2-azabicyclo[2.2.1]heptane KRAS inhibitor

Abstract

Compounds of formula (I), methods of using the compound to inhibit KRAS activity, and pharmaceutical compositions comprising such compounds are disclosed. The compounds are useful for treating, preventing, or improving diseases or disorders associated with KRAS activity, such as cancer.

Description

[Technical Field]

[0001] Related applications This application relates to U.S. Provisional Application No. 63 / 496,859 filed on 18 April 2023, U.S. Provisional Application No. 63 / 580,824 filed on 6 September 2023, and U.S. Provisional Application No. 63 / 557,251 filed on 23 February 2024, and its contents are incorporated in their entirety.

[0002] Field of Invention This disclosure provides compounds, as well as compositions and methods of use thereof. The compounds modulate KRAS activity and are useful in the treatment of various diseases, including cancer. [Background technology]

[0003] Ras proteins are part of a family of small GTPases activated by growth factors and various extracellular stimuli. The Ras family regulates intracellular signaling pathways involved in cell growth, migration, survival, and differentiation. Activation of Ras proteins at the cell membrane leads to the binding of major effectors, as well as the initiation of a cascade of intracellular signaling pathways, including the RAF and PI3K kinase pathways. Somatic mutations in RAS can result in uncontrolled cell growth and malignant transformation, while RAS protein activation is tightly regulated in normal cells (D. Simanshu, et al., Cell, 2017, 170(1), 17-33).

[0004] The Ras family consists of three members: KRAS, NRAS, and HRAS. RAS-mutated cancers account for approximately 25% of human cancers. KRAS is the most frequently mutated isoform, accounting for 85% of all RAS mutations, while NRAS and HRAS mutations are found in 12% and 3% of all Ras-mutated cancers, respectively (D. Simanshu, et al., Cell, 2017, 170(1), 17-33). KRAS mutations are widely found among the top three most deadly cancer types: pancreatic cancer (97%), colorectal cancer (44%), and lung cancer (30%) (ADCox, et al. Nat. Rev. Drug. Discov., 2014, 13(11), 828-51). The majority of RAS mutations occur at amino acid residues 12, 13, and 61. The frequency of specific mutations differs among RAS gene isoforms, with G12 and Q61 mutations being dominant in KRAS and NRAS, respectively, while G12, G13, and Q61 mutations are most frequent in HRAS. Furthermore, the range of mutations in RAS isoforms differs among cancer types. For example, KRAS G12D mutations are dominant in pancreatic cancer (51%), followed by colorectal adenocarcinoma (45%) and lung cancer (17%), while KRAS G12V mutations are associated with pancreatic cancer (30%), followed by colorectal adenocarcinoma (27%) and lung adenocarcinoma (23%) (ADCox, et al. Nat. Rev. Drug. Discov., 2014, 13(11), 828-51). In contrast, KRAS G12C mutations are predominant in non-small cell lung cancer (NSCLC), including 11–16% of lung adenocarcinomas, as well as in 2–5% of pancreatic and colorectal adenocarcinomas (ADCox, et al. Nat. Rev. Drug. Discov., 2014, 13(11), 828-51). Genomic studies across hundreds of cancer cell lines have demonstrated that cancer cells with KRAS mutations are highly dependent on KRAS function for cell growth and survival (R. McDonald, et al., Cell, 2017, 170(3), 577-92).The role of mutant KRAS as an oncogenic driver is further supported by extensive in vivo experimental evidence showing that mutant KRAS is necessary for the early onset and maintenance of tumors in animal models (ADCox, et al. Nat. Rev. Drug. Discov., 2014, 13(11), 828-51).

[0005] In summary, these findings indicate that KRAS mutations play a crucial role in human cancer. Therefore, the development of KRAS-targeting inhibitors, including those targeting mutant KRAS, would be useful in the clinical treatment of KRAS-related diseases, including those characterized by the involvement or presence of KRAS mutations. [Overview of the project]

[0006] This disclosure, in particular, includes formula (I): [ka] We provide compounds of or pharmaceutically acceptable salts thereof, the variable components of which are defined herein.

[0007] This disclosure further provides a pharmaceutical composition comprising a compound of the disclosure or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0008] This disclosure further provides methods for inhibiting KRAS activity, comprising administering the compounds of this disclosure or pharmaceutically acceptable salts thereof to an individual. This disclosure also provides the use of the compounds described herein in the manufacture of pharmaceuticals for therapeutic use. This disclosure also provides the compounds described herein for therapeutic use.

[0009] This disclosure further provides a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of the compound of this disclosure or a pharmaceutically acceptable salt thereof.

[0010] Details of one or more embodiments are set forth in the following description. Other features, objects, and advantages will be apparent from the description and claims.

Mode for Carrying Out the Invention

[0011] For the terms “for example” and “such as” and their grammatical equivalents, it is understood that they are accompanied by the phrase “without limitation” unless otherwise stated.

[0012] Unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “the” include plural referents.

[0013] The term “about” means “approximately” (e.g., approximately plus or minus 10% of the indicated value).

[0014] I. Compound In one aspect, provided herein is a compound of formula (I):

Chemical formula

[0015] In one embodiment, the compounds of formula (I) are formulas (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (IJ), (IK), (IL), and (IM): [ka] [ka] It is one of the following compounds, or a pharmaceutically acceptable salt thereof.

[0016] In another embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Cy1 However, D and C respectively 1-3 Alkyl, C 1-3 Haloalkyl, halo, OH, and C 1-3 A phenyl compound optionally substituted with one or two substituents selected from alkoxy compounds. R 1 But it's a halo, R 2 However, C is arbitrarily substituted with OH. 1-3 It is alkyl, R 3 However, C is arbitrarily substituted with halo. 3-10 It is a cycloalkyl, Each R 4 However, H is, 1 R 5 However, R 5A And each other R 5 However, independently, H, D, Halo, C 1-3 Alkyl, OC 1-3 Alkyl, C 1-3 Selected from haloalkyl groups, or optionally, two other R groups bonded to adjacent carbon atoms. 5 However, along with the carbon atoms to which they are bonded, each of them is D, C 1-3 Condensed C optionally substituted with one or two substituents selected from alkyl and halo 3-6 Forming a cycloalkyl ring, R 5A However, H, halo, or OR a5A And, R a5A However, C 1-3 Alkyl, C 1-3 Haloalkyl and Cy 2 Selected from, R a5A C that forms 1-3 The alkyl group is optionally substituted with 1, 2, or 3 D atoms, and Cy 2 However, it can be arbitrarily replaced, Cy 2 However, C 6-10 Selected from aryl and 5-10 membered heteroaryls.

[0017] In another embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Cy 1 However, D and C respectively 1-3 Alkyl, C 1-3 Haloalkyl, halo, OH, and C 1-3 A phenyl compound optionally substituted with one or two substituents selected from alkoxy compounds. R 1 But it's a halo, R 2 However, C is arbitrarily substituted with OH. 1-3 It is alkyl, R 3 However, C is arbitrarily substituted with halo. 3-10 It is a cycloalkyl, Each R 4 However, H is, 1 R 5 However, R 5A And each other R 5 However, independently, H, D, Halo, C 1-3 Alkyl, OC 1-3 Alkyl, C 1-3 Selected from haloalkyl groups, or optionally, two other R groups bonded to adjacent carbon atoms. 5 However, along with the carbon atoms to which they are bonded, each of them is D, C 1-3 Condensed C optionally substituted with one or two substituents selected from alkyl and halo 3-6 Forming a cycloalkyl ring, R 5A However, H, halo, or OR a5A And, R a5A However, C 1-3 Alkyl, C 1-3 Haloalkyl and Cy 2 Selected from, R a5A C that forms 1-3 The alkyl group is optionally substituted with 1, 2, or 3 D atoms, and Cy 2 However, it can be arbitrarily replaced, Cy 2 However, C 3-7 Cycloalkyl, C 6-10 Selected from aryls and 5- to 10-membered heteroaryls.

[0018] In yet another embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Cy 1 However, each is a phenyl molecule optionally substituted with two substituents selected from the halo. R 1 But it's a halo, R 2 However, C is arbitrarily substituted with OH. 1-3 It is alkyl, R 3 However, it is a cyclopropyl arbitrarily substituted with a halo, Each R 4 However, H is, 1 R 5 However, R 5A And each other R 5 However, independently, H, Haro, C 1-3 Alkyl, OC 1-3 Alkyl, C 1-3 Selected from haloalkyl groups, or optionally, two other R groups bonded to adjacent carbon atoms. 5 However, along with the carbon atoms to which they are bonded, each of them is D, C 1-3 A condensed cyclopropyl ring is formed which is optionally substituted with one or two substituents selected from alkyl and halo, R 5A However, H, halo, or OR a5A And, R a5A However, C 1-3 Alkyl, C 1-3 Haloalkyl and Cy 2 Selected from, R a5A C that forms 1-3 The alkyl group is optionally substituted with 1, 2, or 3 D atoms, and Cy 2 However, it can be arbitrarily replaced, Cy 2 However, it is selected from phenyl and pyridinyl compounds.

[0019] In yet another embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Cy 1 However, it is 2,3-dichlorophenyl, R 1But it's a halo, R 2 However, it is methyl or 1-hydroxyethyl, R 3 However, it is a cyclopropyl that is optionally substituted with a fluoropolymer. Each R 4 However, H is, 1 R 5 However, R 5A And each other R 5 However, independently, H, Haro, C 1-3 Alkyl, OC 1-3 Alkyl, C 1-3 Selected from haloalkyl groups, or optionally, two other R groups bonded to adjacent carbon atoms. 5 However, along with the carbon atoms to which they are bonded, each of them is D, C 1-3 A condensed cyclopropyl ring is formed which is optionally substituted with one or two substituents selected from alkyl and halo, R 5A However, H, Haro, OC 1-3 Alkyl, OC 1-3 These are haloalkyl, OCD3, O-pyridinyl, and O-benzyl. Cy 2 However, it is selected from phenyl and pyridinyl compounds.

[0020] In other embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Cy 1 However, it is 2,3-dichlorophenyl, R 1 But it's a halo, R 2 However, it is methyl or 1-hydroxyethyl, R 3 However, it is a cyclopropyl that is optionally substituted with a fluoropolymer. Each R 4 However, H is, 1 R 5 However, R 5A And each other R 5 However, independently, H, Haro, C 1-3 Alkyl, OC 1-3 Alkyl, C 1-3Selected from haloalkyl or optionally two other Rs attached to adjacent carbon atoms 5 which, together with the carbon atom to which each is attached, each form a fused cyclopropyl ring optionally substituted with one or two substituents selected from D, C 1-3 alkyl, and halo R 5A is H, halo, OC 1-3 alkyl, OC 1-3 haloalkyl, OCD3, O-pyridinyl, and O-benzyl

[0021] In another embodiment of formula (I), or a pharmaceutically acceptable salt thereof Cy 1 is 2,3-dichlorophenyl R 1 is halo R 2 is methyl or 1-hydroxyethyl R 3 is cyclopropyl optionally substituted with fluoro each R 4 is H one R 5 is R 5A and each other R 5 is independently selected from H, halo, C 1-3 alkyl, OC 1-3 alkyl, C 1-3 haloalkyl or optionally two other Rs attached to adjacent carbon atoms 5 which, together with the carbon atom to which each is attached, each form a fused cyclopropyl ring optionally substituted with one or two substituents selected from D, C 1-3 alkyl, and halo R 5A is H, halo, OC 1-3 alkyl, OC 1-3 haloalkyl, OCD3, O-cyclopropyl, O-pyridinyl, and O-benzyl

[0022] In another embodiment, Cy 1 is independently C1-3 Alkyl (e.g., methyl), C 1-3 Haloalkyl, C 2-3 Alkenil, C 2-3 Alkynyl, halo (e.g., fluoro, or chloro), OH, C 1-3 Alkoxy, and C 1-3 Phenyl is optionally substituted with one, two, or three substituents (or one or two substituents, or one substituent) selected from haloalkoxys. In yet another embodiment, Cy 1 However, independently, C 1-3 The phenyl is optionally substituted with one, two, or three substituents (or one or two substituents, or one substituent) selected from alkyl (e.g., methyl) and halo (e.g., fluoro, or chloro). In yet another embodiment, Cy 1 However, it is 2-chloro-3-methylphenyl. In one embodiment, Cy 1 However, it is 2,3-dichlorophenyl.

[0023] In another embodiment, R 1 However, it is a halo. In yet another embodiment, R 1 However, it is fluoro. In yet another embodiment, R 1 However, it is H.

[0024] In another embodiment, R 4 However, it is H.

[0025] In one embodiment, R 2 However, C 1-3 Alkyl, C 1-3 Haloalkyl, C 2-3 Alkenil, C 2-3 It is alkinyl, R 2 C that forms 1-3 Alkyl, C 2-3 Alkenyl and C 2-3 Each alkynyl independently, R 2B It is optionally substituted with one, two, or three substituents (or one or two substituents, or one substituent) selected from the following.

[0026] In another embodiment, R 2 However, independently, R 2B C optionally substituted with 1, 2, or 3 substituents (or 1 or 2 substituents, or 1 substituent) selected from 1-3 Alkyl (e.g., methyl or ethyl). In yet another embodiment, R 2 However, independently, R 2B A methyl molecule optionally substituted with one, two, or three substituents (or one or two substituents, or one substituent) selected from the above. In yet another embodiment, R 2 However, it is methyl. In one embodiment, R 2 However, independently, R 2B Ethyl is optionally substituted with one, two, or three substituents (or one or two substituents, or one substituent) selected from. In another embodiment, R 2 However, it is ethyl. In yet another embodiment, R 2 However, it is 1-hydroxyethyl.

[0027] In yet another embodiment, R 2 However, independently, R 2A A 4- to 6-membered heterocycloalkyl (or 4-membered, 5-membered, or 6-membered heterocycloalkyl) optionally substituted with one, two, or three substituents (or one or two substituents, or one substituent) selected from the above. In one embodiment, R 2 However, independently, R 2A Azetidine-1-yl is optionally substituted with one, two, or three substituents (or one or two substituents, or one substituent) selected from the above. In another embodiment, R 2 However, it is 2-methyl-2-(N,N-dimethylamino)-2-methylazetidine-1-yl.

[0028] In yet another embodiment, R 2 However, independently, R 2AA 5- to 6-membered heteroaryl (or 5- or 6-membered heteroaryl) optionally substituted with 1, 2, or 3 substituents (or 1 or 2 substituents, or 1 substituent) selected from 2 wherein R 2A is independently a 6-membered heteroaryl (e.g., pyridyl, e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl) optionally substituted with 1, 2, or 3 substituents (or 1 or 2 substituents, or 1 substituent) selected from

[0029] In one embodiment, R 2 is 2-hydroxypropyl or a 6-membered heteroaryl (e.g., pyridyl, e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl) optionally substituted with C(O)NR c2B R c2D (e.g., C(O)NH2, C(O)NHMe, or C(O)NMe2). In another embodiment, R 2 is OR[[ID=1十七]] a2 .

[0030] In yet another embodiment, each R 2A is independently selected from C 1-3 alkyl, NR c2B R c2D (e.g., NH2, NHMe, or NMe2), or C(O)NR c2B R c2D (e.g., C(O)NH2, C(O)NHMe, or C(O)NMe2), and the C 2A alkyl forming R 1-3 is each independently optionally substituted with 1, 2, or 3 substituents (or 1 or 2 substituents, or 1 substituent) selected from 2B . In yet another embodiment, each R 2A is independently selected from C 2B alkyl optionally substituted with 1, 2, or 3 substituents (or 1 or 2 substituents, or 1 substituent) selected from 1-3 . In one embodiment, R 2A is R 2BThat is the case.

[0031] In another embodiment, R 3 However, independently, R 3E C optionally substituted with 1, 2, or 3 substituents (or 1 or 2 substituents, or 1 substituent) selected from 1-3 It is alkyl (for example, methyl or ethyl).

[0032] In yet another embodiment, R 3 However, independently, R 3E C optionally substituted with 1, 2, or 3 substituents (or 1 or 2 substituents, or 1 substituent) selected from 3-10 It is cycloalkyl. In yet another embodiment, R 3 However, independently, R 3E C optionally substituted with 1, 2, or 3 substituents (or 1 or 2 substituents, or 1 substituent) selected from 3-7 It is a cycloalkyl. In one embodiment, R 3 However, independently, R 3E C optionally substituted with 1, 2, or 3 substituents (or 1 or 2 substituents, or 1 substituent) selected from 3-6 These are cycloalkyl compounds (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).

[0033] In another embodiment, R 3 However, independently, R 3E Cyclobutyl is optionally substituted with one, two, or three substituents (or one or two substituents, or one substituent) selected from the above. In yet another embodiment, R 3 However, independently, R 3E Cyclopropyl is optionally substituted with one, two, or three substituents (or one or two substituents, or one substituent) selected from. In yet another embodiment, R 3 However, it is cyclopropyl. In one embodiment, R 3 However, it is 1-fluorocyclopropane-1-yl. In another embodiment, R 3However, it is 1-methylcyclopropane-1-yl.

[0034] In another embodiment, R 3 However, independently, R 3E C optionally substituted with 1, 2, or 3 substituents (or 1 or 2 substituents, or 1 substituent) selected from 6-10 It is an aryl (e.g., phenyl). In yet another embodiment, R 3 However, independently, R 3E It is a 5- to 10-membered heteroaryl substituted with one, two, or three substituents (or one or two substituents, or one substituent) selected from the above.

[0035] In yet another embodiment, R 3 However, OR 3A In one embodiment, R 3 However, NR 3B R 3C That is the case.

[0036] In another embodiment, each R 4 However, independently, H, D, C 1-3 Alkyl (e.g., methyl or ethyl), C 1-3 Selected from haloalkyl (e.g., trifluoroalkyl) and halo (e.g., fluoro). In yet another embodiment, each R 4 However, independently, H, D, C 1-3 Selected from alkyl (e.g., methyl or ethyl) and halo (e.g., fluoro). In yet another embodiment, each R 4 However, each R is independently selected from H, methyl, and fluoro. In one embodiment, each R 4 However, these are independently selected from H and methyl. In another embodiment, one R 4 However, H is and one R 4 However, it is methyl. In yet another embodiment, each R 4 However, H. In yet another embodiment, each R 4 However, it is methyl.

[0037] In one embodiment, one R 5However, R 5A And each other R 5 However, independently, two other R atoms are selected from H, methyl, and fluoro, or optionally bonded to the same carbon atom. 5 However, both of them, along with the carbon atoms to which they are bonded, are optionally substituted with 1, 2, 3, or 4 substituents (or 1, 2, or 3 substituents, or 1 or 2 substituents, or 1 substituent) selected from methyl and fluoro, respectively, and spiro-C 3-6 A cycloalkyl ring (e.g., cyclopropyl) is formed, or optionally, two other R atoms bonded to adjacent carbon atoms. 5 However, each of these condensed C atoms may be optionally substituted with one, two, three, or four substituents (or one, two, or three substituents, or one or two substituents, or one substituent) selected from methyl and fluoro atoms, along with the carbon atom to which they are bonded. 3-6 It forms a cycloalkyl ring (e.g., cyclopropyl).

[0038] In another embodiment, one R 5 However, R 5A And each other R 5 However, these are independently selected from H, methyl, and fluoro. In yet another embodiment, one R 5 However, R 5A And each other R 5 However, independently, two other R atoms are selected from H and methyl, or optionally bonded to the same carbon atom. 5 However, both of them, along with the carbon atom to which they are bonded, are optionally substituted with 1, 2, 3, or 4 substituents (or 1, 2, or 3 substituents, or 1 or 2 substituents, or 1 substituent) selected from methyl, and are spiro-C 3-6 A cycloalkyl ring (e.g., cyclopropyl) is formed, or optionally, two other R atoms bonded to adjacent carbon atoms. 5 However, each of these condensed C atoms may be optionally substituted with one, two, three, or four substituents (or one, two, or three substituents, or one or two substituents, or one substituent) selected from methyl, along with the carbon atom to which they are bonded.3-6 It forms a cycloalkyl ring (e.g., cyclopropyl).

[0039] In yet another embodiment, one R 5 However, R 5A And each other R 5 However, these are independently selected from H and methyl. In one embodiment, one R 5 However, R 5A And each other R 5 However, it is either H, or optionally, two other R atoms bonded to the same carbon atom. 5 However, both of them, along with the carbon atom to which they are bonded, are optionally substituted with 1, 2, 3, or 4 substituents (or 1, 2, or 3 substituents, or 1 or 2 substituents, or 1 substituent) selected from methyl, and are spiro-C 3-6 A cycloalkyl ring (e.g., cyclopropyl) is formed, or optionally, two other R atoms bonded to adjacent carbon atoms. 5 However, each of these condensed C atoms may be optionally substituted with one, two, three, or four substituents (or one, two, or three substituents, or one or two substituents, or one substituent) selected from methyl, along with the carbon atom to which they are bonded. 3-6 It forms a cycloalkyl ring (e.g., cyclopropyl). In another embodiment, one R 5 However, R 5A And each other R 5 However, it is H.

[0040] In yet another embodiment, R 5A However, H, D, C 1-3 Alkyl (e.g., methyl), C 1-3 Haloalkyl (e.g., trifluoromethyl), C 2-3 Alkenil, C 2-3 Alkinyl, halo (e.g., fluoro), OR a5A , and CN, or optionally, R bonded to the same carbon atom 5A and R 5 However, along with the carbon atoms to which they are bonded, D and C respectively 1-3SpiroC optionally substituted with 1, 2, 3, or 4 substituents (or 1, 2, or 3 substituents, or 1 or 2 substituents, or 1 substituent) selected from alkyl (e.g., methyl) and halo (e.g., fluoro) 3-6 A cycloalkyl ring, for example, one that forms a cyclopropyl group, or optionally, one that is bonded to an adjacent carbon atom. 5A and R 5 However, along with the carbon atoms to which they are bonded, each of them is D, C 1-3 Condensed C molecules optionally substituted with 1, 2, 3, or 4 substituents (or 1, 2, or 3 substituents, or 1 or 2 substituents, or 1 substituent) selected from alkyl (e.g., methyl) and halo (e.g., fluoro) elements. 3-6 Forming a cycloalkyl ring (e.g., cyclopropyl), R a5A However, H, C 1-3 Alkyl, C 1-3 Haloalkyl and Cy 2 Selected from, R a5A C that forms 1-3 Each alkyl group is R 5B It is optionally substituted with one, two, three, or four substituents (or one, two, or three substituents, or one or two substituents, or one substituent) selected from the above.

[0041] In yet another embodiment, R 5A However, H, C 1-3 The R is alkyl (e.g., methyl), halo (e.g., fluoro), or optionally bonded to the same carbon atom. 5A and R 5 However, along with the carbon atoms to which they are bonded, each of them is C 1-3 SpiroC optionally substituted with 1, 2, 3, or 4 substituents (or 1, 2, or 3 substituents, or 1 or 2 substituents, or 1 substituent) selected from alkyl (e.g., methyl) and halo (e.g., fluoro) 3-6 A cycloalkyl ring, for example, one that forms a cyclopropyl group, or optionally, one that is bonded to an adjacent carbon atom.5A and R 5 However, along with the carbon atoms to which they are bonded, each of them is C 1-3 Condensed C molecules optionally substituted with one, two, three, or four substituents (or one, two, or three substituents, or one or two substituents, or one substituent) selected from alkyl (e.g., methyl) and halo. 3-6 It forms a cycloalkyl ring (e.g., cyclopropyl).

[0042] In one embodiment, R 5A However, H or C 1-3 It is alkyl (e.g., methyl), or optionally, R bonded to the same carbon atom. 5A and R 5 However, along with the carbon atoms to which they are bonded, each of them is C 1-3 SpiroC optionally substituted with 1, 2, 3, or 4 substituents (or 1, 2, or 3 substituents, or 1 or 2 substituents, or 1 substituent) selected from alkyl (e.g., methyl) 3-6 A cycloalkyl ring, for example, one that forms a cyclopropyl group, or optionally, one that is bonded to an adjacent carbon atom. 5A and R 5 However, along with the carbon atoms to which they are bonded, each of them is C 1-3 Condensed C molecules optionally substituted with 1, 2, 3, or 4 substituents (or 1, 2, or 3 substituents, or 1 or 2 substituents, or 1 substituent) selected from alkyl groups (e.g., methyl groups). 3-6 It forms a cycloalkyl ring (e.g., cyclopropyl).

[0043] In another embodiment, R 5A However, H, D, C 1-3 Alkyl (e.g., methyl), C 1-3 Haloalkyl (e.g., trifluoromethyl), C 2-3 Alkenil, C 2-3 Alkinyl, halo (e.g., fluoro), OR a5A , and CN, R a5A However, H, C1-3 Alkyl, C 1-3 Haloalkyl and Cy 2 Selected from, R a5A C that forms 1-3 Each alkyl group is R 5B It is optionally substituted with one, two, three, or four substituents (or one, two, or three substituents, or one or two substituents, or one substituent) selected from the above.

[0044] In yet another embodiment, R 5A However, H, C 1-3 The alkyl (e.g., methyl) or halo (e.g., fluoro) is used. In yet another embodiment, R 5A However, H or C 1-3 It is an alkyl group (for example, methyl). In one embodiment, R 5A However, H. In another embodiment, R 5A However, Cy 2 In yet another embodiment, R 5A However, C 1-3 Alkyl (e.g., methyl or ethyl), R 5A C that forms 1-3 Alkyl (or methyl or ethyl) 2 Replaced by, and each, R 5B It is also optionally substituted with one, two, three, or four substituents (or one, two, or three substituents, or one or two substituents, or one substituent) selected from the above.

[0045] In yet another embodiment, R 5A However, C 1-3 Alkyl (e.g., methyl or ethyl), R 5A C that forms 1-3 Alkyl (or methyl or ethyl) 2 It is replaced by R 5A However, CH2Cy 2 In one embodiment, R 5A However, CH2CH2Cy 2 In another embodiment, R 5A However, OR a5AAnd R a5A However, Cy 2 That is the case.

[0046] In yet another embodiment, R 5A However, C 1-3 Alkyl (e.g., methyl or ethyl), R a5A C that forms 1-3 Alkyl, Cy 2 Replaced by, and each, R 5B It is optionally substituted with one, two, three, or four substituents selected from, or one, two, or three substituents, or one or two substituents, or one substituent. In yet another embodiment, R 5A However, OCH2Cy 2 In one embodiment, R 5A However, OCH2CH2Cy 2 That is the case.

