3 kinases (PI3K), in particular PI3K-alpha (PI3Ka), such as those having activating mutations (e.g., at least one mutation selected from H1047R, E542K, and E545K mutations). Such diseases or conditions include proliferative diseases (e.g., cancer).

[0292] In some embodiments, the present disclosure provides a method of inhibiting the activity of phosphoinositide 3 kinases (PI3K), in particular PI3K-alpha (PI3Ka), in a cell, comprising contacting the cell with an effective amount of one or more compounds of the present disclosure (e.g., a compound of Formula I (e.g., Formula I-1, I-1-A, I-1-B, I-1-C, I-1-D, I-2, I-2-A, I-2-B, I-2-C, I-2-D, I-3, I-3-A, I-3-B, I-3-C, I-4, I-4-A, I-4-B, or I-4-C, or Formula X-1, X-la, X-lb, X-lc, X-2, X-3, X-3a, X-3b, X-4a, X-4a-l, X-4a-2, X-4b, X-4b-l, X-4b-2, X-4c, X-4c-l, or X-4c-2), any compound selected from the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof). As used herein, the term "cell" is intended to refer to a cell 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 bringing the indicated moieties together in an in vitro system or in an in vivo system. For example, "contacting" a PI3K with a compound of the present disclosure includes administering a compound of the present disclosure to a subject (e.g., a human) having a PI3K, as well as, for example, introducing a compound of the present disclosure into a sample containing a cell or purified preparation containing a PI3K enzyme. The term "PI3K inhibitor" such as a PI3Ka inhibitor refers to an agent capable of inhibiting the activity of a PI3K.

[0293] In some embodiments, the present disclosure provides a method of treating a disease associated with the activity or expression of PI3K, including abnormal activity and / or overexpression, 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 I (e.g., Formula I-1, I-1-A, I-1-B, I-1-C, I-1-D, I-2, I-2-A, I-2-B, I-2-C, I-2-D, I-3, I-3-A, I-3-B, I-3-C, I-4, I-4-A, I-4-B, or I-4-C, or Formula X-1, X-la, X-lb, X-lc, X-2, X-3, X-3a, X-3b, X-4a, X-4a-l, X-4a-2, X-4b, X-4b-l, X-4b-2, X-4c, X-4c-l, or X-4c-2), 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 associated with the expression or activity of PI3K enzymes, such as overexpression or abnormal activity. PI3K-related diseases can also include any disease, disorder, or condition that can be prevented, ameliorated, or cured by modulating PI3K enzyme activity. Examples of PI3K-related diseases include various cancers described herein. In any of the embodiments described herein, unless otherwise stated or contradicted, the PI3K enzyme can be a PI3Ka enzyme, such as those with E545K mutations. Examples of PI3K-related cancers include breast cancer, endometrial cancer, gastric cancer, colorectal cancer, ovarian cancer, cervical cancer, head and neck cancer, liver cancer, lung cancer, prostate cancer. Examples of PI3K-related diseases also include CLOVES syndrome (congenital lipomatous overgrowth, vascular malformation, epidermal nevus, scoliosis / osteofascial, and spinal syndrome) or PIK3CA-related overgrowth syndrome (PROS). In some embodiments, the disease or disorder associated with PI3K is a cancer (e.g., a cancer described herein, such as breast cancer, endometrial cancer, gastric cancer, colorectal cancer, ovarian cancer, cervical cancer, head and neck cancer, liver cancer, lung cancer, prostate cancer, leukemia, lymphoma, sarcoma, and melanoma.In some embodiments, the disease or disorder associated with PI3K includes, but is not limited to, CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis / skeletal and spinal syndrome), PIK3CA-related overgrowth syndrome (PROS), endometrial cancer, breast cancer, esophageal squamous cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, glioblastoma, ovarian cancer, non-small cell lung cancer, esophagogastric cancer, schwannoma, head and neck squamous cell carcinoma, melanoma, esophagogastric adenocarcinoma, soft tissue sarcoma, prostate cancer, fibroplastic carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, cholangiocarcinoma, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, kidney non-clear cell carcinoma, kidney clear cell carcinoma, germ cell carcinoma, thymic tumor, pheochromocytoma, miscellaneous. Additional diseases or disorders associated with PI3K are described herein and also include those described in WO 2021 / 202964, WO 2022 / 235574, WO 2022235575, WO 2022251482, WO 2021 / 222556, WO 2022265993, WO 2023 / 018636, and WO 2023 / 288242.

[0294] In some embodiments, the present disclosure provides a method of treating a 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 I (e.g., Formula I-1, I-1-A, I-1-B, I-1-C, I-1-D, I-2, I-2-A, I-2-B, I-2-C, I-2-D, I-3, I-3-A, I-3-B, I-3-C, I-4, I-4-A, I-4-B, or I-4-C, or Formula X-1, X-la, X-lb, X-lc, X-2, X-3, X-3a, X-3b, X-4a, X-4a-l, X-4a-2, X-4b, X-4b-l, X-4b-2, X-4c, X-4c-l, or X-4c-2), 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 associated with PI3K (e.g., PI3Ka). In some embodiments, the cancer is breast cancer, endometrial cancer, gastric cancer, colorectal cancer, ovarian cancer, cervical cancer, head and neck cancer, liver cancer, lung cancer, prostate cancer. Additional cancers suitable for treatment include those described herein.

[0295] In some embodiments, the cancer is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer, astrocytic tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, osteosarcoma, malignant fibrous histiocytoma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, carcinoma of unknown primary origin, cardiac (heart) tumor, atypical teratoid / rhabdoid tumor, primary CNS lymphoma, cervical cancer, cholangiocarcinoma, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, mycosis fungoides, Sezary Syndrome, ductal carcinoma in situ (DCIS), embryonal tumor, medulloblastoma, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic disease, hairy cell leukemia, head and neck cancer, hepatocellular cancer, Langerhans cell histiocytosis, Hodgkin lymphoma, islet cell tumor, pancreatic neuroendocrine tumor, Kaposi sarcoma, kidney cancer, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, male breast cancer, intraocular melanoma, Merkel cell carcinoma, malignant mesothelioma, metastatic cancer, metastatic squamous neck cancer, midline tract carcinoma with nut gene alterations, mouth cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasm, myelodysplastic syndrome, myelodysplastic neoplasm, myeloproliferative neoplasm, chronic myelogenous neoplasm, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, lip and oral cavity cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumor (islet cell tumor), papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, plasma cell neoplasm, multiple myeloma, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, recurrent cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, childhood vascular tumor, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, skin squamous cell carcinoma, testicular cancer, tonsil cancer, hypopharyngeal cancer, thymoma, thymic carcinoma, thyroid cancer, tracheal bronchial tumor, renal pelvis and ureter transitional cell cancer, urethral cancer, uterine sarcoma, vaginal cancer, vascular tumor, vulvar cancer, and Wilms tumor.

[0296] In some embodiments, the cancer is endometrial cancer, breast cancer, esophageal squamous cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, urothelial carcinoma of the bladder, glioblastoma, ovarian cancer, non-small cell lung cancer, esophagogastric cancer, schwannoma, head and neck squamous cell carcinoma, melanoma, esophagogastric adenocarcinoma, soft tissue sarcoma, prostate cancer, fibroblastic carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, cholangiocarcinoma, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, renal non-clear cell carcinoma, renal clear cell carcinoma, germ cell carcinoma, thymic tumor, pheochromocytoma, miscellaneous neuroepithelial tumor, thyroid cancer, leukemia, or ependymal glioma.

[0297] In some embodiments, the cancer is breast cancer, prostate cancer, or brain cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is brain cancer.

[0298] In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is ductal carcinoma in situ (DCIS). In some embodiments, the breast cancer is invasive ductal carcinoma. In some embodiments, the breast cancer is triple negative breast cancer. In some embodiments, the breast cancer is medullary carcinoma. In some embodiments, the breast cancer is tubular carcinoma. In some embodiments, the breast cancer is mucinous carcinoma. In some embodiments, the breast cancer is Paget's disease of the breast or nipple. In some embodiments, the breast cancer is inflammatory breast cancer (IBC).

[0299] In some embodiments, the prostate cancer is adenocarcinoma. In some embodiments, the prostate cancer is small cell carcinoma. In some embodiments, the prostate cancer is neuroendocrine tumor. In some embodiments, the prostate cancer is transitional cell carcinoma. In some embodiments, the prostate cancer is sarcoma.

[0300] In some embodiments, the brain cancer is acoustic neuroma. In some embodiments, the brain cancer is astrocytoma. In some embodiments, the brain cancer is brain metastasis. In some embodiments, the brain cancer is choroid plexus carcinoma. In some embodiments, the brain cancer is craniopharyngioma. In some embodiments, the brain cancer is embryonal tumor. In some embodiments, the brain cancer is ependymoma. In some embodiments, the brain cancer is glioblastoma. In some embodiments, the brain cancer is glioma. In some embodiments, the brain cancer is medulloblastoma. In some embodiments, the brain cancer is meningioma. In some embodiments, the brain cancer is oligodendroglioma. In some embodiments, the brain cancer is pediatric brain tumor. In some embodiments, the brain cancer is pineal cell tumor. In some embodiments, the brain cancer is pituitary tumor.

[0301] In some embodiments, the cancer is endometrial cancer, head and neck cancer, or sarcoma.

[0302] In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is a sarcoma.

[0303] In some embodiments, the sarcoma is a soft tissue sarcoma, a bone sarcoma, a chondrosarcoma, an Ewing sarcoma, an angioendothelioma, an angiosarcoma, a fibrosarcoma, a myofibrosarcoma, a chordoma, an adamantinoma, a liposarcoma, a leiomyosarcoma, a malignant peripheral nerve sheath tumor, a rhabdomyosarcoma, a synovial sarcoma, or a malignant solitary fibrous tumor.

[0304] In some embodiments, the sarcoma is a soft tissue sarcoma. In some embodiments, the soft tissue sarcoma is a liposarcoma, an atypical lipoma, a dermatofibrosarcoma protuberans, a malignant solitary fibrous tumor, an inflammatory myofibroblastic tumor, a low-grade myofibroblastic sarcoma, a fibrosarcoma, a myxofibrosarcoma, a low-grade fibromyxoid sarcoma, a soft tissue giant cell tumor, a leiomyosarcoma, a malignant glomus tumor, a rhabdomyosarcoma, an angioendothelioma, a soft tissue angiosarcoma, an extraskeletal osteosarcoma, a gastrointestinal stromal tumor, a malignant gastrointestinal stromal tumor (GIST), a malignant peripheral nerve sheath tumor, a malignant Triton tumor, a malignant granular cell tumor, a malignant ossifying fibromyxoid tumor, a stromal sarcoma, a myoepithelial carcinoma, a malignant phosphaturic mesenchymal tumor, a synovial sarcoma, an epithelioid sarcoma, a alveolar soft part sarcoma, a clear cell sarcoma of soft tissue, an extraskeletal myxoid chondrosarcoma, an extraskeletal Ewing sarcoma, a desmoplastic small round cell tumor, an extrarenal rhabdoid tumor, a perivascular epithelioid cell tumor, an endometrial stromal sarcoma, an undifferentiated spindle cell sarcoma, an undifferentiated pleomorphic sarcoma, an undifferentiated round cell sarcoma, an undifferentiated epithelioid sarcoma, or an undifferentiated sarcoma not otherwise specified.

[0305] In some embodiments, the present disclosure provides a method of treating a disease or disorder 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 I (e.g., Formula I-1, I-1-A, I-1-B, I-1-C, I-1-D, I-2, I-2-A, I-2-B, I-2-C, I-2-D, I-3, I-3-A, I-3-B, I-3-C, I-4, I-4-A, I-4-B, or I-4-C, or Formula X-1, X-la, X-lb, X-lc, X-2, X-3, X-3a, X-3b, X-4a, X-4a-l, X-4a-2, X-4b, X-4b-l, X-4b-2, X-4c, X-4c-l, or X-4c-2), 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, wherein the disease or disorder is selected from CLOVES syndrome (congenital lipomatous overgrowth, vascular malformation, epidermal nevus, scoliosis / skeletal and spinal syndrome), PIK3CA- related overgrowth syndrome (PROS), breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer. In some embodiments, the disease or disorder is leukemia, lymphoma, or sarcoma.

[0306] In some preferred embodiments, the compounds of the present disclosure for use in the methods herein are selected from those compounds having an IC50 value of less than 1 micromolar (preferably less than 100 nM, or less than 50 nM) when tested in a PI3Ka_E545K kinase assay.

[0307] The compounds of the present disclosure can be used as monotherapy or in combination therapy. In some embodiments, the combination therapy comprises treating the subject with a targeted therapeutic agent, a chemotherapeutic agent, a therapeutic antibody, radiation, cell therapy, and / or immunotherapy. In some embodiments, the compounds of the present disclosure can also be co-administered to a subject in need thereof simultaneously or sequentially in any order with an additional pharmaceutically active compound. In some embodiments, the combination therapy comprises treating the subject with one or more additional therapies such as a chemotherapeutic agent or other anticancer agent.

[0308] The combination therapy can also comprise administering the therapeutic agent as described above in further combination with other biologically active ingredients and / or non-pharmaceutical therapies (e.g., surgery or radiation therapy).

[0309] Administration herein is not limited to any particular route of administration. For example, in some embodiments, the administration can be oral, nasal, transdermal, pulmonary, inhalation, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal, or parenteral. In some embodiments, the administration is oral administration.

[0310] The dosage regimen (including dosage amounts) can vary and can be adjusted by the individualizing physician depending upon the recipient's condition, the disease or disorder being treated, its severity, the composition administered, the time of administration, the route of administration, the duration of the treatment, the potency of the compound, its clearance rate, and whether or not another drug is being administered in combination.

[0311] Definitions

[0312] It is understood that all moieties and combinations thereof are maintained as appropriate charge valencies.

[0313] It is also understood that a particular embodiment of a variable moiety herein can be the same as or different from another particular embodiment of the same variable moiety.

[0314] Non-limiting useful groups for the variables in the compounds of Formula I or its subformulae (as applicable) include any corresponding group, individually or in any combination, as shown in the specific compounds described in the Examples or in Table A herein. In addition, it is understood that the definition of a variable in Formula I can have the same definition as defined for a variable in a subformula of Formula I. Similarly, unless otherwise indicated or contrary to context, the definition of a subformula of Formula I can have the same definition as a variable defined with respect to Formula I or another subformula of Formula I.

[0315] The atoms or groups suitable for the variables herein are selected independently. The definitions of the variables can be combined. Using Formula I as an example, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, X a , X b , X c , Y, Z, R a , R ax , R b , R bx , R c , R cx , R d , R e , R f , R A , R B , R B’ , R C , R C’ , R DR D’ R E R E’ G and G A Any definition of R in Equation I or its applicable sub-equations can be used with Equation I. 1 R 2 R 3 R 4 R 5 R 6 X, X a X b X c Y, Z, R a R ax R b R bx R c R cx R d R e R f R A R B R B’ R C R C’ R D R D’ R E R E’ G and G A Any other combination of definitions in the present invention. Such combinations are contemplated and are within the scope of the invention.

[0316] Definitions of specific functional groups and chemical terms are described below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. inside cover, and specific functional groups are generally defined as in the Handbook of Synthetic Organic Chemistry, 3rdEd., John Wiley & Sons, Inc., New York, 1989. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity principles, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5thEd., 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, 3rdEd., Cambridge University Press, Cambridge, 1987. The disclosure is not intended to be limited in any way by the exemplary list of substituents described herein.

[0317] The compounds of the present disclosure can contain one or more asymmetric centers and / or axial chirality, and thus can exist in various isomeric forms (e.g., enantiomeric and / or diastereomeric forms). 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 a racemic mixture and a mixture enriched in one or more stereoisomer. Isomers can be separated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) or supercritical fluid chromatography (SFC) and formation and crystallization of chiral salts; or, preferred isomers can be made by asymmetric synthesis. See, e.g., 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 present disclosure also encompasses the compounds described herein as individual isomers substantially free of other isomers and, alternatively, as mixtures of various isomers, including racemic mixtures. Where stereochemistry is drawn explicitly, it is understood that, for that particular chiral center or axial chirality, the compound predominantly exists as the stereoisomer as drawn, e.g., has less than 20% by weight, less than 10% by weight, less than 5% by weight, less than 1% by weight of the other stereoisomer, or the amount of the other stereoisomer is not detectable, e.g., has an enantiomeric excess (“ee”) of greater than 50% (e.g., 60% ee or greater, 80% ee or greater, 90% ee or greater, 95% ee or greater, 98% ee or greater, or 99% ee or greater), according to HPLC or SFC area or both. One skilled in the art can determine the presence and / or amount of stereoisomer(s) according to the present disclosure, including by using chiral HPLC or SFC.

[0318] 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 , C1–3 , 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 .

[0319] As used herein, the term “compound of the present disclosure” or “compound of the invention” refers to any one of the compounds described herein according to Formula I (e.g., Formula I-1, I-1-A, I-1-B, I-1-C, I-1-D, I-2, I-2-A, I-2-B, I-2-C, I-2-D, I-3, I-3-A, I-3-B, I-3-C, I-4, I-4-A, I-4-B, or I-4-C, or any one of those according to embodiments 1-88), any one of the compounds shown in Table A and in the Examples section, isotopically-labeled compounds thereof (such as deuterated analogs in which one or more hydrogen atoms are replaced by deuterium atoms having an abundance higher than their natural abundance), possible stereoisomers thereof (including diastereomers, enantiomers, and racemic mixtures), geometric isomers thereof, atropisomers thereof, tautomers thereof, conformational isomers thereof, and / or pharmaceutically acceptable salts thereof (e.g., acid addition salts such as HC1 salts, or base addition salts such as Na salts). Hydrates and solvates of the compounds of the present disclosure are considered compositions of the present disclosure, wherein the compound is associated with water or a solvent, respectively. In some embodiments, the compound of the present disclosure refers to those defined in any one of claims 1-65. In some embodiments, the compound of the present disclosure refers to any one of those defined in embodiments 1-88 listed herein.

[0320] The compounds of the present disclosure can exist in isotopically-labeled or isotopically-enriched forms, which contain one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most abundant in nature. The isotopes can be radioactive or non-radioactive. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine include, but are not limited to 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 32 P, 35 S, 18 F, 36 Cl and 125I. Compounds containing other isotopes of these and / or other atoms are within the scope of this invention.

[0321] As used herein, the term "one or more species" means one or more species. For example, in some embodiments, the term "one or more species" means one or two species. In some embodiments, the term "one or more species" means one, two, or three species. In some embodiments, the term "one or more species" means one, two, three, or four species. In some embodiments, the term "one or more species" means one, two, three, four, or five species.

[0322] As used herein, the term "alkyl" on its own or as part of another group refers to a straight-chain or branched aliphatic saturated hydrocarbon. In some embodiments, the alkyl group may contain one to twelve carbon atoms (i.e., C64 ... 1-12 Alkyl group or a specified number of carbon atoms (i.e., C1 alkyl such as methyl, C2 alkyl such as ethyl, C3 alkyl such as propyl or isopropyl, etc.). In one embodiment, the alkyl group is a straight-chain C1 alkyl group. 1-10 Alkyl group. In another embodiment, the alkyl group is a branched C-chain. 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 C-chain. 3-6 Alkyl group. In another embodiment, the alkyl group is a straight-chain C. 1-4 Alkyl groups. For example, C as used herein. 1-4 Alkyl groups are selected from methyl, ethyl, propyl (n-propyl), isopropyl, butyl (n-butyl), sec-butyl, tert-butyl, and isobutyl groups. The substituted C- group is optional. 1-4 Alkyl groups refer to C14 groups that are optionally substituted with one or more permissible substituents as defined herein. 1-4 Alkyl groups. As used herein, the term "alkylene" on its own or as part of another group refers to a divalent group derived from an alkyl group. For example, non-limiting straight-chain alkylene groups include -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-, etc.

[0323] As used herein, the term "heteroalkyl" on its own or in combination with another term, unless otherwise specified, refers to a stable straight-chain or branched alkyl group having, for example, 2 to 14 carbons, such as 2 to 10 carbons, in the chain, wherein one or more carbons have been replaced with heteroatoms selected from S, O, P, and N, and wherein nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and nitrogen heteroatoms may optionally be quaternized. Heteroatoms S, O, P, and N may be located at any internal position of the heteroalkyl group or at a position where the alkyl group is attached to the remainder of the molecule. When heteroalkyl is described as substituted, a substituent may replace one or more carbon atoms and / or hydrogen atoms attached to the heteroalkyl group. In some embodiments, the heteroalkyl is C 1-4 Heteroalkyl, as defined herein, refers to a heteroalkyl group having 1-4 carbon atoms. C 1-4 Examples of heteroalkyl groups include, but are not limited to, C4 heteroalkyl groups such as -CH2-CH2-N(CH3)-CH3, C3 heteroalkyl groups 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 groups such as -CH2-CH2-OH, -CH2-CH2-NH2, -CH2-NH(CH3), -O-CH2-CH3, and C1 heteroalkyl groups such as -CH2-OH, -CH2-NH2, -O-CH3. Preferably, C... 1-4 Heteroalkyl (or C) 1-4 Heteroalkyl groups contain one or two heteroatoms, such as one oxygen, one nitrogen, two oxygens, two nitrogens, or one oxygen and one nitrogen. Similarly, the term "heteroalkyl" itself, or as part of another substituent, refers to a divalent group derived from a heteroalkyl group, such as, but not limited to, -CH2-CH2-O-CH2-CH2- and –O-CH2-CH2-NH-CH2-. For heteroalkyl groups, the heteroatom may also occupy one or both of the chain ends (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Furthermore, for alkylene and heteroalkyl linking groups, the direction in which the formula of the linking group is written does not imply the orientation of the linking group. When referring to "heteroalkyl" followed by specific heteroalkyl groups such as "-NR'R", it should be understood that the terms "heteroalkyl" and "-NR'R" are not redundant or mutually exclusive. Rather, specific heteroalkyl groups are described for clarity. Therefore, the term "heteroalkyl" should not be construed herein as excluding specific heteroalkyl groups such as "-NR'R".

[0324] As used herein, the term "alkenyl" on its own or as part of another group refers to an alkyl group as defined above that contains one, two, or three carbon-carbon double bonds. In one embodiment, the alkenyl group is C 2-6Alkenyl group. In another embodiment, the alkenyl group is C 2-4 Alkenyl group. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

[0325] As used herein, the term "alkynyl," by itself or as part of another substituent, refers to an alkyl group, as defined above, containing from one to three carbon-carbon triple bonds. In one embodiment, the alkynyl group has one carbon-carbon triple bond. In one embodiment, the alkynyl group is C 2-6 Alkynyl group. In another embodiment, the alkynyl group is C 2-4 Alkynyl group. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl.

[0326] As used herein, the term "alkoxy," by itself or as part of another substituent, refers to a group of the formula -OR a1 where R a1 is an alkyl group.

[0327] As used herein, the term "haloalkyl," by itself or as part of another substituent, refers to an alkyl group that is substituted with one or more fluorine, chlorine, bromine, and / or iodine atoms. In a preferred embodiment, the haloalkyl is an alkyl group that is substituted with one, two, or three fluorine atoms. In one embodiment, the haloalkyl group is C 1-10 Haloalkyl group. In one embodiment, the haloalkyl group is C 1-6 Haloalkyl group. In one embodiment, the haloalkyl group is C 1-4 Haloalkyl group.

[0328] "Carbocyclyl" or "carbocyclic" by itself or as part of another substituent refers to a non-aromatic, cyclic hydrocarbon group of 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 monocyclic ("monocyclic carbocyclyl") or contain fused, bridged or spiro ring systems, such as a bicyclic ring system ("bicyclic carbocyclyl"), and can be saturated or can be partially unsaturated. In a bicyclic carbocyclyl, one of the rings can be an aryl ring, provided that the bicyclic carbocyclyl as a whole is non-aromatic. Non-limiting exemplary carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalinyl, adamantyl, cyclopentenyl, and cyclohexenyl.

[0329] In some embodiments, "carbocyclyl" is a saturated carbocyclyl group having from 3 to 14 ring carbon atoms ("C 3–14cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 10 cyclic carbon atoms (“C”). 3–10 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 8 cyclic carbon atoms (“C”). 3–8 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 6 cyclic carbon atoms (“C”). 5–6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 10 cyclic carbon atoms (“C”). 5–10 cycloalkyl).

[0330] When used alone or as part of another group, "heterocyclic group" or "heterocyclic" refers to a group having a 3- to 14-membered non-aromatic ring system with a ring carbon atom and one to four ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 14-membered heterocyclic group"). In heterocyclic groups containing one or more nitrogen atoms, the linking point can be a carbon or nitrogen atom, where the valence allows. Heterocyclic groups can be monocyclic ("monocyclic heterocyclic group") or fused, bridged, or spirocyclic ring systems, such as bicyclic systems ("bicyclic heterocyclic group"), and can be saturated or partially unsaturated. A bicyclic heterocyclic system can contain one or more heteroatoms in one or both rings. In a bicyclic heterocyclic group, one of the rings can be a carbocyclic ring, an aryl ring, or a heteroaryl ring, provided that the bicyclic heterocyclic group as a whole is non-aromatic.

[0331] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, azircyclopropane, oxacyclopropane, and thiocyclopropane. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azircyclobutane, oxacyclobutane, and thiocyclobutane. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxasulfuranyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and tetrahydrothiaranyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithiaalkyl, and dioxaneyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, triazinealkyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxetaneheptyl, and thioheptanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxetaneheptyl, and thioheptanyl. Exemplary 5-membered heterocyclic groups fused with a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic rings) include, but are not limited to, dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolidinone, etc. Exemplary 6-membered heterocyclic groups fused with aryl rings (also referred to herein as 6,6-bicyclic heterocyclic rings) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0332] When used alone or as part of another group, "aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) group with a 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the ring array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system. 6–14 Aryl group (“C6 aryl”); in some embodiments, the aryl group has six ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has ten ring carbon atoms (“C6 aryl”). 10 Aryl group; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen ring carbon atoms (“C14”). 14 "Aryl"; for example, anthracene.

[0333] "Aryl" by itself or as part of another group refers to a 6-14 carbon aromatic ring system (e.g., having 4n+2 electrons shared in a cyclic array) having one or more aromatic rings (e.g., phenyl, naphthyl, indanyl, indenyl, etc.). The point of attachment can be to a carbon or, if valence permits, to a nitrogen of the aryl group. The aryl group can be optionally substituted.

[0334] "Heteroaryl" by itself or as part of another group refers to a 5-14 membered monocyclic or bicyclic ring system having ring carbon atoms and 1-4 ring heteroatoms (where each heteroatom is independently selected from nitrogen, oxygen, and sulfur) provided in an aromatic ring system (e.g., having 4n+2 electrons shared in a cyclic array) ("5-14 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or a nitrogen atom, if valence permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. Bicyclic heteroaryl groups in which one ring contains no heteroatoms (e.g., indolyl, quinolyl, etc.), the point of attachment can be on either ring, either the ring with the heteroatom (e.g., 2-indolyl) or the ring with no heteroatoms (e.g., 5-indolyl). For the avoidance of doubt, the term "heteroaryl" herein also includes those heteroaromatic rings in which a nitrogen is oxidized, such as pyridyl N-oxides, and those heteroaromatic rings in which one or more ring carbon atoms are present as C(O) in one tautomeric form, such as pyridonyl.

[0335] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0336] "Heteroaralkyl," by itself or as part of another group, means an alkyl group, preferably a lower alkyl group, substituted with one or more heteroaryl groups, preferably one heteroaryl group. When a heteroaralkyl group is described as optionally substituted, the alkyl portion or the heteroaryl portion of the heteroaralkyl group can be optionally substituted.

[0337] As is generally understood by those skilled in the art, alkylene, alkenylene, alkynylene, carbocyclylene, heterocyclylene, arylene, and heteroarylene refer to the corresponding bivalent groups derived from, respectively, an alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl radical.

[0338] "Optionally substituted" groups, such as optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl groups, refer to unsubstituted or substituted corresponding groups. In general, the term "substituted", whether preceded by the term "optionally" or not, refers to the replacement of hydrogen by a permissible substituent, such as, for example, a substituent that results in a stable compound, i.e., a compound that does not spontaneously undergo transformation (e.g., by rearrangement, cyclization, elimination, or other reaction) under reasonable chemical conditions. Unless otherwise indicated, a "substituted" group is substituted at one or more substitutable positions with substituents, and when more than one position is substituted, the substituents can be the same or different at each position. Generally, when substituted, an optionally substituted group herein can be substituted with 1-5 substituents. As applicable, substituents can be carbon atom substituents, nitrogen atom substituents, oxygen atom substituents, or sulfur atom substituents.

[0339] Unless specifically indicated otherwise, the combination of substituents and / or variables is only permitted where such combination is chemically allowed and produces a stable compound. A "stable compound" is a compound that can be prepared and isolated without the presence of steps that result in the spontaneous loss of the compound, such as, for example, a compound that can be prepared and isolated, and whose structure and properties remain essentially the same for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic administration to a subject), or can be made to remain essentially the same.

[0340] In some embodiments, an "optionally substituted" non-aromatic group herein can be unsubstituted or substituted with 1, 2, or 3 substituents, or even 4 or 5 substituents, independently selected from F, Cl, -OH, oxo (as applicable), 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 or 2 ring heteroatoms independently selected from O, S, and N, or even 3 or 4 ring heteroatoms independently selected from O, S, and N, 4-7 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, or even 3 or 4 ring heteroatoms independently selected from O, S, and N, or independently selected from Br, I, -NH2, and -CN, wherein each of the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy, phenyl, heteroaryl, and heterocyclyl groups is optionally substituted with 1, 2, or 3 substituents, or even 4 or 5 substituents, independently selected from F, -OH, oxo (as applicable), C 1-4 alkyl, fluoro-substituted C1-4 alkyl (e.g., CF3), C 1-4 alkoxy and fluorine-substituted C 1-4 alkoxy, or independently selected from Cl, Br, I, -NH2, and -CN. In some embodiments, "optionally substituted" aromatic groups (including aryl and heteroaryl groups) herein can be unsubstituted or substituted with 1, 2, or 3 substituents or even 4 or 5 substituents independently selected from F, Cl, -OH, -CN, 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 or 2 ring heteroatoms independently selected from O, S, and N or even 3 or 4 ring heteroatoms independently selected from O, S, and N, 4-7 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S, and N or even 3 or 4 ring heteroatoms independently selected from O, S, and N, or independently selected from Br, I, and -NH2, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy, phenyl, heteroaryl, and heterocyclyl is optionally substituted with 1, 2, or 3 substituents or even 4 or 5 substituents independently selected from F, -OH, oxo (as applicable), C 1-4 alkyl, fluorine-substituted C 1-4 alkyl, C 1-4 alkoxy and fluorine-substituted C 1-4 alkoxy, or independently selected from Cl, Br, -NH2, and -CN.

[0341] Exemplary carbon atom substituents include, without limitation, 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(Rbb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=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 bb C(=NR bb )N(R bb )2, -C(=O)NR bb SO2R aa , -NR bb SO2R 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 bb P(=O)(OR cc )2、–NR bb P(=O)(N(R bb )2)2、–P(R cc 2. -P(OR) cc )2、–P(R cc )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 )3 + X - -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 group, C 3–10 Carbocyclic groups, 3–14 membered heterocyclic groups, C 6–14 Aryl and 5–14-membered heteroaryl groups, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Substituted by a group; wherein X - To counteract ions;

[0342] Or the two hydrogen atoms on the carbon atom are replaced by the groups =O, =S, =NN(R) bb )2、=NNR bb C(=O)R aa =NNR bb C(=O)OR aa =NNR bb S(=O)2R aa =NR bb or = NOR cc ;

[0343] R in each caseaa 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;

[0344] 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;

[0345] R for each occurrence cc 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;

[0346] R for each occurrence dd 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 ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=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 ff C(=NR ffN(R ff )2, -NR ff SO2R 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 1-6 alkyl, C 1–6 1-6 haloalkyl, C 2–6 1-6 alkenyl, C 2–6 1-6 alkynyl, C 3–10 arbon ring group, 3-10 membered heterocyclyl, C 6–10 aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbon ring group, 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;

[0347] R ee is independently selected for each occurrence from C 1–6 1-6 alkyl, C 1–6 1-6 haloalkyl, C 2–6 1-6 alkenyl, C 2–6 1-6 alkynyl, C 3–10 arbon ring group, C 6–10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbon ring group, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;

[0348] R ff is independently selected for each occurrence from hydrogen, C 1–6 1-6 alkyl, C 1–6 1-6 haloalkyl, C 2–6 1-6 alkenyl, C 2–6 1-6 alkynyl, C3–10 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

[0349] 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 1–6alkyl, -C(=NH)N(C 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 1–6 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. In reference to the term “-N(C 1–6 alkyl)2”, “-N(OC 1–6 alkyl)(C 1–6 alkyl)”, or “-N(C 1–6 alkyl)3 + X – ”, two or three groups “C 1–6 alkyl” can be the same C1–6 alkyl or different C 1–6 alkyl. The same applies to similar terms like “–N(C 1–4 alkyl)2”, “–N(C 1–2 alkyl)2”, “–C(C 1–6 alkyl)2–”, “–C(C 1–6 alkyl)3”, “–P(=O)(C 1–6 alkyl)2”, “–P(=O)(OC 1–6 alkyl)2”, “–Si(C 1–6 alkyl)3”, and the like.

[0350] “Counterion” or “anionic counterion” is a negatively charged group that associates with a positively charged group to maintain electronic neutrality. An anionic counterion can be monovalent (i.e., include one formal negative charge). An anionic counterion can also be multivalent (i.e., include 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., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethyl-1-sulfonic acid-2-sulfonate, etc.), carboxylate ions (e.g., acetate, propionate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, etc.), BF4 – , PF4 – , PF6 – , AsF6 – , SbF6 – , B[3,5-(CF3)2C6H3]4] – , BPh4 – , Al(OC(CF3)3)4 – , and carborane anions (e.g., CB 11 H 12 – or (HCB 11 Me5Br6) – ). Exemplary counterions that can be multivalent include CO3 2- , HPO4 2- , PO4 3- , B4O7 2- , SO42- S2O3 2- carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalate, aspartate, glutamate, etc.), and carboranes.

[0351] “halo” or “halogen” means fluoro (fluorinated, -F), chloro (chlorinated, -Cl), bromo (brominated, -Br), or iodo (iodinated, -I).

[0352] “acyl” means a moiety selected from –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 bb SO2R 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.

[0353] When valence permits, a nitrogen atom can be substituted or unsubstituted, and includes primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, 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 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 carbon ring, 3-14 membered heterocyclyl, C 6–14 aryl and 5-14 membered heteroaryl, or two R cc groups attached to a nitrogen atom are linked to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbon ring, 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和 R dd are as defined above.

[0354] 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 include, but are not limited to, -OH, -OR aa , -N(R cc )2, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc )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 , C 1–10 alkyl, aryl-C 1-10 alkyl, heteroaryl-C 1-10 alkyl, C 2–10 alkenyl, C 2–10 alkynyl.alkynyl, C 3–10 carbocyclyl, 3-14 membered heterocyclyl, C 6–14 aryl and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, 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 herein. 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, 3rdedition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0355] 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 aa )2, -P(=O)(OR cc )2, and -P(=O)(N(R bb )2)2, wherein X - , R aa , R bb , and R ccFor example, an 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, 3rdedition, John Wiley & Sons, 1999 (which is 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 benzyl (such as 4-methoxybenzyl), methoxymethyl (MOM), benzyloxymethyl (BOM), 2-methoxyethoxymethyl (MEM), and the like; silyl ethers such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBDMS), and the like; acetals or ketals such as tetrahydropyranyl (THP); esters such as formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, and the like; carbonates; sulfonates such as methanesulfonate (mesylate), benzy sulfonate, and tosylate (Ts), and the like.

[0356] The term“leaving group” has its ordinary meaning in the field of synthetic organic chemistry, for example, it can refer to an atom or a group that can be displaced by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry 6thEd. (501-502). Examples of suitable leaving groups include, but are not limited to, halogen (such as F, CI, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkylsulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, 9-phenylxanthyl (pixyl), and haloformate.

[0357] 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.

[0358] The term "tautomer" or "tautomerization" refers to two or more compounds that can interconvert by at least one formal migration of a hydrogen atom and at least one change in the hybridization state (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact proportion of tautomers depends on several factors, including temperature, solvent, and pH. Tautomerization (i.e., reactions that provide tautomeric pairs) can be catalyzed by acids or bases. Exemplary tautomerizations include keto to enol, amide to imide, lactam to lactim, enamine to imine, and enamine to (a different enamine).

[0359] As used herein, the term "subject" (alternatively referred to as "patient" herein) refers to an animal, preferably a mammal, most preferably a human, who is the object of treatment, observation or experiment.

[0360] 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, can include "prophylactic treatment," which refers to reducing the likelihood of developing a disease or condition in a subject who does not yet have the disease or condition, but who is at risk or susceptible to developing the disease or condition or recurrence of a previously controlled disease or condition. The terms "treatment" and synonyms thereof encompass administration of a therapeutically effective amount of a compound described herein to a subject in need of such treatment.

[0361] As used herein, the expression "administration" of a compound, "administering" a compound, or other variations thereof, means providing a compound or a prodrug of a compound to an individual in need of treatment.

[0362] Examples

[0363] The various starting materials, intermediates, and compounds of the preferred embodiments can be isolated and purified, if appropriate, using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. The characterization of these compounds can be performed using conventional methods, such as by melting point, mass spectrometry, nuclear magnetic resonance, and various other spectroscopic analyses.

[0364] Exemplary embodiments of the steps used to carry out the synthesis of the products described herein are described in greater detail below. Some of the examples discussed herein can be prepared by separation of the corresponding racemic mixtures. As will be appreciated by persons 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 as racemic and / or stereoisomeric mixtures. It is to be understood that the enantiomeric excess (“ee”) and / or diastereomeric excess (“de”) reported for these examples are representative and not limiting from the procedures exemplified herein; persons of ordinary skill in the art will appreciate that such enantiomers and / or diastereomers having different ees and / or des, such as higher ees and / or des, can be obtained in accordance with the present disclosure. In general, when a pair of diastereomers (only one chiral center different) is separated from the corresponding diastereomeric mixture, a “de” value is reported herein. In such cases, the “de” value indicates the degree of enrichment of one of the diastereomers.

[0365] The abbreviations used in the Examples section are to be understood as having their ordinary meaning in the art unless otherwise explicitly stated or apparent from the context. Certain abbreviations used in the Examples section herein are shown below.

[0366]

[0367]

[0368]

[0369] Example 1. Synthesis of compounds 3 and 4

[0370]

[0371] Step 1: To a solution of sodium hydride (15.6 g, 389 mmol, 60 wt%) in DMSO (700 mL) was added trimethylsulfoxonium iodide (85.6 g, 389 mmol). The mixture was stirred at 25 °C for 1 h. To this mixture was then added dropwise 1-(5-fluoro-2-hydroxyphenyl)ethanone (40 g, 259 mmol) in DMSO (100 mL). The mixture was stirred at 80 °C for 16 h, cooled, diluted with EtOAc. The resulting mixture was washed with saturated NH4Cl solution and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether) to give 3-1.

[0372] Step 2: To a solution of 3-1 (6.41 g, 42.69 mmol) in THF (2.4 mL) was added dropwise 2.4 M n-BuLi / hexanes (18.8 mL) at -78 °C. The mixture was stirred at -78 °C for 1 h. Then ethyl 2,2,2-trifluoroacetate (12.13 g, 85.38 mmol) was added. The mixture was stirred at -78 °C for another 1 h. The reaction was quenched with saturated NH4Cl solution at -78 °C and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 3-2.

[0373] Step 3: To a solution of 3-2 (7 g, 28.43 mmol) in EtOH (58 mL) was added hydroxylamine hydrochloride (20.1 g, 142.18 mmol) and NaOAc (11.7 g, 142.18 mmol). The mixture was stirred at 100 °C for 1 h. The mixture was cooled, diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give 3-3, which was used directly in the next step without further purification.

[0374] Step 4: To a solution of 3-3 (7.2 g, 27.48 mmol) in EtOH (100 mL) and H2O (20 mL) was added NH4Cl (13.3 g, 248.6 mmol) and Zn (16.2 g, 247.8 mmol). The mixture was stirred at 80 °C for 1 h. The mixture was cooled, diluted with EtOAc and saturated NaHCO3 solution. The organic layer was separated, washed with brine and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 3 / 1) to give 3-4.

[0375] Step 5: A mixture of 2-amino-3-nitrobenzoic acid (5.00 g, 27.45 mmol) and urea (16.50 g, 274.53 mmol) was stirred at 200 °C for 2 h. The mixture was cooled to 100 °C and then water was added dropwise. The resulting mixture was cooled to room temperature and filtered. The filter cake was washed with water and dried to give crude 3-5, which was used directly in the next step without further purification.

[0376] Step 6: A mixture of 3-5 (4.50 g, 13.03 mmol) and DIEA (6.5 mL, 39.32 mmol) in POCl3 (30 mL) was stirred at 130 °C for 4 h. The mixture was cooled and poured into ice water (500 mL). The aqueous layer was extracted with DCM. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 3-6, which was used directly in the next step without further purification.

[0377] Step 7: A mixture of 3-6 (1.50 g, 6.15 mmol) in 1.5 M NaOH (12.3 mL, 18.45 mmol) was stirred at 20 °C for 1.5 h. The mixture was adjusted to pH ~4 with 1 M HC1. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 3-7, which was used directly in the next step without further purification.

[0378] Step 8: A solution of 3-7 (0.50 g, 2.22 mmol) and 3-4 (1.37 g, 5.54 mmol) in isopropanol (15 mL) was stirred at 90 °C for 16 h. The mixture was cooled and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether to petroleum ether / ethyl acetate = 4 / 1) to give 3-8.

[0379] Step 9: A mixture of 3-8 (320 mg, 0.73 mmol), Fe powder (205 mg, 3.67 mmol) and 5 M NH4CI (1.47 mL, 7.34 mmol) in EtOH (30 mL) was stirred at 80 °C for 0.5 h. The mixture was cooled and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether to petroleum ether / ethyl acetate = 4 / 1) to give 3-9.

[0380] Step 10: 3-9 (260 mg) was purified by preparative-SFC (column: ChiralPak AD, 250 x 30 mm I.D., 10 pm, EtOH / supercritical CO2 = 15 / 85) to give 3 (97.8 mg) and 4 (98.5 mg), respectively. 3: SFC analysis: 99.36% ee; Retention time: 1.923 min; Column: ChiralPak AD, 50 x 4.6 mm I.D., 3 pm, A = CO2 and B = EtOH (0.05% DEA), 5 to 40%; Pressure: 100 bar; Flow rate: 3 mL / min. LCMS (ESI, m / z): [M+H] + = 407.0; 1 H NMR (400 MHz, CDC13, ppm): 11.24 (br s, 1H), 7.82-7.74 (m, 1H), 7.50-7.40 (m, 1H), 7.16-7.00 (m, 4H), 7.00-6.88 (m, 1H), 6.47-6.34 (m, 1H), 4.62 (br s, 2H), 2.34 (s, 3H). 19F NMR (376 MHz, CDC13, ppm): δ -73.13 (3F), -120.30 (IF). SFC analysis: 98.74% ee; Retention time: 2.326 min; Column: ChiralPak AD, 50 x 4.6 mm I.D., 3 μm, A is CO2 and B is EtOH (0.05% DEA), 5 to 40%; Pressure: 100 bar; Flow rate: 3 mL / min. LCMS (ESI, m / z): [M+H] + = 407.0; 1 H NMR (400 MHz, CDC13, ppm): δ 11.25 (br s, 1H), 7.85-7.74 (m, 1H), 7.53-7.42 (m, 1H), 7.18-7.05 (m, 4H), 7.00-6.88 (m, 1H), 6.47-6.34 (m, 1H), 4.62 (br s, 2H), 2.34 (s, 3H). 19 F NMR (376 MHz, CDC13, ppm): δ -73.13 (3F), -120.30 (IF).

[0381] Example 2. Synthesis of compound 5

[0382]

[0383] Step 1: A mixture of 5-fluoro-N-methyl-2-nitroaniline (1.5 g, 8.82 mmol), Fe powder (2.5 g, 44.08 mmol) and NH4CI (4.7 g, 88.16 mmol) in EtOH (45 mL) and H2O (15 mL) was stirred at 80 °C for 2 h. The mixture was cooled, filtered and concentrated to give 5-1, which was used directly in the next step without further purification.

[0384] Step 2: To a solution of 5-1 (1.20 g, 8.56 mmol) in DMF (40 mL) was added Boc-L-valine (2.05 g, 9.42 mmol), Et3N (1.31 mL, 9.42 mmol), HOAT (1.51 g, 11.13 mmol) and EDCI (2.13 g, 11.13 mmol) successively at 0 °C. The mixture was stirred at room temperature for 2 h. The reaction was quenched with aqueous NaHC03solution and extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 5-2.

[0385] Step 3: A solution of 5-2 (2.7 g, 7.96 mmol) in AcOH (40 mL) was stirred at 80 °C for 12 h. The reaction was quenched with aqueous NaHC03solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether / Ethyl acetate = 1 / 1) to give 5-3.

[0386] Step 4: A mixture of 5-3 (2 g, 6.22 mmol) and HC1 in dioxane (15.6 mL, 4 M) was stirred at 0 °C for 2 h. Petroleum ether was added to the mixture, the precipitate was filtered and dried to give 5-4, which was used directly in the next step without further purification.

[0387] Step 5: Compound 5-5 was prepared from compound 5-4 and compound 3-7 following the synthetic procedure of compound 3-8 in Example 1.

[0388] Step 6: Compound 5 was prepared from compound 5-5 following the synthetic procedure of compound 3-9 in Example 1 as 0.42 FA salt. LCMS (ESI, m / z): [M+H] + = 381.2; 1 H NMR (400 MHz, DMSO-d6, ppm): δ 10.78 (s, 1H), 7.59 (dd, J = 8.8, 4.8 Hz, 1H), 7.46 (dd, J = 9.6, 2.8 Hz, 1H), 7.09-7.04 (m, 2H), 6.94-6.89 (m, 1H), 6.84-6.74 (m, 2H), 5.49 (t, J = 7.2 Hz 1H), 5.37 (br s, 2H), 3.93 (s, 3H), 2.33-2.26 (m, 1H), 1.03 (d, J = 6.8 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H). 19 F NMR (376 MHz, DMSO-d6, ppm): δ -120.06 (1F).

[0389] Example 3. Synthesis of compound 6

[0390]

[0391] Step 1: Methyl 3-bromo-2-oxobutyrate (2.49 g, 12.76 mmol) was dissolved in DME (13 mL). The solution was cooled to 0 °C and 5-fluoropyridin-2-amine (1.3 g, 11.60 mmol) was added. The mixture was stirred at room temperature for 2 days. The thick suspension was filtered to give 6-1, which was used directly in the next step without further purification.

[0392] Step 2: A solution of 6-1 (3.1 g, 11.11 mmol) in MeOH (30 mL) was stirred at 80 °C for 2.5 h. The mixture was cooled and concentrated. The yellow solid was triturated with ether, filtered and dried to give 6-2, which was used directly in the next step without further purification.

[0393] Step 3: To a solution of 6-2 (2.11 g, 10.14 mmol) in THF (40 mL) was added LiAlH4(0.4 g, 10.14 mmol) at 0 °C and the mixture was stirred at room temperature for 1 h. The reaction was quenched with Na2SO4.10H2O at 0 °C. Then filtered and the organic layer was concentrated. The solid was washed with DCM and filtered. The organic layer was concentrated to give 6-3, which was used directly in the next step without further purification.

[0394] Step 4: To a solution of 6-3 (1.8 g, 9.99 mmol) in DCM (12 mL) was added MnO2(8.7 g, 99.9 mmol). The mixture was stirred at room temperature for 12 h. The mixture was diluted with EtOAc, filtered and concentrated to give 6-4, which was used directly in the next step without further purification.

[0395] Step 5: To a solution of 6-4 (1.7 g, 9.54 mmol) in THF (20 mL) was added TMSCF3(1.63 g, 11.45 mmol) and TBAF (0.48 mL, 0.48 mmol). The mixture was stirred at room temperature for 1 h. Then 1 N HC1 (9.54 mL) was added and the resulting mixture was stirred at room temperature for another 1 h. The mixture was diluted with EtOAc and saturated NaHCO3solution. 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 / 1) to give 6-5.

[0396] Step 6: To a solution of 6-5 (380 mg, 1.53 mmol) in DCM (15 mL) was added NaHCO3(514.5 mg, 6.13 mmol) and DMP (1.30 g, 3.06 mmol) at 0 °C. The mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc and saturated NaHCO3solution. 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 / 1) to give 6-6.

[0397] Step 7: Compound 6-7 was prepared from compound 6-6 following the synthetic procedure of compound 3-3 in Example 1.

[0398] Step 8: Compound 6-8 was prepared from compound 6-7 following the synthetic procedure of compound 3-4 in Example 1.

[0399] Step 9: Compound 6-9 was prepared from compound 6-8 and compound 3-7 following the synthetic procedure of compound 3-8 in Example 1.

[0400] Step 10: Compound 6 was prepared from compound 6-9 following the synthetic procedure of compound 3-9 in Example 1. LCMS (ESI, m / z): [M+H] + = 407.2; 1 H NMR (400MHz, DMSO-d6, ppm): δ 10.86 (s, 1H), 8.60-8.51 (m, 1H), 7.72-7.62 (m, 1H), 7.46-7.31 (m, 2H), 7.24-7.13 (m, 1H), 6.99-6.86 (m, 2H), 6.66-6.54 (m, 1H), 2.62 (s, 3H); 19 F NMR (376MHz, DMSO-d6, ppm): δ -72.77 (3F), -140.56 (1F).

[0401] Example 4. Synthesis of compounds 7 and 8

[0402]

[0403] Step 1: To a mixture of 1-(5-fluoro-2-hydroxyphenyl)ethan-1-one (3.00 g, 19.46 mmol) and 1-bromo-3-methylbutan-2-one (3.21 g, 19.46 mmol) in CH3CN (30 mL) was added K2CO3 (5.4 g, 38.97 mmol). The mixture was then stirred at 80 °C for 16 hours. The mixture was cooled, diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 7-1.

[0404] Step 2: To a mixture of 7-1 (1.4 g, 6.36 mmol) in MeOH (30 mL) was added ammonium acetate (4.90 g, 63.56 mmol) and sodium sulfate (270.9 mg, 1.91 mmol). After stirring for 30 minutes, sodium cyanoborohydride (399.5 mg, 6.36 mmol) was added. The mixture was then stirred at 80 °C for 5 hours. The mixture was cooled, diluted with water and extracted with DCM. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give 7-2.

[0405] Step 3: Compound 7-3 was prepared from compound 7-2 and compound 3-7 following the synthetic procedure of compound 3-8 in Example 1.

[0406] Step 4: Compound 7-4 was prepared from compound 7-3 following the synthetic procedure of compound 3-9 in Example 1.

[0407] Step 5: Purification of 7-4 (100 mg) by prep-SFC (column: ChiralPak AD, 250 x 30 mm I.D., 10 pm, EtOH (0.1% NH3H2O) / supercritical CO2 = 30 / 70) gave 7 (10.4 mg) and 8 (21.3 mg), respectively. 7: SFC analysis: 100% ee; Retention time: 0.428 min; Column: ChiralPak AD, 50 x 4.6 mm I.D., 3 pm, A = CO2 and B = EtOH (0.05% DEA), 40%; Pressure: 100 bar; Flow rate: 3 mL / min. LCMS (ESI, m / z): [M+H] + = 381.2; 1 HNMR (400MHz, CDC13, ppm): δ 10.95 (brs, 1H), 7.58-7.47 (m, 1H), 7.15-6.88 (m, 4H), 6.87-6.76 (m, 1H), 6.23 (brs, 1H), 5.18-5.06 (m, 1H), 2.36-2.18 (m, 4H), 1.08 (d, J = 6.4 Hz, 3H), 0.87 (d, J = 6.4 Hz, 3H). 19 F NMR (376MHz, CDC13, ppm): δ -121.44 (1F). 8: SFC analysis: 99.46% ee; Retention time: 0.723 min; Column: ChiralPak AD, 50 x 4.6 mm I.D., 3 pm, A = CO2 and B = EtOH (0.05% DEA), 40%; Pressure: 100 bar; Flow rate: 3 mL / min. LCMS (ESI, m / z): [M+H] + = 381.2; 1 HNMR (400MHz, CDC13, ppm): δ 10.97 (brs, 1H), 7.65-7.54 (m, 1H), 7.25-6.95 (m, 4H), 6.95-6.86 (m, 1H), 6.23 (brs, 1H), 5.27-5.15 (m, 1H), 2.45-2.29 (m, 4H), 1.18 (d, J = 6.4 Hz, 3H), 0.96 (d, J = 6.4 Hz, 3H). 19F NMR (376 MHz, CDC13, ppm): δ -121.44 (IF).

[0408] Example 5. Synthesis of compound 9

[0409]

[0410] Step 1 : To a stirred solution of 4 (29 mg, 0.071 mmol) in DCE (2 mL) was added formaldehyde (17.1 mg, 0.57 mmol), sodium triacetoxyborohydride (121.0 mg, 0.57 mmol) and AcOH (45.7 mg, 0.57 mmol). The reaction was then stirred at 20 °C for 26 h. The reaction mixture was quenched with H20 and MeOH and then concentrated at 30 °C. The residue was purified by C18 reverse phase column (ACN / H20 (0.05% HCOOH), 5-95%) to give 9 as 0.36FA salt. LCMS (ESI, m / z): [M+H] + = 421.2. 1 H NMR (400 MHz, DMSO-d6, ppm): δ 10.95 (s, 1H), 7.85 (s, 1H), 7.67-7.58 (m, 1H), 7.50-7.42 (m, 1H), 7.26-7.15 (m, 1H), 7.10-7.04 (m, 1H), 7.03-6.95 (m, 1H), 6.94-6.81 (m, 1H), 6.64-6.56 (m, 1H), 6.31-6.19 (m, 1H), 2.85 (d, J = 4.8 Hz, 3H), 2.38 (s, 3H); 19 F NMR (376 MHz, DMSO-d6, ppm): δ -71.81 (3F), -120.12 (IF).

[0411] Example 6. Synthesis of compound 11

[0412]

[0413] Step 1: To a mixture of 1-(3,5-difluoro-2-hydroxyphenyl)ethan-1-one (25 g, 145 mmol) and methyl bromoacetate (24.4 g, 160 mmol) in DMF (200 mL) was added K2CO3(30.1 g, 218 mmol). The mixture was then stirred at room temperature for 2 hours. DBU (22.1 g, 145 mmol) was then added and the mixture was stirred at 80 °C for another 6 hours. The mixture was quenched with water and the aqueous layer was extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 9 / 1) to give 11-1.