[0047] In another embodiment, Cy 2 However, independently, R Cy2 C is optionally substituted with 1, 2, 3, or 4 substituents (or 1, 2, or 3 substituents, or 1 or 2 substituents, or 1 substituent) selected from the above. 6-10 In yet another embodiment, Cy 2 However, independently, R Cy2 Phenyl is optionally substituted with 1, 2, 3, or 4 substituents selected from. In yet another embodiment, Cy 2 However, C 6-10 It is an arrow. In one embodiment, Cy 2 But it is phenyl.

[0048] In another embodiment, Cy 2 However, independently, R Cy2 A 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents (or 1, 2, or 3 substituents, or 1 or 2 substituents, or 1 substituent) selected from the above. In yet another embodiment, Cy 2 However, independently, R Cy2It is a 6-membered heteroaryl optionally substituted with 1, 2, 3, or 4 substituents selected from. In yet another embodiment, Cy 2 However, it is a 6-membered heteroaryl. In one embodiment, Cy 2 However, independently, R Cy2 A pyridinyl optionally substituted with 1, 2, 3, or 4 substituents selected from. In another embodiment, Cy 2 However, it is pyridinyl.

[0049] In yet another embodiment, Cy 2 However, independently, R Cy2 C is optionally substituted with 1, 2, 3, or 4 substituents (or 1, 2, or 3 substituents, or 1 or 2 substituents, or 1 substituent) selected from the above. 3-7 It is cycloalkyl. In yet another embodiment, Cy 2 However, independently, R Cy2 It is a 4- to 10-membered heterocycloalkyl that is optionally substituted with 1, 2, 3, or 4 substituents (or 1, 2, or 3 substituents, or 1 or 2 substituents, or 1 substituent) selected from the above.

[0050] One embodiment, each R Cy2 However, independently, D and C 1-3 Alkyl, C 1-3 Haloalkyl, C 2-3 Alkenil, C 2-3 Selected from alkynyl and halo. In another embodiment, each R Cy2 However, it is now independent and is called Haro.

[0051] In yet another embodiment, the compound of formula (I) is selected from the compounds in Table 1 and their pharmaceutically acceptable salts. [Table 1-1] [Table 1-2] [Table 1-3]

[0052] In other embodiments, the compound of formula (I) is selected from the compounds in Table 2 and their pharmaceutically acceptable salts. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12] [Table 2-13]

[0053] In other embodiments, the compound of formula (I) is in the form of a pharmaceutically acceptable salt. In other embodiments, the compound of formula (I) is in the form of a free base or a free acid, or in a form other than a salt.

[0054] In another embodiment, provided herein are pharmaceutical compositions comprising a compound of formula (I), or any of its embodiments, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0055] For clarity, it is further understood that certain features of the present invention described in the context of separate embodiments may also be provided in combination in a single embodiment (wherein these embodiments are intended to be combined as if described in a multiple dependency form). Conversely, various features of the present invention described in the context of a single embodiment for the sake of brevity may also be provided separately or in any preferred partial combination. Thus, it is intended that embodiments of the compound of formula (I) may be combined in any preferred combination.

[0056] In various parts of this specification, certain characteristics of compounds are disclosed in groups or ranges. Such disclosures are specifically intended to include each of the members of such groups and ranges, and each individual partial combination. For example, "C 1-6The term "alkyl" is specifically intended to disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl individually (without limitation).

[0057] The term "n-membered," where n is an integer, typically refers to the number of ring-forming atoms at a site where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydronaphthalene is an example of a 10-membered cycloalkyl group.

[0058] Throughout this specification, variables defining divalent linking groups may be described. Specifically, each linking substituent is intended to include both forward and backward linking substituents. For example, -NR(CR'R'') n - is -NR(CR'R'') n -and-(CR'R'') n Both NR- forms are included, and each form is intended to be disclosed separately. If a structure requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if a structure requires a linking group and the definition of the Markush group for that variable lists "alkyl" or "aryl," then "alkyl" or "aryl" are understood to represent a linked alkylene group or an arylene group, respectively.

[0059] The term "substituted" means that an atom or group of atoms formally replaces a hydrogen atom as a "substituent" bonded to another group. The hydrogen atom is formally removed and replaced by the substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms. The term "optionally substituted" means either unsubstituted or substituted. Unless otherwise indicated, the term "substituted" refers to any level of substitution, e.g., mono-substituted, di-substituted, tri-substituted, tetra-substituted, or penta-substituted, where such substitutions are permitted. Substituents are independently selected, and substitutions may be at any chemically accessible position. It should be understood that substitutions at a given atom are limited by their valency. It should be understood that substitutions at a given atom result in a chemically stable molecule.

[0060] "C n-m The term "C" indicates a range including the endpoints, where n and m are integers indicating the number of carbon atoms present in the chemical part. The term is intended to include each member and all members within the indicated range. Thus, C n-m This is a series of C n , C n+1 ...C m-1 , and C m This includes each member. For example, C 1-4 (Including C1, C2, C3, and C4), C 1-6 Examples include (including C1, C2, C3, C4, C5, and C6).

[0061] The term "alkyl," used alone or in combination with other terms, refers to a saturated hydrocarbon group that may be linear or branched. n-mThe term "alkyl" refers to an alkyl group having n to m carbon atoms. Formally, an alkyl group corresponds to an alkane having one CH bond replaced by the alkyl group bond site to the rest of the compound. In some embodiments, the alkyl group contains 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, and sec-butyl; and higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, and 1,2,2-trimethylpropyl.

[0062] When used alone or in combination with other terms, the term "alkylene" refers to a divalent alkyl linking group. Formally, an alkylene group corresponds to an alkane in which two CH bonds are replaced by the alkylene group's bonding points to the rest of the compound. n-m The term "alkylene" refers to an alkylene group having n to m carbon atoms. Examples of alkylene groups include, but are not limited to, methylene, ethane-1,2-diyl, ethane-1,1-diyl, propane-1,3-diyl, propane-1,2-diyl, propane-1,1-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, and 2-methylpropane-1,3-diyl.

[0063] When used alone or in combination with other terms, the term "alkenyl" refers to a linear or branched hydrocarbon group corresponding to an alkyl group having one or more carbon-carbon double bonds. n-m Alkirenyl 」The term "alkenyl" refers to an alkenyl group having n to m carbon atoms. Formally, an alkenyl group corresponds to an alkene in which one CH bond is replaced by the bonding site of the alkenyl group to the rest of the compound. In some embodiments, the alkenyl moiety contains 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, and sec-butenyl.

[0064] When used alone or in combination with other terms, the term "alkynyl" refers to a linear or branched hydrocarbon group corresponding to an alkyl group having one or more carbon-carbon triple bonds. n-m Alkinyl 」 The term refers to an alkynyl group having n to m carbon atoms. Formally, an alkynyl group corresponds to an alkyne having one CH bond replaced by an alkyl group bond to the rest of the compound. In some embodiments, the alkynyl moiety contains 2 to 6 or 2 to 4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, propyne-1-yl, and propyne-2-yl.

[0065] The term "alkoxy," used alone or in combination with other terms, refers to a group of the formula -O-alkyl, where alkyl groups are defined above. n-m The term "alkoxy" refers to an alkoxy group in which the alkyl group has n to m carbon atoms. Examples of alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. n-m The term "dialkoxy" refers to the formula -O-(C n-m This refers to an alkyl)-O- linking group, where the alkyl group has n to m carbon atoms. Exemplary dialkoxy groups include -OCH2CH2O- and OCH2CH2CH2O-. In some embodiments, C n-mThe two oxygen atoms of the dialkoxy group can bond with the same boron atom to form a five-membered or six-membered heterocycloalkyl group.

[0066] When used alone or in combination with other terms, the term “amino” refers to the group of formula -NH2, where the hydrogen atom may be substituted with substituents as described herein. For example, “alkylamino” can refer to -NH(alkyl) and -N(alkyl)2.

[0067] When used alone or in combination with other terms, the term "carbonyl" refers to the -C(=O)- group.

[0068] The term "halo" or "halogen," used alone or in combination with other terms, refers to fluoro, chloro, bromo, and iodine. In some embodiments, "halo" refers to a halogen atom selected from F, Cl, or Br. In some embodiments, the halo group is F.

[0069] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen atoms. n-m The term "haloalkyl" refers to a C14-C n-m This refers to an alkyl group, which may be the same or different. In some embodiments, the halogen atom is a fluoro atom. In some embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms. Examples of haloalkyl groups include CF3, C2F5, CHF2, CH2F, CCl3, CHCl2, and C2Cl5. In some embodiments, the haloalkyl group is a fluoroalkyl group.

[0070] The term "haloalkoxy," used alone or in combination with other terms, refers to a group of the formula -O-haloalkyl, where a haloalkyl is defined above. n-mThe term "haloalkoxy" refers to a haloalkoxy group in which the haloalkyl group has n to m carbon atoms. Examples of haloalkoxy groups include trifluoromethoxy. In some embodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0071] The terms "oxo" or "oxy" refer to an oxygen atom as a divalent substituent that forms a carbonyl group when bonded to carbon, or when bonded to a heteroatom that forms a sulfoxide or sulfone group, or an N-oxide group. In some embodiments, the heterocyclic group may be optionally substituted with one or two oxo (=O) substituents.

[0072] The term "oxidized" with respect to ring-forming N atoms refers to the ring-forming N-oxide.

[0073] The term "oxidized" with respect to the ring-forming sulfonyl atom refers to ring-forming sulfonyl or ring-forming sulfinyl.

[0074] The term "aromatic" refers to a carbocyclic or heterocyclic ring having one or more polyvalent unsaturated rings that possess aromatic properties (i.e., having (4n+2) delocalized π (pi) electrons where n is an integer).

[0075] The term "aryl," used alone or in combination with other terms, refers to an aromatic hydrocarbon group that may be monocyclic or polycyclic (e.g., having two fused rings). n-m The term "aryl" refers to an aryl group having n to m ring carbon atoms. Examples of aryl groups include phenyl and naphthyl. In some embodiments, the aryl group has 6 to about 10 carbon atoms. In some embodiments, the aryl group has 6 carbon atoms. In some embodiments, the aryl group has 10 carbon atoms. In some embodiments, the aryl group is phenyl. In some embodiments, the aryl group is naphthyl.

[0076] The terms “heteroaryl” or “heteroaromatic,” used alone or in combination with other terms, refer to monocyclic or polycyclic aromatic heterocycles having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl ring independently has 1, 2, 3, or 4 heteroatom ring members selected from nitrogen, sulfur, and oxygen. In some embodiments, any ring-forming N in the heteroaryl portion can be an N-oxide. In some embodiments, the heteroaryl has 5 to 14 ring atoms including carbon atoms, and independently 1, 2, 3, or 4 heteroatom ring members selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl has 5 to 10 ring atoms including carbon atoms, and independently 1, 2, 3, or 4 heteroatom ring members selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl has 5 to 6 ring atoms, and independently 1 or 2 heteroatom ring members selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a 5-membered or 6-membered heteroaryl ring. In other embodiments, the heteroaryl is an 8-membered, 9-membered, or 10-membered fused bicyclic heteroaryl ring. Examples of heteroaryl groups include, but are not limited to, pyridinyl (pyridyl), pyrimidinyl, pyrazinyl, pyridadinyl, pyrrolyl, pyrazolyl, azolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, furanil, thiophenyl, quinolinyl, isoquinolinyl, naphthyridine (including 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3-, and 2,6-naphthyridines), indolyl, isoindolyl, benzothiophenyl, benzofuranil, benzisoxazolyl, imidazo[1,2-b]thiazolyl, prinyl, and others. In some embodiments, the heteroaryl group is pyridone (e.g., 2-pyridone).

[0077] A five-membered heteroaryl ring is a heteroaryl group having five ring atoms, where one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary five-membered heteroaryl rings include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.

[0078] A six-membered heteroaryl ring is a heteroaryl group having six ring atoms, where one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary six-membered heteroaryl rings are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, isoindolyl, and pyridadinyl.

[0079] The term "cycloalkyl," used alone or in combination with other terms, refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic) containing cyclized alkyl and alkenyl groups. n-m The term "cycloalkyl" refers to a cycloalkyl group having n to m ring-member carbon atoms. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spiro rings. Cycloalkyl groups have 3, 4, 5, 6, or 7 ring-forming carbon atoms (C 3-7 ) may have. In some embodiments, the cycloalkyl group has 3-6 ring members, 3-5 ring members, or 3-4 ring members. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is C 3-6These are monocyclic cycloalkyl groups. The ring-forming carbon atoms of the cycloalkyl group can optionally be oxidized to form oxo or sulfide groups. Cycloalkyl groups also include cycloalkylides. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The definition of a cycloalkyl group also includes moieties having one or more aromatic rings condensed (i.e., sharing a common bond) to a cycloalkyl ring, such as benzo or thienyl derivatives of cyclopentane, cyclohexane, etc. Cycloalkyl groups containing condensed aromatic rings can be bonded via any ring-forming atoms, including the ring-forming atoms of the condensed aromatic ring. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, bicyclo[1.1.1]pentanyl, and bicyclo[2.1.1]hexanyl. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the cycloalkyl group is tetrahydronaphthalenyl (e.g., 1,2,3,4-tetrahydronaphthalenyl).

[0080] When used alone or in combination with other terms, the term “heterocycloalkyl” refers to a non-aromatic ring or ring system which may optionally contain one or more alkenylene groups as part of its ring structure, independently having at least one heteroatom ring member selected from nitrogen, sulfur, oxygen, and phosphorus, and having 4-10, 4-7, or 4-6 ring members. The term “heterocycloalkyl” includes monocyclic 4, 5, 6, and 7-membered heterocycloalkyl groups. Heterocycloalkyl groups can include monocyclic or bicyclic (e.g., having two fused or bridging rings) or spirocyclic ring systems. In some embodiments, the heterocycloalkyl group is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. The ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can optionally be oxidized to form oxo or sulfide groups or other oxidative bonds (e.g., C(O), S(O), C(S), or S(O)2, N-oxide, etc.), or the nitrogen atom can be quaternized. Heterocycloalkyl groups can be bonded via ring-forming carbon atoms or ring-forming heteroatoms. In some embodiments, heterocycloalkyl groups contain 0 to 3 double bonds. In some embodiments, heterocycloalkyl groups contain 0 to 2 double bonds. The definition of a heterocycloalkyl group also includes moieties having one or more aromatic rings condensed (i.e., sharing a common bond) to a heterocycloalkyl ring, such as benzo or thienyl derivatives of piperidine, morpholine, and azepines. Heterocycloalkyl groups containing condensed aromatic rings can be bonded via any ring-forming atoms, including the ring-forming atoms of the condensed aromatic ring. Examples of heterocycloalkyl groups include 2,5-diazobicyclo[2.2.1]heptanyl, pyrrolidinyl, hexahydropyrrolo[3,4-b]pyrrole-1(2H)-yl, 1,6-dihydropyridinyl, morpholinyl, azetidinyl, piperazinyl, and 4,7-diazaspiro[2.5]octan-7-yl.

[0081] In certain contexts, definitions or embodiments refer to specific rings (e.g., azetidine rings, pyridine rings, etc.). Unless otherwise specified, these rings can bond to any ring member, provided that the valence of the atoms is not exceeded. For example, an azetidine ring can bond at any position on the ring, while an azetidine-3-yl ring bonds at position 3.

[0082] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are intended. Compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods relating to preparing optically active forms from optically inert starting materials are known in the art, such as by the separation or stereoselective synthesis of racemic mixtures. Many geometric isomers, such as olefins and C=N double bonds, may also exist among the compounds described herein, and all such stable isomers are intended in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and can be isolated as mixtures of isomers or as separated isomers.

[0083] The separation of racemic mixtures of compounds can be carried out by any of a number of methods known in the art. One method involves fractional recrystallization using chiral dividing acids, which are optically active salt-forming organic acids. Suitable dividing agents for fractional recrystallization methods are optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or the D and L forms of various optically active camphorsulfonic acids such as β-camphorsulfonic acid. Other suitable dividing agents for fractional recrystallization methods include stereoisomerically pure forms of α-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norefedrine, ephedrine, N-methylfedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

[0084] The separation of racemic mixtures can also be carried out by elution onto a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by those skilled in the art.

[0085] If a compound described herein contains a chiral center, unless otherwise indicated, the compound may be any of the possible stereoisomers. In some embodiments, the compounds provided herein have an (R) configuration. In other embodiments, the compounds have an (S) configuration. In compounds having two or more chiral centers, unless otherwise indicated, each chiral center in the compound may independently be (R) or (S). In a compound having a single chiral center, the stereochemistry of the chiral center may be (R) or (S). In a compound having two chiral centers, since the stereochemistry of each chiral center may independently be (R) or (S), the configurations of the chiral centers may be (R) and (R), (R) and (S); (S) and (R), or (S) and (S). In a compound having three chiral centers, the stereochemistry of each of the three chiral centers can be independently (R) or (S), so the arrangement of the chiral centers can be (R), (R) and (R); (R), (R) and (S); (R), (S) and (R); (R), (S) and (S); (S), (R) and (R); (S), (R) and (S); (S), (S) and (R); or (S), (S) and (S).

[0086] The compounds of the present invention also include tautomeric forms. Tautomeric forms result from the exchange of a single bond with an adjacent double bond and the associated transfer of protons. Tautomeric forms include prototropic tautomers, which are isomeric protonation states having the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imoid acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions in the heterocyclic system, such as 1H- and 3H-imidazoles, 1H-, 2H-, and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles. Tautomeric forms can be in equilibrium or sterically fixed into a single form by appropriate substitution. Compounds herein identified by name or structure as a specific tautomer, unless otherwise specified, are intended to include other tautomers (for example, in the case of a purine ring, unless otherwise indicated, it will be understood that in the case of a name or structure of a compound describing a 9H tautomer, the 7H tautomer is also included).

[0087] The compounds of the present invention are stable at ambient temperature and can exist in the form of atropisomers (i.e., structural diastereoisomers) that can be separated, for example, by chromatography. 1A compound of the present invention, wherein is 2,3-dichlorophenyl, or any of its embodiments, may exist in the form of an atropisomer in which the stereostructure of phenyl relative to the rest of the molecule is represented by the following subformula (II-A) or (II-B). References to any of the compounds or embodiments described herein are understood to include, but are not limited to, all such atropisomer forms of the compound, including the atropisomer form represented by the following subformula (II-A) or (II-B). Without being limited to any theory, for a given compound, the atropisomer represented by formula (II-A) is generally understood to be more potent as an inhibitor of KRAS (including G12C, G12D, or G12V variants of KRAS) than the atropisomer represented by formula (II-B). [ka]

[0088] The compounds of the present invention may also contain all isotopes of atoms that occur in the intermediate or final compound. Isotopes include atoms that have the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more constituent atoms of the compounds of the present invention may be replaced or substituted with isotopes of the atom in natural or unnatural abundance. In some embodiments, the compound contains at least one deuterium atom. For example, one or more hydrogen atoms in the compounds of this disclosure may be replaced or substituted with deuterium. In some embodiments, the compound contains two or more deuterium atoms. In some embodiments, the compound contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 deuterium atoms. In the compounds provided herein, any atom that is not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.

[0089] Substitution with heavier isotopes such as deuterium may result in certain therapeutic benefits arising from greater metabolic stability, e.g., increased in vivo half-life or reduced drug requirements, thereby being preferable in some situations. (A. Kerekes et al. J. Med. Chem. 2011, 54, 201-210; R. Xu et al. J. Label Compd. Radiopharm. 2015, 58, 308-312). Unless otherwise specified, where a position is specifically designated as "D" or "deuterium," that position is understood to have deuterium in an abundance at least 3000 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 45% of deuterium incorporated). In embodiments, the compounds provided herein have an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporated at each designated deuterium atom), at least 4000 (60% deuterium incorporated), at least 4500 (67.5% deuterium incorporated), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporated), at least 6000 (90% deuterium incorporated), at least 6333.3 (95% deuterium incorporated), at least 6466.7 (97% deuterium incorporated), at least 6600 (99% deuterium incorporated), or at least 6633.3 (99.5% deuterium incorporated).

[0090] The term “compound” is intended to include, unless otherwise specified, all stereoisomers, including but not limited to, geometric isomers, configuration isomers, structural isomers, rotational isomers, and atropisomers of the illustrated structure, including each of those embodiments. The term is also intended to refer to the compounds described herein, regardless of how they are prepared, for example, by synthesis, by biological processes (e.g., metabolism or enzymatic conversion), or by a combination thereof.

[0091] All compounds and their pharmaceutically acceptable salts can be found together with other substances such as water and solvents (e.g., hydrates and solvates), or isolated. When in the solid state, the compounds and salts described herein may occur in various forms, for example, as solvates containing hydrates. Since compounds can be polymorphs or in any solid state form such as solvates, unless otherwise explicitly indicated, references to compounds and salts herein should be understood to encompass any solid state form of the compounds.

[0092] In some embodiments, the compounds or salts thereof provided herein are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial isolation may include, for example, a composition in which the compounds of the present invention are concentrated. Substantial isolation may include a composition containing at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the compounds of the present invention or a salt thereof.

[0093] The term "pharmaceutically acceptable" refers to a compound, material, composition, and / or dosage form that, within reasonable limits of medical judgment, is suitable for use in contact with human and animal tissues without causing excessive toxicity, irritation, allergic reactions, or other problems or complications, and that is commensurate with a reasonable benefit / risk ratio.

[0094] The terms "ambient temperature" and "room temperature" are understood in the art to generally refer to the temperature of the room in which the reaction takes place, for example, a temperature close to approximately 20°C to 30°C, or the reaction temperature.

[0095] This disclosure also includes pharmaceutically acceptable salts of the compounds described herein, including any of those embodiments. The term “pharmaceutically acceptable salt” refers to a derivative of the disclosed compound, wherein the parent compound is modified by converting an existing acidic or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. The pharmaceutically acceptable salts of the present invention include, for example, non-toxic salts of parent compounds formed from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acidic or base form of these compounds with a stoichiometric amount of a suitable base or acid in water, an organic solvent, or a mixture thereof. Generally, non-aqueous media such as ether, ethyl acetate, alcohol (e.g., methanol, ethanol, isopropanol, or butanol) or MeCN are preferred. A list of suitable salts can be found in ARGennaro (Ed.), Remington's Pharmaceutical Sciences, 17 th Ed., (Mack Publishing Company, Easton, 1985), p. 1418, SMBerge et al., J. Pharm. Sci., 1977, 66(1), 1-19, S. Gaisford in A. Adejare (Ed.), Remington, The Science and Practice of Pharmacy, 23 rdEd.,(Elsevier,2020),Chapter 17,pp.307-14, SMBerge et al.,J.Pharm.Sci.,1977,66(1),1-19,TSWiedmann,et al.,.Asian J.Pharm.Sci.,2016;11,722-34,D.Gupta et al. al.,Molecules,2018,23(7),1719, PHStahl et al.,Handbook of Pharmaceutical Salts:Properties,Selection,and Use,(Wiley,2002), and PHStahl et al.,Handbook of Pharmaceutical Salts:Properties,Selection,and Use,2 nd Found in Ed. (Wiley, 2011). In some embodiments, the compounds described herein include N-oxide forms.

[0096] II.Synthesis The compounds of the present invention, including the salt, can be prepared using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes, such as those in the following scheme.

[0097] The reactions for preparing the compounds of the present invention can be carried out in suitable solvents that can be readily selected by those skilled in the art of organic synthesis. Suitable solvents can be substantially inactive with the starting materials (reactants), intermediates, or products at the temperature in which the reaction is carried out, which can be, for example, in the range from the freezing temperature to the boiling temperature of the solvent. A given reaction can be carried out in one solvent or a mixture of two or more solvents. Depending on the specific reaction step, a solvent suitable for that particular reaction step can be selected by those skilled in the art.

[0098] The preparation of the compounds of the present invention may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, as well as the selection of appropriate protecting groups, can be readily determined by those skilled in the art. The chemistry of protecting groups can be found, for example, in Kocienski, Protecting Groups (Thieme, 2007), Robertson, Protecting Group Chemistry (Oxford University Press, 2000), and Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6. th This is described in Ed. (Wiley, 2007), Peturssion et al., “Protecting Groups in Carbohydrate Chemistry,” J. Chem. Educ., 1997, 74(11), 1297, and Wuts et al., Protective Groups in Organic Synthesis, 4th Ed., (Wiley, 2006).

[0099] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) It can be monitored by spectroscopic means such as infrared spectroscopy, spectrophotometric methods (e.g., UV-visible light), and mass spectrometry, or by chromatographic methods such as high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or thin-layer chromatography (TLC).

[0100] The compound can be purified by those skilled in the art by various methods, including high-performance liquid chromatography (HPLC) ("Preparative LCMS Purification: Improved Compound Specific Method Optimization," Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs, J. Combi. Chem. 2004, 6(6), 874-883) and normal-phase silica chromatography.

[0101] The following scheme provides general guidance relating to the preparation of the compounds of the present invention. Those skilled in the art will understand that the preparations shown in the scheme can be modified or optimized using general knowledge of organic chemistry to prepare various compounds of the present invention.

[0102] Scheme 1 [ka] The compounds of formula 2-15 can be prepared via the synthetic route outlined in Scheme 1. Bromo of 2-1 can be prepared via Cy under standard Suzuki cross-coupling conditions (e.g., in the presence of a palladium catalyst and a suitable base), standard Negishi cross-coupling conditions, standard Still cross-coupling conditions, or other suitable methods. 1This is converted to obtain 2-2. Halogenation of 2-2 using a suitable reagent such as N-iodosuccinimide (NIS) yields intermediate 2-3 (where Hal is a halide such as F, Cl, Br, or I). Intermediate 2-3 is treated with a reagent such as triphosgene to obtain compound 2-4. Intermediate 2-4 can then be reacted with ketoester 2-5 and a suitable base to produce compound 2-6. Halogen coupling of 2-6 under standard Heck cross-coupling conditions, standard Suzuki cross-coupling conditions, or other preferred methods yields 2-7. Compound 2-8 can be prepared by treating 2-7 with a suitable chlorinating reagent such as POCl3. AS of intermediate 2-8 with amine 2-9 N Compound 2-10 can be produced by carrying out an Ar reaction (PG is a suitable protecting group such as Boc). Subsequent hydrolysis of the ester of 2-10 yields 2-11, which is then treated with NIS and a suitable base (e.g., K3PO4) to obtain the corresponding iodide 2-12. Compounds having formulas 2-12 and 2-13 are subjected to Sonogashira coupling followed by cyclization to obtain 2-14. Compound 2-14 can optionally undergo functionalization followed by deprotection of the protecting group PG to obtain compound 2-15. The order of the above chemical reactions can be appropriately rearranged to suit the preparation of different analogs.

[0103] For the synthesis of specific compounds, the general scheme described above and the specific methods described herein for preparing specific compounds can be modified. For example, the product or intermediate can be modified to introduce a specific functional group. Alternatively, substituents can be modified by methods known to those skilled in the art, e.g., RCLarock, Comprehensive Organic Transformations: A Guide to Functional Group Preparations (Wiley, 1999), RCLarock, et al., Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3 rd Ed.Vols.1-4(Wiley,2018), ARKatritzky,et al.(Eds.),Comprehensive Organic Functional Group Transformations,Vols.1-6(Pergamon Press,1995), and ARKatritzky et al.(Eds.),Comprehensive Organic Functional Group Transformations II,Vols.1-6(Elsevier,2 nd Any step in the entire synthesis can be modified by the method described in Edition, 2005.

[0104] Starting materials, reagents, and intermediates whose synthesis is not described herein may be commercially available, known in the literature, or prepared by methods known to those skilled in the art.

[0105] Those skilled in the art will understand that the described processes are not exclusive means of synthesizing the compounds of the present invention, and that a broad repertoire of synthetic organic reactions is potentially available in the synthesis of the compounds of the present invention. Those skilled in the art will know how to select and implement appropriate synthetic routes. Preferred methods for the synthesis of starting materials, intermediates, and products can be identified by referring to the following sources: Advances in Heterocyclic Chemistry, Vols. 1-114 (Elsevier, 1963-2023), Journal of Heterocyclic Chemistry Vols. 1-60 (Journal of Heterocyclic Chemistry, 1964-2023), E.M. Carreira, et al. (Eds.) Science of Synthesis, Vols. 1-48 (2001-2010), and Knowledge Updates. KU2010 / 1-4;2011 / 1-4;2012 / 1-4, 2013 / 1-4;2014 / 1-4, 2015 / 1-2;2016 / 1-3, 2017 / 1-3;2018 / 1-4 , 2019 / 1-3; 2020 / 1-3, 2021 / 1-3, 2022 / 1-3, 2023 / 1(Thieme,2001-2023), Houben-Weyl,Methoden der Organischen Chemie,4 th Ed.Vols.1-67(Thieme,1952-1987), Houben-Weyl,Methoden der Organischen Chemie,E-Series.Vols.1-23(Thieme,1982-2003), ARKatritzky,et al.(Eds.),Comprehensive Organic Functional Group Transformations,Vols.1-6(Pergamon Press, 1995), ARKatritzky et al. (Eds.), Comprehensive Organic Functional Group Transformations II, Vols. 1-6 (Elsevier, 2 ndEdition, 2005), A.R. Katritzky et al. (Eds.); Comprehensive Heterocyclic Chemistry, Vols. 1 - 8 (Pergamon Press, 1984), A.R. Katritzky, et al. (Eds.); Comprehensive Heterocyclic Chemistry II, Vols. 1 - 10 (Pergamon Press, 1996), A.R. Katritzky, et al. (Eds.); Comprehensive Heterocyclic Chemistry III, Vols. 1 - 14 (Elsevier Science, 2008), D.St.C. Black, et al. (Eds.); Comprehensive Heterocyclic Chemistry IV, Vols. 1 - 14 (Elsevier Science, 2022), M.B. Smith et al., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6 th Ed. (Wiley, 2007), M.B. Smith et al., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 8 th Ed. (Wiley, 2020), B.M. Trost et al. (Ed.), Comprehensive Organic Synthesis, Vols. 1 - 9 (Pergamon Press, 1991), and Patai’s Chemistry of Functional Groups, 100 Vols. (Wiley 1964 - 2022).

[0106] III. Use of the Compound Compounds of the present disclosure, including a compound of formula (I) or any of its embodiments, are therapeutically useful as described in more detail below. The present disclosure provides a compound of formula (I) for use as a pharmaceutical or for use in a pharmaceutical. The present disclosure provides a compound of formula (I) for use as a pharmaceutical or for use in the treatment of a disease, as described in more detail below. The present disclosure also provides the use of a compound of formula (I) or any of its embodiments as a pharmaceutical or for the treatment of a disease, as described in more detail below. The present disclosure also provides the use of a compound of formula (I) or any of its embodiments in the manufacture of a pharmaceutical for the treatment of a disease, as described in more detail below.

[0107] The compounds of this disclosure are KRAS inhibitors and are therefore useful for treating diseases and disorders related to KRAS activity. Any of the compounds of formula (I), including any of the embodiments thereof, may be used for the uses described herein.

[0108] In particular, the compounds of the present invention are KRAS inhibitors that are active against one or more variants of KRAS, and are therefore useful in treating diseases and disorders associated with the presence or activity of KRAS variants such as G12C, G12D, and / or G12V variants of KRAS.

[0109] The Ras family consists of three members: KRAS, NRAS, and HRAS. RAS mutations account for approximately 25% of human cancers. KRAS is the most frequently mutated isoform in human cancers, with 85% of all RAS mutations occurring in KRAS, compared to 12% in NRAS and 3% in HRAS (D. Simanshu, et al., Cell, 2017, 170(1), 17-33). KRAS mutations are widely found among the top three most deadly cancer types: pancreatic cancer (97%), colorectal cancer (44%), and lung cancer (30%) (ADCox, et al. Nat. Rev. Drug. Discov., 2014, 13(11), 828-51). The majority of RAS mutations occur at amino acid residues / codons 12, 13, and 61, with codon 12 mutations being the most frequent in KRAS. The frequency of specific mutations that vary between the RAS gene and the G12D mutation is most prevalent in KRAS, while Q61R and G12R mutations are most frequent in NRAS and HRAS. Furthermore, the range of mutations in RAS isoforms differs among cancer types. For example, the KRAS G12D mutation is prevalent in pancreatic cancer (51%), followed by colorectal adenocarcinoma (45%), and lung cancer (17%) (ADCox, et al. Nat. Rev. Drug. Discov., 2014, 13(11), 828-51). In contrast, KRAS G12C mutations are prevalent in non-small cell lung cancer (NSCLC), which accounts for 11–16% of lung adenocarcinomas (nearly half of mutated KRAS cells are G12C), as well as in 2–5% of pancreatic adenocarcinomas and colorectal adenocarcinomas, respectively (ADCox, et al. Nat. Rev. Drug. Discov., 2014, 13(11), 828-51). Using shRNA knockdown of thousands of genes across hundreds of cancer cell lines, genomic studies have demonstrated that cancer cells exhibiting KRAS mutations are highly dependent on KRAS function for cell growth (R. McDonald, et al., Cell, 2017, 170(3), 577-92).

[0110] In summary, these findings indicate that KRAS mutations play a crucial role in human cancer. Therefore, the development of KRAS-targeting inhibitors, including those targeting mutant KRAS, would be useful in the clinical treatment of KRAS-related diseases, including those characterized by the involvement or presence of KRAS mutations.

[0111] Diseases that can be treated with compounds of formula (I) include cancer. Cancers include adrenal cancer, acinar cell carcinoma, acoustic neuroma, acral lentiginous melanoma, hidradenoma, acute eosinophilic leukemia, acute erythroleukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenoid odontogenic tumor, adenosquamous carcinoma, adipose tissue tumor, adrenocortical carcinoma, adult T-cell leukemia / lymphoma, aggressive NK-cell leukemia, and AIDS-associated lymphoma. Alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastoma, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, astrocytoma, atypical teratomatoid rhabdoid tumor, B-cell chronic lymphocytic leukemia, B-cell prelymphocytic leukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, Brenner tumor, pheochromocytoma, Burkitt lymphoma Breast cancer, brain tumor, carcinoma, carcinoma in situ, carcinosarcoma, chondroma, cementoma, myelosarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, clear cell sarcoma of the kidney, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos disease, fibroplastic round cell tumor, diffuse large B-cell lymphoma, germinal dysplastic neuroepithelial tumor, undifferentiated germ cell tumor, embryonic cancer, endocrine gland tumor, endoderm sinus tumor, enteropathy-related T-cell lymphoma Cellular lymphoma, esophageal cancer, fetal-in-fetus cancer, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, gangliomas, gastrointestinal cancer, germ cell tumors, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of bone, glial tumors, giant cell tumor of bone, glial cell tumors, glioblastoma multiforme, glioma, cerebral gliomatosis, glucagon-producing tumors, gonadoblastoma, granulosa cell tumor, gynandrocyte blastoma, gallbladder cancer, gastric cancerCancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, hematological malignancies, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, lentigo malignant, lethal linea nephroma, leukemia, Leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphoblastic leukemia, liver cancer, small cell carcinoma Lung cancer, non-small cell lung cancer, MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant Triton's tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary mammary carcinoma, medullary thyroid cancer, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesothelioma, metastatic urothelial carcinoma, Müllerian mixed tumor, myxoid tumor, multiple myeloma, muscular tissue tumor, mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal cancer, Transschwannoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, ocular cancer, oligodendroglioma, oligodendroglioma, eosinophilic granuloma, optic nerve sheath meningioma, optic nerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroid carcinoma, paraganglioma, pineoblastoma, pineocytoma, pituitary cell tumor, pituitary adenoma, pituitary tumor, plasmacytoma, polygermoma, progenitor T lymphoblastic lymphoma, primary central nervous system lymphoma, primary exudative lymphoma, primary peritoneal cancer, prostate Cancer, pancreatic cancer, pharyngeal cancer, pseudomyxoma peritonei, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter transformation, rectal cancer, sarcoma, schwannomatous disease, seminomas, Sertoli cell tumor, sex cord-stromal tumor, signet ring cell carcinoma, skin cancer, small blue round cell tumor, small cell carcinoma, soft tissue sarcoma, somatostatinoma, sooty warts, spinal cord tumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, Sézary's disease, small intestine cancer, squamous cell carcinoma, stomach cancerThis may include cancers such as T-cell lymphoma, testicular cancer, theca cell tumor, thyroid cancer, transitional cell carcinoma, pharyngeal cancer, urachal cancer, genitourinary cancer, urothelial carcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, optic tract glioma, vulvar cancer, vaginal cancer, Waldenström macroglobulinemia, Warthin's tumor, and Wilms' tumor. In some embodiments, cancer is defined as adenocarcinoma, adult T-cell leukemia / lymphoma, bladder cancer, blastoma, bone cancer, breast cancer, brain cancer, carcinoma, myelosarcoma, cervical cancer, colorectal cancer, esophageal cancer, gastrointestinal cancer, glioblastoma multiforme, glioma, gallbladder cancer, gastric cancer, head and neck cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, intestinal cancer, kidney cancer, laryngeal cancer, leukemia, lung cancer, lymphoma, liver cancer, small cell lung cancer, non-small cell lung cancer, mesothelioma, multiple myeloma, eye cancer, optic nerve tumor, oral cancer, ovarian cancer, pituitary tumor, primary central nervous system lymphoma, prostate cancer, pancreatic cancer, pharyngeal cancer, renal cell carcinoma, rectal cancer, sarcoma, skin cancer, spinal cord tumor, small intestine cancer, stomach cancer. It can be cancer, T-cell lymphoma, testicular cancer, thyroid cancer, throat cancer, genitourinary cancer, urothelial carcinoma, uterine cancer, vaginal cancer, or Wilms' tumor.

[0112] Cancers involving KRAS with G12C, G12V, and G12D mutations that can be treated with compounds of formula (I) or any of their embodiments include, but are not limited to, carcinomas (e.g., pancreatic, colorectal, lung, bladder, stomach, esophagus, breast, head and neck, cervical skin, thyroid), hematopoietic malignancies (e.g., myeloproliferative disorders (MPN), myelodysplastic syndromes (MDS), chronic and juvenile myelomonocytic leukemia (CMML and JMML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and multiple myeloma (MM)), as well as other neoplasms (e.g., glioblastoma and sarcoma). In addition, KRAS mutations have been found in acquired resistance to anti-EGFR therapy (Knickelbein, K. et al. Genes & Cancer, (2015):4-12). KRAS mutations have been found in immunological and inflammatory disorders such as Ras-associated lymphoproliferative disorder (RALD) or juvenile myelomonocytic leukemia (JMML) caused by somatic mutations in KRAS or NRAS (Fernandez-Medarde, A. et al. Genes & Cancer, (2011):344-358).

[0113] The compounds of the Disclosure can inhibit the activity of the KRAS protein, including in any of the embodiments thereof. For example, the compounds of the Disclosure can be used to inhibit the activity of KRAS intracellularly or in an individual or patient requiring enzyme inhibition by administering an inhibitory amount of one or more of the compounds of the Disclosure to cells, an organism, or a patient.

[0114] As KRAS inhibitors, the compounds of this disclosure, or any of their embodiments, are useful in treating a variety of diseases associated with abnormal expression or activity of KRAS. Compounds that inhibit KRAS would be useful in providing a means of preventing tumor growth or inducing apoptosis by inhibiting angiogenesis. Therefore, it is expected that the compounds of this disclosure will prove useful in treating or preventing proliferative disorders such as cancer. In particular, tumors with activating mutants of receptor tyrosine kinases or upregulation of receptor tyrosine kinases may be especially sensitive to inhibitors.

[0115] In one embodiment, a method for inhibiting KRAS activity is provided herein, the method comprising contacting KRAS with a compound of the disclosure. In one embodiment, contact comprises administering the compound to a patient. In one embodiment, KRAS is characterized by having a G12C somatic mutation. In another embodiment, KRAS is characterized by having a G12D somatic mutation. In yet another embodiment, KRAS is characterized by having a G12V somatic mutation.

[0116] In one embodiment, the foregoing provides a method for inhibiting a KRAS protein having a G12C mutation, the method comprising contacting KRAS with a compound of formula (I), or any of its embodiments.

[0117] In one embodiment, the foregoing provides a method for inhibiting a KRAS protein having the G12D mutation, the method comprising contacting a compound of formula (I), or any of its embodiments, with KRAS having the G12D mutation.

[0118] In one embodiment, the foregoing provides a method for inhibiting a KRAS protein having a G12V mutation, the method comprising contacting a compound of formula (I), or any of its embodiments, with KRAS having a G12V mutation.

[0119] In another embodiment, the foregoing provides a method for treating a disease or disorder related to the inhibition of KRAS interaction, the method comprising administering to a patient in need a therapeutically effective amount of a compound of formula (I), or any of its embodiments.

[0120] In one embodiment, the disease or disorder is an immunological or inflammatory disorder. In another embodiment, the immunological or inflammatory disorder is Ras-associated lymphoproliferative disorder or juvenile myelomonocytic leukemia caused by a somatic mutation in KRAS. In one embodiment, the immunological or inflammatory disorder is caused by a somatic mutation in KRAS.

[0121] In another embodiment, the somatic mutation of KRAS is G12C. In another embodiment, the somatic mutation of KRAS is G12D. In another embodiment, the somatic mutation of KRAS is G12V.

[0122] In another embodiment, the immunological or inflammatory disorder is associated with the activity of KRAS having a G12C mutation. In another embodiment, the immunological or inflammatory disorder is associated with the activity of KRAS having a G12D mutation. In yet another embodiment, the immunological or inflammatory disorder is associated with the activity of KRAS having a G12V mutation.

[0123] In yet another embodiment, provided herein is a method for treating a disease or disorder associated with inhibiting the KRAS protein having a G12C mutation, the method comprising administering a therapeutically effective amount of a compound of formula (I), or any of its embodiments, to a patient in need thereof.

[0124] In yet another embodiment, the foregoing provides a method for treating a disease or disorder associated with inhibiting the KRAS protein having a G12D mutation, the method comprising administering a therapeutically effective amount of a compound of formula (I), or any of its embodiments, to a patient in need thereof.

[0125] In another embodiment, the foregoing provides a method for treating a disease or disorder associated with inhibiting the KRAS protein having a G12V mutation, the method comprising administering a therapeutically effective amount of a compound of formula (I), or any of its embodiments, to a patient in need thereof.

[0126] In yet another embodiment, the foregoing provides a method for treating a disease or disorder related to the activity of the KRAS protein having a G12C mutation, the method comprising administering a therapeutically effective amount of a compound of formula (I), or any of its embodiments, to a patient in need thereof.

[0127] In yet another embodiment, the foregoing provides a method for treating a disease or disorder related to the activity of the KRAS protein having a G12D mutation, the method comprising administering a therapeutically effective amount of a compound of formula (I), or any of its embodiments, to a patient in need thereof.

[0128] In another embodiment, the foregoing provides a method for treating a disease or disorder related to the activity of the KRAS protein having a G12V mutation, the method comprising administering a therapeutically effective amount of a compound of formula (I), or any of its embodiments, to a patient in need thereof.

[0129] In another embodiment, also provided herein are methods for carrying out treatment in a patient who requires treatment for cancer, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), or any of the embodiments thereof.

[0130] In yet another embodiment, also provided herein are methods for carrying out treatment in a patient who requires treatment for cancer, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), or any of its embodiments, wherein the cancer is characterized by interaction with a KRAS protein having a G12C mutation.

[0131] In yet another embodiment, also provided herein are methods for carrying out treatment in a patient who requires treatment for cancer, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), or any of its embodiments, wherein the cancer is characterized by interaction with the KRAS protein having a G12D mutation.

[0132] In another embodiment, also provided herein are methods for carrying out treatment in a patient who requires treatment for cancer, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), or any of its embodiments, wherein the cancer is characterized by interaction with the KRAS protein having a G12V mutation.

[0133] In yet another embodiment, the foregoing provides a method for treating cancer in a patient, the method comprising administering to the patient a therapeutically effective amount of any one of the compounds disclosed herein or a pharmaceutically acceptable salt thereof.

[0134] In another embodiment, provided herein is a method for treating cancer in a patient, comprising: identifying that the patient is in need of cancer treatment and that the abnormally proliferating cancer cells contain a KRAS having a G12C mutation; and administering to the patient a therapeutically effective amount of any one of the compounds disclosed herein or a pharmaceutically acceptable salt thereof.

[0135] In another embodiment, provided herein is a method for treating cancer in a patient, comprising: identifying that the patient is in need of cancer treatment and that the abnormally proliferating cancer cells contain a KRAS having a G12D mutation; and administering to the patient a therapeutically effective amount of any one of the compounds disclosed herein or a pharmaceutically acceptable salt thereof.

[0136] In another embodiment, the foregoing provides a method for treating cancer in a patient, comprising: identifying that the patient is in need of cancer treatment and that the abnormally proliferating cancer cells contain a KRAS having a G12V mutation; and administering to the patient a therapeutically effective amount of any one of the compounds disclosed herein or a pharmaceutically acceptable salt thereof.

[0137] In one embodiment, the cancer is selected from carcinomas, hematological cancers, sarcomas, and glioblastomas. In another embodiment, hematological cancers are selected from myeloproliferative disorders, myelodysplastic syndromes, chronic and juvenile myelomonocytic leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, and multiple myeloma. In yet another embodiment, the carcinoma is selected from carcinomas of the pancreas, colorectal, lung, bladder, stomach, esophagus, breast, head and neck, cervix, skin, and thyroid. In yet another embodiment, the cancer is colorectal cancer, pancreatic cancer, or lung cancer. In yet another embodiment, pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). In yet another embodiment, the cancer is non-small cell lung cancer (NSCLC).

[0138] In one embodiment, the cancer is metastatic.

[0139] In one embodiment, the foregoing provides a method for treating a patient who requires treatment for a disease or disorder related to the inhibition of KRAS interaction or mutation thereof, comprising the step of administering to the patient, in combination with another therapy or therapeutic agent described herein, a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0140] In one embodiment, the foregoing provides a method for treating a patient who requires treatment for a disease or disorder related to the activity of KRAS interaction or mutation thereof, comprising the step of administering to the patient, in combination with another therapy or therapeutic agent described herein, a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0141] In one embodiment, the cancer is selected from blood cancers, sarcomas, lung cancers, gastrointestinal cancers, urogenital cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.

[0142] In another embodiment, lung cancer is selected from non-small cell lung cancer (NSCLC), small cell lung cancer, bronchogenic carcinoma, squamous cell bronchogenic carcinoma, undifferentiated small cell bronchogenic carcinoma, undifferentiated large cell bronchogenic carcinoma, adenocarcinoma, bronchogenic carcinoma, alveolar carcinoma, bronchial carcinoma, bronchial adenoma, chondromatous hamartoma, mesothelioma, small cell (pavicellular) and non-small cell (non-pavicellular) carcinoma, bronchial adenoma, and pleuroblastoma.

[0143] In yet another embodiment, the lung cancer is non-small cell lung cancer (NSCLC). In yet another embodiment, the lung cancer is adenocarcinoma.

[0144] In one embodiment, gastrointestinal cancers are selected from esophageal squamous cell carcinoma, esophageal adenocarcinoma, esophageal leiomyosarcoma, esophageal lymphoma, gastric cancer, gastric lymphoma, gastric leiomyosarcoma, exocrine pancreatic cancer, pancreatic ductal adenocarcinoma, pancreatic insulinoma, pancreatic glucagonoma, pancreatic gastrinoma, pancreatic carcinoid tumor, pancreatic vipoma, small intestinal adenocarcinoma, small intestinal lymphoma, small intestinal carcinoid tumor, Kaposi's sarcoma, small intestinal leiomyoma, small intestinal hemangioma, small intestinal lipoma, small intestinal neurofibroma, small intestinal fibroma, colorectal adenocarcinoma, large intestinal ductal adenoma, large intestinal villous adenoma, large intestinal hamartoma, large intestinal leiomyoma, colorectal cancer, gallbladder cancer, and anal cancer.

[0145] In one embodiment, the gastrointestinal cancer is colorectal cancer.

[0146] In another embodiment, cancer is a carcinoma. In yet another embodiment, the carcinoma is selected from pancreatic carcinoma, colorectal carcinoma, lung carcinoma, bladder carcinoma, stomach carcinoma, esophageal carcinoma, breast carcinoma, head and neck carcinoma, cervical carcinoma, skin carcinoma, and thyroid carcinoma.

[0147] In yet another embodiment, the cancer is a hematopoietic malignancy. In one embodiment, the hematopoietic malignancy is selected from multiple myeloma, acute myeloid leukemia, and myeloproliferative disorders.

[0148] In another embodiment, cancer is a neoplasm. In yet another embodiment, the neoplasm is a glioblastoma or sarcoma.

[0149] In certain embodiments, the present disclosure provides a method for carrying out treatment in a patient requiring treatment for a KRAS-mediated disorder, comprising the step of administering a compound according to the present invention, or a pharmaceutically acceptable composition thereof, to the patient.

[0150] In some embodiments, the diseases and indications treatable with the compounds of this disclosure include, but are not limited to, hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, urogenital cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.

[0151] Exemplary blood cancers include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin lymphoma (including relapsed or refractory NHL and relapsed follicular lymphoma), Hodgkin lymphoma, and myeloproliferative disorders (e.g., primary myeloglycytosis). This includes lymphomas and leukemias such as vascular fibrosis (PMF), polycythemia eugenics (PV), essential thrombocythemia (ET), 8p11 myeloproliferative syndrome, myelodysplastic syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-cell lymphoma, adult T-cell leukemia, Waldenström macrobuloidemia, hairy cell lymphoma, marginal zone lymphoma, chronic myeloid lymphoma, and Burkitt lymphoma.

[0152] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyosarcoma, rhabdomyosarcoma, fibroma, lipoma, hamartoma, lymphosarcoma, leiomyosarcoma, and teratoma.

[0153] Examples of lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer, bronchogenic carcinoma (squamous cell, anaplastic small cell, anaplastic large cell, adenocarcinoma), alveolar (bronchial) carcinoma, bronchial adenoma, chondrolytic hamartoma, mesothelioma, small cell (pavicellular) and non-small cell (non-pavicellular) carcinoma, bronchial adenoma, and pleuroblastoma.

[0154] Examples of similar gastrointestinal cancers include cancers of the esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (exocrine pancreatic carcinoma, tubular adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, leiomyoma), colorectal cancer, gallbladder cancer, and anal cancer.

[0155] Exemplary urogenital cancers include cancers of the kidney (adenocarcinoma, Wilms' tumor [nephroblastoma], renal cell carcinoma), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testes (seminocarcinoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma), and urothelial carcinoma.

[0156] Exemplary liver cancers include hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0157] Examples of bone cancers include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondrial exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor.

[0158] Exemplary neurological cancers include cancers of the skull (osteoma, hemangioma, granuloma, xanthomas, degenerative osteitis), meninges (meningioma, meningiosarcoma, gliomas), brain (astrocytoma, meduoblastoma, glioma, ependymoma, germ cell tumor (pineal gland tumor), glioblastoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, neuroectodermal tumors), and spinal cord (neurofibroma, meningioma, glioma, non-epithelial malignant tumors), neuroblastoma, Lhermitte-Dacross disease, and pineal gland tumors.

[0159] Exemplary gynecological cancers include cancers of the breast (ductal carcinoma, lobular carcinoma, mammary sarcoma, triple-negative breast cancer, HER2-positive breast cancer, inflammatory breast cancer, papillary carcinoma), uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiable carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, staphylosarcoma (embryonic rhabdomyosarcoma)), and fallopian tubes (epithelial malignant tumors).

[0160] Examples of skin cancers include melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell carcinoma, moles, lipomas, hemangiomas, dermatofibromas, and keloids.

[0161] Exemplary head and neck cancers include glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinoma, adenocarcinoma, oral cancer, laryngeal cancer, nasopharyngeal cancer, nasal cavity cancer and sinus cancer, thyroid cancer and parathyroid cancer, tumors of the eye, tumors of the lips and mouth, and squamous cell carcinoma of the head and neck.

[0162] The compounds of this disclosure may also be useful in inhibiting tumor metastasis.

[0163] In addition to carcinogenic tumors, the compounds of the present invention are useful in treating skeletal and chondrocyte disorders, including, but not limited to, achondroplasia, hypochondrosis, dwarfism, fatal dysplasia of bone (TD) (clinical forms TD I and TD II), Apert syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Behle-Stevenson gyroscal syndrome, Pfeiffer syndrome, and craniosynostosis. In some embodiments, the present disclosure provides methods for treating patients suffering from skeletal and chondrocyte disorders.

[0164] In some embodiments, the compounds described herein can be used to treat Alzheimer's disease, HIV, or tuberculosis.