[0414] Step 2: To a solution of 11-1 (9 g, 39.8 mmol) in THF (150 mL) was added LiAlH4(9.55 mL, 23.9 mmol, 2.5 M in THF) at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours, then quenched slowly with saturated aqueous potassium carbonate solution and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 11-2.

[0415] Step 3: To a solution of 11-2 (3.1 g, 16.6 mmol) in CH3CN (40 mL) was added IBX (7.0 g, 25.0 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 2 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 9 / 1) to give 11-3.

[0416] Step 4: To a solution of 11-3 (3.1 g, 15.8 mmol) in DCM (50 mL) was added (S)-(2-methylpropan-2-yl)(oxo)-λ4-sulfanamide (2.87 g, 23.7 mmol) and K2CO3(106 mg, 0.77 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. The mixture was quenched with ice water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give 11-4.

[0417] Step 5: To a -60 °C solution of 11-4 (3 g, 10 mmol) in THF (75 mL) was added tetrabutylammonium difluorotriphenyl-λ6-silicate (5.95 g, 11.0 mmol). The mixture was stirred at -60 °C for 1 h. Then trimethyl(trifluoromethyl)silane (5.7 g, 40.1 mmol) in THF (75 mL) was added at -60 °C. The mixture was stirred at -30 °C for 30 min, then quenched with saturated aqueous NH4Cl at 0 °C. The mixture was extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered and concentrated to give crude 11-5, which was used directly in the next step without further purification.

[0418] Step 6: To a solution of 11-5 (4 g, 10.8 mmol) in EtOAc (20 mL) was added 4 M HC1 / dioxane (10 mL) at 0 °C. The mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated to give crude 11-6, which was used directly in the next step without further purification.

[0419] Step 7: Compound 11-7 was prepared from compound 11-6 and compound 3-7 following the procedure of the synthesis of compound 3-8 in Example 1.

[0420] Step 8: Compound 11 was prepared from compound 11-7 following the procedure of the synthesis of compound 3-9 in Example 1. LCMS (ESI, m / z): [M+H] + = 425.2; 1 H NMR (400 MHz, DMSO-d6, ppm) δ 11.01 (br s, 1H), 7.97 (br s, 1H), 7.48-7.32 (m, 2H), 7.10-7.00 (m, 1H), 6.92-6.82 (m, 2H), 6.81-6.75 (m, 1H), 5.63 (br s, 2H), 2.40 (s, 3H). 19 F NMR (376 MHz, DMSO-d6, ppm): δ -71.84 (3F), -116.30 (1F), -133.12 (1F).

[0421] Example 7. Synthesis of compounds 28 and 29

[0422]

[0423] Step 1 : To a solution of 2-methoxyaniline (15 g, 121.8 mmol) in EtOAc (200 mL) was added [(sulfoxyldimethylene)amino]carbamic acid ethyl ester (16.0 g, 121.8 mmol) and tetramethylethylenediamine (1.4 g, 12.2 mmol). The mixture was stirred at room temperature for 4 h. The reaction was concentrated. The residue was triturated with EtOH to give 28-1 which was used directly in the next step without further purification.

[0424] Step 2: To a mixture of 28-1 (513 mg, 2.0 mmol), 3-4 (748 mg, 3.0 mmol) and DIEA (782 mg, 6.1 mmol) in anhydrous dichloromethane (8 mL) was added EDCI (464 mg, 2.4 mmol) at 0 °C. The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5 / 1) to give 28-2.

[0425] Step 3: To a solution of 28-2 (300 mg, 0.64 mmol) in DMF (6 mL) was added TMSC1 (697 mg, 6.4 mmol) and the mixture was stirred at 80 °C for 12 h. The mixture was cooled, diluted with EtOAc and saturated NaHC03solution. 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 / 1) to give 28-3.

[0426] Step 4: To a solution of 28-3 (131 mg, 0.31 mmol) in DCE (4 mL) was added BBr3(1 M in DCM, 4.6 mL, 4.6 mmol). The mixture was stirred at 50 °C for 18 h. The mixture was cooled, diluted with EtOAc and saturated NaHC03solution. The organic layer was separated, washed with brine and concentrated. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 15 / 1) to give 28-4.

[0427] Step 5: 28-4 (90 mg) was purified by preparative-SFC (column: ChiralCel OJ, 250 x 30 mm I.D., 10 pm, EtOH (0.1% NH3H20) / supercritical CO2 = 30 / 70) to give 28 (11 mg) and 29 (12 mg), respectively. 28: SFC analysis: 100% ee; Retention time: 3.442 min; Column: ChiralCel OJ, 150 x 4.6 mm I.D., 3 pm, A is CO2 and B is Ethanol (0.05% DEA), 5% to 40%; Pressure: 100 bar; Flow rate: 2.5 mL / min. LCMS (ESI, m / z): [M+H]+ = 408.2; 1 H NMR (400 MHz, Methanol-d4, ppm): δ 7.53-7.43 (m, 2H), 7.35-7.27 (m, 1H), 7.15-7.05 (m, 3H), 6.91-6.82 (m, 1H), 2.44-2.33 (m, 3H). 19 F NMR (376 MHz, Methanol-d4, ppm): δ -75.16 (3F), -122.20 (1F). 29: SFC analysis: 99.28% ee; Retention time: 4.075 min; Column: ChiralCel OJ, 150 x 4.6 mm I.D., 3 pm, A is CO2 and B is ethanol (0.05% DEA), 5% to 40%; Pressure: 100 bar; Flow rate: 2.5 mL / min. LCMS (ESI, m / z): [M+H] + = 408.2; 1 H NMR (400 MHz, Methanol-d4, ppm): δ

[0428] 7.54-7.43 (m, 2H), 7.36-7.25 (m, 1H), 7.17-7.05 (m, 3H), 6.92-6.81 (m, 1H), 2.40 (s, 3H). 19 F NMR (376 MHz, Methanol-d4, ppm): δ -75.16 (3F), -122.19 (1F).

[0429] Example 8. Synthesis of compound 17

[0430]

[0431] Step 1: To a solution of 4-hydroxypyridine-3-carboxylic acid (15.0 g, 107.8 mmol) in concentrated H2SO4(130 mL) was added HNO3(69%, 31.5 mL, 754.8 mmol) at 0 °C. The mixture was stirred at 120 °C for 48 h. The reaction was quenched by the addition of ice water. Then filtered and dried to give 17-1 which was used directly in the next step without further purification.

[0432] Step 2: To a solution of 17-1 (11.0 g, 59.7 mmol) in CHCl3(200 mL) was added DMF (0.46 mL, 6.0 mmol) and SOCl2(43.3 mL, 597 mmol) at 20 °C. The mixture was concentrated to give 17-2 which was used directly in the next step without further purification.

[0433] Step 3: To a solution of 17-2 (12.0 g, 54.3 mmol) in CH3CN (50 mL) was added ammonia (28%, 20 mL) at 0 °C. The mixture was stirred at 20 °C for 3 h. The precipitated solid was filtered, washed with CH3CN and dried to give 17-3.

[0434] Step 4: A mixture of NaH (1.1 g, 27.45 mmol, 60%) in THF (100 mL) was stirred at 50 °C for 20 min. Then 17-3 (2 g, 10.98 mmol) was added. The mixture was stirred at 50 °C for 20 min. Then TCDI (3.9 g, 21.96 mmol) was added. The mixture was stirred at 80 °C for 1 h. The mixture was cooled and quenched with water. The water layer was acidified to pH = 4 with 1M HCl. The filter cake was filtered, washed with water and dried to give 17-4.

[0435] Step 5: To a mixture of 17-4 (200 mg, 0.90 mmol) in dioxane (10 mL) was added thiophosgene (272 μL, 3.57 mmol). The mixture was stirred at 80 °C for 4 h. The mixture was concentrated to give crude 17-5, which was used directly in the next step without further purification.

[0436] Step 6: Compound 17-6 was prepared according to the procedure for synthesis of compound 3-8 in Example 1 from compound 17-5 and compound 11-6.

[0437] Step 7: Compound 17 was prepared according to the procedure for synthesis of compound 3-9 in Example 1 from compound 17-6. LCMS (ESI, m / z): [M+H] + = 426.2; 1 H NMR (400 MHz, DMSO-d6, ppm) δ 10.68 (br s, 1H), 8.25 (s, 1H), 8.03-7.85 (m, 2H), 7.47-7.36 (m, 2H), 6.99 (m, 1H), 5.74 (br s, 2H), 2.41 (s, 3H). 19 F NMR (376 MHz, DMSO-d6, ppm): δ -72.07 (3F), -116.15 (1F), -133.10 (1F).

[0438] Example 9. Synthesis of compound 31

[0439]

[0440] Step 1: A mixture of 2-chloro-4-fluoropyridine (53.0 g, 403 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (62.0 g, 403 mmol), Na2C03(85.0 g, 802 mmol) and Pd(PPh3)4(23.0 g, 19.9 mmol) in 1,4-dioxane (1.20 L) and water (0.24 L) was degassed under nitrogen three times and stirred at 110 °C for 12 h. The mixture was cooled, diluted with water and extracted with EtOAc. The organic layers were combined, dried over Na2S04, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / Ethyl acetate = 3 / 1) to give 31-1.

[0441] Step 2: A mixture of 4-fluoro-2-vinylpyridine (60.0 g, 487 mmol) and 10 wt% wet Pd / C (12 g) in MeOH (1 L) was hydrogenated under 1 atm of hydrogen atmosphere for 4 h. Then filtered and concentrated the filtrate to give 31-2.

[0442] Step 3: To TFA (750 mL) was added ((mesthylsulfonyl)oxy)carbamic acid tert-butyl ester (115.0 g, 364.6 mmol) portionwise at 0 to 5 °C and the mixture was stirred at this temperature for 1 h. The reaction mixture was poured into ice water and stirred for 15 min. A large amount of white solid precipitated and was filtered. The filter cake was washed with water until the aqueous solution was neutral. The filter cake was dried and then redissolved in DCM, dried over anhydrous Na2S04, filtered and concentrated to give 31-3.

[0443] Step 4: To a solution of 31-2 (32.2 g, 257.29 mmol) in 500 mL of dichloromethane was added dropwise a solution of 31-3 (72.0 g, 334.5 mmol) in 1 L of dry dichloromethane at -10 to 0 °C. The mixture was stirred at room temperature for 36 h. After dilution with MTBE, the mixture was concentrated, filtered and the filter cake was recrystallized in EtOH to give 31-4.

[0444] Step 5: To a solution of 31-4 (1.02 g, 3.00 mmol) in pyridine (20 mL) was added dropwise 2-chloro-2-oxoethyl acetate (1.84 g, 13.48 mmol) followed by anhydrous Na2S04(0.84 g, 5.91 mmol) at 0 °C. The mixture was stirred at 120 °C for 2 h. The mixture was diluted with water and extracted with ethyl acetate / petroleum (1 / 1), the combined extracts were washed with 2 M HC1 solution and brine, dried over anhydrous Na2S04, filtered and concentrated to give 31-5 which was used directly in the next step without further purification.

[0445] Step 6: To a solution of 31-5 (915.0 mg, 4.1 mmol) in MeOH (20 mL) and THF (10 mL) was added 2.5 M aqueous solution of lithium hydroxide (5 mL, 12.50 mmol). The reaction mixture was stirred at room temperature for 4 hours. The mixture was diluted with water, acidified to pH = 5 with 1 N HC1 solution and extracted with EtOAc. The organic layers were combined, dried over anhydrous Na2S04, filtered and concentrated to give 31-6 which was used directly in the next step without further purification.

[0446] Step 7: To a mixture of 31-6 (1.55 g, 7.98 mmol) and TEA (1.05 g, 10.38 mmol) in THF (100 mL) was added isopropyl chloroformate (1.28 g, 10.45 mmol) and the reaction mixture was stirred at 20 °C for 0.5 hours. Then to the mixture was added a solution of NaBH4(1.63 g, 43.09 mmol) in H20 (20 mL) at 0 °C and the reaction mixture was stirred at 20 °C for 0.5 hours. After quenching with saturated aqueous NH4C1 solution, the mixture was extracted with DCM. The organic layers were combined, dried over Na2S04, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane to dichloromethane / methanol = 7 / 1) to give 31-7.

[0447] Step 8: To a solution of 31-7 (0.89 g, 4.94 mmol) in DCM (50 mL) was added Dess-Martin periodinane (5.16 g, 12.17 mmol) portionwise at 0 °C. The mixture was stirred at 25 °C for 1 hour. After cooling to 0 °C, the mixture was quenched with saturated aqueous NaHC03solution and aqueous Na2S03solution (30 mL, v / v = 1 / 1). The mixture was stirred at room temperature for 1 hour and extracted with DCM. The organic layers were combined, dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to ethyl acetate) to give 31-8.

[0448] Step 9: To a solution of 31-8 (515.5 mg, 2.9 mmol) in THF (15 mL) was added trimethyl-(trifluoromethyl)silane (515.0 mg, 3.6 mmol) and 1 M TBAF / THF solution (0.15 mL, 0.15 mmol) at 0 °C. The mixture was stirred at room temperature for 1 hour. Then 1 N HC1 was added and the resulting mixture was stirred at room temperature for another 1 hour. The mixture was diluted with EtOAc, washed with saturated aqueous NaHC03solution and brine, dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 31-9.

[0449] Step 10: To a solution of 31-9 (487.0 mg, 1.96 mmol) in DCM (20 mL) was added Dess-Martin periodinane (1.66 g, 3.91 mmol) and NaHC03(660.0 mg, 7.86 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. After cooling to 0 °C, the mixture was quenched with saturated aqueous NaHC03and aqueous Na2S03(30 mL, v / v = 1 / 1). The mixture was stirred at room temperature for 1 h and extracted with DCM. The organic layers were combined and concentrated. The residue was purified by silica gel column (petroleum ether / ethyl acetate = 3 / 2) to give 31-10.

[0450] Step 11: To a solution of 31-10 (155.0 mg, 0.59 mmol) in EtOH (14 mL) was added hydroxylamine hydrochloride (204.0 mg, 2.94 mmol) and AcONa (242.0 mg, 2.94 mmol) and the reaction was stirred at 90 °C for 6 h. After cooling to room temperature, the mixture was diluted with EtOAc, washed with saturated aqueous NaHC03and brine, dried over anhydrous Na2S04, filtered and concentrated to give 31-11, which was used directly in the next step without further purification.

[0451] Step 12: To a solution of 31-11 (130.0 mg, 0.50 mmol) in EtOH (5 mL) and H20 (1.5 mL) was added Zn (650.0 mg, 9.94 mmol) and NH4C1 (270.0 mg, 5.05 mmol) and the reaction was stirred at 85 °C for 5 h. After cooling to room temperature, the mixture was diluted with EtOAc, washed with saturated aqueous NaHC03and brine, dried over anhydrous Na2S04, filtered and concentrated to give 31-12, which was used directly in the next step without further purification.

[0452] Step 13: Compound 31-13 was prepared from compound 31-12 and compound 11-6 following the procedure of the synthesis of compound 3-8 in Example 1.

[0453] Step 14: Compound 31 was prepared from compound 31-13 following the procedure of the synthesis of compound 3-9 in Example 1. LCMS (ESI, m / z): [M+H] + = 407.0; 1H NMR (400 MHz, Methanol-d4, ppm) δ 8.52 (dd, J = 7.6 Hz, 4.8 Hz, 1H), 7.87 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.50 (dd, J = 7.6 Hz, 1.2 Hz, 1H), 7.31 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 7.21 (t, J = 8.0 Hz, 1H), 6.87-6.77 (m, 1H), 6.58-6.48 (m, 1H), 2.38 (s, 3H); 19 F NMR (376 MHz, Methanol-d4, ppm): δ -75.32 (3F), -116.53 (1F).

[0454] Example 10. Synthesis of compound 34

[0455]

[0456] Step 1: To a solution of 5-bromo-2-nitroaniline (20 g, 92.16 mmol) in H2O (200 mL) was added 2N HCl (40 mL, 80.0 mmol). After the mixture was stirred at room temperature for 2 hours, to the above solution was added Na2SO4 (131 g, 0.922 mol), hydroxylamine hydrochloride (32.0 g, 0.461 mol) and 2,2,2-trichloroethane-1,1-diol (76.21 g, 461 mmol). The mixture was stirred at 75 °C for 8 hours. The mixture was cooled and extracted with EtOAc. The organic layers were 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 = 8 / 1) to give 34-1.

[0457] Step 2: To 34-1 (30 g, 104 mmol) was slowly added concentrated H2SO4 (120 mL) at 50 °C. The mixture was stirred at 80 °C for 1 hour. The mixture was cooled and poured into ice water. The precipitate was filtered and dried to give 34-2, which was used directly in the next step without further purification.

[0458] Step 3: To a solution of 34-2 (25 g, 92.2 mmol) in 2N NaOH (350 mL, 700.0 mmol) was slowly added hydrogen peroxide (10 mL, 114.76 mmol) at 0 °C. Then the mixture was stirred at 20 °C for 1 hour. The reaction mixture was adjusted to pH = 4 with 2N HCl and extracted with DCM. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give 34-3, which was used directly in the next step without further purification.

[0459] Step 4: To a solution of 34-3 (21 g, 80.5 mmol) in DMF (200 mL) was added K2CO3 (30 g, 217 mmol) and iodomethane (6 mL, 96.4 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc, washed with H2O and brine, dried over anhydrous Na2SO4, filtered and concentrated to give 34-4, which was used directly in the next step without further purification.

[0460] Step 5: To a solution of methyl ester 34-4 (20 g, 72.7 mmol) in THF (300 mL) at 0 °C was added 2,2,2-trichloro-1-isocyanoxyethan-1-one (10 mL, 83.9 mmol). The mixture was stirred at 20 °C for 1 hour. The mixture was concentrated to give 34-5, which was used directly in the next step without further purification.

[0461] Step 6: To a solution of 34-5 (30 g, 64.7 mmol) in MeOH (1000 mL) at 0 °C was added NH3 in MeOH (100 mL, 700.0 mmol). The mixture was stirred at 20 °C for 1 hour. The mixture was filtered and the filtrate was concentrated to give 34-6, which was used directly in the next step without further purification.

[0462] Step 7: To a mixture of 34-6 (500 mg, 1.75 mmol), Zn(CN)2 (615.8 mg, 5.24 mmol) and Zn (57.1 mg, 0.87 mmol) in DMA (20 mL) was added Pd(PPh3)4 (404.0 mg, 0.35 mmol). The mixture was stirred at 80 °C for 2 hours. Then cooled, filtered and concentrated. The residue was purified by reverse phase column (acetonitrile / 0.05% aqueous FA: 5-95%, hold at 25%) to give 34-7.

[0463] Step 8: To a solution of 34-7 (38 mg, 0.16 mmol) in MeCN (1 mL) and POCl3 (1.0 mL) was added DIEA (0.136 mL, 0.82 mmol). The mixture was stirred at 100 °C for 1 hour. The reaction was directly concentrated. Then the residue was diluted with EtOAc and washed with 1 M HC1 and brine. Then the organic layer was dried over Na2SO4, filtered and concentrated to give 34-8, which was used directly in the next step without further purification.

[0464] Step 9: To a solution of 34-8 (44 mg, 23.6 mmol) in THF (5 mL) was added 1M NaOH dropwise at 0 °C to keep pH = 10. Then the reaction was stirred at the same temperature for 1 h. The pH of the mixture was adjusted to 5 with 1M HC1. The mixture was concentrated and the residue was purified by reverse phase column (acetonitrile / 0.05% aqueous FA: 5-95%, hold at 45%) to give 34-9.

[0465] Step 10: Compound 34-10 was prepared from compound 34-9 and compound 11-6 following the procedure of the synthesis of compound 3-8 in Example 1.

[0466] Step 11: Compound 34 was prepared from compound 34-10 following the procedure of the synthesis of compound 3-9 in Example 1. LCMS (ESI, m / z): [M+H] + = 449.9; 1 H NMR (400 MHz, DMSO-d6, ppm): δ 8.00 (br s, 1H), 7.45-7.36 (m, 2H), 7.32 (d, J = 8.0 Hz, 1H), 7.05-6.92 (m, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.70 (s, 2H), 2.39 (s, 3H). 19 F NMR (376 MHz, DMSO-d6, ppm): δ -71.93 (3F), -116.24 (1F), -133.07 (1F).

[0467] Example 11. Synthesis of compound 35

[0468]

[0469] Step 1: Compound 35-1 was prepared from 3-bromo-2-nitroaniline following the procedure of the synthesis of compound 34-1 in Example 10.

[0470] Step 2: A solution of 35-1 (14 g, 48.60 mmol) in TfOH (130 mL) was stirred at 130 °C for 1 h. The reaction mixture was cooled and poured into ice water. The resulting mixture was extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by silica gel column chromatography (EtOAc / DCM = 1 / 1) to give 35-2.

[0471] Step 3: TBHP (8.9 mL, 92.25 mmol) and Na₂CO₃ (19.6 g, 184.48 mmol) were slowly added to a solution of 35⁻² (12.5 g, 46.12 mmol) in MeOH (100 mL) at 0 °C. The mixture was then stirred at 20 °C for 3 hours. The reaction mixture was adjusted to pH 6 with 1 N HCl and extracted with DCM. The organic layers were combined, washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with 0–35% EtOAc / DCM) to give 35⁻³.

[0472] Steps 4 and 5: Prepare compound 35-5 according to the synthesis procedure of compound 34-6 in Example 10.

[0473] Step 6: A mixture of 35-5 (500 mg, 1.74 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)imidazolium (727 mg, 3.49 mmol), Pd(PPh3)4 (202 mg, 0.17 mmol), and K3PO4 (927 mg, 4.37 mmol) in H2O (10 mL) and dioxane (50 mL) was stirred at 70 °C for 16 hours under N2. The mixture was cooled, diluted with water, acidified to pH 4 with 1N HCl solution, and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was stirred in petroleum ether / ethyl acetate (20 / 1) at room temperature for 30 minutes. The mixture was filtered and the filter cake was dried to give 35-6.

[0474] Step 7: Add DIEA (404 mg, 3.13 mmol) to a solution of 35-6 (300 mg, 1.04 mmol) in POCl3 (10 mL). Then stir the mixture at 110 °C for 2 hours. Cool the mixture, dilute with ice water, and extract with DCM. Combine the organic extracts, wash with brine, dry over Na2SO4, filter, and concentrate to obtain 35-7.

[0475] Step 8: Add 1M NaOH (3 mL) to a solution of 35-7 (300 mg, 0.92 mmol) in 10 mL of THF at 0 °C. Stir the mixture at room temperature for 2 hours. Then acidify the mixture to pH 4 with 1N HCl solution. Extract the mixture with DCM. Combine the organic layers, dry over Na2SO4, filter and concentrate to obtain 35-8.

[0476] Step 9: A mixture of 35-8 (130 mg, 0.42 mmol) and 11-6 (225 mg, 0.85 mmol) in 2-methylbutan-2-ol (10 mL) was stirred at 140 °C for 72 h under N2. The mixture was concentrated. The residue was purified by reverse phase column (acetonitrile in water: 0 to 95%, hold at 55%) to give 35-9.

[0477] Step 10: Compound 35 was prepared from compound 35-9 following the procedure of synthesis of compound 3-9 in Example 1. LCMS (ESI, m / z): [M+H] + = 505.2; 1 H NMR (400 MHz, DMSO-d6, ppm): δ 10.58 (s, 1H), 7.80 (d, J = 2.4 Hz, 1H), 7.64 (s, 1H), 7.44-7.33 (m, 3H), 7.10 (d, J = 8.4 Hz, 1H), 7.04-6.90 (m, 3H), 6.79 (d, J = 2.4 Hz, 1H), 3.96 (s, 3H), 2.43 (s, 3H); 19 F NMR (376 MHz, DMSO-d6, ppm): δ -71.87 (3F), -116.23 (1F), -133.13 (1F).

[0478] Synthesis of compound 30 in Example 12

[0479]

[0480] Step 1: To a mixture of 5-fluoro-1H-benzo[d]imidazole (10 g, 73.46 mmol) in H2SO4 (60 mL) was added HNO3 (13.77 mL) at 0 °C. Then the mixture was stirred at room temperature for 3 h. The mixture was diluted with water and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (EtOAc / DCM = 1 / 1) to give 30-1 (less polar) and 30-1’.

[0481] Step 2: To a mixture of 30-1 (8 g, 44.16 mmol) in acetone (60 mL) was added iodomethane (27.49 mL, 441.67 mmol). Then the mixture was stirred at 50 °C for 48 h. Then filtered, the filter cake was washed with acetone and dried to give 30-2.

[0482] Step 3: To a mixture of 30-2 (8 g, 40.99 mmol) was added ammonia (28%, 100 mL). The mixture was stirred at 80 °C for 16 hours. Then cooled, filtered, the filter cake was washed with water, and dried to give 30-3.

[0483] Step 4: To a solution of 30-3 (6 g, 31.22 mmol) in AcOH (80 mL) was added Br2(1.71 mL, 31.22 mmol). Then the mixture was stirred at room temperature for 10 minutes. The reaction was quenched by adjusting pH to 8 by adding saturated aqueous NaHC03solution, and the aqueous layer was extracted with DCM. The combined organic extracts were washed with brine, dried over anhydrous Na2S04, filtered and concentrated to give 30-4, which was used directly in the next step without further purification.

[0484] Step 5: To a mixture of 30-4 (2.00 g, 7.37 mmol) in DMF (40 mL) was added Zn(CN)2(2.6 g, 22.14 mmol), Zn (0.2 g, 3.69 mmol) and bis[tris(2-methylpropan-2-yl)phosphane]palladium(0) (0.8 g, 1.47 mmol) under N2. Then the mixture was stirred at 100 °C for 1 hour. The mixture was concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 9 / 1) to give 30-5.

[0485] Step 6: To a mixture of 30-5 (400 mg, 1.84 mmol) was added H2S04(10 mL). Then the mixture was stirred at 70 °C for 1 hour. The reaction was quenched by adding ammonia to pH = 10, and the aqueous layer was extracted with DCM. The combined organic extracts were washed with brine, dried over anhydrous Na2S04, filtered and concentrated to give 30-6.

[0486] Step 7: To a mixture of 30-6 (220 mg, 0.93 mmol) in THF (8 mL) was added NaH (224.4 mg, 5.61 mmol). After stirring for 30 minutes, CDI (606 mg, 3.74 mmol) was added. The mixture was stirred at 70 °C for 3 hours. The reaction was quenched by adding water and the mixture was concentrated. The residue was purified by reverse phase column (30% CAN / H20) to give 30-7.

[0487] Step 8: To a mixture of 30-7 (130 mg, 0.50 mmol) in POCl3(10 mL) was added ethyl[ technologies, inc. di(prop-2-yl)]amine (0.33 mL, 1.99 mmol). The mixture was then stirred at 110 °C for 0.5 h. The mixture was cooled, diluted with water and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give 30-8, which was used directly in the next step without further purification.

[0488] Step 9: To a mixture of 30-8 (40 mg, 0.13 mmol) in THF (1 mL) was added NaOH (0.40 mL, 0.40 mmol). The mixture was then stirred at room temperature for 1 h. The mixture was quenched by adjusting the pH to 5 by the addition of 1 N HC1 and the aqueous layer was extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give 30-9, which was used directly in the next step without further purification.

[0489] Step 10: To a mixture of 30-9 (20 mg, 0.07 mmol) in 2-methylbutan-2-ol (1 mL) was added 11-6 (76 mg, 0.29 mmol). The mixture was then stirred at 130 °C for 72 h. The mixture was concentrated. The residue was purified by reverse phase column (aqueous acetonitrile: 0 to 50%) to give 30-10.