[0165] The term "8p11 myeloproliferative syndrome" refers to a myeloid / lymphoid neoplasm associated with eosinophilia and FGFR1 abnormalities.

[0166] The term "cell" refers to in vitro, ex vivo, or in vivo cells. In some embodiments, ex vivo cells may be part of a tissue sample excised from an organism such as a mammal. In some embodiments, in vitro cells may be cells in a cell culture. In some embodiments, in vivo cells are cells residing in an organism such as a mammal.

[0167] The term "contact" refers to bringing together the indicated parts in an in vitro or in vivo system. For example, "contacting" KRAS with the compounds described herein includes administering the compounds described herein to an individual or patient, such as a human, having KRAS, and introducing the compounds described herein into a sample, for example, a cell preparation or purified preparation containing KRAS.

[0168] The terms “individual,” “subject,” or “patient” are used interchangeably and refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, and most preferably humans.

[0169] The term "therapeutic effective dose" refers to the amount of an active compound or pharmaceutical agent, such as any of the solid forms or salts thereof disclosed herein, that elicits a biological or pharmacokinetic response in a tissue, system, animal, individual, or human, as sought by researchers, veterinarians, physicians, or other clinicians. The appropriate "effective" dose in any individual case can be determined using techniques known to those skilled in the art.

[0170] The phrase “pharmaceutically acceptable carrier or excipient” refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. Excipients or carriers include those that are generally safe and non-toxic, not biologically or otherwise undesirable, and are acceptable for veterinary and human pharmaceutical applications. In one embodiment, each component is “pharmaceutically acceptable” as defined herein. For example, P. Beringer, et al., (Eds.), Remington: The Science and Practice of Pharmacy, 21 st Ed.; (Lippincott Williams & Wilkins: Philadelphia, Pa., 2005), A. Adejare (Ed.), Remington, The Science and Practice of Pharmacy, 23 rd Ed.,(Elsevier,2020), RCRowe et al.,Eds.,Handbook of Pharmaceutical Excipients,6 th Ed.; (Pharmaceutical Press, 2009), PJ Shesky et al., Eds., Handbook of Pharmaceutical Excipients, 9 th Ed.;(The Pharmaceutical Press,2020), M.Ash,et al.,(Eds.),Handbook of Pharmaceutical Additives,3 rd Ed.; (Gower Publishing Company: 2007), and M. Gibson (Ed.), Pharmaceutical Preformulation and Formulation, 2 nd See Ed. (CRC Press LLC, 2009).

[0171] The terms “to treat” or “to treat” mean to inhibit a disease, for example, inhibiting a disease, condition, or disorder in an individual who is experiencing or exhibiting the pathology or total symptoms of a disease, condition, or disorder (i.e., stopping the further development of the pathology and / or total symptoms), or to improve a disease, for example, improving a disease, condition, or disorder in an individual who is experiencing or exhibiting the pathology or total symptoms of a disease, condition, or disorder (i.e., reversing the pathology and / or total symptoms), for example, reducing the severity of the disease.

[0172] The terms “prevent,” “prevention,” or “prevention” include the prevention of at least one symptom associated with or caused by the condition, disease, or disorder being prevented.

[0173] III. Combination Therapy Compounds of the present disclosure, including the compound of formula (I) or any of its embodiments, may be therapeutically useful when used in combination with one or more additional pharmaceutical agents, as described in more detail below.

[0174] a. Cancer therapy Compounds of the present invention, comprising the compound of formula (I) or any of its embodiments, may be useful in the treatment of cancer when used in combination with one or more additional pharmaceutical agents, as described in more detail below.

[0175] Cancer cell growth and survival can be affected by dysfunction of multiple signaling pathways. Therefore, combining different enzyme / protein / receptor inhibitors that exhibit different preferences at targets that modulate their activity is useful for treating such conditions. Targeting two or more signaling pathways (or two or more biological molecules involved in a given signaling pathway) can reduce the potential for drug resistance to develop in a cell population and / or reduce the toxicity of treatment.

[0176] For example, one or more additional pharmaceutical agents such as chemotherapeutic agents, anti-inflammatory agents, steroids, immunosuppressants, immuno-oncological agents, metabolic enzyme inhibitors, chemokine receptor inhibitors, and phosphatase inhibitors, as well as targeted therapies such as CDK4 / 6 kinase inhibitors, such as Bcr-Abl, Flt-3, EGFR, HER2, JAK, c-MET, VEGFR, PDGFR, c-Kit, IGF-1R, RAF, FAK, and those described in, for example, WO2006 / 056399, may be used in combination with the compounds of the Disclosure for the treatment of KRAS-related diseases, disorders, or conditions. Other agents, such as therapeutic antibodies, may be used in combination with the compounds of the Disclosure for the treatment of KRAS-related diseases, disorders, or conditions. One or more additional pharmaceutical agents may be administered to the patient simultaneously or sequentially.

[0177] In some embodiments, KRAS inhibitors are administered or used in combination with BCL2 inhibitors or CDK4 / 6 inhibitors.

[0178] The compounds disclosed herein can be used in combination with one or more other enzyme / protein / receptor inhibitor therapies for the treatment of diseases such as cancer and other diseases or disorders described herein. Examples of diseases and indications treatable with combination therapy are listed herein. Examples of cancer include solid tumors and non-solid tumors such as liquid tumors and hematological malignancies. Examples of infections include viral infections, bacterial infections, fungal infections, or parasitic infections. For example, the compounds disclosed herein can be used in combination with one or more inhibitors of the following kinases for the treatment of cancer: Akt1, Akt2, Akt3, BCL2, CDK4 / 6, TGF-βR, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IDH2, IGF-1R, IR-R, PDGFαR, PDGFβR, PI3K (alpha, beta, gamma, delta, and multiple or selective) ), CSF1R, KIT, FLK-II, KDR / FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, PARP, Ron, Sea, TRKA, TRKB, TRKC, TAM kinase (Axl, Mer, Tyro3), FLT3, VEGFR / Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK, and B-Raf. In some embodiments, the compounds of the present disclosure can be combined with one or more of the following inhibitors for the treatment of cancer or infection. Non-limiting examples of inhibitors that can be combined with the compounds of this disclosure for the treatment of cancer and infectious diseases include FGFR inhibitors (FGFR1, FGFR2, FGFR3, or FGFR4, e.g., pemigatinib (INCB54828), INCB62079), EGFR inhibitors (also known as ErB-1 or HER-1, e.g., erlotinib, gefitinib, vandetanib, osimertinib, cetuximab, nesitumumab, or panitumumab), VEGFR inhibitors or pathway blockers (e.g., bevacizumab, pazopanib, sunitinib, sorafenib,Axitinib, regorafenib, ponatinib, cabozantinib, vandetanib, ramucirumab, lenvatinib, ziv-aflibercept), PARP inhibitors (e.g., olaparib, rucaparib, veliparib, or niraparib), JAK inhibitors (JAK1 and / or JAK2, e.g., ruxolitinib or baricitinib; or JAK1, e.g., itacitinib (INCB39110), INCB052793, or INCB054707), IDO inhibitors (e.g., epacadostat, NLG919, or BMS-986205, MK7162), LSD1 inhibitors (e.g., GSK2979552, INCB59872 and INCB60003), TDO inhibitors, PI3K-delta inhibitors (e.g., pulsacrisib (INCB50465) or INCB50797), PI3K-gamma inhibitors such as PI3K-gamma selective inhibitors, Pim Examples include inhibitors (e.g., INCB53914), CSF1R inhibitors, TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer, e.g., INCB081776), adenosine receptor antagonists (e.g., A2a / A2b receptor antagonists), HPK1 inhibitors, chemokine receptor inhibitors (e.g., CCR2 or CCR5 inhibitors), SHP1 / 2 phosphatase inhibitors, histone deacetylase inhibitors (HDACs) such as HDAC8 inhibitors, angiogenesis inhibitors, interleukin receptor inhibitors, bromo and extra-terminal family member inhibitors (e.g., bromodomain inhibitors or BET inhibitors, e.g., INCB54329 and INCB57643), c-MET inhibitors (e.g., capmatinib), anti-CD19 antibodies (e.g., tafacitamab), ALK2 inhibitors (e.g., dilurgycertive), or combinations thereof.

[0179] In some embodiments, the compounds or salts described herein are administered together with a PI3Kδ inhibitor. In some embodiments, the compounds or salts described herein are administered together with a JAK inhibitor. In some embodiments, the compounds or salts described herein are administered together with a JAK1 or JAK2 inhibitor (e.g., baricitinib or ruxolitinib). In some embodiments, the compounds or salts described herein are administered together with a JAK1 inhibitor. In some embodiments, the compounds or salts described herein are administered together with a JAK1 inhibitor that is more selective to JAK2 than to JAK2.

[0180] Examples of antibodies for use in combination therapy include, but are not limited to, antibodies against trastuzumab (e.g., anti-HER2), ranibizumab (e.g., anti-VEGF-A), bevacizumab (Avastin®, e.g., anti-VEGF), panitumumab (e.g., anti-EGFR), cetuximab (e.g., anti-EGFR), rituxan (e.g., anti-CD20), and c-MET.

[0181] One or more of the following drugs may be used in combination with the compounds of this disclosure, and are presented as a non-limiting list: cell division inhibitors, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptosal, topotecan, paclitaxel, docetaxel, epotilon, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, SCH66336, R115777, L778,123, BMS214662, IRESSA® (gefitinib), TARCEVA® (erlotinib), antibodies against EGFR, intron, ara-C, adriamycin, cytoxane, gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipobrutin Man, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN (trademark) (oxaliplatin), pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitramycin, deoxycoformycin, mitomycin C, L-asparaginase, teniposide 17.alpha.- Ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testactone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianicene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremifene, goserelin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, navelbine, anastrozole, letrazole, capecitabine, reloxafine, droloxafine, hexamethylmelamine, avastin, HERCEPTIN (trademark) (trastuzumab) BEXXAR (trademark) (tositumomab), VELCADE (trademark) (bortezomib), ZEVALIN (trademark) (ibritumomab tiuxetan), TRISENOX (trademark) (arsenic trioxide), XELODA (trademark) (capecitabine), vinorelbine, porfimer, ERBITUX (trademark) (cetuximab), thiotepa, altretamine, melphalan, trastuzumab, lerozole, fulvestura This includes ant, exemestane, ifosfomide, rituximab, C225 (cetuximab), Campus (alemtuzumab), clofarabine, cladribine, aphidicolon, rituxan, sunitinib, dasatinib, tezacitabine, Sml1, fludarabine, pentostatin, triapin, zidox, trimidox, amidox, 3-AP, and MDL-101,731.

[0182] The compounds of this disclosure can be further used in combination with other methods of treating cancer, such as chemotherapy, radiotherapy, tumor-targeted therapy, adjuvant therapy, immunotherapy, or surgery. Examples of immunotherapies include cytokine therapy (e.g., interferon, GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccines, monoclonal antibodies, bispecific or multispecific antibodies, antibody-drug conjugates, adoptive T cell transfer, Toll receptor agonists, RIG-I agonists, oncolytic virus therapy, and immunomodulatory small molecules including thalidomide or JAK1 / 2 inhibitors, PI3Kδ inhibitors, etc. The compounds can be administered in combination with one or more anticancer agents, such as chemotherapeutic agents. Examples of chemotherapy agents include avalerix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib, bleomycin, bortezomib, intravenous busulfan, oral busulfan, carsterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin difutitox, dexylazoxane, docetaxel, doxorubicin, and dromostanolone propione. Eculizumab, Epirubicin, Erlotinib, Estramustine, Etoposide phosphate, Etoposide, Exemestane, Fentanyl citrate, Filgrastim, Floroxyuridine, Fludarabine, Fluorouracil, Fulvestrant, Gefitinib, Gemcitabine, Gemtuzumab ozogamicin, Goserelin acetate, Histrelin acetate, Ibritumomab tiuxetan, Idarubicin, Ifosfamide, Imatinib mesylate, Interferon alpha-2a, Irinotecan, Lapatinib ditosylate, Lenalidomide, Letrozole, Leucovorin, Leuprolide acetate, Levamizole, Lomustine, Mechloretamine, Megestrol acetate, Melphalan, Mercaptopurine, Methotrexate, Methoxsalen, Mitomycin C,Mitotane, Mitoxantrone, Nandrolonefenpropionate, Nelarabine, Nofetumomab, Oxaliplatin, Paclitaxel, Pamidronate, Panitumumab, Pegaspargase, Pegfilgrastim, Pemetrexed disodium, Pentostatin, Pipobroman, Plicamycin, Procarbazine, Quinacrine, Rasburicase, Rituximab, Ruxolitinib, Sorafenib, Stre Examples include any of the following: putozosin, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide, testactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tocitumomab, trastuzumab, tretinoin, uracil mustard, barrubicin, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronate.

[0183] Examples of additional chemotherapeutic agents include proteasome inhibitors (e.g., bortezomib), thalidomide, revlimide, and DNA damage agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, and carmustine.

[0184] Examples of steroids include corticosteroids such as dexamethasone or prednisone.

[0185] Examples of Bcr-Abl inhibitors include imatinib mesylate (GLEEVAC®), nilotinib, dasatinib, bosutinib, and ponatinib, as well as pharmaceutically acceptable salts. Other examples of suitable Bcr-Abl inhibitors include compounds of the genera and species disclosed in U.S. Patent No. 5,521,184, WO04 / 005281, and U.S. Patent No. 7,745,437, as well as their pharmaceutically acceptable salts.

[0186] Examples of suitable Flt-3 inhibitors include midostaurin, restaurtinib, linifanib, sunitinib, sunitinib maleate, sorafenib, quizartinib, clenolanib, pacritinib, tandutinib, PLX3397 and ASP2215, and their pharmaceutically acceptable salts. Other examples of suitable Flt-3 inhibitors include compounds such as those disclosed in WO03 / 037347, WO03 / 099771 and WO04 / 046120, and their pharmaceutically acceptable salts.

[0187] Examples of suitable RAF inhibitors include dabrafenib, sorafenib, and vemurafenib, as well as their pharmaceutically acceptable salts. Other examples of suitable RAF inhibitors include compounds such as those disclosed in WO00 / 09495 and WO05 / 028444, as well as their pharmaceutically acceptable salts.

[0188] Examples of suitable FAK inhibitors include VS-4718, VS-5095, VS-6062, VS-6063, BI853520, and GSK2256098, as well as their pharmaceutically acceptable salts. Other examples of suitable FAK inhibitors include compounds such as those disclosed in WO04 / 080980, WO04 / 056786, WO03 / 024967, WO01 / 064655, WO00 / 053595, and WO01 / 014402, as well as their pharmaceutically acceptable salts.

[0189] Examples of suitable CDK4 / 6 inhibitors include palbociclib, ribociclib, trilaciclib, rerocyclib, and abemaciclib, as well as pharmaceutically acceptable salts thereof. Other examples of suitable CDK4 / 6 inhibitors include compounds such as those disclosed in WO09 / 085185, WO12 / 129344, WO11 / 101409, WO03 / 062236, WO10 / 075074, and WO12 / 061156, as well as pharmaceutically acceptable salts thereof.

[0190] In some embodiments, the compounds of the present disclosure can be used in combination with one or more other kinase inhibitors, including imatinib, particularly to treat patients resistant to imatinib or other kinase inhibitors.

[0191] In some embodiments, the compounds of this disclosure can be used in combination with chemotherapeutic agents in the treatment of cancer, and may improve the therapeutic response compared to the response of the chemotherapeutic agent alone, without exacerbating its toxic effects. In some embodiments, the compounds of this disclosure can be used in combination with chemotherapeutic agents provided herein. For example, additional pharmaceutical agents used in the treatment of multiple myeloma may include, but are not limited to, melphalan, melphalan + prednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib). Further additional agents used in the treatment of multiple myeloma include Bcr-Abl, Flt-3, RAF, and FAK kinase inhibitors. In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulator. Examples of alkylating agents include cyclophosphamide (CY), melphalan (MEL), and bendamustine. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulator is lenalidomide (LEN) or pomalidomide (POM). Additive or synergistic effects are desirable outcomes of combining the CDK2 inhibitors of this disclosure with additional agents.

[0192] The drugs can be combined with this compound in a single or sequential dosage form, or the drugs can be administered simultaneously or sequentially in separate dosage forms.

[0193] The compounds of this disclosure may be used in combination with one or more other inhibitors or one or more therapies for the treatment of infections. Examples of infections include viral infections, bacterial infections, fungal infections, or parasitic infections.

[0194] In some embodiments, a corticosteroid such as dexamethasone is administered to the patient in combination with the compounds of the present disclosure, and the dexamethasone is administered intermittently rather than continuously.

[0195] Compounds of formula (I) described herein or any of their embodiments, compounds described herein as described in any of the claims, or salts thereof may be combined with other immunogenic agents such as cancer cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immunostimulatory cytokines. Non-limiting examples of tumor vaccines that can be used include melanoma antigen peptides, such as gp100, MAGE antigen, Trp-2, MARTI, and / or tyrosinase peptides, or tumor cells transfected to express the cytokine GM-CSF.

[0196] Compounds of formula (I) described herein or any of their embodiments, compounds described herein as described in any of the claims, or salts thereof can be used in combination with vaccination protocols for the treatment of cancer. In some embodiments, tumor cells are transduced to express GM-CSF. In some embodiments, tumor vaccines include proteins derived from viruses involved in human cancer, such as human papillomavirus (HPV), hepatitis viruses (HBV and HCV), and Kaposi's herpes sarcoma virus (KHSV). In some embodiments, the compounds of the Disclosure can be used in combination with tumor-specific antigens, such as heat shock proteins isolated from tumor tissue itself. In some embodiments, compounds of formula (I) or any of the formulas described herein, compounds described herein as described in any of the claims, or salts thereof can be combined with dendritic cell immunity to activate a potent antitumor response.

[0197] The compounds of this disclosure can be used in combination with bispecific macrocyclic peptides that target Fe-alpha or Fe-gamma receptor-expressing effector cells to tumor cells. The compounds of this disclosure can also be used in combination with macrocyclic peptides that activate the host immune response.

[0198] In some further embodiments, the compounds of the present disclosure can be administered to a patient in combination with other therapeutic agents before, during, and / or after bone marrow transplantation or stem cell transplantation. The compounds of the present disclosure can be used in combination with bone marrow transplantation for the treatment of various hematopoietic tumors.

[0199] Compounds of formula (I) or any of the formulas described herein, or compounds described in any of the claims and described herein, or salts thereof, can be used in combination with a vaccine to stimulate an immune response to pathogens, toxins, and autoantigens. Examples of pathogens for which this therapeutic approach may be particularly useful include pathogens for which there are currently no effective vaccines, or pathogens for which conventional vaccines are not entirely effective. These include, but are not limited to, HIV, hepatitis (types A, B, and C), influenza, herpes, giardia, malaria, leishmania, Staphylococcus aureus, and Pseudomonas Aeruginosa.

[0200] Viruses that cause infections treatable by the methods of this disclosure include, but are not limited to, human papillomavirus, influenza, hepatitis A, B, C, or D viruses, adenovirus, poxvirus, herpes simplex virus, human cytomegalovirus, severe acute respiratory syndrome virus, Ebola virus, measles virus, herpesvirus (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein-Barr virus), flavivirus, echovirus, rhinovirus, coxsackievirus, cornovirus, respiratory syncytial virus, Mampus virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, infectious viruses, poliovirus, rabies virus, JC virus, and arboviral encephalitis virus.

[0201] Pathogenic bacteria that cause infections treatable by the methods of this disclosure include, but are not limited to, Chlamydia, Rickettsial bacteria, Mycobacteria, Staphylococci, Streptococci, Pneumococci, Meningococci and Conococci, Klebsiella, Proteus, Serratia, Pseudomonas, Legionella, Diphtheria, Salmonella, Bacilli, Cholera, Tetanus, Botulism, Anthrax, Plague, Leptospirosis, and Lyme disease bacteria.

[0202] Pathogenic fungi that cause infections treatable by the methods of this disclosure include, but are not limited to, Candida (albicans, krusei, glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, rhizophus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis, and Histoplasma capsulatum.

[0203] Pathogenic parasites that cause infections treatable by the methods of this disclosure include, but are not limited to, Entamoeba histolytica, Balantidium coli, Naegleria fowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, and Nippostrongylus brasiliensis.

[0204] When two or more pharmaceutical agents are administered to a patient, they may be administered simultaneously, separately, sequentially, or in combination (for example, three or more agents).

[0205] Methods for safely and effectively administering most of these chemotherapeutic agents are known to those skilled in the art. Furthermore, their administration is described in standard literature. For example, the administration of many chemotherapeutic agents is described in the "Physicians' Desk Reference" (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), and its disclosure is incorporated herein by reference as if it were described in its entirety.

[0206] b. Immune checkpoint therapy The compounds of this disclosure can be used in combination with one or more immune checkpoint inhibitors for the treatment of diseases such as cancer or infectious diseases. Exemplary immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CBL-B, CD20, CD28, CD40, CD70, CD122, CD96, CD73, CD47, CDK2, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, HPK1, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, TLR (TLR7 / 8), TIGIT, CD112R, VISTA, PD-1, PD-L1, and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulating checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR, and CD137. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, TIGIT, and VISTA. In some embodiments, the compounds provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors, and TGFR beta inhibitors.

[0207] In some embodiments, the compounds provided herein can be used in combination with one or more agonists of immune checkpoint molecules, such as OX40, CD27, GITR, and CD137 (also known as 4-1BB).

[0208] In some embodiments, the inhibitor of the immune checkpoint molecule is an anti-PD1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

[0209] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-1 or PD-L1, for example, an anti-PD-1 or anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-1 or anti-PD-L1 antibody is nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, semiprimab, atezolizumab, avelumab, tislerizumab, spartalizumab (PDR001), cetrelimab (JNJ-63723283), tripalimab (JS001), camrelizumab (SHR-1210), cintilimab (IBI308), AB122 (GLS-010), AMP-224, AMP-514 / MEDI- These are 0680, BMS936559, JTX-4014, BGB-108, SHR-1210, MEDI4736, FAZ053, BCD-100, KN035, CS1001, BAT1306, LZM009, AK105, HLX10, SHR-1316, CBT-502(TQB2450), A167(KL-A167), STI-A101(ZKAB001), CK-301, BGB-A333, MSB-2311, HLX20, TSR-042, or LY3300054.In some embodiments, inhibitors of PD-1 or PD-L1 are referred to in U.S. Patent Nos. 7,488,802, 7,943,743, 8,008,449, 8,168,757, 8,217,149, or 10,308,644, U.S. Publication Nos. 2017 / 0145025, 2017 / 0174671, and 2017 / 0174679. Same No. 2017 / 0320875, No. 2017 / 0342060, No. 2017 / 0362253, No. 2018 / 0016260, No. 2018 / 0057486, No. 2 018 / 0177784, 2018 / 0177870, 2018 / 0179179, 2018 / 0179201, 2018 / 0179202, 2018 / Nos. 0273519, 2019 / 0040082, 2019 / 0062345, 2019 / 0071439, 2019 / 0127467, 2019 / 0144439, 2019 / 0202824, 2019 / 0225601, 2019 / 0300524, or 2019 / 0345170, or PCT Publication No. W These are disclosed in O03042402, WO2008156712, WO2010089411, WO2010036959, WO2011066342, WO2011159877, WO2011082400, or WO2011161699, each of which is incorporated herein by reference in its entirety. In some embodiments, the PD-L1 inhibitor is INCB086550.

[0210] In some embodiments, the PD-L1 inhibitor is selected from the compounds in Table A or their pharmaceutically acceptable salts. [Table 3-1] [Table 3-2] Table 3-3 Table 3-4 Table 3-5 Table 3-6 Table 3-7 Table 3-8 Table 3-9 Table 3-10

[0211] In some embodiments, the antibody is an anti-PD-1 antibody, such as an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab, semiprimab, spartalizumab, camrelizumab, cetrelimab, tripalimab, scintirimab, AB122, AMP-224, JTX-4014, BGB-108, BCD-100, BAT1306, LZM009, AK105, HLX10, or TSR-042. In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab, semiprimab, spartalizumab, camrelizumab, cetrelimab, tripalimab, or scintirimab. In some embodiments, the anti-PD-1 antibody is pembrolizumab. In some embodiments, the anti-PD-1 antibody is nivolumab. In some embodiments, the anti-PD-1 antibody is semiprimab. In some embodiments, the anti-PD-1 antibody is spartalizumab. In some embodiments, the anti-PD-1 antibody is camrelizumab. In some embodiments, the anti-PD-1 antibody is cetrelimab. In some embodiments, the anti-PD-1 antibody is tripalimab. In some embodiments, the anti-PD-1 antibody is cintilimab. In some embodiments, the anti-PD-1 antibody is AB122. In some embodiments, the anti-PD-1 antibody is AMP-224. In some embodiments, the anti-PD-1 antibody is JTX-4014. In some embodiments, the anti-PD-1 antibody is BGB-108. In some embodiments, the anti-PD-1 antibody is BCD-100. In some embodiments, the anti-PD-1 antibody is BAT1306. In some embodiments, the anti-PD-1 antibody is LZM009. In some embodiments, the anti-PD-1 antibody is AK105. In some embodiments, the anti-PD-1 antibody is HLX10. In some embodiments, the anti-PD-1 antibody is TSR-042. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD-1 monoclonal antibody is MGA012 (INCMGA0012, retifanlimab). In some embodiments, the anti-PD-1 antibody is SHR-1210.Other anticancer drugs(s) may include antibody therapies such as 4-1BB (e.g., urelumab, utomirumab). In some embodiments, the inhibitor of the immune checkpoint molecule is a PD-L1 inhibitor, such as an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is atezolizumab, avelumab, durvalumab, tislerizumab, BMS-935559, MEDI4736, atezolizumab (also known as MPDL3280A, RG7446), avelumab (MSB0010718C), FAZ053, KN035, CS1001, SHR-1316, CBT-502, A167, STI-A101, CK-301, BGB-A333, MSB-2311, HLX20, or LY3300054. In some embodiments, the anti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, or tislerizumab. In some embodiments, the anti-PD-L1 antibody is atezolizumab. In some embodiments, the anti-PD-L1 antibody is avelumab. In some embodiments, the anti-PD-L1 antibody is durvalumab. In some embodiments, the anti-PD-L1 antibody is tislerizumab. In some embodiments, the anti-PD-L1 antibody is BMS-935559. In some embodiments, the anti-PD-L1 antibody is MEDI4736. In some embodiments, the anti-PD-L1 antibody is FAZ053. In some embodiments, the anti-PD-L1 antibody is KN035. In some embodiments, the anti-PD-L1 antibody is CS1001. In some embodiments, the anti-PD-L1 antibody is SHR-1316. In some embodiments, the anti-PD-L1 antibody is CBT-502. In some embodiments, the anti-PD-L1 antibody is A167. In some embodiments, the anti-PD-L1 antibody is STI-A101. In some embodiments, the anti-PD-L1 antibody is CK-301. In some embodiments, the anti-PD-L1 antibody is BGB-A333. In some embodiments, the anti-PD-L1 antibody is MSB-2311. In some embodiments, the anti-PD-L1 antibody is HLX20. In some embodiments, the anti-PD-L1 antibody is LY3300054.

[0212] In some embodiments, the inhibitor of the immune checkpoint molecule is a small molecule that binds to PD-L1, or a pharmaceutically acceptable salt thereof. In some embodiments, the inhibitor of the immune checkpoint molecule is a small molecule that binds to and internally migrates to PD-L1, or a pharmaceutically acceptable salt thereof. In some embodiments, the inhibitor of the immune checkpoint molecule is a compound selected from those in US2018 / 0179201, US2018 / 0179197, US2018 / 0179179, US2018 / 0179202, US2018 / 0177784, US2018 / 0177870, US2019 / 0300524, and US2019 / 0345170, or a pharmaceutically acceptable salt thereof, each of which is incorporated herein by reference in whole.

[0213] In some embodiments, the inhibitors of immune checkpoint molecules are inhibitors of KIR, TIGIT, LAIR1, CD160, 2B4, and TGFR beta.

[0214] In some embodiments, the inhibitor is MCLA-145.

[0215] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CTLA-4, such as an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab, AGEN1884, or CP-675,206.

[0216] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of LAG3, for example, an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016, LAG525, INCAGN2385, or eftyragimod alfa (IMP321).

[0217] In some embodiments, the inhibitor of the immune checkpoint molecule is a CD73 inhibitor. In some embodiments, the CD73 inhibitor is oleculumab.

[0218] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of TIGIT. In some embodiments, the inhibitor of TIGIT is OMP-31M32.

[0219] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of VISTA. In some embodiments, the inhibitor of VISTA is JNJ-61610588 or CA-170.

[0220] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of B7-H3. In some embodiments, the inhibitor of B7-H3 is enobrituzumab, MGD009, or 8H9.

[0221] In some embodiments, the inhibitor of the immune checkpoint molecule is a KIR inhibitor. In some embodiments, the KIR inhibitor is lirirumab or IPH4102.

[0222] In some embodiments, the inhibitor of the immune checkpoint molecule is an A2aR inhibitor. In some embodiments, the A2aR inhibitor is CPI-444.

[0223] In some embodiments, the inhibitor of the immune checkpoint molecule is a TGF-beta inhibitor. In some embodiments, the TGF-beta inhibitor is travedersen, garcertinib, or M7824.

[0224] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PI3K-gamma. In some embodiments, the inhibitor of PI3K-gamma is IPI-549.

[0225] In some embodiments, the inhibitor of the immune checkpoint molecule is a CD47 inhibitor. In some embodiments, the CD47 inhibitor is Hu5F9-G4 or TTI-621.

[0226] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CD73. In some embodiments, the inhibitor of CD73 is MEDI9447.

[0227] In some embodiments, the inhibitor of the immune checkpoint molecule is a CD70 inhibitor. In some embodiments, the CD70 inhibitor is xatuzumab or BMS-936561.

[0228] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of TIM3, for example, an anti-TIM3 antibody. In some embodiments, the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

[0229] In some embodiments, the inhibitor of the immune checkpoint molecule is a CD20 inhibitor, such as an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is obinutuzumab or rituximab.

[0230] In some embodiments, the agonists of immune checkpoint molecules are agonists of OX40, CD27, CD28, GITR, ICOS, CD40, TLR7 / 8, and CD137 (also known as 4-1BB).

[0231] In some embodiments, the agonist of CD137 is urelumab. In some embodiments, the agonist of CD137 is utomirumab.

[0232] In some embodiments, the agonist of the immune checkpoint molecule is an inhibitor of GITR. In some embodiments, the GITR agonist is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323, MEDI1873, or MEDI6469. In some embodiments, the agonist of the immune checkpoint molecule is an agonist of OX40, such as an OX40 agonist antibody or an OX40L fusion protein. In some embodiments, the anti-OX40 antibody is INCAGN01949, MEDI0562 (tavolimab), MOXR-0916, PF-04518600, GSK3174998, BMS-986178, or 9B12. In some embodiments, the OX40L fusion protein is MEDI6383.

[0233] In some embodiments, the agonist of the immune checkpoint molecule is a CD40 agonist. In some embodiments, the CD40 agonist is CP-870893, ADC-1013, CDX-1140, SEA-CD40, RO7009789, JNJ-64457107, APX-005M, or Chi Lob 7 / 4.

[0234] In some embodiments, the immune checkpoint molecule agonist is an ICOS agonist. In some embodiments, the ICOS agonist is GSK-3359609, JTX-2011, or MEDI-570.

[0235] In some embodiments, the agonist of the immune checkpoint molecule is a CD28 agonist. In some embodiments, the CD28 agonist is ceralizumab.

[0236] In some embodiments, the agonist of the immune checkpoint molecule is a CD27 agonist. In some embodiments, the CD27 agonist is valirumab.

[0237] In some embodiments, the immune checkpoint molecule agonist is a TLR7 / 8 agonist. In some embodiments, the TLR7 / 8 agonist is MEDI9197.

[0238] The compounds of this disclosure can be used in combination with bispecific antibodies. In some embodiments, one of the domains of the bispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3, or the TGFβ receptor. In some embodiments, the bispecific antibody binds to PD-1 and PD-L1. In some embodiments, the bispecific antibody that binds to PD-1 and PD-L1 is MCLA-136. In some embodiments, the bispecific antibody binds to PD-L1 and CTLA-4. In some embodiments, the bispecific antibody that binds to PD-L1 and CTLA-4 is AK104.

[0239] In some embodiments, the compounds of this disclosure can be used in combination with one or more metabolic enzyme inhibitors. In some embodiments, the metabolic enzyme inhibitors are inhibitors of IDO1, TDO, or arginase. Examples of IDO1 inhibitors include epacadostat, NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099, and LY338196. An example of an arginase inhibitor is INCB1158.

[0240] As provided throughout, additional compounds, inhibitors, drugs, etc., can be combined with the compounds of the present invention in single or sequential dosage forms, or they can be administered simultaneously or sequentially in separate dosage forms.

[0241] IV. Formulation, Dosage Form, and Administration When used as a pharmaceutical agent, the compounds of this disclosure may be administered in the form of pharmaceutical compositions. Accordingly, this disclosure provides compositions comprising a compound of formula (I), a compound described in any of the claims and described herein, a pharmaceutically acceptable salt thereof, any of its embodiments, and at least one pharmaceutically acceptable carrier or excipient. These compositions may be prepared in methods well known in the pharmaceutical field and may be administered by various routes depending on whether topical or systemic treatment is indicated and the area to be treated. Administration may be topical (including percutaneous, epidermal, ophthalmic, and mucosal delivery, as well as intranasal, vaginal, and rectal delivery), pulmonary (intratracheal or intranasal, for example, by inhalation or filling of powder or aerosol, including by a nebulizer), oral, or parenteral. Parenteral administration may include intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, or injection or infusion, or intracranial, for example, intrathecal or intraventricular administration. Parenteral administration may be in the form of a single bolus dose, or, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, droplets, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder, or oily bases, thickeners, etc., may be necessary or desirable.

[0242] The present invention also includes pharmaceutical compositions comprising, as an active ingredient, one or more pharmaceutically acceptable carriers or excipients, the compounds of the present disclosure or pharmaceutically acceptable salts thereof. In some embodiments, the compositions are suitable for topical administration. When preparing compositions of the present invention, the active ingredient is typically mixed with an excipient, diluted by the excipient, or encapsulated in such a carrier in the form of, for example, a capsule, sachet, paper, or other container. If the excipient functions as a diluent, it can be a solid, semi-solid, or liquid substance acting as a vehicle, carrier, or medium for the active ingredient. Thus, compositions can be in the form of tablets, pills, powders, licks, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or in a liquid medium), for example, ointments, soft and hard gelatin capsules, suppositories, sterile infusion solutions, and sterile packaged powders containing up to 10% by weight of the active compound.

[0243] When preparing a formulation, the active compound can be ground to an appropriate particle size before being combined with other components. If the active compound is substantially insoluble, it can be ground to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, the particle size can be adjusted by grinding to, for example, about 40 mesh to provide a substantially uniform distribution in the formulation.

[0244] The compounds of the present invention can be ground using known grinding procedures, such as wet grinding, to obtain particle sizes suitable for tablet formation and other formulations. Finely divided (nanoparticle) preparations of the compounds of the present invention can be prepared by processes known in the art; see, for example, WO2002 / 000196.

[0245] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. In addition, formulations may contain lubricants, wetting agents, emulsifiers and suspending agents such as talc, magnesium stearate, and mineral oil, preservatives such as methyl and propyl hydroxybenzoates, sweeteners, and flavorings. Compositions of the present invention can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient using procedures known in the art.

[0246] In some embodiments, the pharmaceutical composition comprises crystalline cellulose silicate (SMCC) and at least one compound described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the crystalline cellulose silicate comprises about 98% microcrystalline cellulose and about 2% silicon dioxide w / w.

[0247] In some embodiments, the composition is a sustained-release composition comprising at least one compound described herein or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient. In some embodiments, the composition comprises at least one compound described herein or a pharmaceutically acceptable salt thereof, and at least one component selected from microcrystalline cellulose, lactose monohydrate, hydroxypropyl methylcellulose, and polyethylene oxide. In some embodiments, the composition comprises at least one compound described herein or a pharmaceutically acceptable salt thereof, and microcrystalline cellulose, lactose monohydrate, and hydroxypropyl methylcellulose. In some embodiments, the composition comprises at least one compound described herein or a pharmaceutically acceptable salt thereof, and microcrystalline cellulose, lactose monohydrate, and polyethylene oxide. In some embodiments, the composition further comprises magnesium stearate or silicon dioxide. In some embodiments, the microcrystalline cellulose is Avicel PH102™. In some embodiments, the lactose monohydrate is Fast-flo 316™. In some embodiments, hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208 K4M (e.g., Methocel K4 M Premier®) and / or hydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel K00LV®). In some embodiments, polyethylene oxide is polyethylene oxide WSR1105 (e.g., Polyox WSR 1105®).

[0248] In some embodiments, a wet granulation process is used to produce the composition. In some embodiments, a dry granulation process is used to produce the composition.

[0249] The composition can be formulated in unit dosage forms, each dose containing approximately 5 to approximately 1,000 mg (1 g) of the active ingredient, more typically approximately 100 mg to approximately 500 mg. In some embodiments, each dose contains approximately 10 mg of the active ingredient. In some embodiments, each dose contains approximately 50 mg of the active ingredient. In some embodiments, each dose contains approximately 25 mg of the active ingredient. The term "unit dosage form" refers to a physically distinct unit suitable as a unit dosage form for human subjects and other mammals, each unit containing a predetermined amount of the active substance calculated to produce a desired therapeutic effect in conjunction with a suitable pharmaceutically acceptable excipient.

[0250] The components used to formulate pharmaceutical compositions are of high purity and substantially free of potentially harmful contaminants (e.g., at least national food grade, generally at least analytical grade, and more typically at least pharmaceutical grade). Particularly for human consumption, compositions are preferably manufactured or formulated under Good Manufacturing Practice (POP) standards as defined by applicable regulations of the U.S. Food and Drug Administration. For example, a suitable formulation may be sterile and / or substantially isotonic and / or fully compliant with all PAP regulations of the U.S. Food and Drug Administration.

[0251] Active compounds can be effective across a wide range of dosages and are generally administered at therapeutically effective doses. However, it should be understood that the actual amount of compound administered is usually determined by the physician, depending on the condition being treated, the chosen route of administration, the actual compound administered, the individual patient's age, weight, and response, the severity of the patient's symptoms, and other relevant circumstances.

[0252] The therapeutic dosage of the compounds of the present invention may vary, for example, according to the specific use in which the treatment is administered, the mode of administration of the compounds, the patient's health and condition, and the judgment of the prescribing physician. The ratio or concentration of the compounds of the present invention in a pharmaceutical composition may vary depending on several factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, when administered parenterally, the compounds of the present invention can be provided in a physiologically buffered aqueous solution containing about 0.1 to about 10% w / v of the compound. Some typical dose ranges are about 1 μg / kg to about 1 g / kg body weight per day. In some embodiments, the dose range is about 0.01 mg / kg to about 100 mg / kg body weight per day. The dosage is likely to depend on variables such as the type and degree of disease or disability progression, the overall health status of the particular patient, the relative biological efficacy of the selected compounds, the formulation of the excipients, and the route of administration. The effective dose can be estimated from dose-response curves derived from in vitro or animal model test systems.

[0253] To prepare solid compositions such as tablets, the main active ingredient is mixed with pharmaceutically acceptable excipients to form a solid preliminary formulation composition containing a homogeneous mixture of the compounds of the present invention. When these preliminary formulation compositions are referred to as homogeneous, the active ingredient is typically uniformly dispersed throughout the composition, and the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. This solid preliminary formulation is then subdivided into the above-mentioned unit dosage forms, for example, containing about 0.1 to about 1000 mg of the active ingredient of the present invention.

[0254] The tablets or pills of the present invention can be coated or otherwise compounded to provide dosage forms that offer the benefit of long-lasting action. For example, the tablets or pills may consist of an inner and outer administration component, the outer administration component being in the form of an envelope over the inner administration component. The two components are separated by an enteric coating, which can resist disintegration in the stomach and allow the inner component to pass through the duodenum intact or delay its release. Various substances can be used for such enteric coatings or coatings, including several polymer acids, as well as mixtures of polymer acids with substances such as shellac, cetyl alcohol, and cellulose acetate.

[0255] Liquid forms into which the compounds and compositions of the present invention can be incorporated for oral or injectable administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0256] Compositions for inhalation or inhalation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, compositions are administered orally or via nasal respiratory routes for topical or systemic effects. Compositions can be sprayed using an inert gas. The sprayed solution may be inhaled directly from a spraying device, or the spraying device may be attached to a face mask, tent, or intermittent positive airway. Compositions in solution, suspension, or powder form may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0257] Topical formulations may include one or more conventional carriers. In some embodiments, an ointment may include water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white petrolatum, etc. The carrier composition of a cream may be based on a combination of water and glycerol and one or more other components, for example, glycerin monostearate, PEG-glycerin monostearate, and cetyl stearyl alcohol. Gels can be formulated using isopropyl alcohol and water, preferably in combination with other components such as glycerol, hydroxyethylcellulose, etc. In some embodiments, a topical formulation may contain at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2, or at least about 5% by weight of the compound of the present invention. Optionally, topical formulations associated with a selected indication, for example, the treatment of psoriasis or other skin conditions, may be preferably packaged in, for example, a 100 g tube.

[0258] The amount of compound or composition administered to a patient varies depending on the substance being administered, the purpose of administration (such as prevention or treatment), the patient's condition, and the mode of administration. For therapeutic purposes, a composition may be administered to a patient already suffering from the disease in an amount sufficient to cure or at least partially halt the symptoms of the disease and its complications. The effective dose depends on the judgment of the attending physician, based on factors such as the disease condition being treated, the severity of the disease, the patient's age, weight, and general condition.

[0259] The compositions administered to patients may be in the form of the pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques or by sterile filtration. Aqueous solutions may be packaged for immediate use, or they may be lyophilized and the lyophilized preparations may be used in combination with a sterile aqueous carrier before administration. The pH of the compound preparations is typically 3 to 11, more preferably 5 to 9, and most preferably 7 to 8. It will be understood that the use of some of the aforementioned excipients, carriers, or stabilizers results in the formation of pharmaceutical salts.

[0260] The therapeutic dosage of the compounds of the present invention may vary, for example, according to the specific use in which the treatment is administered, the mode of administration of the compounds, the patient's health and condition, and the judgment of the prescribing physician. The ratio or concentration of the compounds of the present invention in a pharmaceutical composition may vary depending on several factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, when administered parenterally, the compounds of the present invention can be provided in a physiologically buffered aqueous solution containing about 0.1 to about 10% w / v of the compound. Some typical dose ranges are about 1 μg / kg to about 1 g / kg body weight per day. In some embodiments, the dose range is about 0.01 mg / kg to about 100 mg / kg body weight per day. The dosage is likely to depend on variables such as the type and degree of disease or disability progression, the overall health status of the particular patient, the relative biological efficacy of the selected compounds, the formulation of the excipients, and the route of administration. The effective dose can be estimated from dose-response curves derived from in vitro or animal model test systems.

[0261] V. Labeled Compounds and Assay Methods Another aspect of the present invention relates to labeled compounds (radioactively labeled, fluorescently labeled, etc.) of the present disclosure that would be useful not only for imaging techniques but also for localizing and quantifying KRAS proteins in tissue samples, including human, both in vitro and in vivo, and for identifying KRAS ligands by inhibitory binding of labeled compounds. Substitution of one or more atoms in the compounds of the present disclosure may also be useful for generating differentiated ADMEs (adsorption, distribution, metabolism, and excretion). Accordingly, the present invention includes KRAS binding assays containing such labeled or substituted compounds.

[0262] This disclosure further includes the isotope-labeled compounds of this disclosure. An “isotope” or “radio-labeled” compound is a compound of this disclosure in which one or more atoms are replaced or substituted with atoms having an atomic mass or mass number different from that which is normally found in nature (i.e., naturally occurring). A “radio-labeled” compound may refer to an isotope-labeled compound in which one or more atoms are replaced or substituted with atoms of radioactive isotopes.

[0263] Suitable isotopes that can be incorporated into the compounds disclosed herein include: 2 H (also written as D for deuterium), 3 H (also written as T as tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I, and 131 This includes, but is not limited to, formula (I). For example, one or more hydrogen atoms in the compounds of this disclosure can be replaced by deuterium atoms (e.g., C in formula (I)).1-6 One or more hydrogen atoms in the alkyl group can be optionally substituted with deuterium atoms, such as -CH3 substituted for -CD3. In some embodiments, the alkyl group of formula (I) can be perdeuterated.

[0264] One or more constituent atoms of the compounds presented herein may be replaced or substituted with isotopes of atoms of natural or unnatural abundance. In some embodiments, the compounds contain at least one deuterium atom. In some embodiments, the compounds contain two or more deuterium atoms. In some embodiments, the compounds contain 1-2, 1-3, 1-4, 1-5, or 1-6 deuterium atoms. In some embodiments, all hydrogen atoms in the compound can be replaced, i.e., substituted, with deuterium atoms. For example, one or more hydrogen atoms in the compounds of this disclosure can be replaced with deuterium atoms (e.g., C of formula (I)). 1-6 One or more hydrogen atoms in the alkyl group can be optionally substituted with deuterium atoms, such as -CH3 substituted for -CD3. In some embodiments, the alkyl group of formula (I) can be perdeuterated. The symbol D, whether in the chemical formula or as a substituent, indicates that deuterium is incorporated at the labeled position in excess of its natural abundance, typically in amounts of 50% or more, preferably 90% or more, or 95%, 96%, 97%, 98%, 99%, 99.5%, 99.95%, or 99.99% or more compared to other forms of hydrogen.

[0265] Synthetic methods for incorporating isotopes into organic compounds are known in the art (AF Thomas, Deuterium Labeling in Organic Chemistry, (Appleton-Century-Crofts, New York, NY, 1971), J. Atzrodt, et al., Angew. Chem. Int. Ed., 2007, 7744-65, JRHanson, The Organic Chemistry of Isotopic Labelling, (Royal Society of Chemistry, 2011)). Isotopic-labeled compounds can be used in a variety of studies, including NMR spectroscopy, metabolic experiments, and / or assays.

[0266] Substitution with heavier isotopes, such as deuterium, may result in greater metabolic stability, leading to certain therapeutic benefits such as increased in vivo half-life or reduced dosing requirements, which may be preferable in some situations (see, for example, A. Kerekes, et al., J. Med. Chem. 2011, 54(1), 201-10 and R. Xu et al., J. Label. Compd. Radiopharm. 2015, 58, 308-12). In particular, substitution at one or more metabolic sites may result in one or more therapeutic benefits.

[0267] The radionuclides incorporated into the radiolabeled compound depend on the specific application of that radiolabeled compound. For example, in the case of in vitro adenosine receptor labeling and competitive assays, 3 H, 14 C, 82 Br, 125 I, 131 I, or 35 Compounds incorporating S can be useful. For radioimaging applications, 11 C, 18 F, 125 I, 123 I, 124 I, 131 I, 75 Br, 76 Br, or 77Br can be useful.

[0268] It is understood that a “radioactive label” or “labeled compound” is a compound incorporating at least one radionuclide. In some embodiments, the radionuclide is: 3 H, 14 C, 125 I, 35 S, and 82 Selected from Br.

[0269] This disclosure may further include synthetic methods for incorporating radioisotopes into the compounds of this disclosure. Synthetic methods for incorporating radioisotopes into organic compounds are well known in the art, and those skilled in the art will readily recognize methods applicable to the compounds of this disclosure.

[0270] The labeled compounds of the present invention can be used in screening assays to identify and / or evaluate compounds. For example, a newly synthesized or identified compound labeled (i.e., a test compound) can be evaluated for its ability to bind to the KRAS protein by monitoring its concentration fluctuations upon contact with KRAS through tracking the label. For example, a test compound (labeled) can be evaluated for its ability to reduce the binding of another compound known to bind to the KRAS protein (i.e., a standard compound). Thus, the ability of a test compound to compete with a standard compound for binding to the KRAS protein is directly correlated to its binding affinity. Conversely, in some other screening assays, the standard compound is labeled and the test compound is not. Therefore, to evaluate the competition between the standard compound and the test compound, the concentration of the labeled standard compound is monitored, thereby confirming the relative binding affinity of the test compound.

[0271] VI. Kit The disclosure also includes, for example, pharmaceutical kits useful for the treatment or prevention of diseases or disorders associated with KRAS activity, such as cancer or infectious diseases, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or any of its embodiments. Such kits may further include one or more of a variety of conventional pharmaceutical kit components, such as containers having one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions indicating the amount of components to be administered, guidelines for administration, and / or guidelines for mixing the components may also be included in the kit, either as an insert or a label.

[0272] The present invention will be described in more detail using specific examples. The following examples are provided for illustrative purposes only and are not intended to limit the invention in any way. Those skilled in the art will readily recognize a variety of non-essential parameters that can be changed or modified to produce essentially the same results. The compounds of the examples have been found to inhibit KRAS activity according to at least one assay described herein. [Examples]

[0273] The experimental procedure for the compounds of the present invention is provided below. Partial LC-MS purification of the prepared compounds was performed using Waters mass fractionation systems. Basic instrument setup, protocols, and control software for operating these systems are described in detail in the literature. See, for example, KFBlom, J. Combi. Chem., 2002, 4(4), 295-301; KFBlom, et al., J. Combi. Chem., 2003, 5(5), 670-683; and KFBlom, et al., J. Combi. Chem., 2004, 6(6), 874-83. The separated compounds were typically subjected to analytical liquid chromatography-mass spectrometry (LCMS) for purity checks.

[0274] The separated compounds were typically subjected to analytical liquid chromatography-mass spectrometry (LCMS) for purity checks under the following conditions: Instrument: Agilent 1100 series, LC / MSD; Column: Waters SUNFIRE® C 18 5 μm particle size, 2.1 × 5.0 mm, buffer: mobile phase A: 0.025% TFA in water and mobile phase B: MeCN; gradient of B 2% to 80% over 3 minutes, flow rate 2.0 mL / min.

[0275] Furthermore, some of the prepared compounds were separated on a preparative scale by reversed-phase high-performance liquid chromatography (RP-HPLC) or flash chromatography (silica gel) with the MS detector shown in the examples. Typical preparative reversed-phase high-performance liquid chromatography (RP-HPLC) column conditions are as follows:

[0276] pH=2 Purification: Waters SUNFIRE(registered trademark) C 18 A 5 μm particle size, 19 × 100 mm column was used, with mobile phase A: 0.1% TFA (trifluoroacetic acid) in water and mobile phase B: MeCN; the flow rate was 30 mL / min, and the separation gradient was optimized for each compound using compound-specific method optimization protocols described in the literature [see KFBlom, et al., J. Combi. Chem. 2004, 6(6), 874-83]. Typically, a flow rate of 60 mL / min was used with a 30 × 100 mm column.

[0277] pH=10 Purification: Waters XBRIDGE(registered trademark) C 18 A 5 μm particle size, 19 × 100 mm column, mobile phase A: 0.15% NH4OH in water, and mobile phase B: MeCN; flow rate 30 mL / min; separation gradient optimized for each compound using compound-specific method optimization protocols described in the literature [see KFBlom, et al., J. Combi. Chem. 2004, 6(6), 874-83]. Typically, a flow rate of 60 mL / min was used with a 30 × 100 mm column.