[0490] Step 11: Following the procedure for the synthesis of compound 3-9 in Example 1, compound 30 was prepared from compound 30-10. LCMS (ESI, m / z): [M+H] + = 479.0; 1 H NMR (400 MHz, DMSO-d6, ppm): δ 10.60 (s, 1H), 8.80 (s, 1H), 7.52-7.48 (m, 1H), 7.47-7.42 (m, 1H), 7.41-7.36 (m, 1H), 7.08-6.92 (m, 1H), 3.90 (s, 3H), 2.43 (s, 3H). 19 F NMR (376 MHz, DMSO-d6, ppm): δ -72.04 (3F), -116.22 (1F), -133.13 (1F).

[0491] Example 13. Synthesis of compounds 24 and 25

[0492]

[0493] Step 1: A mixture of 2-amino-5-bromobenzene-l-sulfonamide (3 g, 11.95 mmol) and urea (8 g, 133.20 mmol) was stirred at 165 °C for 2 h. The mixture was cooled to 100 °C. To the mixture was added H2O (30 mL) and purified by reverse phase column (ACN / H2O, 0-60%) to give 24-1.

[0494] Step 2: To a solution of 24-1 (500 mg, 1.80 mmol) in cone. H2SO4(2 mL) was added HNO3(69%, 4 mL, 67.1 mmol). The mixture was then stirred at 80 °C for 2 h. The mixture was cooled, poured into ice water (20 mL) and concentrated. The residue was purified by reverse phase column (ACN / H2O, 0-10%) to give 24-2.

[0495] Step 3: To a solution of 24-2 (200 mg, 0.62 mmol) in POCl3(2 mL, 21.52 mmol) was added DIEA (two drops). The mixture was stirred at 110 °C for 16 h. The reaction mixture was concentrated, diluted with EtOAc and washed with saturated aqueous NaHCO3and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude product was triturated with EtOAc / PE (1 / 10) at 20 °C for 10 min. The precipitate was collected and dried to give 24-3.

[0496] Step 4: A mixture of 24-3 (50 mg, 0.147 mmol), 11-6 (100 mg, 0.377 mmol) and 2-methyl-2-butanol (2 mL) was stirred at 100 °C for 2 h. The mixture was concentrated. The residue was purified by reverse phase column (ACN / H2O, 0-80%) to give 24-4.

[0497] Step 5: To a solution of 24-4 (25 mg, 0.044 mmol) in MeOH (3 mL) was added Pd / C (4.7 mg, 5% Pd / C with 50% water). The mixture was stirred under H2(1 atm.) at 20 °C for 1 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by reverse phase column (ACN / H2O, 0-65%) to give 24. LCMS (ESI, m / z): [M+H] + = 461.2; 1 HNMR (400MHz, DMSO-d6, ppm): δ 9.91 (s, 1H), 8.64 (d, J = 9.6 Hz, 1H), 7.54-7.37 (m, 2H), 7.13-7.03 (m, 1H), 7.02-6.95 (m, 2H), 6.36-6.19 (m, 1H), 5.21 (s, 2H), 2.37 (s, 3H);19 F NMR (376 MHz, DMSO-d6, ppm): δ -71.86 (3F), -115.99 (1F), -133.08 (1F).

[0498] Step 5: Compound 25 was prepared from compound 24-4 following the procedure of synthesis of compound 3-9 in Example 1. LCMS (ESI, m / z): [M+H] + = 539.0; 1 H NMR (400 MHz, DMSO-d6, ppm): δ 10.03 (s, 1H), 8.70 (d, J = 8.8 Hz, 1H), 7.51-7.37 (m, 2H), 7.18-7.01 (m, 2H), 6.34-6.22 (m, 1H), 5.52 (s, 2H), 2.36 (s, 3H); 19 F NMR (376 MHz, DMSO-d6, ppm): δ -71.86 (3F), -115.99 (1F), -133.08 (1F).

[0499] Example 14. Synthesis of compound 16

[0500]

[0501] Step 1: To a solution of 2,3-dihydro-1H-inden-5-amine (25 g, 187.7 mmol) in CH2Cl2(100 mL) was added Ac2O (21.2 mL, 225.2 mmol) dropwise at 0 °C. Then the reaction was stirred at room temperature for 2 h. The solution was diluted with water, stirred for 20 min and filtered. The filter cake was washed with water and dried to give 16-1.

[0502] Step 2: To a solution of 16-1 (25 g, 142.7 mmol) in AcOH (200 mL) was added HNO3 (69%, 27 mL, 302.4 mmol) dropwise. Then the mixture was stirred at room temperature for 12 h. The mixture was poured into ice water and the mixture was stirred for 0.5 h. The precipitate was filtered and washed with H2O. Then it was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give 16-2.

[0503] Step 3: To a solution of 16-2 (5.2 g, 23.6 mmol) in EtOH (45 mL) was added concentrated HCl (20 mL) dropwise at 80 °C. Then the mixture was stirred at the same temperature for 2 h. The mixture was cooled, diluted with H2O. The precipitate was filtered, washed with H2O and dried to give 16-3.

[0504] Step 4: To a solution of 16-3 (4 g, 22.4 mmol) in MeCN (80 mL) was added NBS (4.8 g, 26.9 mmol). The mixture was stirred at room temperature for 2 h. The mixture was poured into ice water. The precipitate was filtered, washed with H2O, MeCN and dried to give 16-4.

[0505] Step 5: To a solution of 16-4 (3.9 g, 15.2 mmol), Zn powder (0.5 g, 7.6 mmol) and Zn(CN)2(5.3 g, 45.5 mmol) in DMA (80 mL) was added (tBu3P)2Pd (1.6 g, 3.0 mmol). The mixture was stirred at 100 °C for 2 h under N2atmosphere. The mixture was diluted with H2O and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether (0.5% Et3N) / ethyl acetate = 2 / 1) to give 16-5.

[0506] Step 6: A solution of 16-5 (2.3 g, 11.3 mmol) in concentrated H2SO4(11.5 mL, 215.8 mmol) was stirred at 60 °C overnight. The mixture was diluted with ice water and the pH value of the mixture was adjusted to 8-9 with ammonia. Then filtered, the filter cake was washed with H2O, and dried to give 16-6.

[0507] Step 7: To a solution of 16-6 (1.2 g, 5.4 mmol) and 4A MS (4 g) in dioxane (40 mL) was added thionyl chloride (1.03 mL, 13.6 mmol). The mixture was stirred at room temperature for 1 h, then at 120 °C for 1 h. The mixture was diluted with aqueous NaHCO3solution and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 1) to give 16-7.

[0508] Step 8: Compound 16-8 was prepared from compound 16-7 and compound 11-6 following the synthetic procedure of compound 3-8 in Example 1.

[0509] Step 9: Compound 16 was prepared from compound 16-8 following the synthetic procedure of compound 3-9 in Example 1. LCMS (ESI, m / z): [M+H]=465.0. + 1 ​H NMR (400 MHz, DMSO-d6, ppm): δ 10.34 (s, 1H), 7.49-7.32 (m, 3H), 6.92-6.80 (m, 1H), 6.76 (s, 1H), 5.41 (s, 2H), 3.13 (t, J = 6.8 Hz, 2H), 2.72 (t, J = 7.2 Hz, 2H), 2.39 (s, 3H), 2.00-1.90 (m, 2H). 19 F NMR (376 MHz, DMSO-d6, ppm): δ -72.03 (3F), -116.24 (1F), -133.17 (1F).

[0510] Example 15. Synthesis of compounds 37 and 38

[0511]

[0512] Step 1: To a mixture of methyl 2-amino-6-fluoro-3-nitrobenzoate (7.8 g, 36.42 mmol) in THF (100 mL) was added 2,2,2-trichloro-1-isocyanoyl ethan-1-one (10.29 g, 54.64 mmol) and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated. The crude product was triturated with PE and filtered to give 37-1.

[0513] Step 2: To a mixture of 37-1 (13 g, 32.295 mmol) in MeOH (100 mL) was added NH3(14 mL, 7 M in MeOH) and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated. The crude product was triturated with PE and filtered to give 37-2.

[0514] Step 3: To a mixture of 37-2 (1.00 g, 4.44 mmol) in CH3CN (30 mL) was added sodium thiomethoxide (0.9 g, 13.32 mmol). The mixture was then stirred at room temperature for 16 hours. The mixture was concentrated. The crude product was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give 37-3.

[0515] Step 4: To a mixture of 37-3 (500 mg, 1.97 mmol) in ACN (10 mL) was added POCl3(10 mL) and DIPEA (1.63 mL, 9.87 mmol). The mixture was then stirred at 100 °C for 1 hour. The mixture was concentrated to give 37-4, which was used directly in the next step without further purification.

[0516] Step 5: To a mixture of 37-4 (300 mg, 1.03 mmol) in THF (20 mL) was added 2 N NaOH (1.55 mL, 3.10 mmol). The mixture was then stirred at room temperature for 30 min. The mixture was diluted with water and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (DCM / MeOH = 9 / 1) to give 37-5.

[0517] Step 6: Compound 37-6 was prepared according to the procedure for synthesis of compound 3-8 in Example 1 from compound 37-5 and compound 11-6.

[0518] Step 7: Compound 37 was prepared according to the procedure for synthesis of compound 3-9 in Example 1 from compound 37-6. LCMS (ESI, m / z): [M+H] + = 471.2. 1 H NMR (400 MHz, DMSO-d6, ppm): δ 10.56 (s, 1H), 7.70 (d, J = 9.2 Hz, 1H), 7.46-7.37 (m, 2H), 7.13-7.05 (m, 1H), 6.94-6.83 (m, 1H), 6.80-6.74 (m, 1H), 2.40 (s, 3H), 2.30 (s, 3H). 19 F NMR (376 MHz, DMSO-d6, ppm): δ -72.15 (3F), -116.15 (1F), -133.10 (1F).

[0519] Step 7: To a mixture of 37-6 (50 mg, 0.10 mmol) in CH3CN (5 mL) and H2O (5 mL) was added ruthenium (III) chloride (1.0 mg, 0.005 mmol) and sodium periodate (106.9 mg, 0.50 mmol). The mixture was then stirred at room temperature for 1 h. The mixture was diluted with water and the aqueous layer was extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give 38-1, which was used directly in the next step without further purification.

[0520] Step 8: Compound 38 was prepared according to the procedure for synthesis of compound 3-9 in Example 1 from compound 38-1. LCMS (ESI, m / z): [M+H] + = 503.2. 1H NMR (400 MHz, DMSO-d6, ppm): δ 7.90-7.70 (br s, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.45-7.37 (m, 2H), 7.13-6.95 (m, 1H), 6.8 (d, J = 8.6 Hz, 1H), 6.72 (s, 2H), 3.38 (s, 3H), 2.40 (s, 3H). 19 F NMR (376 MHz, DMSO-d6, ppm): δ -72.06 (3F), -116.21 (1F), -133.10 (1F).

[0521] Example 16. Synthesis of compound 45

[0522]

[0523] Step 1: To a solution of 11-6 (1.5 g, 5.66 mmol) and NaHC03(5.7 g, 67.88 mmol) in DCM (60 mL) and H20 (30 mL) was added thionyl chloride (1.3 g, 0.86 mL, 11.31 mmol) at 0 °C. The mixture was stirred at 0 °C under N2for 2 h. This solution containing 45-1 was used directly in the next step.

[0524] Step 2: To the above solution was added ammonia (10 mL, 72.7 mmol, 25%) at 0 °C. The reaction mixture was stirred at 25 °C under N2for 5 min. This solution containing 45-2 was used directly in the next step.

[0525] Step 3: To the above solution was added CH3I (8.0 g, 56.56 mmol) at 0 °C. The reaction mixture was stirred at 25 °C under N2for 40 h. The reaction mixture was poured into H20 (50 mL) and DCM (50 mL) and the organic layer was separated. The organic layer was extracted with 20% aqueous NaCl (100 mL) twice, dried over Na2S04and concentrated. The residue was purified by reverse phase column (ACN / H20 (0.05% NH3.H20), 5-95%) to give 45-3.

[0526] Step 4: To a solution of methyl 2-amino-6-fluoro-3-nitrobenzoate (1.0 g, 4.67 mmol) in THF (10 mL) and MeOH (10 mL) was added 10% Pd(OH)2 / C (328 mg). The reaction mixture was stirred at 25 °C under H2for 18 h. The reaction mixture was filtered and the filter cake was washed with THF. The organic layers were combined and concentrated to give 45-4 which was used directly in the next step without further purification.

[0527] Step 5: To a solution of 45-4 (860 mg, 4.67 mmol) and pyridine (739 mg, 0.75 mL, 9.34 mmol) in THF (16 mL) and MeOH (10 mL) was added (Boc)20 (1.12 g, 1.18 mL, 5.14 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated. The residue was purified by reverse phase column (ACN / H20 (0.05% NH3.H20), 5-95%) to give 45-5.

[0528] Step 6: To a solution of 45-5 (400 mg, 1.41 mmol) in THF (5 mL) and H20 (5 mL) was added LiOH (236 mg, 5.63 mmol). The reaction mixture was stirred at room temperature for 18 h. The mixture was acidified to pH = 4 with 1 N HC1. The mixture was diluted with DCM and water. The organic layer was separated, washed with 20% aqueous NaCl and concentrated to give 45-6, which was used directly in the next step without further purification.

[0529] Step 7: A mixture of 45-6 (303 mg, 1.12 mmol), EDCI (258 mg, 1.35 mmol), HOBT (189 mg, 1.40 mmol) and DIEA (435 mg, 3.37 mmol) in DMF (10 mL) was stirred at 0 °C under N2for 0.5 h. Then 45-3 (95 mg, 0.28 mmol) was added at 0 °C and the resulting mixture was stirred at 40 °C under N2for 72 h. The mixture was purified by reverse phase column (ACN / H20 (0.05% TFA), 5-95%) to give 45-7.

[0530] Step 8: To a solution of 45-7 (40 mg, 0.074 mmol) in DCM (5 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 1 h. The mixture was concentrated. The residue was purified by reverse phase column (ACN / H20 (0.05% FA), 5-95%) to give 45. LCMS (ESI, m / z): [M+H] + 443.2; 1 H NMR (400 MHz, DMSO-d6, ppm): δ 11.14 (br s, 1H), 8.23 (br s, 1H), 7.41-7.30 (m, 2H), 6.95-6.83 (m, 1H), 6.80-6.70 (m, 1H), 6.68-6.55 (m, 1H), 5.43 (br s, 2H), 2.38 (s, 3H); 19F NMR (376 MHz, DMSO-d6, ppm): δ -71.78 (3F), -116.30 (1F), -129.10 (1F), -133.09 (1F).

[0531] Example 17. Synthesis of compound 52

[0532]

[0533] Step 1: To a solution of 5-bromo-2-fluoro-3-nitrobenzoic acid (30 g, 113.64 mmol) in MeOH (300 mL) was added NH3 in MeOH (100 mL, 7 M). The mixture was then stirred at room temperature for 16 hours. The mixture was concentrated to give 52-1, which was used directly in the next step without purification.

[0534] Step 2: To a solution of 52-1 (30 g, 115.38 mmol) in DMF (300 mL) was added K2CO3 (47.7 g, 346.15 mmol) and iodomethane (19.6 g, 8.6 mL, 138.46 mmol). The mixture was then stirred at room temperature for 16 hours. The reaction was diluted with EtOAc and water. The organic layer was separated, washed with 20% NaCl aqueous solution and concentrated to give 52-2, which was used directly in the next step without purification.

[0535] Step 3: To a mixture of 52-2 (1.0 g, 3.636 mmol) and 3-furanyl borane diol (813 mg, 7.27 mmol) in dioxane (10 mL) and H2O (1 mL) was added Pd(PPh3)4 (420 mg, 0.364 mmol) and K2CO3 (1.51 g, 10.91 mmol) under N2. The mixture was then stirred at 80 °C for 2 hours. The mixture was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 52-3.

[0536] Step 4: To a solution of 52-3 (200 mg, 0.76 mmol) in THF (10 mL) and H2O (4 mL) was added LiOH (160.0 mg, 3.81 mmol). The mixture was then stirred at room temperature for 3 hours. The mixture was acidified to pH ~ 3 by the addition of 1 N HC1 and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give 52-4, which was used directly in the next step.

[0537] Step 5: To a mixture of 52-4 (176 mg, 0.709 mmol) in THF (10 mL) was added EDCI (170.0 mg, 0.88 mmol), HOBT (119.8 mg, 0.88 mmol) and ethyl[di(propan-2-yl)]amine (0.23 mL, 1.42 mmol). The mixture was stirred at room temperature for 30 min, followed by the addition of 45-3 (60 mg, 0.177 mmol). The mixture was then stirred at room temperature for 16 h. The mixture was concentrated. The residue was purified by reverse phase column (acetonitrile / water: 5% to 100%) to give 52-5.

[0538] Step 6: To a mixture of 52-5 (50 mg, 0.09 mmol) in EtOH (2 mL) and H2O (0.5 mL) was added Fe powder (24.6 mg, 0.440 mmol) and NH4Cl (47.0 mg, 0.88 mmol). The mixture was then stirred at 80 °C for 0.5 h. The mixture was concentrated. The residue was purified by preparative-HPLC with (ACN / H2O, 5% to 70%) to give 52. LCMS (ESI, m / z): [M+H] + = 491.2; 1 H NMR (400 MHz, DMSO-d6, ppm): δ 10.50 (s, 1H), 8.06 (s, 1H), 7.72 (s, 1H), 7.55 (d, J = 9.2 Hz, 1H), 7.46-7.35 (m, 2H), 7.27 (d, J = 1.6 Hz, 1H), 7.05 (d, J = 1.6 Hz, 1H), 7.02-6.88 (m, 1H), 6.87-6.80 (m, 1H), 5.74 (s, 2H), 2.41 (s, 3H). 19 F NMR (376 MHz, DMSO-d6, ppm): δ -72.03 (3F), -116.22 (1F), -133.12 (1F).

[0539] Example 18. Synthesis of compound 51

[0540]

[0541] Step 1: To a solution of l-(3-chloro-5-fluoro-2-hydroxyphenyl)ethan-l-one (10 g, 53 mmol) in DMF (150 mL) was added K2CO3 (11 g, 79.5 mmol) and 2-methylprop-2-yl bromoacetate (11.9 g, 60 mmol) at 20 °C. The mixture was stirred at 50 °C for 2 h, then DBU (8 g, 53 mmol) was added. The mixture was stirred at 90 °C for another 2 h. The mixture was cooled, diluted with H2O and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether / Ethyl acetate = 10 / 1) to give 51-1.

[0542] Step 2: 51-1 (6 g, 88 mmol) was added to a solution of HCl (4 M in dioxane) at 20 °C. The mixture was stirred at 45 °C for 3 h. The mixture was diluted with H2O and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered and concentrated to give 51-2, which was used directly in the next step without further purification.

[0543] Step 3: To a solution of 51-2 (4 g, 17.5 mmol) in DMF (40 mL) was added N,O- dimethylhydroxylamine (2.4 g, 24 mmol), TEA (6 mL, 41 mmol) and HATU (7.6 g, 20 mmol) at 20 °C. The mixture was stirred at 20 °C for 1 h. The mixture was diluted with H2O and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered and concentrated to give 51-3, which was used directly in the next step without further purification.

[0544] Step 4: To a solution of 51-3 (3.6 g, 13.2 mmol) in THF (60 mL) was added LiAlH4 (7.9 mL, 2.5 mol / L in THF) at -70 °C. The mixture was then stirred at -70 °C for 1 h. The reaction was quenched with H2O (5 mL) and NaOH (15%, 0.9 mL). The mixture was filtered and the filtrate was concentrated to give 51-4, which was used directly in the next step without further purification.

[0545] Step 5-7: Follow the procedure of compound 11-6 synthesis in Example 6 to prepare compound 51-7 from compound 51-4.

[0546] Step 8: Follow the procedure of compound 3-8 synthesis in Example 1 to prepare compound 51-8 from compound 51-7 and compound 11-6.

[0547] Step 9: Compound 51 was prepared from compound 51-8 following the synthetic procedure of compound 3-9 in Example 1. LCMS (ESI, m / z): [M+H] + = 441.2; 1 H NMR (400 MHz, DMSO-d6, ppm): δ 10.71 (s, 1H), 7.63 (s, 1H), 7.56 (d, J = 9.2 Hz, 2H), 7.08 (d, J = 8.0 Hz, 1H), 6.98-6.88 (m, 2H), 6.82 (d, J = 6.8 Hz, 1H), 5.67 (br s, 2H), 2.41 (s, 3H). 19 F NMR (376 MHz, DMSO-d6, ppm): δ -71.83 (3F), -117.61 (1F).

[0548] Example 19. Synthesis of compound 44

[0549]

[0550] Step 1-2: Compound 44-2 was prepared from compound 52-1 following the synthetic procedure of compound 34-6 in Example 10.

[0551] Step 3: Compound 44-3 was prepared from compound 44-2 and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the synthetic procedure of compound 35-6 in Example 11.

[0552] Step 4-7: Compound 44 was prepared from compound 44-3 following the synthetic procedure of compound 35 in Example 11. LCMS (ESI, m / z): [M+H] + = 505.2; 1 H NMR (400 MHz, DMSO-d6, ppm) δ 10.71 (br s, 1H), 7.81-7.64 (m, 2H), 7.48-7.32 (m, 4H), 6.96-6.85 (m, 1H), 6.55 (d, J = 2.4 Hz, 1H), 5.71 (br s, 2H), 3.86 (s, 3H), 2.41 (s, 3H); 19 F NMR (376 MHz, DMSO-d6, ppm): δ -71.94 (3F), -116.26 (1F), -133.13 (1F).

[0553] Example 20. Synthesis of compound 59

[0554]

[0555] Step 1: To a solution of 2,4,6-trifluorobenzoic acid (20 g, 113 mmol) in concentrated H2SO4(80 mL) was added concentrated HNO3(69%, 8.2 mL, 136.3 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 h. The mixture was quenched by the addition of ice water. The mixture was filtered and the filter cake was dried to give 59-1.

[0556] Step 2: To a solution of 59-1 (10 g, 45.23 mmol) in MeOH (10 mL) was added ammonia (28%, 8.2 g, 67.8 mmol) at room temperature. The mixture was stirred at 30 °C for 48 h. The mixture was then concentrated to give a residue, which was stirred in MeOH at room temperature for 30 min. The mixture was then filtered and the filter cake was dried to give 59-2.

[0557] Step 3: To a solution of 59-2 (1 g, 4.6 mmol) in THF (100 mL) was added Pd(OH)2 / C (10%, 0.6 g). The reaction was stirred at room temperature under H2atmosphere for 12 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by reverse phase column (acetonitrile / 0.05% aqueous HC1: 5-95%) to give 59-3.

[0558] Step 4: To a solution of 59-3 (67.7 mg, 0.36 mmol), EDCI (86.3 mg, 0.45 mmol), HOBT (60.8 mg, 0.45 mmol) and 45-3 (10 mg, 0.030 mmol) in THF (5 mL) was added DIEA (0.060 mL, 0.36 mmol) dropwise at room temperature. The mixture was then stirred at 40 °C for 3 days. The mixture was concentrated. The residue was purified by reverse phase column (acetonitrile / 0.05% aqueous TFA: 5-95%) to give 59. LCMS (ESI, m / z): [M+H] + = 461.2; 1 H NMR (400 MHz, DMSO-d6, ppm): δ 10.53 (s, 1H), 7.72 (d, J = 10.0 Hz, 1H), 7.50-7.34 (m, 2H), 7.09-6.96 (m, 1H), 6.89 (t, J = 11.2 Hz, 1H), 2.40 (s, 3H). 19 F NMR (376 MHz, DMSO-d6, ppm): δ -72.04 (3F), -116.18 (1F), -125.21 (1F), -126.79 (1F), -133.12 (1F).

[0559] Example 21. Synthesis of compound 53

[0560]

[0561] Step 1: To a solution of tetrahydropyran-3,5-dione (5.0 g, 43.8 mmol) in DCM (100 mL) was added ethyl 2-chloro-3-oxobutanoate (7.2 g, 43.7 mmol) and TEA (7.3 mL, 52.4 mmol). The reaction mixture was stirred at 50 °C for 16 h. The mixture was cooled to room temperature and acidified to pH = 2 by the addition of 2 M HC1. The resulting mixture was stirred at room temperature for 18 h. Water was added and the mixture was extracted with DCM. The organic layers were combined, washed with brine, dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by silica gel column chromatography (0 to 70% EtOAc in petroleum ether) to give 53-1.

[0562] Step 2: To a solution of 53-1 (1.37 g, 6.11 mmol) in THF (20 mL) and MeOH (40 mL) was added NaBH4(0.61 g, 16.13 mmol) portionwise at 0 °C. The mixture was stirred at this temperature for 1 h. After quenching with water, the mixture was extracted with DCM. The organic layers were combined, washed with brine, dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by silica gel column chromatography (0-50% EtOAc in petroleum ether) to give 53-2.

[0563] Step 3: To a solution of 53-2 (1.50 g, 6.63 mmol) in DCE (40 mL) was added Et3SiH (3.86 g, 33.20 mmol) followed by boron trifluoride-etherate (2.85 g, 20.08 mmol). The solution was stirred at room temperature for 8 h. The mixture was quenched with water, basified with saturated aqueous NaHC03(pH = 8) and extracted with dichloromethane. The organic layers were combined, washed with brine, dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by silica gel column chromatography (35% EtOAc in petroleum ether) to give 53-3.

[0564] Step 4-10: Follow the procedure for synthesis of compound 11 in Example 6 to prepare compound 53 from compound 53-3. LCMS (ESI, m / z): [M+H] = 395.0; + 1 ​H NMR (400 MHz, Methanol-d4, ppm): δ 7.84 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.48 (dd, J = 7.6 Hz, 1.2 Hz, 1H), 7.21 (t, J = 8.0 Hz, 1H), 6.40-6.30 (m, 1H), 4.64-4.52 (m, 2H), 3.93-3.82 (m, 2H), 2.54-2.44 (m, 2H), 2.11 (s, 3H); 19 F NMR (376 MHz, Methanol-d4, ppm): δ -75.66 (3F).

[0565] Example 22. Synthesis of compound 70

[0566]

[0567] Step 1: To a mixture of 34-4 (500.0 mg, 1.81 mmol) in 1,4-dioxane (10 mL) and H2O (1 mL) was added (2-cyano-phenyl)boronic acid (400.7 mg, 2.73 mmol), Pd(dppf)Cl2(133.0 mg, 0.18 mmol) and K3PO4(771.8 mg, 3.64 mmol). The reaction mixture was stirred at 70 °C for 2 h under N2. Then cooled and concentrated. The residue was purified by silica gel column chromatography (0% to 80% EtOAc in petroleum ether) to give 70-1.

[0568] Step 2: To a solution of 70-1 (380.0 mg, 1.23 mmol) in MeOH (5 mL) was added a solution of lithium hydroxide monohydrate (107.2 mg, 2.46 mmol) in H2O (2 mL) and the reaction mixture was stirred at 40 °C for 24 h. After cooling to room temperature, the mixture was purified by C18 reverse phase column (aqueous acetonitrile: 5 to 95%) to give 70-2.

[0569] Step 3: To a solution of 45-3 (100.0 mg, 0.30 mmol) in MeCN (2 mL) was added TCFH (300.0 mg, 1.07 mmol), NMI (150.0 mg, 1.83 mmol) and 70-2 (138.5 mg, 0.53 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (30% EtOAc in petroleum ether) to give 70-3.