[0278] The following abbreviations may be used herein: AcOH (acetic acid); Ac2O (acetic anhydride); aq. (aqueous); atm. (atmosphere); Boc (t-butoxycarbonyl); Boc2O (di-t-butyl dicarbonate); BOP ((benzotriazole-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate); br (broad); Cbz (carboxybenzyl); calc. (calculated); CO2 (carbon dioxide); Cs2CO 3 (Cesium carbonate); CsF (Cesium fluoride); d (double line); dd (double line of double lines); DBU (1,8-Diazabicyclo[5.4.0]undec-7-ene); DCM (Dichloromethane); DIAD (N,N'-Diisopropyl azido dicarboxylate); DIPEA (N,N-Diisopropyl ethylamine); DIBAL (Diisobutylaluminum hydride); DMF (N,N-Dimethylformamide); DMSO (Dimethyl sulfoxide); eq. (equivalents); Et (ethyl); EtOH (ethanol); Â (ethyl acetate); Ex. (examples); FCC (flash column chromatography); g (grams); h (hours); H2 (hydrogen); HATU (N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium hexafluorophosphate); HCl (hydrochloric acid or hydrogen chloride); HPLC (high-performance liquid chromatography); Hz (Hertz); J (bonding constant); K2CO3 (potassium carbonate); LCMS (liquid chromatography-mass spectrometry); LiBH4 (lithium borohydride); LDA (lithium diisopropylamide); m (multiline); M (moles); mCPBA (3-chloroperoxybenzoic acid); MS (mass spectrometry); Me (methyl); MeCN (acetonitrile); MeOH (methanol); mg (milligrams); MgSO4 (magnesium sulfate); min.(minutes (multiple possible)); mL (milliliters (multiple possible)); mmol (millimoles (multiple possible)); N (normal); NaBH4 (sodium borohydride); NaCl (sodium chloride); NADPH (nicotinamide adenine dinucleotide phosphate); NaHCO3 (sodium bicarbonate); NaIO4 (sodium metaperiodate); NaOH (sodium hydroxide); NCS (N-chlorosuccinimide); NEt3 (triethylamine); NH4OH (ammonium hydroxide); nM (nanomoles); NMP (N-methylpyrrolidinone); NMR (nuclear magnetic resonance spectroscopy); OTf (trifluoromethanesulfonate); Ph (phenyl); Pd (PPh3)4 (tetrakiss (Triphenylphosphine)palladium(0)); pM (picomoles); PPT (precipitate); RP-HPLC (reverse-phase high-performance liquid chromatography); rt (room temperature), s (singular line); sat. (saturated); t (tripular line or tertiary term); TBDPS (tert-butyldiphenylsilyl); TBS (tert-butyldimethylsilyl); tert (tertiary); tt (tripular line of the triplet); TFA (trifluoroacetic acid); THF (tetrahydrofuran); μg (micrograms); μL (microliters); μM (micromoles); wt% (weight percent); xanthophos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene). The brine is saturated aqueous NaCl. Under vacuum, the solution is under vacuum.

[0279] Intermediate 1. Ethyl(R)-4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate [ka] Step 1. 3-amino-2',3'-dichloro-2-fluoro-[1,1'-biphenyl]-4-carboxylic acid [ka] A mixture of 2-amino-4-bromo-3-fluorobenzoic acid (28.0 g, 120 mmol), (2,3-dichlorophenyl)boronic acid (25.1 g, 132 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (2.12 g, 3.00 mmol), and potassium phosphate (50.8 g, 239 mmol) in 1,4-dioxane (170 mL) and water (30 mL) was sparged with N2 and heated at 70°C for 1 hour. Upon completion, the reaction mixture was cooled to room temperature and poured into 1N HCl (200 mL). The mixture was stirred for a further 10 minutes to produce a precipitate. The solid was collected on a frit filter, washed with water, then hexane, and dried under reduced pressure to obtain the subtitle compound in near-quantitative yield. The crude product was used in the next step without further purification. 13 H9Cl2FNO2(M+H) + LC-MS calculated value for this: m / z = 300.0; measured value: 300.0.

[0280] Step 2: 3-Amino-6-Bromo-2',3'-Dichloro-2-Fluoro-[1,1'-Biphenyl]-4-carboxylic acid [ka] To a solution of 3-amino-2',3'-dichloro-2-fluoro-[1,1'-biphenyl]-4-carboxylic acid (35.8 g, 119 mmol) in DMSO (100 mL), N-bromosuccinimide (22.3 g, 125 mmol) was added. The resulting mixture was heated at 50 °C for 1 hour. After completion, the reaction mixture was cooled to room temperature and poured into ice water (400 mL). To the suspension, 20 mL of saturated Na₂S₂O₃ solution was added. After stirring for 15 minutes, the solid was collected on a frit filter, washed with water, then hexane, and dried under reduced pressure to obtain the subtitle compound (43.0 g, 95% yield). The crude product was used in the next step without further purification. 13 H8BrCl2FNO2(M+H) + LC-MS calculated values ​​for this: m / z = 377.9, 379.9; measured values: 378.0, 380.0.

[0281] Step 3. 6-Bromo-7-(2,3-dichlorophenyl)-8-fluoro-2H-benzo[d][1,3]oxazine-2,4(1H)-dione [ka] To a solution of 3-amino-6-bromo-2',3'-dichloro-2-fluoro-[1,1'-biphenyl]-4-carboxylic acid (38.6 g, 102 mmol) in THF (300 mL), triphosgene (10.6 g, 35.6 mmol) was gradually added. After addition, the mixture was heated at 60 °C for 0.5 hours. Once complete, the reaction mixture was cooled to room temperature and poured into heptane (1000 mL). After stirring for 1 hour, the solid was collected on a frit filter, washed with hexane, and dried under reduced pressure to obtain the subtitle compound in near quantitative yield. The crude product was used in the next step without further purification.

[0282] Step 4. Ethyl 6-bromo-7-(2,3-dichlorophenyl)-8-fluoro-4-hydroxy-2-methylquinoline-3-carboxylate [ka] To a solution of 6-bromo-7-(2,3-dichlorophenyl)-8-fluoro-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (41.5 g, 102 mmol) in DMSO (200 mL), (1-ethoxy-1,3-dioxobutan-2-yl) sodium (18.7 g, 123 mmol) was gradually added. After addition, the mixture was heated at 80°C for 1 hour. Once complete, the reaction mixture was cooled to room temperature and poured into 1N HCl (400 mL). After stirring for 1 hour, the solid was collected on a frit filter, washed with water, then hexane, and dried under reduced pressure to obtain the subtitle compound (40.0 g, 83% yield). The crude product was used in the next step without further purification. 19 H 14 BrCl2FNO3(M+H) + LC-MS calculated values ​​for this: m / z = 471.9, 473.9; measured values: 471.9, 474.0.

[0283] Step 5. Ethyl(E)-6-(2-cyanovinyl)-7-(2,3-dichlorophenyl)-8-fluoro-4-hydroxy-2-methylquinoline-3-carboxylate [ka] To a solution of ethyl 6-bromo-7-(2,3-dichlorophenyl)-8-fluoro-4-hydroxy-2-methylquinoline-3-carboxylate (35.0 g, 74.0 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (2.62 g, 3.70 mmol) in DMF (100 mL), acrylonitrile (12.3 mL, 185 mmol) and NEt3 (30.9 mL, 222 mmol) were added. The mixture was spurged with N2 and heated at 85°C for 1 hour. After completion, the reaction mixture was cooled to room temperature and poured into 1N HCl (500 mL). After stirring for 1 hour, the solid was collected on a frit filter, washed with water, then hexane, and dried under reduced pressure to obtain the subtitle compound (19.2 g, 58% yield). The crude product was used in the next step without further purification. 22 H 16 Cl2FN2O3(M+H) + LC-MS calculated value for this: m / z = 445.0; measured value 445.0.

[0284] Step 6. Ethyl(E)-4-chloro-6-(2-cyanovinyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate [ka] To a slurry of ethyl(E)-6-(2-cyanovinyl)-7-(2,3-dichlorophenyl)-8-fluoro-4-hydroxy-2-methylquinoline-3-carboxylate (30.0 g, 67.4 mmol) and benzyltriethylammonium chloride (15.4 g, 67.4 mmol) in MeCN (150 mL), DIPEA (23.5 mL, 135 mmol) was added at 0°C. After stirring at 0°C, phosphoryl chloride (12.6 mL, 135 mmol) was added dropwise to the mixture. The mixture was then heated at 60°C for 1 hour. After completion, the reaction mixture was cooled to room temperature and slowly poured into ice water (1000 mL). The mixture was extracted three times with DCM, dried over Na2SO4, filtered, and concentrated. The crude product was further purified by FCC (0-50% alkylammonium hexane) to obtain the subtitle compound (4.5 g, 14% yield). 22 H 15 Cl3FN2O2(M+H) + LC-MS calculated value for this: m / z = 463.0; measured value 463.0.

[0285] Step 7. Ethyl(R)-4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate A mixture of copper(II) acetate monohydrate (0.19 g, 0.97 mmol) and xanthophos (0.56 g, 0.97 mmol) was stirred in toluene (1 mL) and tert-butanol (9 mL) at 60°C for 0.5 hours to obtain a homogeneous solution. In a separate vial, a mixture of ethyl(E)-4-chloro-6-(2-cyanovinyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate (4.5 g, 9.70 mmol) and polymethylhydrosiloxane (3.5 g, 58.2 mmol) in toluene (12 mL) was added to the previous copper-containing solution at 60°C. The mixture was stirred at 60°C for 0.5 hours. Upon completion, the reaction mixture was filtered through diatomaceous earth and concentrated. The crude product was purified using FCC (0-40% siRNA / DCM) to obtain a mixture of two atropisomers (2.0 g, 44% yield). The title compound was separated from its atropisomers by chiral supercritical fluid chromatography (ChiralPak IJ column, 40% MeOH in CO2, eluted at a flow rate of 70 mL / min, with the title compound eluted after its atropisomers). 22 H 17 Cl3FN2O2(M+H) + LC-MS calculated value for this: m / z = 465.0; measured value 465.0.

[0286] Intermediate 2. tert-butyl(1R,4R,5S)-5-(((R)-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-3-iodo-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] Step 1. tert-butyl(1R,4R,5S)-5-(((R)-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-3-(ethoxycarbonyl)-8-fluoro-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] To a solution of ethyl(R)-4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate (intermediate 1, 7.2 g, 15.5 mmol) in N-methyl-2-pyrrolidone (21 mL), tert-butyl(1R,4R,5S)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylate (5.52 g, 27.8 mmol) and DIPEA (8.1 mL, 46.4 mmol) were added. The resulting mixture was heated at 80°C for 18 hours. After completion, the reaction mixture was cooled to room temperature and poured into a mixture of 1N HCl (300 mL) and ice. After stirring for 0.5 hours, the solid was collected on a frit filter, washed with water, then hexane, and dried under reduced pressure to obtain a white solid (8.2 g, 85% yield). The crude product was used in the next step without further purification. 32 H 34 Cl2FN4O4(M+H) + LC-MS calculated value for this: m / z = 627.2; measured value: 627.1.

[0287] Step 2. (R)-4-(((1R,4R,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-yl)amino)-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylic acid [ka] To a solution of tert-butyl(1R,4R,5S)-5-(((R)-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-3-(ethoxycarbonyl)-8-fluoro-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (4.0 g, 6.37 mmol) in MeCN (13 mL), 1N NaOH (16 mL, 15.94 mmol) was added. The mixture was heated at 50 °C for 2 hours. After completion, the reaction mixture was cooled to room temperature and acidified to pH 5 using 1N HCl. Organic volatile substances were removed under reduced pressure. The residual aqueous phase was extracted three times with ELISA. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a yellow solid (3.70 g, 97% yield). The crude material was used in the next step without further purification. 30 H 30 Cl2FN4O4(M+H) + LC-MS calculated value for this: m / z = 599.2; measured value 599.1.

[0288] Step 3. tert-butyl(1R,4R,5S)-5-(((R)-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-3-iodo-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate To a solution of (R)-4-(((1R,4R,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-yl)amino)-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylic acid (3.70 g, 6.17 mmol) in MeCN (6.2 mL), potassium phosphate (2.62 g, 12.34 mmol) and N-iodosuccinimide (2.50 g, 11.1 mmol) were added. The mixture was stirred at room temperature for 1 hour. After completion, the reaction mixture was poured into a saturated Na2S2O3 solution. After stirring for 10 minutes, the mixture was extracted three times with ELISA. The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was further purified with FCC (0-100% siRNA / hexane) to obtain the title compound as an off-white solid (1.95 g, 46% yield). 29 H 29 Cl2FIN4O2(M+H) + LC-MS calculated value for this: m / z = 681.1; measured value: 681.0.

[0289] Intermediate 3. Methyl(1R,3R,4S)-2-((S)-1-phenylethyl)-2-azabicyclo[2.2.1]hepta-5-ene-3-carboxylate [ka] Step 1. Methyl 2-hydroxy-2-methoxyacetate [ka] A solution of glyoxylic acid monohydrate (41.4 g, 450 mmol) in anhydrous MeOH (200 mL) was heated overnight to 70°C. After cooling to room temperature, the mixture was stirred with solid NaHCO3 for 10 minutes. The resulting mixture was filtered and concentrated under reduced pressure to obtain an oily residue. The residue was dissolved in CH2Cl2, dried over Na2SO4, filtered, and concentrated to obtain the product (40.0 g, 82% yield). The product was used in the next step without further purification.

[0290] Step 2. Methyl(S,E)-2-((1-phenylethyl)imino)acetate [ka] To a solution of methyl 2-hydroxy-2-methoxyacetate (40.0 g, 333 mmol) in toluene (95 mL), (S)-1-phenylethane-1-amine (40.4 g, 333 mmol) was slowly added. The mixture was stirred at room temperature for 1 hour and diluted with siRNA. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a yellow oil. The crude product was used in the next step without further purification.

[0291] Step 3. Methyl(1R,3R,4S)-2-((S)-1-phenylethyl)-2-azabicyclo[2.2.1]hepta-5-ene-3-carboxylate To a solution of methyl(S,E)-2-((1-phenylethyl)imino)acetate (63.7 g, 333 mmol) in 2,2,2-trifluoroethanol (800 mL), TFA (25.5 mL, 333 mmol) was added at -10°C. The reaction mixture was stirred at -10°C for 1 hour, after which cyclopentadiene (24.2 g, 366 mmol) was slowly added. The mixture was stirred at -10°C for a further 0.5 hours, and then warmed to room temperature. After removing volatile substances, the residue was diluted with 2N hydrochloric acid (500 mL) and washed with diethyl ether. The organic layer was extracted with 2N hydrochloric acid (100 mL). The combined aqueous layer was neutralized with 28% ammonium hydroxide and extracted three times with ethyl acetate. The combined organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was batch purified by FCC (0-10% RINKAN / hexane) to obtain the title compound as a colorless solid. 16 H 20 NO2(M+H) + LC-MS calculated value for this: m / z = 258.1; measured value 258.2. 1H NMR(500MHz,CDCl3)δ 7.32-7.27(m,2H), 7.25(m,2H), 7.22-7.16(m,1H), 6.44(ddd,J=5.7,3.1,1.2Hz,1H), 6.29(dd,J=5.7,2.0Hz,1H), 4.33(h,J=1.5Hz,1H) , 3.37(s,3H), 3.06(q,J=6.5Hz,1H), 2.93(dq,J=3.3,1.6Hz,1H), 2.24(d,J=0.9Hz,1H), 2.13(dt,J=8.4,1.7Hz,1H), 1.48-1.41(m,4H).

[0292] Intermediate 4.2-(tert-butyl)3-methyl(1R,3R,4R,5S)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate [ka] Step 1. Methyl(1R,3R,4R,5S)-5-hydroxy-2-((S)-1-phenylethyl)-2-azabicyclo[2.2.1]heptane-3-carboxylate [ka] To a solution of methyl(1R,3R,4S)-2-((S)-1-phenylethyl)-2-azabicyclo[2.2.1]hepta-5-ene-3-carboxylate (intermediate 3, 5.3 g, 20.6 mmol) in THF (70 mL), a 0.5 N THF solution of 9-borabicyclo[3.3.1]nonane (51.5 mL, 25.7 mmol) was added at 0°C. The reaction mixture was warmed to room temperature and stirred for 18 hours. The reaction mixture was then cooled to 0°C, and a 2 N NaOH solution (36.0 mL, 72.1 mmol) was added, followed by hydrogen peroxide (30% aqueous solution, 10.5 mL, 103 mmol). The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was diluted with Â, washed with brine, dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by FCC (50%-70% alkylammonium sulfate / hexane) to obtain the secondary compound (2.0 g, 38% yield). 16 H 22NO3 (M+H) + LC-MS calculated value for this: m / z = 276.2; measured value 276.2.

[0293] Step 2. Methyl(1R,3R,4R,5S)-5-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylate [ka] To a solution of methyl (1R,3R,4R,5S)-5-hydroxy-2-((S)-1-phenylethyl)-2-azabicyclo[2.2.1]heptane-3-carboxylate (2.00 g, 7.26 mmol) in EtOH (35 mL), 20% Pd(OH)2 / C (0.58 g) was added. The mixture was stirred under an H2 atmosphere for 18 hours. The resulting mixture was filtered through diatomaceous earth and concentrated to obtain the sub-subject compound. The crude material was used in the next step without further purification. C8H 14 NO3 (M+H) + LC-MS calculated value for this: m / z = 172.1; measured value 172.1.

[0294] Step 3. 2-(tert-butyl)3-methyl(1R,3R,4R,5S)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate Methyl (1R,3R,4R,5S)-5-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylate (1.24 g, 7.26 mmol) dissolved in THF (10 mL) was mixed with DIPEA (5.10 mL, 29.1 mmol) and Boc2O (3.96 g, 18.2 mmol). The reaction mixture was stirred at room temperature for 0.5 hours and diluted with SiO2. After washing with 0.01 N HCl and brine, the organic fraction was dried over Na2SO4, filtered, and concentrated. The crude product was further purified by FCC (0%~100% SiO2 / hexane) to obtain the title compound (1.88 g, 95% yield). C9H 14 NO5(M- t Bu+2H) + LC-MS calculated value for this: m / z = 216.1; measured value 216.1.

[0295] Intermediate 5. tert-butyl(1R,3R,4R,5S)-5-((tert-butyldiphenylsilyl)oxy)-3-ethynyl-2-azabicyclo[2.2.1]heptane-2-carboxylate [ka] Step 1.2-(tert-butyl)3-methyl(1R,3R,4R,5S)-5-((tert-butyldiphenylsilyl)oxy)-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate [ka] To a solution of 2-(tert-butyl)3-methyl(1R,3R,4R,5S)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (intermediate 4, 1.88 g, 6.92 mmol) in DMF (140 mL), tert-butylchlorodiphenylsilane (2.08 g, 7.64 mmol) and imidazole (1.40 g, 20.8 mmol) were added. The reaction mixture was stirred at room temperature for 18 hours. The mixture was diluted with SiO2, washed five times with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by FCC (0%~40% SiO2 / hexane) to obtain the subtitle compound. 25 H 32 NO5Si(M- t Bu+2H) + LC-MS calculated value for this: m / z = 454.2; measured value 454.2.

[0296] Step 2. tert-butyl(1R,3R,4R,5S)-5-((tert-butyldiphenylsilyl)oxy)-3-(hydroxymethyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate [ka] To a solution of 2-(tert-butyl)3-methyl(1R,3R,4R,5S)-5-((tert-butyldiphenylsilyl)oxy)-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (1.53 g, 3.01 mmol) in THF (15 mL), a 2N THF solution of LiBH4 (3.8 mL, 7.52 mmol) was added. The mixture was stirred at room temperature for 8 hours, then quenched by slowly adding a saturated NH4Cl solution. The mixture was diluted with ethyl acetate, washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by FCC (0-60% ethyl acetate / hexane) to obtain the subtitle compound (1.39 g, 96% yield). 24 H 32 NO4Si(M- t Bu+2H) + LC-MS calculated value for this: m / z = 426.2; measured value 426.2.

[0297] Step 3. tert-butyl(1R,3R,4R,5S)-5-((tert-butyldiphenylsilyl)oxy)-3-formyl-2-azabicyclo[2.2.1]heptane-2-carboxylate [ka] To a solution of oxalyl chloride (0.73 g, 5.76 mmol) in DCM (5.3 mL) cooled to -78°C, DMSO (0.61 mL, 8.64 mmol) was slowly added. After stirring for 10 minutes, a solution of tert-butyl(1R,3R,4R,5S)-5-((tert-butyldiphenylsilyl)oxy)-3-(hydroxymethyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.39 g, 2.88 mmol) in DCM (1 mL) was added. The reaction mixture was stirred at -78°C for 1 hour, after which DIPEA (1.5 mL) was added. The reaction mixture was warmed to room temperature and stirred for a further 0.5 hours. The reaction mixture was then poured into a DCM (15 mL) / 28% ammonium hydroxide (1.5 mL) mixture. After stirring for 10 minutes, the mixture was diluted with water. The organic phase was separated, dried over Na2SO4, filtered, and concentrated to obtain the crude product, which was used in the next step without further purification. 24 H 30 NO4Si(M- t Bu+2H) + LC-MS calculated value for this: m / z = 424.2; measured value 424.3.

[0298] Step 4. tert-butyl(1R,3R,4R,5S)-5-((tert-butyldiphenylsilyl)oxy)-3-ethynyl-2-azabicyclo[2.2.1]heptane-2-carboxylate To a solution of tert-butyl(1R,3R,4R,5S)-5-((tert-butyldiphenylsilyl)oxy)-3-formyl-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.38 g, 2.88 mmol) in MeOH (15 mL), dimethyl(1-diazo-2-oxopropyl)phosphonate (0.61 g, 3.17 mmol) and K2CO3 (1.19 g, 8.64 mmol) were added. After stirring for 18 hours, the reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated. The residue was extracted with ELISA, filtered through diatomaceous earth, and concentrated. The crude product was purified by FCC (0-40% ELISA / hexane) to obtain the title compound (0.20 g, 51%) over two steps. 25 H 30NO3Si(M- t Bu+2H) + LC-MS calculated value for this: m / z = 420.2; measured value 420.2.

[0299] Intermediate 6. tert-butyl(1R,3R,4R,5R)-5-((tert-butyldiphenylsilyl)oxy)-3-ethynyl-2-azabicyclo[2.2.1]heptane-2-carboxylate [ka] Step 1.2-(tert-butyl)3-methyl(1R,3R,4R)-5-oxo-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate [ka] To a solution of 2-(tert-butyl)3-methyl(1R,3R,4R,5S)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (intermediate 4, 1.88 g, 6.93 mmol) in DCM (35 mL), des-martin periodinane (3.32 g, 7.83 mmol) was gradually added at 0°C. The reaction mixture was warmed to room temperature and stirred for a further 3 hours. After washing with saturated Na2S2O3 solution and water, the organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was purified by FCC (0-60% siRNA / hexane) to obtain oil (1.29 g, 69% yield). C9H 12 NO5(M- t Bu+2H) + LC-MS calculated value for this: m / z = 214.1; measured value 214.1.

[0300] Step 2.2-(tert-butyl)3-methyl(1R,3R,4R,5R)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate [ka] To a solution of 2-(tert-butyl)3-methyl(1R,3R,4R)-5-oxo-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (0.82 g, 3.04 mmol) in MeOH (15 mL), NaBH4 (0.29 g, 7.61 mmol) was added gradually at 0°C. The resulting mixture was warmed to room temperature and stirred for a further 0.5 hours. The reaction mixture was then placed in an ice bath and quenched by adding saturated NH4Cl solution dropwise. The mixture was diluted with ethyl acetate, washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by FCC (30-60% ethyl acetate / hexane) to obtain the subtitle compound (0.47 g, 57% yield). C9H 14 NO5(M- t Bu+2H) + LC-MS calculated value for this: m / z = 216.1; measured value 216.1.

[0301] Step 3. 2-(tert-butyl)3-methyl(1R,3R,4R,5R)-5-((tert-butyldiphenylsilyl)oxy)-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate [ka] To a solution of 2-(tert-butyl)3-methyl(1R,3R,4R,5R)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (0.47 g, 1.73 mmol) in DMF (3.5 mL), tert-butylchlorodiphenylsilane (0.52 g, 1.91 mmol) and imidazole (0.35 g, 5.20 mmol) were added. The reaction mixture was stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate, washed five times with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by FCC (0-20% ethyl acetate / hexane) to obtain the subtitle compound (0.79 g, 89% yield). 24 H 32 NO3Si(M-Boc+2H) + LC-MS calculated value for this: m / z = 410.2; measured value: 410.3.

[0302] Step 4. tert-butyl(1R,3R,4R,5R)-5-((tert-butyldiphenylsilyl)oxy)-3-(hydroxymethyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate [ka] To a solution of 2-(tert-butyl)3-methyl(1R,3R,4R,5R)-5-((tert-butyldiphenylsilyl)oxy)-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (0.79 g, 1.54 mmol) in THF (4 mL), a 2N THF solution of LiBH4 (1.93 mL, 3.86 mmol) was added. The mixture was stirred at room temperature for 8 hours, then quenched by slowly adding a saturated NH4Cl solution. The mixture was diluted with ethyl acetate, washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by FCC (0-60% ethyl acetate / hexane) to obtain the subtitle compound (0.51 g, 69% yield). 24 H 32 NO4Si(M- t Bu+2H) + LC-MS calculated value for this: m / z = 426.2; measured value: 426.1.

[0303] Step 5. tert-butyl(1R,3R,4R,5R)-5-((tert-butyldiphenylsilyl)oxy)-3-formyl-2-azabicyclo[2.2.1]heptane-2-carboxylate [ka] To a solution of oxalyl chloride (0.27 g, 2.12 mmol) in DCM (5.3 mL) cooled to -78°C, DMSO (0.23 mL, 3.18 mmol) was slowly added. After stirring for 10 minutes, a solution of tert-butyl(1R,3R,4R,5R)-5-((tert-butyldiphenylsilyl)oxy)-3-(hydroxymethyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (0.51 g, 1.06 mmol) in DCM (1 mL) was added. The reaction mixture was stirred at -78°C for 1 hour, after which DIPEA (0.5 mL) was added. The reaction mixture was warmed to room temperature and stirred for a further 0.5 hours. The reaction mixture was then poured into a DCM (5 mL) / 28% ammonium hydroxide (0.5 mL) mixture. After stirring for 10 minutes, the mixture was diluted with water. The organic phase was separated, dried over Na2SO4, filtered, and concentrated to obtain the crude product, which was used in the next step without further purification. 23 H 30 NO2Si(M-Boc+2H) + LC-MS calculated value for this: m / z = 380.2; measured value 380.2.

[0304] Step 6. tert-butyl(1R,3R,4R,5R)-5-((tert-butyldiphenylsilyl)oxy)-3-ethynyl-2-azabicyclo[2.2.1]heptane-2-carboxylate To a solution of tert-butyl(1R,3R,4R,5R)-5-((tert-butyldiphenylsilyl)oxy)-3-formyl-2-azabicyclo[2.2.1]heptane-2-carboxylate (0.51 g, 1.06 mmol) in MeOH (5.3 mL), dimethyl(1-diazo-2-oxopropyl)phosphonate (0.22 g, 1.17 mmol) and K2CO3 (0.44 g, 3.18 mmol) were added. After stirring for 18 hours, the reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated. The residue was extracted with ELISA, filtered through diatomaceous earth, and concentrated. The crude product was purified by FCC (0-40% ELISA / hexane) to obtain the title compound (0.35 g, 70% yield, over two steps). 25 H 30 NO3Si(M-t Bu+2H) + LC-MS calculated value for this: m / z = 420.2; measured value 420.2.

[0305] Intermediate 7. tert-butyl(1S,2S,4R,5R,7R)-7-ethynyl-6-azatricyclo[3.2.1.0 2,4 Octane-6-carboxylate [ka] Step 1. Methyl(1S,2S,4R,5R,7R)-6-((S)-1-phenylethyl)-6-azatricyclo[3.2.1.0 2,4 Octane-7-carboxylate [ka] A mixture of methyl (1R,3R,4S)-2-((S)-1-phenylethyl)-2-azabicyclo[2.2.1]hepta-5-ene-3-carboxylate (intermediate 3, 0.80 g, 3.11 mmol), potassium trifluoro(iodomethyl)borate (1.16 g, 4.66 mmol), trans-bis(acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II) (0.15 g, 0.155 mmol), and K2CO3 (0.64 g, 4.66 mmol) in DMF (13.8 mL) and water (1.7 mL) was spurged with N2 and heated at 90°C for 8 hours. After completion, the reaction mixture was cooled to room temperature and poured into water. The aqueous layer was extracted with SiO2, washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by FCC (0-10% alkylammonium phosphate / hexane) to obtain the secondary compound (0.34 g, 40% yield). 17 H 22 NO2(M+H) + LC-MS calculated value for this: m / z = 272.2; measured value 272.2.

[0306] Step 2. Methyl(1S,2S,4R,5R,7R)-6-Azatricyclo[3.2.1.0 2,4 Octane-7-carboxylate [ka] Methyl(1S,2S,4R,5R,7R)-6-((S)-1-phenylethyl)-6-azatricyclo[3.2.1.0] in EtOH (35 mL) 2,4 To a solution of octane-7-carboxylate (0.68 g, 2.51 mmol), 20% Pd(OH)2 / C (0.20 g) was added. The mixture was stirred under an H2 atmosphere for 18 hours. The resulting mixture was filtered through diatomaceous earth and concentrated to obtain the sub-subject compound. The crude material was used in the next step without further purification. C9H 14 NO2(M+H) + LC-MS calculated value for this: m / z = 168.1; measured value 168.1. 1 1H NMR was collected using TFA salt. 1 H NMR(600MHz,DMSO-d6)δ 9.75(s,1H), 8.55(s,1H), 4.19(s,1H), 4.13(s,1H), 3.78(s,3H), 2.94(s,1H), 1.43(d,J=12.7Hz, 1H), 1.37-1.27(m,2H), 1.01(d,J=12.6Hz,1H), 0.73(dt,J=6.5,3.2Hz,1H), 0.42(q,J=7.1Hz,1H).

[0307] Step 3.6-(tert-butyl)7-methyl(1S,2S,4R,5R,7R)-6-azatricyclo[3.2.1.0 2,4 Octane-6,7-dicarboxylate [ka] Methyl(1S,2S,4R,5R,7R)-6-azatricyclo[3.2.1.0] dissolved in THF (13 mL) 2,4To octane-7-carboxylate (0.42 g, 2.51 mmol), DIPEA (1.32 mL, 7.53 mmol) and Boc2O (1.10 g, 5.02 mmol) were added. The reaction mixture was stirred at room temperature for 0.5 hours and diluted with ethyl acetate. After washing with brine, the organic fraction was dried over Na2SO4, filtered, and concentrated. The crude product was further purified by FCC (0%~100% ethyl acetate / hexane) to obtain the subtitle compound (0.50 g, 75% yield, over two steps). 10 H 14 NO4(M- t Bu+2H) + LC-MS calculated value for this: m / z = 212.1; measured value 212.1.

[0308] Step 4. tert-butyl(1S,2S,4R,5R,7R)-7-(hydroxymethyl)-6-azatricyclo[3.2.1.0 2,4 Octane-6-carboxylate [ka] 6-(tert-butyl)7-methyl(1S,2S,4R,5R,7R)-6-azatricyclo[3.2.1.0] in THF (10 mL) 2,4 To a solution of octane-6,7-dicarboxylate (0.50 g, 1.87 mmol), a 2N THF solution of LiBH4 (2.3 mL, 4.68 mmol) was added. The mixture was stirred at room temperature for 8 hours, then quenched by slowly adding a saturated NH4Cl solution. The mixture was diluted with siRNA, washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by FCC (0-60% siRNA / hexane) to obtain the subtitle compound. C9H 14 NO3(M- t Bu+2H) + LC-MS calculated value for this: m / z = 184.1; measured value 184.1.

[0309] Step 5. tert-butyl(1S,2S,4R,5R,7R)-7-formyl-6-azatricyclo[3.2.1.0 2,4Octane-6-carboxylate [ka] To a solution of oxalyl chloride (0.48 g, 3.76 mmol) in DCM (3.8 mL) cooled to -78°C, DMSO (0.40 mL, 5.64 mmol) was slowly added. After stirring for 10 minutes, tert-butyl(1S,2S,4R,5R,7R)-7-(hydroxymethyl)-6-azatricyclo[3.2.1.0 2,4 A solution of octane-6-carboxylate (0.45 g, 1.88 mmol) in DCM (1 mL) was added. The reaction mixture was stirred at -78°C for 1 hour, after which DIPEA (1.0 mL) was added. The reaction mixture was warmed to room temperature and stirred for a further 0.5 hours. The reaction mixture was then poured into a mixture of DCM (10 mL) / 28% ammonium hydroxide (1.0 mL). After stirring for 10 minutes, the mixture was diluted with water. The organic phase was separated, dried over Na2SO4, filtered, and concentrated to obtain the crude product, which was used in the next step without further purification. C9H 12 NO3(M- t Bu+2H) + LC-MS calculated value for this: m / z = 182.1; measured value 182.1.

[0310] Step 6. tert-butyl(1S,2S,4R,5R,7R)-7-ethynyl-6-azatricyclo[3.2.1.0 2,4 Octane-6-carboxylate tert-butyl(1S,2S,4R,5R,7R)-7-formyl-6-azatricyclo[3.2.1.0] in MeOH (10 mL) 2,4 To a solution of octane-6-carboxylate (0.45 g, 1.88 mmol), dimethyl (1-diazo-2-oxopropyl)phosphonate (0.40 g, 2.07 mmol) and K2CO3 (0.78 g, 5.64 mmol) were added. After stirring for 18 hours, the reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated. The residue was extracted with siRNA, filtered through diatomaceous earth, and concentrated. The crude product was purified by FCC (0-40% siRNA / hexane) to obtain the title compound.10 H 12 NO2(M- t Bu+2H) + LC-MS calculated value for this: m / z = 178.1; measured value 178.1.

[0311] Intermediate 8. tert-butyl(1R,4R,5S)-5-((2-((R)-1-(benzyloxy)ethyl)-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-3-iodoquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] Step 1. Ethyl(R)-4-(benzyloxy)-3-oxopentanoate [ka] When 1,1'-carbonyldiimidazole (7.92 g, 48.8 mmol) was slowly added to a stirred solution of (R)-2-(benzyloxy)propanoic acid (8.00 g, 44.4 mmol) in SiO2 (22 mL), gas was generated. The mixture was stirred at room temperature for 1 hour to obtain a clear solution.

[0312] In a separate reaction vessel containing magnesium chloride (10.6 g, 111 mmol) and potassium 3-ethoxy-3-oxopropanoate (15.1 g, 89.0 mmol), NEt3 (19.8 mL, 142 mmol) and toluene (33 mL) were added. The mixture was vigorously stirred at 60°C for 1 hour. Then, the aforementioned clear solution was slowly added to the mixture. The resulting suspension was stirred at 80°C for 3 hours.

[0313] Once complete, the reaction mixture was cooled to room temperature and acidified to pH < 3 with 1N HCl while stirring. The mixture was diluted with toluene and water. The organic phase was separated, and the aqueous phase was extracted twice with toluene. The combined organic layers were washed with saturated NaHCO3 solution, water, and brine, dried over Na2SO4, filtered, and concentrated to obtain the sub-subject compound as oil in nearly quantitative yield. The crude product was used in the next step without further purification. 14 H 19 O4(M+H) + LC-MS calculated value for this: m / z = 251.1; measured value 251.1.

[0314] Step 2. Ethyl 2-((R)-1-(benzyloxy)ethyl)-6-bromo-7-(2,3-dichlorophenyl)-8-fluoro-4-hydroxyquinoline-3-carboxylate [ka] To a solution of ethyl(R)-4-(benzyloxy)-3-oxopentanoate (43.4 g, 173 mmol) in DMSO (220 mL), 6-bromo-7-(2,3-dichlorophenyl)-8-fluoro-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (intermediate 1, step 3, 45.0 g, 111 mmol), sodium acetate (16.4 g, 200 mmol), and NaCl (11.7 g, 200 mmol) were added. The mixture was heated at 65 °C for 18 hours. After completion, the reaction mixture was cooled to 0 °C in an ice bath, diluted with water (300 mL), and acidified to pH 3-4 using 1N HCl, resulting in the formation of a precipitate. After stirring at 0°C for 1 hour, the solid was collected on a frit filter, washed with a 1:1 mixture of MeCN and water, and dried under reduced pressure to obtain the subtitle compound (54.0 g, 82% yield). The crude product was used in the next step without further purification. 27 H 22 BrCl2FNO4(M+H) + LC-MS calculated values ​​for this: m / z = 592.0, 594.0; measured values: 592.0, 594.0.

[0315] Step 3. Ethyl 2-((R)-1-(benzyloxy)ethyl)-6-((E)-2-cyanovinyl)-7-(2,3-dichlorophenyl)-8-fluoro-4-hydroxyquinoline-3-carboxylate [ka] To a solution of ethyl 2-((R)-1-(benzyloxy)ethyl)-6-bromo-7-(2,3-dichlorophenyl)-8-fluoro-4-hydroxyquinoline-3-carboxylate (47.7 g, 80.0 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (2.28 g, 3.21 mmol) in DMF (191 mL), acrylonitrile (13.3 mL, 201 mmol) and NEt3 (33.6 mL, 241 mmol) were added. The mixture was sparged with N2 and heated at 85°C for 1 hour. Upon completion, the reaction mixture was diluted with brine and SiO2. The organic phase was separated, and the aqueous phase was extracted twice more with SiO2. The combined organic layers were washed five times with brine and 1N HCl, filtered, and dried over Na2SO4. The volatile substances were removed under reduced pressure, and the subtitle compound was obtained in nearly quantitative yield. The crude product was used in the next step without further purification. 30 H 24 Cl2FN2O4(M+H) + LC-MS calculated value for this: m / z = 565.1; measured value 565.1.

[0316] Step 4. Ethyl 2-((R)-1-(benzyloxy)ethyl)-4-chloro-6-((E)-2-cyanovinyl)-7-(2,3-dichlorophenyl)-8-fluoroquinoline-3-carboxylate [ka] To a slurry of ethyl 2-((R)-1-(benzyloxy)ethyl-6-((E)-2-cyanovinyl)-7-(2,3-dichlorophenyl)-8-fluoro-4-hydroxyquinoline-3-carboxylate (48.0 g, 85 mmol) and benzyltriethylammonium chloride (19.3 g, 85 mmol) in MeCN (210 mL), DIPEA (29.6 mL, 170 mmol) was added at 0°C. After stirring at 0°C, Phosphoryl chloride (31.6 mL, 340 mmol) was added dropwise to the mixture. The mixture was then heated at 60°C for 2 hours. After completion, the reaction mixture was cooled to room temperature and slowly poured into ice water (1000 mL). The mixture was extracted three times with toluene, dried over Na2SO4, filtered, and concentrated to obtain the sub-subject compound as a pale brown solid (46.9 g, 95% yield). The crude product was used in the next step without further purification. 30 H 23 Cl3FN2O3(M+H) + LC-MS calculated value for this: m / z = 583.1; measured value 583.0.

[0317] Step 5. Ethyl 2-((R)-1-(benzyloxy)ethyl)-4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoroquinoline-3-carboxylate [ka] A mixture of copper(II) acetate monohydrate (1.60 g, 8.03 mmol) and xanthophos (5.58 g, 9.64 mmol) was stirred in toluene (50 mL) and tert-butanol (62 mL) at 60°C for 0.5 hours to obtain a homogeneous solution. In a separate container, a mixture of ethyl 2-((R)-1-(benzyloxy)ethyl)-4-chloro-6-((E)-2-cyanovinyl)-7-(2,3-dichlorophenyl)-8-fluoroquinoline-3-carboxylate (46.9 g, 80.0 mmol) and polymethylhydrosiloxane (102 g, 402 mmol) in toluene (150 mL) was added to the previous copper-containing solution at 50°C. The mixture was stirred at 50°C for 1 hour. Upon completion, the reaction mixture was filtered through diatomaceous earth and concentrated. The crude product was purified using FCC (0-40% acetone / n-heptane) to obtain the subtitle compound (23.2 g, 49% yield). 30 H 25 Cl3FN2O3(M+H) + LC-MS calculated value for this: m / z = 585.1; measured value 585.1.

[0318] Step 6. tert-butyl(1R,4R,5S)-5-((2-((R)-1-(benzyloxy)ethyl)-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-3-(ethoxycarbonyl)-8-fluoroquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] To a solution of ethyl 2-((R)-1-(benzyloxy)ethyl)-4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoroquinoline-3-carboxylate (34.3 g, 58.6 mmol) in DMSO (110 mL), tert-butyl(1R,4R,5S)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylate (20.9 g, 105 mmol), lithium chloride (4.97 g, 117 mmol), and DIPEA (30.6 mL, 176 mmol) were added. The resulting mixture was heated at 100 °C for 18 hours. After completion, the reaction mixture was diluted with water and SiO2. The organic phase was separated, and the aqueous phase was extracted twice more with SiO2. The combined organic layers were washed with 1N HCl and brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified using FCC (0-40% acetone / n-heptane) to obtain the subtitle compound (33.6 g, 77% yield). 40 H 42 Cl2FN4O5(M+H) + LC-MS calculated value for this: m / z = 747.2; measured value 747.2.

[0319] Step 7.2-((R)-1-(benzyloxy)ethyl)-4-(((1R,4R,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-yl)amino)-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoroquinoline-3-carboxylic acid [ka] A mixture of tert-butyl(1R,4R,5S)-5-((2-((R)-1-(benzyloxy)ethyl)-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-3-(ethoxycarbonyl)-8-fluoroquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (33.6 g, 45 mmol) in THF (100 mL) and water (100 mL) was heated at 60 °C for 3 hours with NaOH (10.0 g, 250 mmol) added. After completion, the reaction mixture was cooled to room temperature and acidified to pH 5 using 1N HCl. Organic volatile substances were removed under reduced pressure. The residual aqueous phase was extracted three times with ELISA. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the subtitle compound as a pale yellow solid in nearly quantitative yield. The crude material was used in the next step without further purification. 38 H 38 Cl2FN4O5(M+H) + LC-MS calculated value for this: m / z = 719.2; measured value 719.2.

[0320] Step 8. tert-butyl(1R,4R,5S)-5-((2-((R)-1-(benzyloxy)ethyl)-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-3-iodoquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate To a solution of 2-((R)-1-(benzyloxy)ethyl)-4-(((1R,4R,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-yl)amino)-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoroquinoline-3-carboxylic acid (34.8 g, 48.3 mmol) in MeCN (242 mL), potassium phosphate (20.5 g, 97.0 mmol) and N-iodosuccinimide (19.6 g, 87.0 mmol) were added. The mixture was stirred at room temperature for 1 hour. After completion, the reaction mixture was poured into a saturated Na2S2O3 solution. After stirring for 10 minutes, the mixture was extracted three times with ELISA. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was further purified by FCC (0-40% acetone / n-heptane) to obtain the title compound as a pale yellow solid (35.0 g, 90% yield). 37 H 37 Cl2FIN4O3(M+H) + LC-MS calculated value for this: m / z = 801.1; measured value: 801.1.

[0321] Intermediate 9. tert-butyl(1R,3R,4S,5S)-5-(difluoromethyl)-3-ethynyl-2-azabicyclo[2.2.1]heptane-2-carboxylate [ka] Step 1. Methyl(1S,3R,4S,5S)-2-((S)-1-phenylethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxylate [ka] A mixture of methyl(1R,3R,4S)-2-((S)-1-phenylethyl)-2-azabicyclo[2.2.1]hepta-5-ene-3-carboxylate (intermediate 3, 5.80 g, 22.5 mmol), bis(1,5-cyclooctadiene)diiridium(I) dichloride (0.23 g, 0.34 mmol), and 1,2-bis(diphenylphosphin)ethane (0.27 g, 0.68 mmol) in DCM (75 mL) was spurged with N2 and cooled to 0°C. Pinacolborane (3.90 mL, 27.0 mmol) was slowly added to this mixture. After addition, the reaction mixture was warmed to room temperature and stirred for 2 hours. After completion, volatile substances were removed under reduced pressure. The crude substance was purified by FCC (0-40% toluene / hexane) to obtain the subtitle compound (4.15 g, 48% yield). 22 H 33 BNO4(M+H) + LC-MS calculated value for this: m / z = 386.2; measured value: 386.3.

[0322] Step 2. Methyl(1S,3R,4S,5R)-2-((S)-1-phenylethyl)-5-vinyl-2-azabicyclo[2.2.1]heptane-3-carboxylate [ka] To a solution of methyl(1S,3R,4S,5S)-2-((S)-1-phenylethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxylate (4.15 g, 10.8 mmol) in THF (54 mL) cooled to 0°C, vinyl magnesium bromide (1N in THF, 43.1 mL, 43.1 mmol) was slowly added. The resulting mixture was stirred at 0°C for 1 hour and then cooled to -78°C. At this temperature, a solution of I2 (10.9 g, 43.1 mmol) in MeOH (54 mL) was slowly added. After stirring at the same temperature for 0.5 hours, sodium methoxide solution (25% in MeOH, 18.6 g, 86 mmol) was added. The reaction mixture was warmed to room temperature and stirred for a further 1 hour. Once complete, the mixture was diluted with RINKAN and washed with saturated Na2S2O3 solution, water, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was purified by FCC (0-40% RINKAN / hexane) to obtain the subtitle compound (0.86 g, 28% yield). 18 H 24 NO2(M+H) + LC-MS calculated value for this: m / z = 286.2; measured value 286.2.

[0323] Step 3. Methyl(1R,3R,4S,5S)-5-formyl-2-((S)-1-phenylethyl)-2-azabicyclo[2.2.1]heptane-3-carboxylate [ka] To a solution of methyl(1S,3R,4S,5R)-2-((S)-1-phenylethyl)-5-vinyl-2-azabicyclo[2.2.1]heptane-3-carboxylate (0.86 g, 3.0 mmol) in 1,4-dioxane (12 mL) and water (4 mL), 2,6-lutidine (0.70 mL, 6.0 mmol), potassium osmium(VI)ate dihydrate (0.033 g, 0.090 mmol), and NaIO4 (2.58 g, 12.1 mmol) were added. The mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was diluted with HCl and water. The organic phase was separated, and the aqueous phase was extracted twice with HCl. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was used in the next step without further purification. 17 H 22 NO3 (M+H) + LC-MS calculated value for this: m / z = 288.2; measured value 288.2.

[0324] Step 4. Methyl(1R,3R,4S,5S)-5-(difluoromethyl)-2-((S)-1-phenylethyl)-2-azabicyclo[2.2.1]heptane-3-carboxylate [ka] To a solution of methyl(1R,3R,4S,5S)-5-formyl-2-((S)-1-phenylethyl)-2-azabicyclo[2.2.1]heptane-3-carboxylate (0.86 g, 3.0 mmol) in DCM (15 mL), diethylaminosulfur trifluoride (1.46 g, 9.0 mmol) was added dropwise at 0°C. The resulting mixture was warmed to room temperature and stirred for 3 hours. After completion, the mixture was cooled to 0°C and quenched by dropwise addition of saturated aqueous solution NaHCO3. The organic phase was separated, and the aqueous phase was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by FCC (0-20% siRNA / hexane) to obtain the subtitle compound (0.52 g, 56% yield, across two steps). 17 H 22 F2NO2(M+H)+ LC-MS calculated value for this: m / z = 310.2; measured value: 310.1.

[0325] Step 5. Methyl(1R,3R,4S,5S)-5-(difluoromethyl)-2-azabicyclo[2.2.1]heptane-3-carboxylate [ka] To a solution of methyl (1R,3R,4S,5S)-5-(difluoromethyl)-2-((S)-1-phenylethyl)-2-azabicyclo[2.2.1]heptane-3-carboxylate (0.52 g, 1.69 mmol) in EtOH (35 mL), 20% Pd(OH)2 / C (0.50 g) was added. The mixture was stirred under an H2 atmosphere for 18 hours. The resulting mixture was filtered through diatomaceous earth and concentrated to obtain the sub-subject compound. The crude substance was used in the next step without further purification. C9H 14 F2NO2(M+H) + LC-MS calculated value for this: m / z = 206.1; measured value 206.1. 1 1H NMR was collected using TFA salt. 1 H NMR(600MHz,DMSO-d6)δ 9.29(br,2H), 6.22-5.96(td,J=54,5.4Hz,1H), 4.29(s,1H), 4.14(s,1H), 3.79(s,3H), 2.93(s,1H), 2 .49-2.38(m,1H), 2.03-1.95(m,1H), 1.82(d,J=11.9Hz,1H), 1.73-1.61(m,1H), 1.53(d,J=12Hz,1H).

[0326] Step 6. 2-(tert-butyl)3-methyl(1R,3R,4S,5S)-5-(difluoromethyl)-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate [ka] Methyl (1R,3R,4S,5S)-5-(difluoromethyl)-2-azabicyclo[2.2.1]heptane-3-carboxylate (0.35 g, 1.69 mmol) dissolved in THF (13 mL) was mixed with DIPEA (0.89 mL, 5.07 mmol) and Boc2O (0.74 g, 3.38 mmol). The reaction mixture was stirred at room temperature for 0.5 hours and diluted with ethyl acetate. After washing with brine, the organic fraction was dried over Na2SO4, filtered, and concentrated. The crude product was further purified by FCC (0%~20% ethyl acetate / hexane) to obtain the subtitle compound (0.40 g, 77% yield, over two steps). 10 H 14 F2NO4(M- t Bu+2H) + LC-MS calculated value for this: m / z = 250.1; measured value 250.2.

[0327] Step 7. tert-butyl(1R,3R,4S,5S)-5-(difluoromethyl)-3-(hydroxymethyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate [ka] To a solution of 2-(tert-butyl)3-methyl(1R,3R,4S,5S)-5-(difluoromethyl)-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (0.40 g, 1.31 mmol) in THF (6.5 mL), a 2N THF solution of LiBH4 (1.64 mL, 3.28 mmol) was added. The mixture was stirred at room temperature for 8 hours, then quenched by slowly adding a saturated NH4Cl solution. The mixture was diluted with HCl, washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by FCC (0-60% HCl / hexane) to obtain the subtitle compound (0.35 g, 95% yield). C9H 14 F2NO3(M- t Bu+2H) + LC-MS calculated value for this: m / z = 222.1; measured value 222.1.

[0328] Step 8. tert-butyl(1R,3R,4S,5S)-5-(difluoromethyl)-3-formyl-2-azabicyclo[2.2.1]heptane-2-carboxylate [ka] To a solution of tert-butyl(1R,3R,4S,5S)-5-(difluoromethyl)-3-(hydroxymethyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (0.35 g, 1.25 mmol) in DCM (6.2 mL), dess-martin periodinane (0.79 g, 1.87 mmol) was gradually added. The resulting mixture was stirred at room temperature for 1 hour. After completion, a saturated Na2S2O3 solution (5 mL) was added to the reaction mixture. The mixture was stirred for a further 0.5 hours. The organic phase was separated, dried over Na2SO4, filtered, and concentrated to obtain the crude product, which was used in the next step without further purification. C9H 12 F2NO3(M- t Bu+2H) + LC-MS calculated value for this: m / z = 220.1; measured value 220.0.

[0329] Step 9. tert-butyl(1R,3R,4S,5S)-5-(difluoromethyl)-3-ethynyl-2-azabicyclo[2.2.1]heptane-2-carboxylate To a solution of tert-butyl(1R,3R,4S,5S)-5-(difluoromethyl)-3-formyl-2-azabicyclo[2.2.1]heptane-2-carboxylate (0.34 g, 1.25 mmol) in MeOH (6 mL), dimethyl(1-diazo-2-oxopropyl)phosphonate (0.36 g, 1.88 mmol) and K2CO3 (0.52 g, 3.75 mmol) were added. After stirring for 18 hours, the reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated. The residue was extracted with ethyl acetate, filtered through diatomaceous earth, and concentrated. The crude product was purified by FCC (0-30% ethyl acetate / hexane) to obtain the title compound (0.080 g, 23% yield, over two steps). 10 H 12 F2NO2(M-t Bu+2H) + LC-MS calculated value for this: m / z = 216.1; measured value 216.1.

[0330] Intermediate 10. ((1R,3R,4R,5S)-5-(difluoromethoxy)-3-ethynyl-2-azabicyclo[2.2.1]heptan-2-yl)(1-fluorocyclopropyl)methanone [ka] Step 1.2-(tert-butyl)3-methyl(1R,3R,4R,5S)-5-(difluoromethoxy)-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate [ka] A flask containing 2-(tert-butyl)3-methyl(1R,3R,4R,5S)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (intermediate 4, 5.30 g, 19.5 mmol) and copper(I) iodide (0.744 g, 3.91 mmol) was filled with MeCN (98 mL). After stirring the mixture at 50°C, a MeCN solution (10 mL) containing 2-(fluorosulfonyl)difluoroacetic acid (5.22 g, 29.3 mmol) was slowly added. The reaction mixture was stirred at 50°C for 1 hour. After completion, the mixture was concentrated under reduced pressure. The residue was dissolved in DCM and washed with saturated NaHCO3 solution and water. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was purified by FCC (0%~40% alkylammonium sulfate / hexane) to obtain the secondary compound (3.12 g, 50% yield). 10 H 14 F2NO5(M- t Bu+2H) + LC-MS calculated value for this: m / z = 266.1; measured value 266.0.