[0570] Step 4: To a solution of 70-3 (120.0 mg, 0.20 mmol) in EtOH (5 mL) was added Fe powder (55.5 mg, 0.99 mmol), NH4CI (53.2 mg, 0.99 mmol) and H2O (1 mL) and the reaction mixture was stirred at 80 °C for 2 h. After cooling to room temperature, the mixture was purified by C18 reverse phase column (aqueous acetonitrile: 5 to 95%) to give 70. LCMS (ESI, m / z): [M+H] + = 526.2; 1 H NMR (400 MHz, DMSO-d6, ppm): δ 10.41 (s, 1H), 7.70 (t, J = 6.8 Hz, 1H), 7.64-7.48 (m, 2H), 7.40 (m, 3H), 7.30 (m, 1H), 6.98 (m, 1H), 6.88 (m, 1H), 6.71 (m, 1H), 5.99 (s, 2H), 2.43 (d, J = 3.6 Hz, 3H).

[0571] Example 23. Synthesis of compound 91

[0572]

[0573] Step 1: To a solution of methyl 2-amino-6-fluoro-3-nitrobenzoate (4 g, 18.7 mmol) in DMF (40 mL) was added methanesulfonamide (2.13 g, 22.4 mmol) and K2CO3 (7.74 g, 56.0 mmol). The reaction mixture was then stirred at room temperature for 24 h. The mixture was diluted with water and extracted with DCM. The pH value of the aqueous layer was adjusted to 6 with 2 M aqueous HC1 at 0 °C. The mixture was filtered, the filter cake was washed with water and dried to give 91-1.

[0574] Step 2: To a solution of 91-1 (1 g, 3.46 mmol) in THF (10 mL) and H2O (1 mL) was added LiOH (0.4 g, 10.37 mmol). The reaction mixture was then stirred at 50 °C for 16 h. The mixture was cooled, diluted with water and extracted with DCM. The pH value of the aqueous layer was adjusted to 3 with 2 M aqueous HC1 at 0 °C. The mixture was filtered, the filter cake was washed with water and dried to give 91-2.

[0575] Step 3: To a solution of 91-2 (382 mg, 1.388 mmol) in THF (17 mL) was added 10% Pd / C (147.7 mg). The mixture was stirred at room temperature under 1 atm H2atmosphere for 18 h. The reaction mixture was filtered and the filter cake was washed with THF. The combined filtrate containing 91-3 was used directly in the next step.

[0576] Step 4: To the above solution of 91-3 was added EDCI (203.6 mg, 1.062 mmol), HOBT (143.5 mg, 1.062 mmol) and DIEA (274.5 mg, 0.351 mL, 2.124 mmol). The mixture was stirred at 0 °C under N2for 0.5 h, followed by the addition of 45-3 (40 mg, 0.118 mmol) at 0 °C. The resulting mixture was stirred at 45 °C under N2for 40 h. The mixture was cooled and concentrated. The residue was purified by C18 reverse phase column (ACN / H2O (0.05% TFA), 5-95%) to give 91. LCMS (ESI, m / z): [M+H] + = 518.2. 1 H NMR (400 MHz, DMSO-d6, ppm): δ 10.95 (s, 1H), 10.51 (s, 1H), 7.69 (d, J = 9.6 Hz, 1H), 7.48-7.37 (m, 2H), 7.06-6.89 (m, 3H), 2.95 (s, 3H), 2.40 (s, 3H); 19 F NMR (376 MHz, DMSO-d6, ppm): δ -72.10 (3F), -116.14 (1F), -133.14 (1F).

[0577] Example 24. Synthesis of compound 108

[0578]

[0579] Step 1: To a solution of naphthalene-1,8-diamine (40 g, 253 mmol) and NaHCO3(63.7 g, 759 mmol) in THF (500 mL) and H2O (500 mL) was added (Boc)2O (66.2 g, 303 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 18 h. The mixture was diluted with EtOAc, washed with water, brine, and dried over anhydrous Na2SO4. Then filtered and the filtrate was concentrated to give crude 108-1, which was used directly in the next step without further purification.

[0580] Step 2: To a solution of 108-1 (63 g, 244 mmol) and TEA (74.0 g, 102 mL, 732 mmol) in DCM (1000 mL) was added ethyl chloroformate (39.70 g, 366 mmol) at 0 °C. The mixture was stirred at 20 °C under N2for 48 h. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give 108-2.

[0581] Step 3: To a solution of 108-2 (20 g, 70 mmol) in DCM (400 mL) was added 69% HNO3(6.8 g, 4.5 mL, 70.3 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. Then filtered and the filter cake was washed with DCM. The filtrate was combined and washed with 8% aqueous NaHCO3solution. The organic layer was concentrated. The residue was purified by silica gel column chromatography (DCM / EtOAc = 10 / 1) to give 108-3.

[0582] Step 4: To a solution of 108-3 (1 g, 3.0 mmol) in ACN (100 mL) was added NBS (594.5 mg, 3.3 mmol) at 0 °C. The reaction mixture was stirred at rt under N2for 18 h. The reaction mixture was filtered, the filter cake was washed with CH3CN and dried to give 108-4.

[0583] Step 5: To a solution of 108-4 (1.1 g, 2.7 mmol) in DCM (50 mL) was added TFA (10 mL, 0.245 mmol). The reaction mixture was stirred at rt for 1 h. The mixture was concentrated to give crude 108-5, which was used directly in the next step without further purification.

[0584] Step 6: To a solution of 108-5 (500 mg, 1.62 mmol) in xylene (60 mL) was added P2S5(1.08 g, 4.87 mmol). The mixture was stirred at 125 °C for 40 h. The mixture was concentrated to give crude 108-6, which was used directly in the next step without further purification.

[0585] Step 7: To a solution of 108-6 (526 mg, 1.6 mmol) in acetone (20 mL) was added CH3I (691.0 mg, 4.87 mmol). The mixture was stirred at 45 °C for 18 h. To the reaction mixture was added 28% ammonia (5 mL) dropwise at 0 °C. Then the mixture was concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc = 6 / 1) to give 108-7.

[0586] Step 8: To a solution of 108-7 (100 mg, 0.3 mmol) in DCM (10 mL) was added m-CPBA (86.7 mg, 0.5 mmol). The mixture was stirred at rt for 20 min. The mixture was concentrated to give crude 108-8, which was used directly in the next step without further purification.

[0587] Step 9: To a solution of 108-8 (105 mg, 0.3 mmol) in 2-methylbutan-2-ol (15 mL) was added 45-3 (628 mg, 2.4 mmol). The mixture was stirred at 105 °C for 24 h. The mixture was cooled and concentrated. The residue was purified by C18 reverse phase column (ACN / H2O (0.05% TFA), 5-100%) to give 108. LCMS (ESI, m / z): [M+H] + = 555.0. 1 H NMR (400 MHz, DMSO-d6, ppm): δ 11.84 (s, 1H), 9.50 (d, J = 9.0 Hz, 1H), 8.00 (d, J = 9.8 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.49-7.36 (m, 2H), 7.22 (d, J = 9.8 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.59-6.47 (m, 1H), 2.42 (s, 3H); 19 F NMR (376 MHz, DMSO-d6, ppm): δ -71.52 (3F), -116.09 (1F), -133.09 (1F).

[0588] Example 25. Synthesis of compound 118

[0589]

[0590] Step 1: To a solution of methyl 3-amino-2-nitrobenzoate (300 mg, 1.53 mmol) in CH3CN (12 mL) was added NBS (299 mg, 1.68 mmol). The mixture was then stirred at rt for 18 h under N2. The mixture was concentrated. The residue was purified by C18 reverse phase column chromatography (ACN / H2O (0.05% FA), 5-95%) to give 118-1.

[0591] Step 2: To a solution of 118-1 (350 mg, 1.27 mmol) and tetrahydropyrrole-2-one (433 mg, 5.09 mmol) in dioxane (20 mL) was added CuI (121.2 mg, 0.636 mmol), trans-N,N’-dimethylcyclohexane-1,2-diamine (90.5 mg, 0.636 mmol) and K3PO4 (810.3 mg, 3.817 mmol). The mixture was then stirred at 95 °C for 18 h under N2. The mixture was concentrated. The residue was purified by C18 reverse phase column chromatography (ACN / H2O (0.05% FA), 5-95%) to give 118-2.

[0592] Step 3: To a solution of 118-2 (50 mg, 0.179 mmol) in THF (5 mL), MeOH (5 mL) and H2O (5 mL) was added LiOH (75 mg, 1.79 mmol). The reaction mixture was stirred at 70 °C for 18 h. The mixture was acidified to pH = 4 with 1 N HC1. The mixture was concentrated. The residue was purified by C18 reverse phase column (ACN / H2O (0.05% HC1), 5-100%) to give 118-3.

[0593] Step 4-5: Follow the procedure for the synthesis of compound 70 in Example 22 to prepare compound 118 from compound 118-3. LCMS (ESI, m / z): [M+H] + = 508.2. 1 H NMR (400 MHz, DMSO-d6, ppm): δ 10.44 (s, 1H), 7.63 (d, J = 9.2 Hz, 1H), 7.47-7.33 (m, 2H), 7.00-6.86 (m, 1H), 6.80 (d, J = 8.2 Hz, 1H), 6.69 (d, J = 8.2 Hz, 1H), 5.81 (s, 2H), 3.76-3.50 (m, 2H), 2.40 (s, 3H), 2.31-2.21 (m, 2H), 2.17-1.93 (m, 2H); 19 F NMR (376 MHz, DMSO-d6, ppm): δ -72.00 (3F), -116.24 (1F), -133.16 (1F).

[0594] Example 26. Synthesis of compound 114

[0595]

[0596] Step 1: To a solution of 34-4 (260 mg, 0.95 mmol) and 4-(dihydroxyboryl)pyridine-3- carbonitrile (209 mg, 1.42 mmol) in dioxane (10 mL) and H2O (1 mL) was added Pd(dppf)Cl2(69.2 mg, 0.10 mmol) and K2CO3(392 mg, 2.84 mmol). The reaction mixture was degassed by bubbling nitrogen through for 5 min. Then the mixture was stirred at 90 °C for 16 h. The mixture was cooled and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 2) to give 114-1.

[0597] Step 2: To a solution of 114-1 (190 mg, 0.64 mmol) in THF (10 mL) and H2O (4 mL) was added LiOH (133 mg, 3.19 mmol). The mixture was then stirred at room temperature for 1 hour. The mixture was acidified to pH ~3 by the addition of 1 N HC1 and the aqueous layer was extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over anhydrous Na2S04, filtered and concentrated to give 114-2.

[0598] Step 3-4: Follow the procedure for the synthesis of compound 52 in Example 17 to prepare compound 114 from compound 114-2. LCMS (ESI, m / z): [M+H] + = 527.2; 1 H NMR (400 MHz, DMSO-d6, ppm): δ 10.57 (s, 1H), 8.88-8.84 (m, 1H), 8.73-8.68 (m, 1H), 7.66-7.57 (m, 1H), 7.46-7.33 (m, 3H), 7.10-6.93 (m, 1H), 6.91-6.87 (m, 1H), 6.81-6.76 (m, 1H), 6.18 (s, 2H), 2.43-2.38 (m, 3H). 19 F NMR (376 MHz, DMSO-d6, ppm): δ -72.10 (3F), -116.19 (1F), -133.15 (1F).

[0599] Example 27. Synthesis of compound 129

[0600]

[0601] Step 1: A mixture of 34-4 (2.5 g, 9.1 mmol), Zn(CN)2(5.3 g, 45.4 mmol) and bis[tris(2-methylpropan-2-yl)phosphane]palladium(0) (0.5 g, 0.90 mmol) in DMA (20 mL) was stirred at 100 °C under N2for 1 hour. The reaction mixture was diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2S04, filtered and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 4 / 1) to give 129-1.

[0602] Step 2: To a solution of 129-1 (1.5 g, 6.78 mmol) in AcOH (20 mL) was added Br2(3.72 mL, 67.82 mmol) at 0 °C. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated and water (20 mL) was added. The mixture was filtered and the filter cake was washed with water. The solid was collected and dried to give 129-2.

[0603] Step 3: To a solution of 129-2 (390 mg, 1.3 mmol) and (1-methyl-1H-pyrazol-4- yl)boronic acid (246 mg, 1.9 mmol) in THF (10 mL) and H2O (2 mL) was added Pd(PPh3)4 (106 mg, 0.13 mmol) and K3PO4 (685 mg, 3.0 mmol). The reaction mixture was degassed by bubbling nitrogen through for 5 minutes. Then the mixture was stirred at 70 °C for 2 hours. The mixture was cooled and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 129-3.

[0604] Step 4-6: Follow the procedure for the synthesis of compound 52 in Example 17 to prepare compound 129 from compound 129-3. LCMS (ESI, m / z): [M+H] + = 530.2; 1 H NMR (400 MHz, DMSO-d6, ppm): δ 11.31 (s, 1H), 8.11 (s, 1H), 8.02-7.83 (m, 1H), 7.77 (s, 1H), 7.45-7.37 (m, 2H), 6.99 (s, 1H), 6.89 (s, 1H), 6.68 (br s, 2H), 3.92 (s, 3H), 2.39 (s, 3H). 19 F NMR (376 MHz, DMSO-d6, ppm): δ -71.94 (3F), -116.25 (1F), -133.09 (1F).

[0605] Example 28. Synthesis of compound 117

[0606]

[0607] Step 1: To a solution of 5-fluoro-1H-benzo[d]imidazole (50.0 g, 367 mmol) in concentrated H2SO4 (375 mL) was added 68 wt% aqueous HNO3 (52 mL, 881 mmol) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water at 0 °C and KOH solid was added slowly to pH = 10. The mixture was extracted with EtOAc and the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (MeOH / DCM from 0% to 10% in 20 minutes, then hold at 3% to 5%) to give 117-1.

[0608] Step 2: To a solution of 117-1 (25.0 g, 138 mmol) in THF (300 mL) was added 60 wt% sodium hydride / mineral oil (7.2 g, 179 mmol) at 0 °C. The mixture was stirred for 30 min before iodomethane (25.5 g, 179 mmol) was added. The resulting mixture was warmed to room temperature and stirred for 4 h. After careful quenching with water, the mixture was extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether from 0% to 100% in 20 min, then kept at 100%) to give a mixture of 117-2 and 117-2'.

[0609] Step 3: To a mixture of 117-2 and 117-2' (20.0 g, 102 mmol) in NMP (15 mL) was added ammonia (28%, 150 mL) at room temperature and the reaction mixture was stirred at 120 °C for 24 h. After cooling to room temperature, the mixture was filtered, the solid was collected and dried to give a mixture of 117-3 and 117-3'.

[0610] Step 4: To a mixture of 117-3 and 117-3' (13.0 g, 67.63 mmol) in HOAc (130 mL) was added Br2(4.6 mL, 83 mmol) dropwise at 0 °C. The mixture was then stirred at room temperature for 0.5 h. The residue was concentrated, diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (PE / DCM / EtOAc = 1 / 1 / 0.2) to give 117-4 (5.1 g, yield: 27.5%) and 117-4' (3.2 g, yield: 17.4%).

[0611] Step 5: To a solution of 117-4 (1.5 g, 5.5 mmol) in NMP (30 mL) was added CuCN (1.1 g, 12.16 mmol) and the mixture was stirred at 210 °C under microwave conditions for 1 h. After cooling to room temperature, the mixture was basified with 28 wt% ammonia (150 mL). The suspension was filtered, the solid was collected and dried to give 117-5.

[0612] Step 6: To a flask containing sulfuric acid (15 mL) was added 117-5 (1.1 g, 5.1 mmol) and the mixture was stirred at 100 °C for 1 h. After cooling to room temperature, the mixture was diluted with ice water. The suspension was filtered, the solid was collected and purified by C18 reverse phase column chromatography (aqueous acetonitrile: 0-80%, kept at 35%) to give 117-6.

[0613] Step 7: To a solution of 117-6 (780.0 mg, 3.32 mmol) in THF (10 mL) was added 60 wt% NaH / mineral oil (398.0 mg, 9.95 mmol) and the mixture was stirred at 50 °C for 2 h. After cooling to room temperature, CDI (1.1 g, 6.63 mmol) was added portionwise to the reaction mixture and the resulting mixture was stirred at 80 °C for 1 h. After cooling to room temperature, the reaction mixture was quenched with ice water. The suspension was filtered, the solid was collected, washed with dichloromethane, and dried to give 117-7.

[0614] Step 8-11: Follow the procedure for the synthesis of compound 35 in Example 11 to prepare compound 117 from compound 117-7. LCMS (ESI, m / z): [M+H] + = 479.2; 1 H NMR (400 MHz, Methanol-d4, ppm): δ 8.84 (s, 1H), 7.25-7.15 (m, 2H), 7.11-7.01 (m, 1H), 6.78-6.68 (m, 1H), 4.40 (s, 3H), 2.42 (s, 3H); 19 F NMR (376 MHz, Methanol-d4, ppm): δ -74.85 (3F), -118.16 (1F), -135.47 (1F).

[0615] Example 29. Synthesis of compound 135

[0616]

[0617] Step 1: To a mixture of 2-chloro-4-methyl-3-nitropyridine (4.0 g, 23.2 mmol) in H2SO4(40 mL) was added sodium dichromate dihydrate (8.5 g, 28.3 mmol) portionwise at 0 °C. The reaction mixture was stirred at 80 °C for 5 h. After cooling to room temperature, the mixture was poured into ice water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give 135-1.

[0618] Step 2: To a solution of 135-1 (1.29 g, 60% purity, 3.8 mmol) in dioxane (10 mL) was added t-BuNH2(8.0 mL, 76.4 mmol) and the reaction was stirred at 80 °C for 16 h. The mixture was diluted with water and washed with EtOAc. The aqueous phase was adjusted to pH = 2 with 6N HCl and then extracted with dichloromethane. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by C18 reverse-phase column chromatography (acetonitrile / water: 5 to 15%) to give 135-2.

[0619] Step 3: A solution of 135-2 (600 mg, 2.51 mmol) in TFA (5 mL) was stirred at 80 °C for 16 h. After cooling to room temperature, the mixture was concentrated. The residue was purified by C18 reverse-phase column chromatography (acetonitrile / 0.05% TFA in water: 5 to 10%) to give 135-3.

[0620] Step 4: To a solution of 135-3 (179 mg, 0.98 mmol) and 11-6 (150 mg, 0.44 mmol) in CH3CN (10 mL) was added NMI (354 μL, 4.44 mmol) and TCFH (746 mg, 2.66 mmol). The reaction mixture was stirred at 20 °C for 4 h. The mixture was diluted with water and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (0~45% EtOAc / PE) to give 135-4.

[0621] Step 5: A mixture of 135-4 (30 mg, 0.06 mmol), Fe (17 mg, 0.30 mmol) and 1 M HCl (300 μL, 0.30 mmol) in EtOH (5 mL) was stirred at 80 °C for 2 h. The mixture was purified by C18 reverse-phase column chromatography (acetonitrile / 0.05% NH3.H2O in water: 5 to 55%) to give 135. LCMS (ESI, m / z): [M+H]=426.2. + 1 H NMR (400 MHz, DMSO-d6, ppm): δ 10.76 (br s, 1H), 7.73-7.61 (m, 2H), 7.46-7.37 (m, 2H), 7.07-6.96 (m, 1H), 6.86-6.70 (m, 3H), 2.41 (s, 3H); 19 F NMR (376 MHz, DMSO-d6, ppm): δ -72.144 (3F), -116.185 (1F), -133.127 (1F).

[0622] Example 30. Synthesis of compound 136

[0623]

[0624] ​Step 1: To a solution of 34-4 (1 g, 3.64 mmol), 2-amino-4-bromopyridine-3- carbonitrile (864 mg, 4.36 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.38 g, 5.45 mmol) in dioxane (20 mL) was added Pd(dppf)Cl2(266.0 mg, 0.36 mmol) and KOAc (1.43 g, 14.5 mmol). The reaction mixture was degassed by bubbling nitrogen through for 5 minutes. The reaction mixture was then stirred at 80 °C for 16 hours. The mixture was cooled, filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 9) to give 136-1.

[0625] Step 2: To a solution of 136-1 (240 mg, 0.77 mmol) in CH3CN (20 mL) was added TMSOK (295 mg, 2.3 mmol). The reaction mixture was then stirred at room temperature overnight. The reaction mixture was filtered, the filter cake was washed with CH3CN and dried to give 136-2.

[0626] Step 3: To a solution of 136-2 (258 mg, 0.77 mmol) and 45-3 (150 mg, 0.44 mmol) in THF (25 mL) was added HOBt (207 mg, 1.53 mmol), EDCI (587 mg, 3.06 mmol) and DIEA (1.0 mL, 6.1 mmol). The reaction mixture was stirred at room temperature for 2 hours, then warmed to 60 °C and stirred for another 16 hours. It was then cooled and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 4) to give 136-3.

[0627] Step 4: To a solution of 136-3 (100 mg, 0.16 mmol) in EtOH (4 mL) and H2O (1 mL) was added Fe (45 mg, 0.80 mmol) and NH4Cl (86 mg, 1.61 mmol). The reaction mixture was then stirred at 80 °C for 0.5 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative-HPLC (acetonitrile / 0.05% NH4HCO3 in water: 5%~52%) to give 136. LCMS (ESI, m / z): [M+H]=542.2; + 1 ​H NMR (400 MHz, DMSO-d6, ppm): δ 10.49-10.46 (m, 1H), 8.09-8.03 (m, 1H), 7.60-7.51 (m, 1H), 7.43-7.36 (m, 2H), 7.06-6.91 (m, 1H), 6.87-6.83 (m, 1H), 6.71-6.67 (m, 1H), 6.61-6.52 (m, 2H), 6.48-6.39 (m, 1H), 6.04 (s, 2H), 2.43-2.38 (m, 3H). 19 F NMR (376 MHz, DMSO-d6, ppm): δ -72.09 (3F), -116.22 (1F), -133.16 (1F).

[0628] Example 31. Synthesis of compound 143

[0629]

[0630] Step 1: To a solution of { [2-amino-4-fluoro-3- (methoxycarbonyl) phenyl] amino} formic acid 2-methylprop-2-yl ester (1 g, 4.7 mmol) in THF (20 mL) was added LiI (3.75 g, 28 mmol). The mixture was stirred at 70 °C for 18 hours. The mixture was acidified with 1 N HCl to pH = 4. The mixture was diluted with DCM and water. The organic layer was separated and washed with 20% NaCl aqueous solution. The organic layer was concentrated to give 143-1.

[0631] Step 2: To a solution of 143-1 (77 mg, 0.39 mmol), 45-3 (100 mg, 0.3 mmol) and HATU (337 mg, 0.89 mmol) in DCM (5 mL) at 0 °C was added DIEA (191 mg, 1.48 mmol) and the mixture was stirred at 0 °C under N2for 1 hour. The solution containing 143-2 was used in the next step without purification.

[0632] Step 3: To the above solution was added tetrahydropyrrole (105 mg, 1.48 mmol) and DIEA (76.5 mg, 0.59 mmol) at 0 °C and the mixture was stirred at room temperature under N2for 1 hour. The mixture was diluted with DCM (5 mL) and 0.5 N HCl (10 mL). The organic layer was separated and concentrated. The residue was purified by C18 reverse phase column (ACN / H2O (0.05% TFA), 5-95%) to give 143-3.

[0633] Step 4: To a solution of 143-3 (100 mg, 0.19 mmol) in EtOH (16 mL) and H2O (4 mL) was added Fe powder (107 mg, 1.9 mmol) and NH4CI (204 mg, 3.8 mmol). The mixture was stirred at 75 °C for 1 h. The reaction was purified by C18 reverse phase column (ACN / H2O (0.05% TFA), 5-95%) to give 143. LCMS (ESI, m / z): [M+H] + = 494.2. 1 HNMR (400 MHz, DMSO-d6, ppm): δ 7.80-7.70 (m, 1H), 7.42-7.30 (m, 2H), 6.90-6.78 (m, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.74-6.45 (m, 1H), 3.25-3.02 (m, 4H), 2.38 (s, 3H), 1.92-1.72 (m, 4H); 19 FNMR (376 MHz, DMSO-d6, ppm): δ -71.70 (3F), -116.37 (1F), -133.16 (1F).

[0634] Example 32. Synthesis of compound 152

[0635]

[0636]

[0637] Step 1: To a solution of 2-bromo-4-fluorophenol (30 g, 157 mmol) in DCM (300 mL) was added TEA (65 mL, 468 mmol) and acetyl chloride (16.7 mL, 235 mmol) at 0 °C. The mixture was stirred at 20 °C for 1 h. The reaction was quenched with H2O and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered and concentrated to give 152-1.

[0638] Step 2: A mixture of 152-1 (30 g, 129 mmol) and AlCl3 (25.8 g, 193 mmol) was stirred at 140 °C for 2 h. The reaction was quenched with H2O and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 152-2.

[0639] Step 3-7: Compound 152-7 was prepared according to the procedure for synthesis of compound 1-5 in Example 1.

[0640] Step 8: To a 20 °C solution of 152-7 (0.8 g, 1.8 mmol) in DMA (20 mL) was added Zn(CN)2(1.1 g, 9.3 mmol) and Pd(t-Bu3P)2(142 mg, 0.28 mmol) at 100 °C. The mixture was stirred at 100 °C for 2 h. The mixture was quenched by adding H2O at 20 °C and extracted with EA. The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10 / 1) to give 152-8.

[0641] Step 9: To a 20 °C solution of 152-8 (0.5 g, 1.3 mmol) in EA (10 mL) was added HCl (4 mL, 4 N in dioxane) at 0 °C. The mixture was stirred at 20 °C for 2 h. The reaction was quenched with ammonium hydroxide solution (25% in H2O). The resulting solution was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 152-9.

[0642] Step 10: A mixture of 118-1 (600 mg, 2.18 mmol), Pd(dppf)Cl2(160 mg, 0.22 mmol), K2CO3(754 mg, 5.45 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-4-carbonitrile (502 mg, 2.18 mmol) in H2O (1 mL) and dioxane (10 mL) was stirred at 90 °C for 16 h under N2. The reaction was concentrated. The residue was purified by column chromatography on silica gel (PE / EA = 3 / 7) to give 152-10.

[0643] Step 11-13: Compound 152 was prepared from compound 152-10 following the procedure of the synthesis of compound 52 in Example 17. LCMS (ESI, m / z): [M+H] + = 534.2. 1 H NMR (400 MHz, DMSO-d6, ppm): δ 10.68 (br s, 1H), 8.75-8.52 (m, 2H), 8.05-7.91 (m, 2H), 7.82-7.53 (m, 2H), 7.17-7.00 (m, 1H), 6.98-6.87 (m, 1H), 6.85-6.71 (m, 1H), 6.12 (s, 2H), 2.48-2.38 (m, 3H). 19 F NMR (376 MHz, DMSO-d6, ppm): δ -71.88 (3F), -117.95 (1F).

[0644] Example 33. Synthesis of compound 146

[0645]

[0646] Step 1: To a solution of (1r,3r)-3-((tert-butyldimethylsilyl)oxy)cyclobutan-1-ol (0.80 g, 4.00 mmol) in THF (20 mL) was added 60 wt% NaH / mineral oil (0.32 g, 8.00 mmol) in portions at 0 °C and the mixture was stirred at this temperature for 0.5 h under N2. Then a solution of methyl 2-amino-6-fluoro-3-nitrobenzoate (1.27 g, 6.00 mmol) in THF (20 mL) was added dropwise and the resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water. The mixture was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (EtOAc / PE = 1 / 4) to give 146-1.

[0647] Step 2: To a solution of 146-1 (600.0 mg, 1.50 mmol) in MeCN (20 mL) was added TMSOK (0.97 g, 7.60 mmol). Then the mixture was stirred at room temperature overnight. The filter cake was filtered and washed with MeCN. The filtrates were combined and concentrated to give 146-2.

[0648] Step 3: To a solution of 146-2 (0.24 g, 0.89 mmol) in DCM (10 mL) was added DIPEA (0.59 mL, 3.55 mmol) and HATU (0.67 g, 1.77 mmol) at 0 °C. The mixture was stirred at this temperature for 20 min and 45-3 (200.0 mg, 0.60 mmol) was added. Then the resulting mixture was stirred at room temperature for 18 h. The mixture was concentrated. The residue was purified by silica gel column chromatography (DCM / EtOAc = 15 / 1) to give 146-3.

[0649] Step 4: To a mixture of 146-3 (80.0 mg, 0.14 mmol) in EtOH (8 mL) and H2O (2 mL) was added Fe powder (38 mg, 0.68 mmol) and NH4Cl (73 mg, 1.36 mmol). Then the mixture was stirred at 80 °C for 1 h. The mixture was concentrated. The residue was purified by prep-HPLC (acetonitrile / 0.05% TFA in water: 5% to 95%) to give 146.

[0650] Example 34. Synthesis of compound 161

[0651]

[0652] Step 1 : A mixture of (2-chloroethyl)(methyl)sulfane (40 mL, 401 mmol) in iodomethane (80 mL, 1.29 mol) was stirred at 20 °C under N2for 18 h. To this dark brown mixture was added acetone (50 mL) and the suspension was filtered. The filter cake was washed with acetone and dried to give 161-1.

[0653] Step 2: To a mixture of tert-butyl 3-oxobutanoate (460.0 g, 2.77 mol) in acetone (270 mL) was added NCS (407.4 g, 3.05 mol) portionwise and the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was diluted with petroleum ether and washed with water. The organic layer was dried over Na2S04, filtered and concentrated to give 161-2.

[0654] Step 3: A mixture of cyclohexane-1,3-dione (300 g, 2.68 mol) and ammonium acetate (226.8 g, 2.94 mol) in EtOH (2.34 L) and H20 (1 L) was stirred at 80 °C for 1 h. To this mixture was then added 161-2 (515.4 g, 2.68 mol) portionwise and the mixture was stirred at 80 °C for 16 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with 0% to 15% EtOAc in petroleum ether to give 161-3.

[0655] Step 4: To a mixture of 161-3 (14.5 g, 57.93 mmol) and 1 M t-BuOK / t-BuOH solution (145.0 mL, 145.00 mmol) was added KI (1.9 g, 11.59 mmol) and the reaction mixture was stirred at 25 °C for 0.5 h. Then 161-1 (19.0 g, 75.31 mmol) was added and the resulting mixture was stirred at room temperature for 16 h. The mixture was diluted with saturated aqueous NH4CI solution and extracted with EtOAc. The organic extracts were combined, washed with brine, dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with 0% to 20% EtOAc in petroleum ether to give 161-4.

[0656] Step 5: To a solution of 161-4 (1.3 g, 4.71 mmol) in MeOH (30 mL) was added NaBH4(0.5 g, 14.11 mmol) at 0 °C and the reaction mixture was stirred at 25 °C for 1 h. The mixture was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc. The organic extracts were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluting with 0-40% EtOAc / petroleum ether) to give 161-5.

[0657] Step 6: To a solution of 161-5 (1.5 g, 5.39 mmol) in 1,2-DCE (20 mL) was added Et3SiH (4.3 mL, 26.94 mmol) followed by boron trifluoride-etherate (2.0 mL, 16.17 mmol). The mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with DCM. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give 161-6.

[0658] Step 7-13: Compound 161 was prepared from compound 161-6 following the procedure of synthesis of compound 51 in Example 18. LCMS (ESI, m / z): [M+H] + = 419.2; 1 H NMR (400 MHz, CDCl3, ppm): δ 11.01 (br s, 1H), 7.71-7.60 (m, 1H), 7.11-6.96 (m, 2H), 6.88-6.77 (m, 1H), 6.18-6.04 (m, 1H), 4.47 (br s, 2H), 2.58-2.39 (m, 2H), 2.26-2.05 (m, 3H), 1.99 (s, 3H), 1.54-1.46 (m, 1H), 0.43-0.27 (m, 4H); 19 F NMR (376 MHz, CDCl3, ppm): δ -73.72 (3F).

[0659] Example 35. Synthesis of compound 166

[0660]

[0661] Step 1 : To a solution of 2,6-dichloro-5-nitropyrimidine-4-carboxylic acid ethyl ester (500 mg, 1.88 mmol) in dioxane (10 mL) was added 0.4 M NH3 / dioxane (5.17 mL, 2.1 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated. The residue was purified by C18 reverse phase column chromatography (ACN / H2O (0.05% FA), 5-100%) to give 166-1.

[0662] Step 2: To a solution of 166-1 (200 mg, 0.81 mmol) in MeOH (20 mL) was added Pd / C 10% (100 mg) and the mixture was stirred at room temperature under H2for 2 h. The mixture was filtered and the filter cake was washed with MeOH. The filtrates were combined and concentrated to give 166-2.

[0663] Step 3: To a solution of 166-2 (150 mg, 0.82 mmol) in THF (10 mL) and H2O (10 mL) was added LiOH (346 mg, 8.24 mmol). The mixture was stirred at 0 °C for 2 h. The mixture was acidified to pH = 4 with 1 N HC1. The mixture was concentrated. The residue was purified by C18 reverse phase column chromatography (ACN / H2O (0.05% HC1), 5-100%) to give 166-3.

[0664] Step 4: A mixture of 166-3 (182 mg, 1.19 mmol), EDCI (340 mg, 1.77 mmol), HOBt (240 mg, 1.77 mmol) and DIEA (459 mg, 3.55 mmol) in THF (15 mL) and DMF (3 mL) was stirred at 0 °C under N2for 0.5 h. Then 45-3 (100 mg, 0.3 mmol) was added at 0 °C and the mixture was stirred at 40 °C under N2for 40 h. The mixture was concentrated. The crude product was purified by C18 reverse phase column chromatography (ACN / H2O (0.05% TFA), 5-95%) to give 166-4.

[0665] Step 5: To a solution of 166-4 (70 mg, 0.15 mmol) in THF (3 mL) was added TFA (168 mg, 1.48 mmol). The reaction mixture was stirred at 70 °C under N2for 18 h. The mixture was concentrated. The crude product was purified by C18 reverse phase column chromatography (ACN / H2O (0.05% FA), 5-95%) to give 166. LCMS (ESI, m / z): [M+H] + = 427.2. 1HNMR (400 MHz, DMSO-d6, ppm): δ 8.16 (s, 1H), 8.05-7.78 (m, 1H), 7.51 (s, 2H), 7.41-7.29 (m, 2H), 7.09-6.84 (m, 1H), 2.37 (s, 3H); 19 F NMR (376 MHz, DMSO-d6, ppm): δ -71.83 (3F), -116.40 (1F), -133.09 (1F).

[0666] Example 36. Synthesis of compound 168

[0667]

[0668] Step 1: To a solution of 4-amino-2-bromonicotinic acid (10.0 g, 46.1 mmol) in DCM (100 mL) was added (diazomethyl)-trimethylsilane (63.2 g, 553 mmol) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated. The residue was purified by silica gel column chromatography eluting with ethyl acetate / petroleum ether (4:1) to give 168-1.

[0669] Step 2: To a solution of 168-1 (210.0 mg, 0.91 mmol) in concentrated sulfuric acid (5 mL) was added 69 wt% aqueous HNO3 (83.0 mg, 0.91 mmol) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 2 h and at 100 °C for another 1 h. The mixture was cooled, diluted with ice water and the solution was purified by C18 reverse phase column chromatography (acetonitrile; 0.05% aqueous FA: 0 to 80%) to give 168-2.

[0670] Step 3: To a mixture of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)nicotinonitrile (350.0 mg, 1.52 mmol) in 1,4-dioxane (5 mL) and H2O (1 mL) was added 168-2 (210.0 mg, 0.76 mmol), K3PO4 (322.9 mg, 1.52 mmol) and Pd(dppf)Cl2 (83.4 mg, 0.11 mmol). The reaction mixture was degassed for 2 min under nitrogen atmosphere and stirred at 100 °C for 2 h. The mixture was cooled, diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, and concentrated. The residue was purified by silica gel column chromatography eluting with ethyl acetate / petroleum ether (3:1) to give 168-3.

[0671] Step 4: To a mixture of 168-3 (159.0 mg, 0.53 mmol) in THF (4 mL) and H2O (2 mL) was added lithium hydroxide monohydrate (156 mg, 3.7 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with water and extracted with EtOAc. The aqueous phase was acidified to pH = 2 with 2N aqueous HC1 and extracted with EtOAc. The organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated to give 168-4.

[0672] Step 5-6: Follow the procedure for synthesis of compound 146 in Example 33 to prepare compound 168 from compound 168-4. LCMS (ESI, m / z): [M+H] + = 528.2; 1 H NMR (400 MHz, DMSO-d6, ppm): δ 8.92 (s, 1H), 8.75 (d, J = 5.2 Hz, 1H), 8.04 (br s, 1H), 7.48 (d, J = 5.2 Hz, 1H), 7.44-7.33 (m, 2H), 7.12-6.97 (m, 1H), 6.10 (br s, 2H), 2.40 (s, 3H); 19 F NMR (376 MHz, DMSO-d6, ppm): δ -71.78 (3F), -116.26 (1F), -133.02 (1F).

[0673] Example 37. Synthesis of compound 178

[0674]

[0675] Step 1: A mixture of 34-4 (500 mg, 1.82 mmol) and NCS (291 mg, 2.18 mmol) in ACN (5 mL) was stirred at 50 °C under N2for 16 hours. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 95 / 5) to give 34-4.

[0676] Step 2-5: Follow the procedure for synthesis of compound 168 in Example 36 to prepare compound 178 from compound 178-1. LCMS (ESI, m / z): [M+H] + = 561.2. 1H NMR (400 MHz, DMSO-d6, ppm): δ 10.61 (s, 1H), 9.00-8.95 (m, 1H), 8.85-8.65 (m, 1H), 7.80-7.65 (m, 1H), 7.50-7.35 (m, 3H), 7.07-6.92 (m, 2H), 6.40 (br s, 2H), 2.43-2.40 (m, 3H). 19 F NMR (376 MHz, DMSO-d6, ppm): δ -72.15 (3F), -116.17 (1F), -133.18 (1F) Example 38. Synthesis of compound 181

[0677]

[0678] Step 1: To a solution of 34-4 (5.78 g, 22.17 mmol), DIEA (24.43 mL, 147.80 mmol) and HATU (11.20 g, 29.56 mmol) in DCM (80 mL) was added 45-3 (5.00 g, 14.78 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with water and extracted with DCM. The organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (DCM / ethyl acetate = 10 / 1) to give 181-1.

[0679] Step 2: To a solution of 181-1 (7.00 g, 12.0 mmol) in THF (400 mL) was added TFA (13.73 g, 120.4 mmol). The mixture was then stirred at 50 °C for 16 hours. The mixture was cooled and diluted with 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 column chromatography on silica gel (petroleum ether / ethyl acetate = 3 / 1) to give 181-2.

[0680] Step 3: To a solution of 181-2 (3 g, 5.63 mmol) in dioxane (50 mL) was added silver carbonate (3.4 g, 12.38 mmol) and iodomethane (5.25 mL, 84.4 mmol). The mixture was then stirred at room temperature for 40 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5 / 1) to give 181-3.

[0681] Step 4: To a solution of 181-3 (1.6 g, 2.92 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.48 g, 5.85 mmol) in dioxane (40 mL) was added Pd(dppf)Cl2(0.4 g, 0.585 mmol) and KOAc (0.7 g, 7.31 mmol). The mixture was degassed by bubbling nitrogen through it for 5 min. The reaction mixture was then stirred at 80 °C for 6 h. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 181-4.

[0682] Step 5: To a solution of 181-4 (103 mg, 0.17 mmol) and 3-chloropyridazine-4- carbonitrile (36.3 mg, 0.26 mmol) in dioxane (9 mL) and H2O (1 mL) was added Pd(dtbpf)Cl2(22.4 mg, 0.035 mmol) and K3PO4(110 mg, 0.52 mmol). The mixture was stirred at 60 °C for 12 h under N2atmosphere. The mixture was concentrated. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate = 8 / 1) to give 181-5.

[0683] Step 6: To a solution of 181-5 (33 mg, 0.058 mmol) in AcOH (6 mL) was added NaI (43 mg, 0.29 mmol). The reaction was stirred at 60 °C for 1 h. The mixture was diluted with saturated NaHCO3and extracted with ethyl acetate. The organic layers were combined, dried over Na2SO4, filtered and concentrated to give 181-6.

[0684] Step 7: To a solution of 181-6 in EtOH (2 mL) and H2O (0.5 mL) was added Fe powder (16.0 mg, 0.29 mmol) and NH4Cl (30.7 mg, 0.57 mmol) at room temperature. The mixture was stirred at 80 °C for 1 h. The mixture was filtered and concentrated. The residue was purified by reverse phase column (acetonitrile / 0.05% aqueous FA: 5-95%) to give 181. LCMS (ESI, m / z): [M+H]=528.2;1H NMR (400 MHz, DMSO-d6, ppm): δ 10.79 (s, 1H), 9.39 (d, J=4.8 Hz, 1H), 8.13 (d, J=5.2 Hz, 1H), 7.72 (s, 1H), 7.42-7.34 (m, 2H), 7.08-6.91 (m, 3H), 6.25 (s, 2H), 2.42 (s, 3H). + ​

[0685] Example 39. Synthesis of Compound 208

[0686]

[0687] Step 1: To a solution of 34-4 (400 mg, 1.45 mmol) and 3-bromo-6-methoxypyridinecarboxynitrile (372 mg, 1.75 mmol) in toluene (15 mL) and H₂O (0.3 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1,3,2-dioxaborhexacyclopentane (554 mg, 2.18 mmol), Pd(dppf)Cl₂ (213 mg, 0.29 mmol), and KOAc (571 mg, 5.82 mmol) were added. The mixture was stirred at 80 °C for 12 hours under a N₂ atmosphere. The mixture was cooled and concentrated. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate = 10 / 1) to give 208-1.

[0688] Steps 2-4: Compound 208 was prepared from compound 208-1 according to the synthetic procedure for compound 168 in Example 36. LCMS (ESI, m / z): [M+H] + =557.2.1H NMR (400MHz, DMSO-d6, ppm): δ10.47(brs,1H),7.67(dd,J=19.6,8.8Hz,1H),7.54(d,J=9.2Hz,1H),7.45-7.35(m,2H),7.07(dd,J=8.8,6.0Hz, 1H),7.04-6.93(m,1H),6.89(dd,J=8.0,1.6Hz,1H),6.78(dd,J=8.0,1.6Hz,1H),6.05(brs,2H),3.90(d,J=2.8Hz,3H),2.42(d,J=2.8Hz,3H).

[0689] Example 40. Synthesis of Compound 209

[0690]

[0691] Step 1: Add m-CPBA (1.02 g, 5.91 mmol) to a solution of 4-bromo-2-cyclopropylpyridine (900 mg, 4.54 mmol) in Et₂O (45 mL). Stir the mixture at room temperature for 2 hours. Concentrate the mixture. Purify the residue by silica gel column chromatography (dichloromethane / methanol = 4 / 1) to give 209-1.

[0692] Step 2: To a solution of 209-1 (970 mg, 4.53 mmol) in MeCN (20 mL) was added Et3N (1.89 mL, 13.59 mmol) and TMSCN (2.84 mL, 22.66 mmol). The mixture was stirred at 80 °C for 12 h. The mixture was cooled and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 4 / 1) to give 209-2.

[0693] Step 3-6: Follow the procedure for synthesis of compound 208 in Example 39 to prepare compound 209 from compound 209-2 and compound 34-4. LCMS (ESI, m / z): [M+H] + = 567.2. 1H NMR (400 MHz, DMSO-d6, ppm): δ 10.45 (s, 1H), 7.67-7.53 (m, 2H), 7.46-7.38 (m, 3H), 7.05-6.94 (m, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.07 (s, 2H), 2.42 (s, 3H), 2.20-2.10 (m, 1H), 1.06-0.91 (m, 4H).

[0694] Example 41. Synthesis of compound 242

[0695]

[0696] Step 1: To a solution of methyl 3-methoxy-3-oxopropionate (1 g, 7.5 mmol) and malononitrile (0.50 g, 7.5 mmol) in THF (10 mL) was added DBU (2.1 g, 15.1 mmol) at -25 °C. The mixture was stirred at 20 °C for 16 h. Next, methylamine (28% in EtOH, 5 mL) was added to the solution. The mixture was stirred at 20 °C for 16 h. Then, NaOH (10 N, 1 mL) was added to the solution. The mixture was stirred at 20 °C for another 6 h. The precipitate was collected and dried to give 242-1.

[0697] Step 2: To a solution of 242-1 (500 mg, 3.0 mmol) in ACN (6 mL) was added POBr3 (3.4 g, 12.0 mmol) at 20 °C. The reaction was stirred at 70 °C for 16 h. The mixture was quenched with 2 M K2CO3 at 0 °C. The resulting solution was extracted with ethyl acetate. The organic phase was collected and concentrated. The residue was purified by reverse phase column chromatography (ACN / H2O = 20 / 80) to give 242-2.

[0698] Step 3-5: Prepare compound 242 starting from compound 242-2 and compound 181-4 following the synthetic procedure of compound 181 in Example 38. LCMS(ESI,m / z):[M+H] + =572.2 ; 1 H NMR (400 MHz, DMSO-d6, ppm): δ

[0699] 10.90 (s, 1H), 7.90 (s, 1H), 7.41-7.37 (m, 2H), 7.24 (d, J = 8.4 Hz, 2H), 7.00-6.91 (m, 1H), 6.82 (dd, J = 8.0, 2.4 Hz 1H), 6.66 (d, J = 7.6 Hz, 1H), 5.91 (br s, 2H), 5.42 (d, J = 15.6 Hz, 1H), 3.34 (s, 3H), 2.42 (d, J = 6.0 Hz, 3H). 19 F NMR (376 MHz, DMSO-d6, ppm): δ -71.91 (3F), -116.31 (1F), -133.15 (1F).

[0700] Example 42. Synthesis of compound 226

[0701]

[0702] Step 1: To TFA (96 mL) was added 2,4,6-trimethylbenzenesulfonic acid {[(2- methylpropan-2-yl)oxy]carbonyl}azanide (12 g, 38.05 mmol) in portions at 0-5 °C and the mixture was stirred at this temperature for 1 hour. The mixture was poured into ice water and stirred for 15 minutes. Filtered and the filter cake was washed with water until the aqueous solution was neutral. The collected solid was re-dissolved in DCM and dried over anhydrous Na2SO4. Filtered and the filtrate was concentrated to give 226-1.

[0703] Step 2: To a solution of 5-bromopyridin-2-amine (4.0 g, 23.12 mmol) in 200 mL of dichloromethane was added 226-1 (6.5 g, 30.38 mmol) in 100 mL of dry dichloromethane dropwise at -10 to 0 °C. The mixture was stirred at room temperature for 20 hours. The mixture was concentrated. The residue was slushed in MTBE and filtered to give 226-2.

[0704] Step 3: To a mixture of 226-2 (5.0 g, 12.88 mmol) and CDI (5.0 g, 30.84 mmol) in THF (100 mL) was added DBU (4.0 mL, 26.77 mmol). The mixture was stirred at 25 °C for 16 h. The mixture was concentrated. The residue was diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by C18 reverse phase column (methanol in water: 5% to 95%) to give 226-3.

[0705] Step 4: To a mixture of 226-3 (3.45 g, 9.42 mmol) and K2CO3 (1.36 g, 9.84 mmol) in DMF (40 mL) was added iodomethane (1.30 g, 9.16 mmol). The mixture was then stirred at room temperature for 16 h. The mixture was diluted with H2O and extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (EtOAc / PE = 1 / 5) to give 226-4.

[0706] Step 5: A mixture of 226-4 (450.0 mg, 1.97 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.5 g, 5.91 mmol), KOAc (390.0 mg, 3.97 mmol) and Pd(dppf)Cl2 (90.0 mg, 0.12 mmol) in 1,4-dioxane (14 mL) was purged with nitrogen for 1 min and stirred at 100 °C for 1 h. The mixture was concentrated. The residue was purified by C18 reverse phase column (acetonitrile / 0.05% TFA in water: 5% to 95%) to give 226-5.

[0707] Step 6-9: Compound 226 was prepared according to the procedures for synthesis of compound 152 in Example 32, starting from compound 226-5 and compound 34-4. LCMS (ESI, m / z): [M+H] = 572.0. + 1 H NMR (400 MHz, DMSO-d6, ppm): δ 10.57 (br s, 1H), 8.49 (s, 1H), 7.78-7.64 (m, 1H), 7.49-7.36 (m, 4H), 7.04-6.90 (m, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 5.91 (br s, 2H), 4.01 (s, 3H), 2.42 (s, 3H); 19 ​FNMR (376 MHz, DMSO-d6, ppm): δ -71.97 (3F), -116.22 (1F), -133.16 (1F).

[0708] Example 43. Synthesis of compound 230

[0709]

[0710] Step 1: To a -78 °C stirring solution of 2-chloro-5-fluoropyridine-3-carboxylic acid (2 g, 11.393 mmol) in THF (50 mL) was added LDA (2 M in THF) (19.94 mL, 39.88 mmol) dropwise. After stirring at -78 °C for 1 h, 1,2-dibromo-1,1,2,2-tetrafluoroethane (4.44 g, 17.09 mmol) in THF (10 mL) was added, then the mixture was slowly warmed to room temperature and stirred at room temperature for 0.5 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution. The mixture was extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase column (acetonitrile / water: 5% - 30%) to give 230-1.

[0711] Step 2: To a solution of 230-1 (500 mg, 1.965 mmol) in DCM (20 mL) was added DMF (1 drop) and oxalyl chloride (0.34 mL, 3.93 mmol). After stirring at room temperature for 1 h, to the reaction mixture was added ammonia (3.03 mL, 19.65 mmol) at 0 °C. The mixture was stirred for another 10 min. The solvent was removed in vacuo. The residue was purified by reverse phase column (acetonitrile / water: 5% - 40%) to give 230-2.

[0712] Step 3: To a stirring solution of 230-2 (330 mg, 1.30 mmol) and TEA (0.91 mL, 6.51 mmol) in DCM (20 mL) at 0 °C was added TFAA (0.55 mL, 3.91 mmol) dropwise. The mixture was then stirred at 0 °C for 0.5 h. The mixture was diluted with H2O and extracted with DCM. The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 230-3.

[0713] Step 4: To a solution of 181-4 (150 mg, 0.252 mmol) and 230-3 (119 mg, 0.505 mmol) in toluene (10 mL) and H2O (1 mL) was added Pd(dtbpf)Cl2 (33 mg, 0.050 mmol) and K3PO4 (161 mg, 0.76 mmol). The reaction mixture was degassed by bubbling nitrogen through it for 5 min. The reaction mixture was then stirred at 60 °C for 1 h. The mixture was cooled, diluted with H2O and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / Ethyl acetate = 5 / 1) to give 230-4.

[0714] Step 5: To a solution of 230-4 (70 mg, 0.112 mmol) in dioxane (5 mL) was added Pd2(dba)3 (11 mg, 0.011 mmol), RuPhos (8 mg, 0.017 mmol) and Cs2CO3 (92 mg, 0.28 mmol). The reaction mixture was degassed by bubbling nitrogen through it for 5 min. The reaction mixture was then stirred at 100 °C for 1 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by reverse phase column (acetonitrile / water: 5%-80%) to give 230-5.

[0715] Step 6: To a solution of 230-5 (42 mg, 0.069 mmol) in ACN (5 mL) was added K2CO3 (20 mg, 0.14 mmol) and iodoethane (55 mg, 0.35 mmol). The reaction mixture was then stirred at room temperature for 16 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / Ethyl acetate = 5 / 2) to give 230-6 and 230-6A.

[0716] Step 7: To a solution of 230-6 (28 mg, 0.044 mmol) in AcOH (1.5 mL) was added NaI (27 mg, 0.18 mmol). The reaction mixture was then stirred at 60 °C for 1 h. This solution containing 230-7 was cooled and used directly in the next step without further purification.

[0717] Step 8: To the above solution of 230-7 in AcOH (1.5 mL) was added Fe powder (13 mg, 0.22 mmol). The reaction mixture was then stirred at 80 °C for 2 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative-HPLC (acetonitrile / 0.05% NH4HCO3 in water: 5%-50%) to give 230. LCMS (ESI, m / z): [M+H]=589.2; + 1 ​HNMR (400 MHz, DMSO-d6, ppm): δ 10.24 (s, 1H), 8.23-8.14 (m, 1H), 7.71-7.53 (m, 1H), 7.42-7.34 (m, 2H), 7.06-6.98 (m, 1H), 6.89 (s, 2H), 6.28 (s, 2H), 3.98-3.89 (m, 2H), 2.41 (s, 3H), 1.31-1.25 (m, 3H). 19 F NMR (376 MHz, DMSO-d6, ppm): δ -72.10 (3F), -116.23 (1F), -133.17 (1F), -148.80 (1F).

[0718] Example 44. Synthesis of compound 234

[0719]

[0720] Step 1: To a solution of 2-bromo-3-amino-5-chloropyridine (5 g, 24.10 mmol) and cyclopropylborane diol (2.48 g, 28.92 mmol) in 1,4-dioxane (20 mL) and H2O (4 mL) was added Cs2CO3(23.6 g, 72.30 mmol) and Pd(dppf)Cl2(1.8 g, 2.41 mmol). The reaction mixture was stirred at 130 °C for 16 h under N2. The mixture was cooled, diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column (eluted with 0% to 20% EtOAc / petroleum ether) to give 234-1.

[0721] Step 2: To a solution of 234-1 (1 g, 5.93 mmol) in ACN (20 mL) was added NBS (1.1 g, 6.23 mmol). The mixture was stirred at 25 °C for 1 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluted with 0% to 25% EtOAc / petroleum ether) to give 234-2.

[0722] Step 3: To a solution of 234-2 (1 g, 4.04 mmol) in DMA (15 mL) was added Zn(CN)2(1.4 g, 12.12 mmol) and Pd(PPh3)4(0.5 g, 0.40 mmol). The mixture was degassed by bubbling nitrogen through it for 5 min, and then the reaction mixture was stirred at 130 °C for 2 h under microwave conditions. The mixture was cooled, diluted with water and extracted with EtOAc. The organic extracts were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluting with 0% to 30% EtOAc in petroleum ether) to give 234-3.

[0723] Step 4: To a solution of 234-3 (550 mg, 2.84 mmol) and 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (2.16 g, 8.52 mmol) in 1,4-dioxane (25 mL) was added Pd2(dba)3(260 mg, 0.28 mmol), PCy3(160 mg, 0.57 mmol) and KOAc (836 mg, 8.52 mmol). The reaction mixture was degassed by bubbling nitrogen through it for 2 min. Then the reaction mixture was stirred at 80 °C for 3 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by C18 reverse phase column (acetonitrile / water: 5 to 35%) to give 234-4.

[0724] Step 5: To a mixture of 181-3 (90 mg, 0.16 mmol), 234-4 (52 mg, 0.26 mmol) and K3PO4(105 mg, 0.50 mmol) in THF (2 mL) and H2O (0.2 mL) was added Pd(dtbpf)Cl2(11 mg, 0.02 mmol). The mixture was degassed by bubbling nitrogen through it for 2 min, and then the reaction mixture was stirred at 80 °C for 3 h. The mixture was cooled and concentrated. The residue was purified by column chromatography on silica gel (eluting with 0% to 60% EtOAc in petroleum ether) to give 234-5.

[0725] Step 6-7: Compound 234 was prepared starting from compound 234-5 following the procedure for the synthesis of compound 230 in Example 43 (Note: Zn powder was used instead of Fe powder in the last step). LCMS (ESI, m / z): [M+H]=582.4. + 1 ​H NMR (400 MHz, DMSO-d6, ppm): δ 10.42 (br s, 1H), 7.56-7.46 (m, 1H), 7.46-7.34 (m, 2H), 7.04-6.92 (m, 1H), 6.89-6.82 (m, 1H), 6.72-6.63 (m, 2H), 6.14-6.04 (m, 2H), 5.96 (br s, 2H), 2.42 (d, J = 0.8 Hz, 3H), 2.17-2.05 (m, 1H), 0.97-0.78 (m, 4H); 19 F NMR (376 MHz, DMSO-d6, ppm): δ -72.106 (3F), -116.233 (1F), -133.181 (1F).

[0726] Example 45. Synthesis of compound 232

[0727]

[0728] Step 1: To a solution of 2,6-dichloropyridine-3-carbonitrile (3 g, 17.3 mmol) in MeOH (75 mL) was added NaOMe (0.9 g, 17.3 mmol) at 0 °C. Then 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 = 10 / 1) to give 232-1.

[0729] Step 2: To a solution of 2,2,6,6-tetramethylpiperidine (2.2 g, 15.7 mmol) and nBuLi (5.7 mL, 2.5 M) in THF (60 mL) was added 232-1 (1.2 g, 7.1 mmol) at -78 °C. Then the mixture was stirred at the same temperature for 0.5 h. Subsequently, B(OiPr)3 (2.9 g, 15.7 mmol) was added at -78 °C. And the mixture was stirred at -78 °C for 1 h. The pH of the mixture was adjusted to 3-4 by adding 1M HC1. The mixture was extracted with ethyl acetate. The organic layers were combined, dried over Na2SO4, filtered and concentrated. Then the residue was purified by reverse phase column (acetonitrile / 0.05% aqueous FA: 5-95%) to give 232-2.

[0730] Step 3: To a solution of 34-4 (600 mg, 2.2 mmol) and 232-2 (695.0 mg, 3.3 mmol) in dioxane (60 mL) and H2O (6 mL) was added Pd(dppf)Cl2(160 mg, 0.22 mmol) and KOAc (428 mg, 4.4 mmol). The mixture was then stirred at 80 °C for 2 h under N2. The mixture was concentrated. The residue was purified by column chromatography on silica gel (dichloromethane / ethyl acetate = 10 / 1) to give 232-3.

[0731] Step 4: To a solution of 232-3 (180 mg, 0.50 mmol) and diphenylmethanimine (269.8 mg, 1.49 mmol) in toluene (18 mL) was added Pd2(dba)3(45 mg, 0.050 mmol), RuPhos (46 mg, 0.10 mmol) and Cs2CO3(404 mg, 1.24 mmol). The mixture was then stirred at 100 °C for 1 h under N2atmosphere. The mixture was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 1) to give 232-4.

[0732] Step 5: To a solution of 232-4 (250 mg, 0.49 mmol) in MeOH (25 mL) was added 1M HCl (2.46 mL). The mixture was then stirred at room temperature for 1 h. The mixture was concentrated. The residue was purified by column chromatography on silica gel (dichloromethane / ethyl acetate = 8 / 1) to give 232-5.

[0733] Step 6-8: Compound 232 was prepared according to the procedure of the synthesis of compound 52 in Example 17, starting from compound 232-5. LCMS (ESI, m / z): [M+H] + = 572.2, 1 H NMR (400 MHz, DMSO-d6, ppm): δ 10.38 (s, 1H), 7.60-7.47 (m, 1H), 7.45-7.35 (m, 2H), 7.05-6.91 (m, 1H), 6.84 (dd, J = 8.0, 2.4 Hz, 1H), 6.70-6.60 (m, 3H), 5.98 (s, 2H), 5.82 (d, J = 16.8 Hz, 1H), 3.81 (d, J = 5.2 Hz, 3H), 2.42 (d, J = 4.8 Hz, 3H). 19 F NMR (376 MHz, DMSO-d6, ppm): δ -72.08 (3F), -116.22 (1F), -133.17 (1F).

[0734] Example 46. Synthesis of compound 251

[0735]

[0736] Step 1: To a mixture of 3-bromo-6-methylpyridine-2-carbonitrile (500 mg, 2.54 mmol) in DCM (10 mL) was added 3-chlorobenzene-1 -peroxoacetic acid (481 mg, 2.8 mmol). The mixture was then stirred at room temperature for 16 hours. The mixture was diluted with 2 M NaHC03and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by column chromatography on silica gel (DCM / MeOH = 9 / 1) to give 251-1.

[0737] Step 2-4: Follow the procedure for synthesis of compound 181 in Example 38 to prepare compound 251 from compound 251-1 and compound 181-4. LCMS (ESI, m / z): [M+H] = 557.2. + 1 H NMR (400 MHz, DMSO-d6, ppm): δ

[0738] 10.80 (s, 1H), 7.85-7.58 (m, 2H), 7.42-7.33 (m, 2H), 7.23-7.14 (m, 1H), 7.05-6.93 (m, 1H), 6.92-6.75 (m, 2H), 6.13 (s, 2H), 2.44-2.31 (m, 6H). 19 F NMR (376 MHz, DMSO-d6, ppm): δ -72.03 (3F), -116.24 (1F), -133.16 (1F).

[0739] Example 47. Synthesis of compound 258

[0740]

[0741] Step 1: To a solution of 3-bromo-6-hydroxypyridine-2-carbonitrile (300 mg, 1.51 mmol) in DMF (5 mL) was added Cs2C03(1.0 g, 3.1 mmol) and sodium 2-chloro-2,2-difluoroacetate (280 mg, 1.84 mmol). The mixture was then stirred at 80 °C for 3 hours. The reaction mixture was diluted with EtOAc, washed with H20 and brine. The organic layer was separated, dried over anhydrous Na2S04, filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 8 / 1) to give 258-1.

[0742] ​Step 2-4: Follow the synthetic procedure of compound 181 in Example 38 to prepare compound 258 from compound 258-1 and compound 181-4. LCMS (ESI, m / z): [M+H] + = 557.2; 1 H NMR (400 MHz, DMSO-d6, ppm): δ

[0743] 10.80 (s, 1H), 7.85-7.58 (m, 2H), 7.42-7.33 (m, 2H), 7.23-7.14 (m, 1H), 7.05-6.93 (m, 1H), 6.92-6.75 (m, 2H), 6.13 (s, 2H), 2.44-2.31 (m, 6H). 19 F NMR (376 MHz, DMSO-d6, ppm): δ -72.03 (3F), -116.24 (1F), -133.16 (1F).

[0744] Example 48. Synthesis of compound 260

[0745]

[0746] Step 1: To a solution of 5-bromo-2-chloropyrimidine (10.0 g, 51.70 mmol) in MeOH (100 mL) was added TFA (6.0 g, 52.73 mmol) and BPO (14.0 g, 57.90 mmol). The mixture was then stirred at 65 °C for 16 hours. After cooling to room temperature, the mixture was diluted with aqueous NaHCO3 solution and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 9 / 1) to give 260-1.

[0747] Step 2: To a mixture of 260-1 (1.5 g, 6.71 mmol) in 1,4-dioxane (20 mL) was added NaOH (492.3 mg, 7.38 mmol) and potassium permanganate (3.2 g, 20.14 mmol). The mixture was then stirred at 25 °C for 5 hours, diluted with saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 9 / 1) to give 260-2.

[0748] Step 3: To a mixture of 260-2 (1.0 g, 4.21 mmol), DIPEA (2.8 mL, 16.85 mmol) and HATU (2.4 g, 6.32 mmol) in DCM (20 mL) was added NH4Cl (337.9 mg, 6.32 mmol) and the mixture was stirred at room temperature for 1 h. The mixture was diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by C18 reverse phase column (acetonitrile / 0.05% aqueous FA: 5% to 95%) to give 260-3.

[0749] Step 4: To a solution of 260-3 (500.0 mg, 2.12 mmol) in DCM (20 mL) was added TEA (2.4 mL, 16.92 mmol) and TFAA (1.8 g, 8.46 mmol). The mixture was stirred at 25 °C for 1 h. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered and concentrated to give 260-4.

[0750] Steps 5-6: Compound 260-6 was prepared according to the procedure for the synthesis of compound 181-6 in Example 38, starting from compound 260-4 and compound 181-4.

[0751] Step 7: To a solution of 260-6 (30.0 mg, 0.051 mmol) in MeOH (2 mL) was added 30 wt% sodium methoxide in MeOH (10.0 mg, 0.055 mmol) and the reaction mixture was stirred at 25 °C for 1 h. The mixture was diluted with saturated aqueous NH4Cl and extracted with EtOAc. The organic extracts were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column (eluted with 0-20% EtOAc in petroleum ether) to give 260-7.

[0752] Step 8: Compound 260 was prepared according to the procedure for the synthesis of compound 181 in Example 38, starting from compound 260-7. LCMS (ESI, m / z): [M+H]=558.2; + 1 H NMR (400 MHz, MeOD-d4, ppm): δ 8.68-8.58 (m, 1H), 7.25-7.10 (m, 2H), 7.10-7.00 (m, 1H), 7.00-6.90 (m, 1H), 6.75-6.60 (m, 1H), 4.06 (s, 3H), 2.43 (s, 3H); 19 ​F NMR (376 MHz, MeOD-d4, ppm): δ -77.31 (3F), -118.30 (1F), -135.52 (1F).

[0753] Example 49. Synthesis of compound 263

[0754]

[0755] Step 1: To a solution of 2-(dimethylamino)ethan-1-ol (100 mg, 1.12 mmol) in THF (10 mL) was added NaH (100 mg, 2.50 mmol, 60% purity in mineral oil) portionwise at 0 °C. After the mixture was stirred at the same temperature for 10 min, 3-bromo-6-chloropyridine-2-carbonitrile (200 mg, 0.92 mmol) in THF (1 mL) was added dropwise at 0 °C and the mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl solution, diluted with H2O and extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (DCM / MeOH = 10 / 1) to give 263-1.

[0756] Step 2: Compound 263 was prepared according to the procedure for synthesis of compound 181 in Example 38, starting from compound 263-1 and compound 181-4. LCMS (ESI, m / z): [M+H] + = 614.3. 1 H NMR (400 MHz, Methanol-d4, ppm): δ

[0757] 7.68-7.60 (m, 1H), 7.23-7.17 (m, 1H), 7.09-6.99 (m, 3H), 6.84-6.80 (m, 1H), 6.72-6.63 (m, 1H), 4.55-4.47 (m, 2H), 2.93-2.84 (m, 2H), 2.44-2.38 (m, 9H); 19 F NMR (376 MHz, Methanol-d4, ppm): δ -74.86 (3F), -118.37 (1F), -135.55 (1F).

[0758] Example 50. Synthesis of compound 264

[0759]

[0760] Step 1: To a solution of 52-1 (600 mg, 2.2 mmol) in THF (10 mL) was added 4-(prop-2-yn-1-yl)morpholine (1.3 g, 10.9 mmol), CuI (42 mg, 0.22 mmol), PdCl2(PPh3)2 (170 mg, 0.22 mmol) and TEA (0.6 mL, 4.4 mmol). The mixture was stirred at 60 °C for 16 h. The mixture was cooled, diluted with H2O and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether / Ethyl acetate = 1 / 3) to give 264-1.

[0761] Step 2: Compound 264 was prepared according to the procedure for the synthesis of compound 52 in Example 17, starting from compound 264-1. LCMS(ESI,m / z):[M+H] + =548.2 ; 1 H NMR (400 MHz, Methanol-d4, ppm): δ 7.37 (d, J = 1.6 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.07-7.01 (m, 1H), 6.99 (d, J = 1.2 Hz, 1H), 6.68-6.62 (m, 1H), 3.74 (t, J = 4.4 Hz, 4H), 3.52 (s, 2H), 2.67 (t, J = 4.4 Hz, 4H), 2.41 (s, 3H). 19 F NMR (376 MHz, Methanol-d4, ppm): δ -74.88 (3F), -118.31 (1F), -135.55 (1F).

[0762] Table 1 below shows the characterization of some exemplary compounds of the present disclosure.

[0763] Table 1: Characterization of some exemplary compounds of the present disclosure

[0764]

[0765]

[0766]

[0767]

[0768]

[0769]

[0770]

[0771]

[0772]

[0773]

[0774]

[0775]

[0776]

[0777]

[0778]

[0779]

[0780]

[0781]

[0782]

[0783]

[0784]

[0785]

[0786]

[0787]

[0788]

[0789]

[0790]

[0791]

[0792]

[0793]

[0794]

[0795] Biological Example A: In vitro kinase inhibition assay

[0796] The PI3Ka_E545K kinase phosphorylates the substrate PIP2 to PIP3 using ATP, which is converted to ADP during the reaction. The ATP-depletion reagent is added to stop the reaction, resulting in only ADP remaining in the reaction mixture with no ATP left over. To quantify the amount of ADP, the ADP-Glo kit (Promega) is used to detect the amount of ADP using a coupled luciferase / luciferin reaction.

[0797] Assay Procedure

[0798] One microliter of test compound dissolved in 5% DMSO at various concentrations is dispensed into a 384-well plate. To the plate containing the compound, recombinant PI3Ka_E545K (Carna Biosciences) in assay buffer (2ul in 50mM HEPES pH 7.5, 50mM NaCl, 3mM MgCl2, 5mM DTT, and 0.03% CHAPS) is added and incubated at 25°C for 1 hour. Then a substrate solution in assay buffer (2ul in 0.025mg / mL PIP2:3PS, 100uM ATP) is added to start the reaction. The reaction mixture is incubated at 25°C for one hour. Five microliters of ADP-Glo reagent (Promega) is added to each well and incubated at room temperature for one hour. Then, 10uL of Kinase Detection Reagent is added and incubated at room temperature for one hour. Luciferase activity is measured for each well via luminescence on a microplate reader (Tecan Spark).

[0799] Data Analysis

[0800] The inhibition rate (IR) of a test compound is determined by the following equation: IR (%) = (average high control - compound well) / (average high control - average low control) * 100%. The IC50 of a compound is determined by fitting the following non-linear regression equation: Y = bottom + (top - bottom) / (1 + 10^((LogIC 50 X)*HillSlope)). X: log of compound concentration; Y: inhibition rate (IR); top and bottom: plateaus with the same unit as Y; logIC 50 : log with the same unit as X; HillSlope: slope coefficient or Hill slope.

[0801] Table 2 below shows the IC 50 values measured and / or calculated according to the present biological example.

[0802] Table 2: PI3Ka_E545K kinase assay IC 50 (A: < 100 nM; B: 100 nM - 1 mM; C: > 1 mM)

[0803]

[0804]

[0805]

[0806]

[0807] Biological Example B: Cell Proliferation Assay in MCF-7 Cell Line

[0808] Assay Procedure

[0809] Breast cancer cells MCF-7 PI3K E545K (ATCC) were cultured in a 37 °C incubator with 5% CO2 and 100% relative humidity. Cells were routinely sub-cultured to maintain exponential growth. Each cell assay plate well was plated with 600 cells as a 100 pL suspension in culture medium. Cells were incubated overnight, then compounds were added to each well. Compounds were prepared as 10 mM stock solutions in dimethyl sulfoxide (DMSO). Serial dilutions were made in DMSO in a 200X stock plate. To each cell well of the cell assay plate, 0.5 pL of the 200X compound solution was added. The final DMSO concentration in each well was 0.5%. High control wells were 0.5% DMSO, where culture medium was added to cells, and low control wells were where only culture medium was added in the wells of the plate. The cell assay plate was incubated for 6 days. Cell viability assay was performed according to the CellTiter 96® AQueous One Solution Cell Proliferation Assay kit.

[0810] Data Analysis

[0811] The inhibition rate (IR) of a test compound was determined by the following formula: IR (%) = (average high control - compound well) / (average high control - average low control) * 100%. Compound IC 50 : Y = bottom + (top - bottom) / (1 + 10^((LogIC 50 - X) * HillSlope)). X: log of compound concentration; Y: inhibition rate (IR); top and bottom: plateaus with the same units as Y; logIC 50 : log units the same as X; HillSlope: slope coefficient or Hill slope.

[0812] Reagents and Materials

[0813]

[0814] Table 3 below shows IC 50 ​Values.

[0815] Table 3: Inhibition of MCF-7 PI3K E545K Inhibition of cancer cell growth (IC 50 [A: < 300 nM; B: 300 nM - 3 mM; C: > 3 mM]

[0816]

[0817]

[0818]

[0819]

[0820] Biological Example C: Cell proliferation assay in different cell lines

[0821] The culture media and reagents used in this study are listed in the table below.

[0822] Culture media or reagents Supplier Catalog No. 96-well TC treated microplate Corning 3610 Master plate Greiner bio-one 651201 T25 flask Thermo Fisher 156367 FBS Excell Bio FND500 0.25% trypsin KEL KC112-01 RPMI1640 KEL KC1325-01 DMEM / F12 KEL KC308-01 McCoy's 5A (modified) medium KEL KC305-01 Beta-estradiol Sigma E8875 Sodium selenite Adamas life 10641B Hydrocortisone MCE HY-NO583 / CS-2226 Transferrin Sigma T8158 Insulin KEL RHI-1000 D-PBS KEL KC310-01 Bio-Pro Luminescent Adamas life RA-GL11-A

[0823] Experimental methods and procedures

[0824] The breast cancer cell line T47D, lung cancer cell line NCI-H1048 and SK-BR-3 (obtained from ATCC) were cultured in a 37°C incubator with 5% CO2 and 100% relative humidity. Cells were routinely subcultured to maintain exponential growth. 1000 to 1500 cells were seeded in 100 pL suspension into each well of a cell assay plate. Cells were incubated and then compound was added to each well. Compounds were prepared as 10 mM stock solutions in dimethyl sulfoxide (DMSO). Serial dilutions were made in DMSO in a 200X compound stock plate. Compound stock solution (0.5 uL) was added to each well of the cell assay plate. The final DMSO concentration in each well was 0.5%. The cell assay plate was incubated for 6 days. Cell viability assay was performed according to the Bio-Pro Luminescent Assay Kit.

[0825] Data analysis

[0826] The inhibition rate (IR) of a test compound was determined by the following formula: IR (%) = (average high control - compound well) / (average high control - average low control) * 100%. The IC 50 : Y = minimum + (maximum - minimum) / (1 + 10^((LogIC 50 ​- HillSlope). X: Log of compound concentration; Y: Inhibition rate (IR): Highest and lowest values: Plateau with the same unit as Y; logIC 50 : Log with the same unit as X; HillSlope: Slope coefficient or Hill slope.

[0827] Table 4: Inhibition of cancer cell growth (IC50) in H1048 cells by representative compounds 50 [A: < 100 nM; B: 100 nM - 1 mM; C: > 1 mM]

[0828]

[0829]

[0830] Table 5: Inhibition of cancer cell growth (IC50) in T47D cells by representative compounds 50 [A: < 300 nM; B: 300 nM - 3 mM; C: > 3 mM]

[0831] Compound No. IC50 Compound No. IC50 9 B 10 C 30 A 32 A 65 A 70 A 77 A 114 A 115 A 120 A 136 A 157 A 158 A 159 A 163 A 167 A 169 A 170 A 176 A 183 A 208 A 211 A 214 A 236 A 239 A

[0832] Table 6: Inhibition of cancer cell growth (IC50) in SK-BR-3 cells by representative compounds 50 [A: < 300 nM; B: 300 nM - 3 mM; C: > 3 mM]

[0833]

[0834]

[0835] Biological Example D: Human microsomal clearance assay

[0836] The objective of this study was to assess the metabolic stability of compounds in human liver microsomes using a microsomal clearance assay.

[0837] Mixtures containing 100 mM potassium phosphate (pH 7.4), 0.5 mg / mL liver microsomes, 2 mM NADPH, and 1 mM compound were prepared and added to 96-well plates. The plates were ...

Claims

1. A compound of Formula I: or a pharmaceutically acceptable salt thereof: wherein: X is -C(=Z)-, -S(O)-, -S(O)(=NH)- or -S(O)2-, wherein Z is O, CHR 5 or NR 5 ; Y is N or CR 6 ; R 1 C is arbitrarily replaced 1-6 Alkyl groups, optionally substituted C 1-6 Halogenated alkyl groups, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 2-6 alkenyl or optionally substituted C 2-6 alkynyl group; R 2 is 5-14 membered heteroaryl optionally substituted with one or more groups independently selected from halo, oxo, hydroxy, -CN, -N3, -N02, -N(R')2, -OR', -SR', -C(=0)R', -C(=0)0R', - R 3 and R 4 , together with the intervening C and C atoms, join to form an optionally substituted C 5-10 carbocyclyl ring, an optionally substituted 5-10 membered heterocyclyl ring, an optionally substituted C 6-10 aryl ring, or an optionally substituted 5-10 membered heteroaryl ring; R 5 H, OH, optionally substituted C 1-4 alkyl, optionally substituted C 1-4 haloalkyl, optionally substituted C 1-4 heteroalkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 2-6 alkenyl or optionally substituted C 2-6 alkynyl; or R 3 , R 4 , and R 5 , together with the intervening C, C, C, and (N or C) atoms, join to form an optionally substituted C 10-14 carbocyclyl ring, an optionally substituted C 10-14 aryl ring, an optionally substituted 10-14 membered heterocyclyl ring, or an optionally substituted 10-14 membered heteroaryl ring; R 6 H, halogen, OH, NH2, CN, optionally substituted C 1-4 alkyl, optionally substituted C 1-4 haloalkyl, optionally substituted C 1-4 heteroalkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 2-6 alkenyl or optionally substituted C 2-6 alkynyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein has Formula I-1, I-2, I-3, or I-4: wherein X a is N or CR a , X b is N or CR b , and X c is N or CR c , wherein R a , R b , R c and R e are each independently hydrogen, halogen, OH, NH2, CN, -C(O)-NH2, G, -(C 1-4 alkylene)-G, O-G, NH-G, O-(C 1-4 alkylene)-G, NH-(C 1-4 alkylene)-G, -C(O)-NH-G, -C(O)-NGG, SG, S(O)-G, or S(O)2-G, wherein G is independently at each occurrence optionally substituted C 1-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-10 carbocyclyl ring, optionally substituted 4-10 membered heterocyclyl ring, optionally substituted C 6-10 aryl, or optionally substituted 5-10 membered heteroaryl; preferably R a , R b , R c and R e are each independently hydrogen, halogen, OH, NH2, CN, -C(O)-NH2, -C(O)-NH(C 1-4 alkyl), -C(O)-N(C 1-4 alkyl)2, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-10 carbocyclyl ring, optionally substituted 4-10 membered heterocyclyl ring, optionally substituted C 6-10 aryl, or optionally substituted 5-10 membered heteroaryl; or R a and R b , or R b and R c , together with the C and C atoms between them, join to form an optionally substituted C 5-10 carbocyclyl ring, an optionally substituted 5-10 membered heterocyclyl ring, an optionally substituted C 6-10 aryl ring, or an optionally substituted 5-10 membered heteroaryl ring; R d is H, halogen, OR 7 or NR 7 R 8 wherein R 7 and R 8 are each independently H, optionally substituted C 1-4 alkyl or optionally substituted C 1-4 haloalkyl; R f is hydrogen, halogen (e.g., F or Cl), G A , -(C 1-4 alkylene)-G A , OH, CN, OG A , O-(C 1-4 alkylene)-G A , SG A , S(O)-G A , or S(O)2-G A , wherein G A is optionally substituted C 1-6 alkyl, optionally substituted C 1-4 heteroalkyl, optionally substituted C 3-6 cycloalkyl, or optionally substituted 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O, and S.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein has Formula I-1-A, I-1-B, I-1-C, or I-1-D:

4. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein has Formula I-2-A, I-2-B, I-2-C, or I-2-D:

5. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein has Formula I-3-A, I-3-B, or I-3-C:

6. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein has Formula I-4-A, I-4-B, or I-4-C:

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is -C(O)-.

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

9. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein Y is N.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R 1 is a C 1-2 alkyl substituted with fluoro.

11. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R 1 is CF3or CHF2.

12. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R 1 is CF3.

13. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-12, wherein R 2 is wherein R A is C 1-3 alkyl (such as methyl), R C is halogen (such as F or CI) or C 1-3 alkyl (such as methyl), and R E is H, halogen (such as F, CI, or Br), CN, C 1-4 alkyl (such as methyl), C 2-4 alkenyl, C 2-4 alkynyl, or C 3-4 cycloalkyl (such as cyclopropyl); preferably, R 2 is wherein R A is C 1-3 alkyl, R C is halogen, and R E is selected from H, halogen, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 3-4 cycloalkyl.

14. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein R 2 is wherein R E is H, F, Cl, Br, CN, methyl, or cyclopropyl.

15. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-12, wherein R 2 is 16. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-12, wherein R 2 is 17. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-16, wherein the carbon in the compound that connects R 1 and R 2 is a chiral carbon and has the chirality:

18. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-16, wherein the carbon in the compound that connects R 1 and R 2 is a chiral carbon and has the chirality:

19. The compound of any one of claims 2-4 and 8-18, or a pharmaceutically acceptable salt thereof, wherein in Formula I-1 or as applicable in Formula I-1-A, I-1-C, or I-1-D, or in Formula I-2 or as applicable in Formula I-2-A, I-2-C, or I-2-D, X a is CR a and R a is H, halogen, CN, R ax , -COR ax , -NHCOR ax , -CONH2, -CONHR ax , -CON(R ax )2, -OR ax , -NHR ax , -N(R ax )2, -SR ax , -SO2R ax , or -NHSO2R ax , wherein R ax is, at each occurrence, independently C 1-6 alkyl which is unsubstituted or substituted by one or more substituents independently selected from halogen (preferably F), OH, or N(CH3)2.

20. The compound of any one of claims 2-4 and 8-18, or a pharmaceutically acceptable salt thereof, wherein in Formula I-1 or as applicable in Formula I-1-A, I-1-C, or I-1-D, or in Formula I-2 or as applicable in Formula I-2-A, I-2-C, or I-2-D, X a is CR a and R a is H, F, Cl, CN, -C(O)-NH2, -C(O)-NH(C 1-4 alkyl), -C(O)-N(C 1-4 alkyl)2, C 1-6 alkyl, C 1-6 haloalkyl, -O-C 1-4 alkyl, -S-C 1-4 alkyl, -S(O)2-C 1-4 alkyl, -C(C 1-2 alkyl)2OH, -NH-S(O)2-C 1-4 alkyl, or -O-C 2-3 alkylene-N(CH3)2.

21. The compound of any one of claims 2-4 and 8-18, or a pharmaceutically acceptable salt thereof, wherein in Formula I-1 (e.g., Formula I-1-A, I-1-C, or I-1-D) or I-2 (e.g., Formula I-2-A, I-2-C, or I-2-D), X a is CR a and R a is C 3-4 cycloalkyl (e.g., cyclopropyl), 4-6 membered monocyclic heterocyclyl containing one or two ring heteroatoms independently selected from N and O (e.g., azetidinyl, pyrrolidinyl, or tetrahydropyranyl), 8-9 membered bicyclic heterocyclyl containing one, two, or three ring heteroatoms independently selected from N and O (e.g., diazaspirooctanyl), phenyl, 5-6 membered heteroaryl containing one, two, or three ring heteroatoms independently selected from N, O, and S (e.g., pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyridinone, pyridyl N-oxide, pyrazinyl, pyrimidinyl, or pyridazinyl), 9-10 membered bicyclic heteroaryl containing one, two, or three ring heteroatoms independently selected from N, O, and S (e.g., triazolopyridinyl), wherein the C 3-4 cycloalkyl (e.g., cyclopropyl), 4-6 membered monocyclic heterocyclyl containing one or two ring heteroatoms independently selected from N and O (e.g., azetidinyl, pyrrolidinyl, or tetrahydropyranyl), 8-9 membered bicyclic heterocyclyl containing one, two, or three ring heteroatoms independently selected from N and O (e.g., diazaspirooctanyl), phenyl, 5-6 membered heteroaryl containing one, two, or three ring heteroatoms independently selected from N, O, and S (e.g., pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyridinone, pyridyl N-oxide, pyrazinyl, pyrimidinyl, or pyridazinyl), 9-10 membered bicyclic heteroaryl containing one, two, or three ring heteroatoms independently selected from N, O, and S (e.g., triazolopyridinyl), wherein the C 1-4 alkyl (e.g., methyl or ethyl), C 1-4 haloalkyl (e.g., CF3), C 1-4 alkoxy (e.g., methoxy and ethoxy), C 3-4 cycloalkyl (e.g., cyclopropyl), NH-C 1-4 alkyl (e.g., NHCH3), O-C 3-4 cycloalkyl (e.g., O-cyclopropyl), O-C 1-4 haloalkyl (e.g., OCHF2), C 1-2 alkylene-O-C 1-4 alkyl (e.g., CH2OCH3), O-C 1-2 alkylene-O-C 1-4 alkyl (e.g., OCH2OCH3), O-C 1-2 alkylene-OH (e.g., OCH2CH2OH), O-C2alkylene-N(C 1-4 alkyl)(C 1-4 alkyl)(e.g., OCH2CH2N(CH3)2), C(O)N(C 1-4 Alkyl)(C 1-4 Alkyl groups (such as C(O)N(CH3)2) and S(O)2 (C 1-4 Substituents of alkyl groups (such as S(O)2CH3) are preferred: X a For CR a And R a C 3-6 The carbonyl ring, the 4-8 membered heterocyclic ring, the phenyl group, or the 5-6 membered heteroaryl group, wherein the carbonyl ring, the heterocyclic ring, the phenyl group, or the heteroaryl group is not substituted or is independently selected from one or more halogens, OH, NH2, CN, oxo, -C(O)-NH2, -C(O)-NH(C 1-4 Alkyl), -C(O)-N(C) 1-4 Alkyl)2, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl group, -NH-S(O)2-C 1-4 Alkyl or -OC 2-3 Alkylene-N(C) 1-4 It is replaced by a substituent of alkyl)2.

22. The compound of any one of claims 2-4 and 8-18, or a pharmaceutically acceptable salt thereof, wherein in Formula I-l (e.g., Formula I-l-A, I-l-C, or I-l-D) or I-2 (e.g., Formula I-2-A, I-2-C, or I-2-D), X a is CR a and R a is a 5- or 6-membered heteroaryl substituted with one or more substituents independently selected from the group consisting of CN, OH, NH2, -C(O)-NH2, C 1-4 alkyl, fluorosubstituted C 1-4 alkyl, -O-C 1-4 alkyl, -S(O)2-C 1-4 alkyl, and 6-membered heterocyclyl containing one oxygen ring atom.

23. The compound or pharmaceutically acceptable salt thereof of any one of claims 2-4 and 8-18, wherein in Formula I-1 (e.g., Formula I-1-A, I-1-C, or I-1-D) or I-2 (e.g., Formula I-2-A, I-2-C, or I-2-D), X a is CR a and R a is 4-, 5-, or 6-membered heterocyclyl containing one or two ring heteroatoms independently selected from N, O, and S, and is unsubstituted or substituted with one or more substituents independently selected from oxo, CN, OH, NH2, C 1-4 alkyl, fluoro-substituted C 1-4 alkyl, and -O-C 1-4 alkyl.

24. The compound of any one of claims 2-4 and 8-18, or a pharmaceutically acceptable salt thereof, wherein in Formula I-l (e.g., Formula I-l-A, I-l-C, or I-l-D) or I-2 (e.g., Formula I-2-A, I-2-C, or I-2-D), X b is CR b and R b is spiro or fused ring, wherein the ring contains one or two ring heteroatoms independently selected from N, O, and S and is unsubstituted or substituted with one or more substituents independently selected from oxo, CN, OH, NH2, C 1-4 alkyl, -O-C 1-4 alkyl, -C(O)-O(C 1-4 alkyl), and -C(O)-NH(C 1-4 alkyl).

25. The compound or pharmaceutically acceptable salt thereof of any one of claims 2-4 and 8-18, wherein in Formula I-1 (e.g., Formula I-1-A, I-1-C, or I-1-D) or I-2 (e.g., Formula I-2-A, I-2-C, or I-2-D), X a is CR a and R a is phenyl which is unsubstituted or substituted with one or more substituents independently selected from halogen, CN, OH, NH2, -C(O)-NH2, C 1-4 alkyl, fluorosubstituted C 1-4 alkyl, -O-C 1-4 alkyl, and -S(O)2-C 1-4 alkyl.

26. The compound of any one of claims 2-4 and 8-18, or a pharmaceutically acceptable salt thereof, wherein in Formula I-l (e.g., Formula I-l-A, I-l-C, or I-l-D) or I-2 (e.g., Formula I-2-A, I-2-C, or I-2-D), X a is CR a and R a is C 1-4 alkyl, fluoro-substituted C 1-4 alkyl, -O-C 1-4 alkyl unsubstituted or substituted by OH, -NH-C 1-4 alkyl unsubstituted or substituted by OH, and -O-C 2-4 alkylene-N(C 1-2 alkyl)2.

27. The compound of any one of claims 2-4 and 8-18, or a pharmaceutically acceptable salt thereof, wherein in Formula I-1 (e.g., Formula I-1-A, I-1-C, or I-1-D) or I-2 (e.g., Formula I-2-A, I-2-C, or I-2-D), X a is CR a and R a is selected from H, F, Cl, CN, CH3, -O-CH3, -S-CH3, -S(O)2-CH3, -NH-S(O)2-CH3, CF3, -C(O)-NH2, or -O-(CH2)2-N(CH3)2.

28. The compound or pharmaceutically acceptable salt thereof of any one of claims 2-4 and 8-18, wherein in Formula I-l (e.g., Formula I-l-A, I-l-C, or I-l-D) or I-2 (e.g., Formula I-2-A, I-2-C, or I-2-D), X a is CR a and R a is H, halogen, CN, or -C(O)-NH2.

29. The compound or pharmaceutically acceptable salt thereof of any one of claims 2-4 and 8-18, wherein in Formula I-l (e.g., Formula I-l-A, I-l-C, or I-l-D) or I-2 (e.g., Formula I-2-A, I-2-C, or I-2-D), X a is CR a and R a is selected from:

30. The compound or pharmaceutically acceptable salt thereof of any one of claims 2-4 and 8-18, wherein in Formula I-l (e.g., Formula I-l-A, I-l-C, or I-l-D) or I-2 (e.g., Formula I-2-A, I-2-C, or I-2-D), X a is CR a and R a is selected from:

31. The compound or pharmaceutically acceptable salt thereof of any one of claims 2-4 and 8-18, wherein in Formula I-l (e.g., Formula I-l-A, I-l-C, or I-l-D) or I-2 (e.g., Formula I-2-A, I-2-C, or I-2-D), X a is CR a and R a is selected from:

32. The compound or pharmaceutically acceptable salt thereof of any one of claims 2-4 and 8-18, wherein in Formula I-l (e.g., Formula I-l-A, I-l-C, or I-l-D) or I-2 (e.g., Formula I-2-A, I-2-C, or I-2-D), X a is CR a and R a is selected from:

33. The compound or pharmaceutically acceptable salt thereof of any one of claims 2-4 and 8-18, wherein in Formula I-l (e.g., Formula I-l-A, I-l-C, or I-l-D) or I-2 (e.g., Formula I-2-A, I-2-C, or I-2-D), X a is CR a and R a is H.

34. The compound or pharmaceutically acceptable salt thereof of any one of claims 2-6 and 8-33, wherein in Formula I-1 (e.g., Formula I-1-A, I-1-B, or I-1-D), Formula I-2 (e.g., Formula I-2-A, I-2-B, or I-2-D), Formula I-3 (e.g., Formula I-3-A, or I-3-C), or Formula I-4 (e.g., Formula I-4-A, or I-4-C), X b is CR b and R b is H, halogen, CN, R bx , -COR bx , -NHCOR bx , -CONH2, -CONHR bx , -CON(R bx )2, -OR bx , -NHR bx , -N(R bx )2, -SR bx , -SO2R bx , or -NHSO2R bx , wherein R bx is, at each occurrence, independently C 1-6 alkyl which is unsubstituted or substituted with one or more substituents independently selected from halogen (preferably F), OH, or N(CH3)2.

35. The compound or pharmaceutically acceptable salt thereof of any one of claims 2-6 and 8-33, wherein in Formula I-1 (e.g., Formula I-1-A, I-1-B, or I-1-D), Formula I-2 (e.g., Formula I-2-A, I-2-B, or I-2-D), Formula I-3 (e.g., Formula I-3-A, or I-3-C), or Formula I-4 (e.g., Formula I-4-A, or I-4-C), X b is CR b and R b is H, F, Cl, CN, -C(O)-NH2, -C(O)-NH(C 1-4 alkyl), -C(O)-N(C 1-4 alkyl)2, C 1-6 alkyl, C 1-6 haloalkyl, -O-C 1-4 alkyl, -S-C 1-4 alkyl, -S(O)2-C 1-4 alkyl, -C(C 1-2 alkyl)2OH, -NH-S(O)2-C 1-4 alkyl, or -O-C 2-3 alkylene-N(CH3)2.

36. The compound of any one of claims 2-6 and 8-33, or a pharmaceutically acceptable salt thereof, wherein in Formula I-l (e.g., Formula I-l-A, I-l-B, or I-l-D), Formula I-2 (e.g., Formula I-2-A, I-2-B, or I-2-D), Formula I-3 (e.g., Formula I-3-A, or I-3-C), or Formula I-4 (e.g., Formula I-4-A, or I-4-C), X b is CR b and R b is C 3-6 carbocyclyl ring, 4-8 membered heterocyclyl ring, phenyl, or 5-6 membered heteroaryl, wherein the carbocyclyl ring, the heterocyclyl ring, phenyl, or the heteroaryl is unsubstituted or substituted with one or more substituents independently selected from halogen, OH, NH2, CN, oxo, -C(O)-NH2, -C(O)-NH(C 1-4 alkyl), -C(O)-N(C 1-4 alkyl)2, C 1-6 alkyl, C 1-6 haloalkyl, -O-C 1-4 alkyl, -S-C 1-4 alkyl, -S(O)2-C 1-4 alkyl, -NH-S(O)2-C 1-4 alkyl, or -O-C 2-3 alkylene-N(C 1-4 alkyl)2.

37. The compound of any one of claims 2-6 and 8-33 or pharmaceutically acceptable salt thereof, wherein in Formula I-1 (e.g., Formula I-1-A, I-1-B, or I-1-D), Formula I-2 (e.g., Formula I-2-A, I-2-B, or I-2-D), Formula I-3 (e.g., Formula I-3-A, or I-3-C), or Formula I-4 (e.g., Formula I-4-A, or I-4-C), X b is CR b and R b is a 5- or 6-membered heteroaryl substituted with one or more substituents independently selected from the group consisting of N, O, and S, and unsubstituted or substituted with one or more substituents independently selected from the group consisting of CN, OH, NH2, -C(O)-NH2, C 1-4 alkyl, and -O-C 1-4 alkyl.

38. The compound or pharmaceutically acceptable salt thereof of any one of claims 2-6 and 8-33, wherein in Formula I-1 (e.g., Formula I-1-A, I-1-B, or I-1-D), Formula I-2 (e.g., Formula I-2-A, I-2-B, or I-2-D), Formula I-3 (e.g., Formula I-3-A, or I-3-C), or Formula I-4 (e.g., Formula I-4-A, or I-4-C), X b is CR b and R b is 4-, 5-, or 6-membered heterocyclyl containing one or two ring heteroatoms independently selected from N, O, and S, and is unsubstituted or substituted with one or more substituents independently selected from oxo, CN, OH, NH2, C 1-4 alkyl, -O-C 1-4 alkyl, and -C(O)-NH(C 1-4 alkyl).

39. The compound of any one of claims 2-6 and 8-33, or a pharmaceutically acceptable salt thereof, wherein in Formula I-l (e.g., Formula I-l-A, I-l-B, or I-l-D), Formula I-2 (e.g., Formula I-2-A, I-2-B, or I-2-D), Formula I-3 (e.g., Formula I-3-A, or I-3-C), or Formula I-4 (e.g., Formula I-4-A, or I-4-C), X b is CR b and R b is spiro or fused ring, wherein the ring contains one or two ring heteroatoms independently selected from N, O, and S and is unsubstituted or substituted with one or more substituents independently selected from oxo, CN, OH, NH2, C 1-4 alkyl, -O-C 1-4 alkyl, -C(O)-O(C 1-4 alkyl), and -C(O)-NH(C 1-4 alkyl).

40. The compound or pharmaceutically acceptable salt thereof of any one of claims 2-6 and 8-33, wherein in Formula I-1 (e.g., Formula I-1-A, I-1-B, or I-1-D), Formula I-2 (e.g., Formula I-2-A, I-2-B, or I-2-D), Formula I-3 (e.g., Formula I-3-A, or I-3-C), or Formula I-4 (e.g., Formula I-4-A, or I-4-C), X b is CR b and R b is phenyl unsubstituted or substituted with one or more substituents independently selected from halogen, CN, OH, NH2, -C(O)-NH2, C 1-4 alkyl, fluoro-substituted C 1-4 alkyl, -O-C 1-4 alkyl, and -S(O)2-C 1-4 alkyl.

41. The compound of any one of claims 2-6 and 8-33, or a pharmaceutically acceptable salt thereof, wherein in Formula I-l (e.g., Formula I-l-A, I-l-B, or I-l-D), Formula I-2 (e.g., Formula I-2-A, I-2-B, or I-2-D), Formula I-3 (e.g., Formula I-3-A, or I-3-C), or Formula I-4 (e.g., Formula I-4-A, or I-4-C), X b is CR b and R b is C 1-4 alkyl, fluoro-substituted C 1-4 alkyl, -O-C 1-4 alkyl, -NH-C 1-4 alkyl, -S-C 1-4 alkyl, -S(O)2-C 1-4 alkyl, and -O-C 2-4 alkylene-N(C 1-2 alkyl)2.

42. The compound or pharmaceutically acceptable salt thereof of any one of claims 2-6 and 8-33, wherein in Formula I-1 (e.g., Formula I-1-A, I-1-B, or I-1-D), Formula I-2 (e.g., Formula I-2-A, I-2-B, or I-2-D), Formula I-3 (e.g., Formula I-3-A, or I-3-C), or Formula I-4 (e.g., Formula I-4-A, or I-4-C), X b is CR b and R b is H, halogen, CN, or -C(O)-NH2.

43. The compound or pharmaceutically acceptable salt thereof of any one of claims 2-6 and 8-33, wherein in Formula I-1 (e.g., Formula I-1-A, I-1-B, or I-1-D), Formula I-2 (e.g., Formula I-2-A, I-2-B, or I-2-D), Formula I-3 (e.g., Formula I-3-A, or I-3-C), or Formula I-4 (e.g., Formula I-4-A, or I-4-C), X b is CR b and R b is selected from F, CN, -O-CH3, -S-CH3, -S(O)2-CH3, or -C(CH3)2OH.

44. The compound or pharmaceutically acceptable salt thereof of any one of claims 2-6 and 8-33, wherein in Formula I-1 (e.g., Formula I-1-A, I-1-B, or I-1-D), Formula I-2 (e.g., Formula I-2-A, I-2-B, or I-2-D), Formula I-3 (e.g., Formula I-3-A, or I-3-C), or Formula I-4 (e.g., Formula I-4-A, or I-4-C), X b is CR b and R b is selected from:

45. The compound or pharmaceutically acceptable salt thereof of any one of claims 2-6 and 8-33, wherein in Formula I-1 (e.g., Formula I-1-A, I-1-B, or I-1-D), Formula I-2 (e.g., Formula I-2-A, I-2-B, or I-2-D), Formula I-3 (e.g., Formula I-3-A, or I-3-C), or Formula I-4 (e.g., Formula I-4-A, or I-4-C), X b is CR b and R b is selected from:

46. The compound or pharmaceutically acceptable salt thereof of any one of claims 2-6 and 8-33, wherein in Formula I-1 (e.g., Formula I-1-A, I-1-B, or I-1-D), Formula I-2 (e.g., Formula I-2-A, I-2-B, or I-2-D), Formula I-3 (e.g., Formula I-3-A, or I-3-C), or Formula I-4 (e.g., Formula I-4-A, or I-4-C), X b is CR b and R b is selected from:

47. The compound or pharmaceutically acceptable salt thereof of any one of claims 2-6 and 8-33, wherein in Formula I-1 (e.g., Formula I-1-A, I-1-B, or I-1-D), Formula I-2 (e.g., Formula I-2-A, I-2-B, or I-2-D), Formula I-3 (e.g., Formula I-3-A, or I-3-C), or Formula I-4 (e.g., Formula I-4-A, or I-4-C), X b is CR b and R b is selected from:

48. The compound or pharmaceutically acceptable salt thereof of any one of claims 2-6 and 8-33, wherein in Formula I-1 (e.g., Formula I-1-A, I-1-B, or I-1-D), Formula I-2 (e.g., Formula I-2-A, I-2-B, or I-2-D), Formula I-3 (e.g., Formula I-3-A, or I-3-C), or Formula I-4 (e.g., Formula I-4-A, or I-4-C), X b is CR b and R b is H.

49. The compound of any one of claims 2-6 and 8-48, or a pharmaceutically acceptable salt thereof, wherein in Formula I-1 (e.g., Formula I-1-A, I-1-B, or I-1-C), I-2 (e.g., Formula I-2-A, I-2-B, or I-2-C), Formula I-3 (e.g., Formula I-3-A or I-3-B), or Formula I-4 (e.g., Formula I-4-A or I-4-B), X c is CR c and R c is H, halogen, CN, R cx , -COR cx , -NHCOR cx , -CONH2, -CONHR cx , -CON(R cx )2, -OR cx , -NHR cx , -N(R cx )2, -SR cx , -SO2R cx , or -NHSO2R cx , wherein R cx is, at each occurrence, independently C 1-6 alkyl which is unsubstituted or substituted with one or more substituents independently selected from halogen (preferably F), OH, or N(CH3)2.

50. The compound or pharmaceutically acceptable salt thereof of any one of claims 2-6 and 8-48, wherein in Formula I-1 (e.g., Formula I-1-A, I-1-B, or I-1-C), I-2 (e.g., Formula I-2-A, I-2-B, or I-2-C), Formula I-3 (e.g., Formula I-3-A or I-3-B), or Formula I-4 (e.g., Formula I-4-A or I-4-B), X c is CR c and R c is H, F, Cl, CN, -C(O)-NH2, -C(O)-NH(C 1-4 alkyl), -C(O)-N(C 1-4 alkyl)2, C 1-6 alkyl, C 1-6 haloalkyl, -O-C 1-4 alkyl, -S-C 1-4 alkyl, -S(O)2-C 1-4 alkyl, -C(C 1-2 alkyl)2OH, -NH-S(O)2-C 1-4 alkyl, or -O-C 2-3 alkylene-N(CH3)2.

51. The compound of any one of claims 2-6 and 8-48, or a pharmaceutically acceptable salt thereof, wherein in Formula I-l (e.g., Formula I-l-A, I-l-B, or I-l-C), I-2 (e.g., Formula I-2-A, I-2-B, or I-2-C), Formula I-3 (e.g., Formula I-3-A or I-3-B), or Formula I-4 (e.g., Formula I-4-A or I-4-B), X c is CR c and R c is C 3-6 carbocyclyl ring, 4-8 membered heterocyclyl ring, phenyl, or 5-6 membered heteroaryl, wherein the carbocyclyl ring, the heterocyclyl ring, phenyl, or the heteroaryl is unsubstituted or substituted with one or more substituents independently selected from F, Cl, OH, NH2, CN, oxo, -C(O)-NH2, -C(O)-NH(C 1-4 alkyl), -C(O)-N(C 1-4 alkyl)2, C 1-6 alkyl, C 1-6 haloalkyl, -O-C 1-4 alkyl, -S-C 1-4 alkyl, -S(O)2-C 1-4 alkyl, -NH-S(O)2-C 1-4 alkyl, or -O-C 2-3 alkylene-N(C 1-4 alkyl)2.

52. The compound or pharmaceutically acceptable salt thereof of any one of claims 2-6 and 8-48, wherein in Formula I-1 (e.g., Formula I-1-A, I-1-B, or I-1-C), I-2 (e.g., Formula I-2-A, I-2-B, or I-2-C), Formula I-3 (e.g., Formula I-3-A or I-3-B), or Formula I-4 (e.g., Formula I-4-A or I-4-B), X c is CR c and R c is selected from F, Cl, CN, or -C(O)-NH2.

53. The compound or pharmaceutically acceptable salt thereof of any one of claims 2-6 and 8-48, wherein in Formula I-1 (e.g., Formula I-1-A, I-1-B, or I-1-C), I-2 (e.g., Formula I-2-A, I-2-B, or I-2-C), Formula I-3 (e.g., Formula I-3-A or I-3-B), or Formula I-4 (e.g., Formula I-4-A or I-4-B), X c is CR c and R c is H.

54. The compound or pharmaceutically acceptable salt thereof of any one of claims 2-6 and 8-48, wherein in Formula I-1 (e.g., Formula I-1-A, I-1-B, or I-1-C), I-2 (e.g., Formula I-2-A, I-2-B, or I-2-C), Formula I-3 (e.g., Formula I-3-A or I-3-B), or Formula I-4 (e.g., Formula I-4-A or I-4-B), X c is CR c and R c is selected from:

55. The compound of any one of claims 2-4, 8-18, and 49-54, or a pharmaceutically acceptable salt thereof, wherein in Formula I-1 (e.g., Formula I-1-A or I-1-D) or I-2 (e.g., Formula I-2-A or I-2-D), when X a is CR a and X b is CR b then R a and R b , together with the C and C atoms therebetween, join to form a 5-membered ring containing zero, one, or two ring heteroatoms independently selected from N, O, and S and unsubstituted or substituted with C 1-4 alkyl.

56. The compound or pharmaceutically acceptable salt thereof of any one of claims 2-4, 8-18, and 49-54, wherein in Formula I-l (e.g., Formula I-l-A or I-l-D) or I-2 (e.g., Formula I-2-A or I-2-D), when X a is CR a and X b is CR b then R a and R b , together with the C and C atoms therebetween, join to form a ring selected from:

57. The compound of any one of claims 2-4 and 8-33, or a pharmaceutically acceptable salt thereof, wherein in Formula I-1 (e.g., Formula I-1-A or I-1-B) or I-2 (e.g., Formula I-2-A or I-2-B), when X b is CR b and X c is CR c then R b and R c , together with the C and C atoms therebetween, join to form a 5-membered ring containing zero, one, or two ring heteroatoms independently selected from N, O, and S and unsubstituted or substituted with C 1-4 alkyl.

58. The compound or pharmaceutically acceptable salt thereof of any one of claims 2-4 and 8-33, wherein in Formula I-l (e.g., Formula I-l-A or I-l-B) or I-2 (e.g., Formula I-2-A or I-2-B), when X b is CR b and X c is CR c then R b and R c , together with the intervening C and C atoms, join to form a ring selected from:

59. The compound or pharmaceutically acceptable salt thereof of any one of claims 2-6 and 8-58, wherein in Formula I-1 (e.g., Formula I-1-A, I-1-B, I-1-C, or I-1-D), I-2 (e.g., Formula I-2-A, I-2-B, I-2-C, or I-2-D), Formula I-3 (e.g., Formula I-3-A, I-3-B, or I-3-C), or Formula I-4 (e.g., Formula I-4-A, I-4-B, or I-4-C), R d is H, Cl, OH, NH2, NHCH3, or NHCH2CH3.

60. The compound or pharmaceutically acceptable salt thereof of any one of claims 2-6 and 8-58, wherein in Formula I-l (e.g., Formula I-l-A, I-l-B, I-l-C, or I-l-D), I-2 (e.g., Formula I-2-A, I-2-B, I-2-C, or I-2-D), Formula I-3 (e.g., Formula I-3-A, I-3-B, or I-3-C), or Formula I-4 (e.g., Formula I-4-A, I-4-B, or I-4-C), R d is NH2.

61. The compound or pharmaceutically acceptable salt thereof of any one of claims 2, 5-6, and 8-60, wherein in Formula I-3 (e.g., Formula I-3-A, I-3-B, or I-3-C) or Formula I-4 (e.g., Formula I-4-A, I-4-B, or I-4-C), R e is H.

62. The compound or pharmaceutically acceptable salt thereof of any one of claims 2, 5-6, and 8-61, wherein in Formula I-3 (e.g., Formula I-3-A, I-3-B, or I-3-C) or Formula I-4 (e.g., Formula I-4-A, I-4-B, or I-4-C), R f is H.

63. The compound or pharmaceutically acceptable salt thereof of any one of claims 2, 5-6, and 8-61, wherein in Formula I-3 (e.g., Formula I-3-A, I-3-B, or I-3-C) or Formula I-4 (e.g., Formula I-4-A, I-4-B, or I-4-C), R f is Br.

64. The compound or pharmaceutically acceptable salt thereof of any one of claims 2, 5-6, and 8-61, wherein in Formula I-3 (e.g., Formula I-3-A, I-3-B, or I-3-C) or Formula I-4 (e.g., Formula I-4-A, I-4-B, or I-4-C), R f selected from the group consisting of:

65. A compound selected from any one of the compounds shown in the Examples section or the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof, or a compound of any one of Embodiments 1-88 listed herein.

66. A pharmaceutical composition comprising a compound according to any one of claims 1-65, or a pharmaceutically acceptable salt thereof.

67. A method of treating a disease or disorder associated with phosphoinositide 3-kinase (PI3K), comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1-65 or a pharmaceutical composition according to claim 66.

68. The method of claim 67, wherein the PI3K is PI3Ka.

69. The method of any one of claims 67-68, wherein the disease or disorder is cancer.

70. The method of claim 69, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer.

71. The method of any one of claims 67-68, wherein the disease or disorder is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformation, epidermal nevus, scoliosis / osteochondro dysplasia syndrome) or PIK3CA-related overgrowth syndrome (PROS).

72. A method of inhibiting phosphoinositide 3-kinase (PI3K), comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1-65 or a pharmaceutical composition according to claim 66.

73. A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1-65 or a pharmaceutical composition according to claim 66.

74. The method of claim 73, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer.

75. A method of treating a disorder selected from CLOVES syndrome (congenital lipomatous overgrowth, vascular malformation, epidermal nevus, scoliosis / skeletal and spinal syndrome) or PIK3CA-related overgrowth syndrome (PROS), the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-65 or a pharmaceutical composition of claim 66.

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