[0331] Step 2. tert-butyl(1R,3R,4R,5S)-5-(difluoromethoxy)-3-(hydroxymethyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate [ka] To a solution of 2-(tert-butyl)3-methyl(1R,3R,4R,5S)-5-(difluoromethoxy)-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (3.12 g, 9.71 mmol) in THF (49 mL), LiBH4 (2 M in THF, 12.1 mL, 24.27 mmol) was added. The mixture was stirred at room temperature for 8 hours, then quenched by slowly adding saturated aqueous NH4Cl solution at 0°C. The mixture was diluted with ethyl acetate, washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by FCC (0-60% ethyl acetate / hexane) to obtain the subtitle compound (1.62 g, 57% yield). C9H 14 F2NO4(M- t Bu+2H) + LC-MS calculated value for this: m / z = 238.1; measured value 238.1.

[0332] Step 3. tert-butyl(1R,3R,4R,5S)-5-(difluoromethoxy)-3-formyl-2-azabicyclo[2.2.1]heptane-2-carboxylate [ka] To a solution of tert-butyl(1R,3R,4R,5S)-5-(difluoromethoxy)-3-(hydroxymethyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.62 g, 5.52 mmol) in DCM (28 mL), des-martin periodinane (3.51 g, 8.28 mmol) was gradually added. The resulting mixture was stirred at room temperature for 1 hour. After completion, a saturated Na2S2O3 solution (5 mL) was added to the reaction mixture. The mixture was stirred for a further 0.5 hours. The organic phase was separated, dried over Na2SO4, filtered, and concentrated to obtain the crude product, which was used in the next step without further purification. C9H 12 F2NO4(M- t Bu+2H) + LC-MS calculated value for this: m / z = 236.1; measured value 236.0.

[0333] Step 4. tert-butyl(1R,3R,4R,5S)-5-(difluoromethoxy)-3-ethynyl-2-azabicyclo[2.2.1]heptane-2-carboxylate [ka] To a solution of tert-butyl(1R,3R,4R,5S)-5-(difluoromethoxy)-3-formyl-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.61 g, 5.52 mmol) in MeOH (28 mL), dimethyl(1-diazo-2-oxopropyl)phosphonate (1.59 g, 8.28 mmol) and K2CO3 (2.29 g, 16.6 mmol) were added. After stirring for 18 hours, the reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated. The residue was extracted with ethyl acetate, filtered through diatomaceous earth, and concentrated. The crude product was purified by FCC (0-60% ethyl acetate / hexane) to obtain the subtitle compound (0.71 g, 45% yield, over two steps). 10 H 12 F2NO3(M- t Bu+2H) + LC-MS calculated value for this: m / z = 232.1; measured value 232.1.

[0334] Step 5. ((1R,3R,4R,5S)-5-(difluoromethoxy)-3-ethynyl-2-azabicyclo[2.2.1]heptan-2-yl)(1-fluorocyclopropyl)methanone To a solution of tert-butyl(1R,3R,4R,5S)-5-(difluoromethoxy)-3-ethynyl-2-azabicyclo[2.2.1]heptane-2-carboxylate (0.71 g, 2.49 mmol) in 1,4-dioxane (7 mL), 4N HCl in 1,4-dioxane (7 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After completion, volatile substances were evaporated under reduced pressure. The residue was dissolved in DMF (0.5 mL).

[0335] In a separate container containing 1-fluorocyclopropane-1-carboxylic acid (0.52 g, 5.00 mmol) in DMF (12 mL), DIPEA (1.30 mL, 7.46 mmol), followed by HATU (1.89 g, 5.00 mmol), was added. After stirring the mixture for 15 minutes, the above solution was added. The resulting mixture was stirred for 0.5 hours. Upon completion, the reaction mixture was diluted with HCl, washed five times with brine, dried over Na2SO4, filtered, and concentrated. The crude product was further purified with FCC (0-30% HCl / hexane) to obtain the title compound. 13 H 15 F3NO2(M+H) + LC-MS calculated value for this: m / z = 274.1; measured value 274.1.

[0336] Intermediate 11. tert-butyl(1R,3R,4R,5S)-5-cyclopropoxy-3-ethynyl-2-azabicyclo[2.2.1]heptane-2-carboxylate [ka] Step 1.2-(tert-butyl)3-methyl(1R,3R,4R,5S)-5-(vinyloxy)-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate [ka] A mixture of 2-(tert-butyl)3-methyl(1R,3R,4R,5S)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (intermediate 4, 0.94 g, 3.46 mmol), palladium(II) acetate (0.16 g, 0.69 mmol), 1,10-phenanthroline (0.13 g, 0.69 mmol), NEt3 (0.95 mL, 6.93 mmol), and n-butyl vinyl ether (13.5 mL, 104 mmol) was spurged with N2 and heated at 90°C for 18 hours. Upon completion, the reaction mixture was cooled to room temperature and poured into water. The aqueous layer was extracted with phenylethylamine, washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by FCC (0-30% RINKAN / hexane) to obtain the subtitle compound (0.86 g, 83% yield). 11 H 16 NO5(M- t Bu+2H) + LC-MS calculated value for this: m / z = 242.1; measured value 242.1.

[0337] Step 2.2-(tert-butyl)3-methyl(1R,3R,4R,5S)-5-cyclopropoxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate [ka] To a flask containing DCM (15 mL), diethylzinc (1N in hexane, 11.6 mL, 11.6 mmol) was added at 0°C, followed by the slow addition of a DCM solution (3 mL) containing methylene iodide (3.10 g, 11.6 mmol). The mixture was stirred at 0°C for 0.5 hours, after which a DCM solution (3 mL) containing 2-(tert-butyl)3-methyl(1R,3R,4R,5S)-5-(vinyloxy)-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (0.86 g, 2.89 mmol) was added. The resulting mixture was stirred at 0°C for 8 hours. Upon completion, the reaction mixture was quenched by slowly adding a NaHCO3 solution. The mixture was filtered through diatomaceous earth. The organic layer was separated, dried over Na2SO4, filtered, and concentrated. The crude product was purified by FCC (0-30% alkylammonium hexane) to obtain the secondary compound (0.70 g, 77% yield). 12 H 18 NO5(M- t Bu+2H) + LC-MS calculated value for this: m / z = 256.1; measured value 256.1.

[0338] Step 3. tert-butyl(1R,3R,4R,5S)-5-cyclopropoxy-3-(hydroxymethyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate [ka] To a solution of 2-(tert-butyl)3-methyl(1R,3R,4R,5S)-5-cyclopropoxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (0.70 g, 2.23 mmol) in THF (11 mL), LiBH4 (2 M in THF, 2.8 mL, 5.58 mmol) was added. The mixture was stirred at room temperature for 16 hours, then quenched by slowly adding saturated aqueous NH4Cl solution at 0°C. The mixture was diluted with ethyl acetate, washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by FCC (0-100% ethyl acetate / hexane) to obtain the subtitle compound (0.47 g, 74% yield). 11 H18 NO4(M- t Bu+2H) + LC-MS calculated value for this: m / z = 228.1; measured value 228.1.

[0339] Step 4. tert-butyl(1R,3R,4R,5S)-5-cyclopropoxy-3-formyl-2-azabicyclo[2.2.1]heptane-2-carboxylate [ka] To a solution of tert-butyl(1R,3R,4R,5S)-5-cyclopropoxy-3-(hydroxymethyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (0.47 g, 1.65 mmol) in DCM (8 mL), des-martin periodinane (1.05 g, 2.48 mmol) was gradually added. The resulting mixture was stirred at room temperature for 0.5 hours. After completion, a saturated Na2S2O3 solution (5 mL) was added to the reaction mixture. The mixture was stirred for a further 0.5 hours. The organic phase was separated, dried over Na2SO4, filtered, and concentrated to obtain the crude product, which was used in the next step without further purification. 11 H 16 NO4(M- t Bu+2H) + LC-MS calculated value for this: m / z = 226.1; measured value 226.0.

[0340] Step 5. tert-butyl(1R,3R,4R,5S)-5-cyclopropoxy-3-ethynyl-2-azabicyclo[2.2.1]heptane-2-carboxylate To a solution of tert-butyl(1R,3R,4R,5S)-5-cyclopropoxy-3-formyl-2-azabicyclo[2.2.1]heptane-2-carboxylate (0.47 g, 1.65 mmol) in MeOH (8 mL), dimethyl(1-diazo-2-oxopropyl)phosphonate (0.48 g, 2.48 mmol) and K2CO3 (0.69 g, 4.96 mmol) were added. After stirring for 18 hours, the reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated. The residue was extracted with ethyl acetate, filtered through diatomaceous earth, and concentrated. The crude product was purified by FCC (0-60% ethyl acetate / hexane) to obtain the title compound (0.30 g, 65% yield, over two steps). 12 H 16 NO3(M- t Bu+2H) + LC-MS calculated value for this: m / z = 222.1; measured value 222.1.

[0341] Intermediate 12. tert-butyl(1R,4R,5S)-5-((6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-3-iodo-2-(methylthio)quinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] Step 1.2-Amino-4-Bromo-3-Fluoro-5-iodobenzoic acid [ka] 1-iodopyrrolidine-2,5-dione (21 g, 94 mmol) was gradually added to a DMF solution (200 mL) containing 2-amino-4-bromo-3-fluorobenzoic acid (20 g, 85 mmol). The mixture was stirred at 80°C for 3 hours, and then cooled to 0°C. When water (500 mL) was added to the stirring mixture, a precipitate formed. The solid was collected on a frit filter, washed with cold water, and dried under reduced pressure to obtain the subtitle compound (28 g, 90% yield).

[0342] Step 2.7-Bromo-8-fluoro-6-iodo-2H-benzo[d][1,3]oxazine-2,4(1H)-dione [ka] To a 1,4-dioxane solution (200 mL) containing 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (28 g, 78 mmol), triphosgene (11.5 g, 39 mmol) was added. After stirring at 80°C for 2 hours, the reaction mixture was cooled to 0°C and filtered. When 1N HCl (100 mL) was added to the filtrate while vigorously stirring, a precipitate formed. The solid was collected on a frit filter and washed with siRNA to obtain the subtitle compound (19 g, 63% yield).

[0343] Step 3. 7-Bromo-8-fluoro-6-iodo-3-nitroquinoline-2,4-diol [ka] DIPEA (17 mL, 98 mmol) was added to a toluene solution (200 mL) containing 7-bromo-8-fluoro-6-iodo-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (19 g, 49 mmol) and ethyl 2-nitroacetate (13 g, 98 mmol). The reaction mixture was stirred at 95°C for 3 hours. After completion, the reaction mixture was cooled to 0°C. The precipitate was collected on a frit filter and washed with a small amount of hexane to obtain the subtitle compound (10 g, 47% yield).

[0344] Step 4.7-Bromo-2,4-dichloro-8-fluoro-6-iodo-3-nitroquinoline [ka] DIPEA (8.1 mL, 47 mmol) was added to a mixture of 7-bromo-8-fluoro-6-iodo-3-nitroquinoline-2,4-diol (10 g, 23 mmol) in POCl3 (11 mL), and the reaction mixture was stirred at 100°C for 2 hours. The solvent was removed under vacuum, and then the mixture was azeotropically mixed with toluene three times to obtain the crude product, which could be further purified by FCC.

[0345] Step 5. tert-butyl(1R,4R,5S)-5-((7-bromo-8-fluoro-6-iodo-2-(methylthio)-3-nitroquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] To a solution of 7-bromo-2,4-dichloro-8-fluoro-6-iodo-3-nitroquinoline (25.0 g, 53.7 mmol) and tert-butyl (1R,4R,5S)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylate (11.2 g, 56.4 mmol) in DMF (107 mL), DIPEA (28.1 mL, 161 mmol) was added, and the reaction mixture was heated to 60 °C for 0.5 hours. The mixture was cooled to 0 °C, and a solution of sodium thiomethoxide (11.3 g, 161 mmol) in MeOH (30 mL) was slowly added, and the reaction mixture was stirred at this temperature for 1 hour. Ice and water were added, and the solid was filtered. The filtrate was extracted with ethyl acetate and combined with the solid. The combined solid was dried on weighing paper to obtain the subtitle compound (20.0 g, 58% yield). 20 H 22 BrFIN4O4S + (M+H) + LC-MS calculated value for this: m / z = 639.0; measured value: 638.9.

[0346] Step 6. tert-butyl(1R,4R,5S)-5-((7-bromo-8-fluoro-6-iodo-2-(methylthio)-3-nitroquinoline-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] To a stirred solution of tert-butyl(1R,4R,5S)-5-((7-bromo-8-fluoro-6-iodo-2-(methylthio)-3-nitroquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (20.0 g, 31.3 mmol) in THF (63 mL), NEt3 (12.8 mL, 94 mmol), DMAP (0.38 g, 3.13 mmol), and Boc2O (13.7 g, 62.6 mmol) were sequentially added at room temperature, and the mixture was stirred for 16 hours. The reaction mixture was diluted with ELISA and washed with saturated NaHCO3 and brine. The organic layer was dried over MgSO4, filtered, and concentrated. The crude product was used without purification. 21 H 22 BrFIN4O6S + (M- t Bu+2H) + LC-MS calculated value for this: m / z = 683.0; measured value: 682.9.

[0347] Step 7. tert-butyl(1R,4R,5S)-5-((3-amino-7-bromo-8-fluoro-6-iodo-2-(methylthio)quinoline-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] A flask equipped with a mechanical stirrer was packed with tert-butyl(1R,4R,5S)-5-((7-bromo-8-fluoro-6-iodo-2-(methylthio)-3-nitroquinoline-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (23.1 g, 31.3 mmol), MeOH (52 mL), water (52 mL), and THF (52 mL). Iron (17.5 g, 313 mmol) and ammonium chloride (16.7 g, 313 mmol) were added, and the reaction mixture was stirred at 60°C for 1 hour. The reaction mixture was diluted with ethyl acetate and filtered through diatomaceous earth. The layers were separated, the organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The product was used without purification. 25 H 32 BrFIN4O4S + (M+H) + LC-MS calculated value for this: m / z = 709.0; measured value: 709.0.

[0348] Step 8. tert-butyl(1R,4R,5S)-5-((3-amino-7-bromo-6-(2-cyanoethyl)-8-fluoro-2-(methylthio)quinoline-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] To a 78 mL DMF solution containing tert-butyl(1R,4R,5S)-5-((3-amino-7-bromo-8-fluoro-6-iodo-2-(methylthio)quinoline-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (20.3 g, 31.0 mmol) and Pd(PPh3)4 (7.2 g, 6.2 mmol), acrylonitrile (20.3 mL, 310 mmol), DIPEA (8.1 mL, 46.5 mmol), and tetramethylammonium formate (25% solution in water, 29.6 mL, 62.0 mmol) were added. The headspace was purged with nitrogen, and the reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed five times with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by FCC (0-70% toluene / hexane) to obtain the subtitle compound (10.3 g, 57% yield, over 3 steps). 24 H 28 BrFN5O4S + (M- t Bu+2H) + LC-MS calculated value for this: m / z = 580.1; measured value 580.1.

[0349] Step 9. tert-butyl(1R,4R,5S)-5-((3-amino-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-(methylthio)quinoline-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] A mixture of tert-butyl(1R,4R,5S)-5-((3-amino-7-bromo-6-(2-cyanoethyl)-8-fluoro-2-(methylthio)-quinoline-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (10.3 g, 16.2 mmol), (2,3-dichlorophenyl)boronic acid (3.70 g, 19.42 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (1.15 g, 1.62 mmol), and potassium fluoride (3.76 g, 64.7 mmol) in 1,4-dioxane (74 mL) and water (7.4 mL) was spurged with N2 and heated at 100°C for 2 hours. Once complete, the mixture was cooled to room temperature and poured into water. The solution was extracted with RINKAN, washed with brine, dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by FCC (0-100% RINKAN / hexane) to obtain the subtitle compound (10.0 g, 88% yield). 30 H 31 Cl2FN5O4S(M- t Bu+2H) + LC-MS calculated value for this: m / z = 646.1; measured value 646.1.

[0350] Step 10. tert-butyl(1R,4R,5S)-5-((tert-butoxycarbonyl)(6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-3-iodo-2-(methylthio)quinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] To a 240 mL MeCN solution of tert-butyl(1R,4R,5S)-5-((3-amino-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-(methylthio)quinoline-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (10.0 g, 14.2 mmol)), cooled to -20°C, 1.5 mL (28.5 mmol) of H2SO4 in 4 mL of water was added, followed by 2.46 g (35.6 mmol) of sodium nitrite in 4 mL of water. The resulting mixture gradually turned red and was stirred for a further 10 minutes at an internal temperature <-10°C. When potassium iodide (9.45 g, 56.9 mmol) was added to the mixture little by little, vigorous bubbling occurred. After adding the reagents, the reaction mixture was stirred for a further 0.5 hours at -10°C, and then warmed to room temperature. The reaction mixture was poured into a sodium thiosulfate solution and then extracted with siRNA. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was used in the next step without purification. 30 H 29 Cl2FIN4O4S + (M- t Bu+2H) + LC-MS calculated value for this: m / z = 757.0; measured value: 757.0.

[0351] Step 11. tert-butyl(1R,4R,5S)-5-((6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-3-iodo-2-(methylthio)quinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate To tert-butyl(1R,4R,5S)-5-((tert-butoxycarbonyl)(6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-3-iodo-2-(methylthio)quinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (11.6 g, 14.2 mmol) dissolved in MeCN (19 mL), TFA (76 mL) was added. The mixture was stirred at room temperature for 5 hours and then concentrated.

[0352] To the residue dissolved in THF (29 mL), DIPEA (12.4 mL, 71.2 mmol) and Boc2O (6.21 g, 28.5 mmol) were added. The mixture was stirred at room temperature for 0.5 hours. After completion, the mixture was diluted with siRNA, washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by FCC (0-100% siRNA / hexane) to obtain the title compound (3.05 g, 30% yield, over two steps). 29 H 29 Cl2FIN4O2S(M+H) + LC-MS calculated value for this: m / z = 713.0; measured value: 713.0.

[0353] Intermediate 13. tert-butyl(1R,3R,4R,5S)-3-ethynyl-5-(trifluoromethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate [ka] Step 1.2-(tert-butyl)3-methyl(1R,3R,4R,5S)-5-(trifluoromethoxy)-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate [ka] To a flask containing 2-(tert-butyl)3-methyl(1R,3R,4R,5S)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (intermediate 4, 4.53 g, 16.7 mmol), potassium fluoride (2.91 g, 50.1 mmol), silver trifluoromethanesulfonate (8.58 g, 33.4 mmol), and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanbis(tetrafluoroborate) (8.87 g, 25.1 mmol), anhydrous ethyl acetate (167 mL), trifluoromethyltrimethylsilane (4.9 mL, 33.4 mmol), and 2-fluoropyridine (2.9 mL, 33.4 mmol) were added under N2 conditions. The reaction mixture was covered with aluminum foil and stirred at room temperature for 12 hours. Once complete, the mixture was filtered through Celite and concentrated. The crude product was further purified by silica chromatography (0%-20% siRNA / hexane) to obtain the title compound as a colorless oil (2.74 g, 48% yield). 10 H 13 F3NO5(M- t Bu+2H) + LC-MS calculated value for this: m / z = 284.1; measured value 284.1.

[0354] Step 2. tert-butyl(1R,3R,4R,5S)-3-(hydroxymethyl)-5-(trifluoromethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate [ka] To a solution of 2-(tert-butyl)3-methyl(1R,3R,4R,5S)-5-(trifluoromethoxy)-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (2.74 g, 8.08 mmol) in THF (40 mL), lithium borohydride (2 M in THF, 10.1 mL, 20.2 mmol) was added. The mixture was stirred at room temperature for 16 hours, then quenched by slowly adding saturated aqueous NH4Cl solution. The mixture was diluted with ethyl acetate, washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica chromatography (0-60% ethyl acetate / hexane) to obtain the title compound as a colorless oil (2.10 g, 84% yield). C9H 13 F3NO4(M- t Bu+2H) + LC-MS calculated value for this: m / z = 256.1; measured value 256.1.

[0355] Step 3. tert-butyl(1R,3R,4R,5S)-3-formyl-5-(trifluoromethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate [ka] To a solution of tert-butyl(1R,3R,4R,5S)-3-(hydroxymethyl)-5-(trifluoromethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate (2.10 g, 6.75 mmol) in DCM (34 mL), des-martin periodinane (4.29 g, 10.1 mmol) was added gradually. The resulting mixture was stirred at room temperature for 1 hour. After completion, saturated aqueous Na2S2O3 (5 mL) was added to the reaction mixture. The mixture was stirred for a further 0.5 hours. The organic phase was separated, dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was used in the next step without further purification. C9H 11 F3NO4(M- t Bu+2H) + LC-MS calculated value for this: m / z = 254.1; measured value 254.1.

[0356] Step 4. tert-butyl(1R,3R,4R,5S)-3-ethynyl-5-(trifluoromethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate To a solution of tert-butyl(1R,3R,4R,5S)-3-formyl-5-(trifluoromethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate (2.09 g, 6.75 mmol) in methanol (34 mL), dimethyl(1-diazo-2-oxopropyl)phosphonate (1.95 g, 10.1 mmol) and potassium carbonate (2.80 g, 20.3 mmol) were added. After stirring for 16 hours, the reaction mixture was filtered through Celite. The filtrate was concentrated. The residue was extracted with ethyl acetate, filtered through Celite, and concentrated. The crude product was purified by silica chromatography (0-20% ethyl acetate / hexane) to obtain the title compound (1.40 g, 68% yield, obtained in two steps). 10 H 11 F3NO3(M- t Bu+2H) + LC-MS calculated value for this: m / z = 250.1; measured value 250.1.

[0357] Example 1.3-((R a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-methoxy-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile [ka] Step 1. ((1R,3R,4R,5S)-5-((tert-butyldiphenylsilyl)oxy)-3-ethynyl-2-azabicyclo[2.2.1]heptan-2-yl)(cyclopropyl)methanone [ka] To a solution of tert-butyl(1R,3R,4R,5S)-5-((tert-butyldiphenylsilyl)oxy)-3-ethynyl-2-azabicyclo[2.2.1]heptane-2-carboxylate (intermediate 5, 0.95 g, 2.00 mmol) in DCM (5 mL), TFA (5 mL) was added. The reaction mixture was stirred at room temperature for 0.5 hours. After completion, volatile substances were evaporated under reduced pressure. The residue was dissolved in DCM (10 mL). After stirring, DIPEA (1.7 mL, 10.0 mmol) was added, followed by cyclopropanecarbonyl chloride (0.26 g, 2.50 mmol). The mixture was stirred for 0.5 hours. After completion, the reaction mixture was diluted with DCM, washed with water, dried over Na2SO4, filtered, and concentrated. The crude product was used directly in the next step without further purification. 28 H 34 NO2Si(M+H) + LC-MS calculated value for this: m / z = 444.2; measured value 444.2.

[0358] Step 2. tert-butyl(1R,4R,5S)-5-((R a )-8-(2-cyanoethyl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-hydroxy-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] tert-butyl(1R,4R,5S)-5-(((R in DMF (13.8 mL) a)-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-3-iodo-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate 2, 0.76g, 1.11mmol), ((1R,3R,4R,5S)-5-((tert-butyldiphenylsilyl)oxy)-3-ethynyl-2-azabicyclo A mixture of ro[2.2.1]heptan-2-yl)(cyclopropyl)methanone (0.84 g, 1.89 mmol), copper(I) iodide (0.085 g, 0.444 mmol), Pd(PPh3)4 (0.26 g, 0.222 mmol), CsF (0.51 g, 3.33 mmol), and DIPEA (1.9 mL, 11.1 mmol) was spurged with N2 and heated at 70°C for 1 hour. Then Cs2CO3 (1.09 g, 3.33 mmol) was added to the reaction mixture. The resulting slurry was stirred further at 90°C for 18 hours. After completion, the mixture was cooled to room temperature and poured into water. The solution was extracted twice with SiO2. The combined organic layer was then washed five times with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by FCC (0-100% alkylammonium sulfate / hexane) to obtain the subtitle compound (0.50 g, 45% yield). 41 H 43 Cl2FN5O4(M+H) + LC-MS calculated value for this: m / z = 758.3; measured value: 758.2.

[0359] Step 3. tert-butyl(1R,4R,5S)-5-((R a )-8-(2-cyanoethyl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-methoxy-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] tert-butyl(1R,4R,5S)-5-((R) in DMF (3.5 mL) aTo a solution of )-8-(2-cyanoethyl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-hydroxy-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (0.50 g, 0.66 mmol), sodium hydride (60% dispersion in mineral oil, 0.079 g, 1.98 mmol) was added gradually. After stirring at room temperature for 0.5 hours, a solution of iodomethane (0.99 mL, 1.98 mmol) in 2N tert-butyl methyl ether was slowly added. The resulting mixture was stirred for a further 15 minutes and quenched by adding saturated NH4Cl solution dropwise. The mixture was diluted with ethyl acetate, washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was further purified using FCC (0-100% ethyl acetate / hexane). 42 H 45 Cl2FN5O4(M+H) + LC-MS calculated value for this: m / z = 772.3; measured value 772.2.

[0360] Step 4.3-((R a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-methoxy-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile tert-butyl(1R,4R,5S)-5-((R) in DCM (1 mL) aTo a solution of )-8-(2-cyanoethyl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-methoxy-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (0.030 g, 0.038 mmol), MeCN (0.1 mL) and TFA (1.1 mL) were added. The reaction mixture was stirred at room temperature for 0.5 hours. After completion, volatile substances were removed under reduced pressure, and the residue was dissolved in MeCN (4 mL) and water (1 mL) and preparatively LC-MS XBRIDGE® C 18 The compound was purified by column chromatography and eluted at a flow rate of 60 mL / min using a MeCN / water gradient containing 0.1% TFA to obtain the title compound. 37 H 37 Cl2FN5O2(M+H) + LC-MS calculated value for this: m / z = 672.2; measured value 672.2. 1 1H NMR was collected using TFA salt. 1 H NMR(600MHz,DMSO-d6)δ 9.26(s,1H), 8.12(s,1H), 8.07(s,1H), 7.85(dd,J=8.2,1.5Hz,1H), 7.59(t,J=7.8Hz,1H), 7.46(dd,J=7.6,1.5Hz,1H) , 6.70(s,1H), 5.76-5.73(m,1H), 4.86(d,J=6.0Hz,1H), 4.78(s,1H), 4.50(s,1H), 3.97(dd,J=7.2,2.7Hz,1H), 3.87(d t,J=6.2,3.0Hz,1H), 3.75(s,1H), 3.39(dd,J=7.4,3.8Hz,1H), 3.34(s,3H), 3.03(dt,J=14.0,6.5Hz,1H), 2.88-2.78( m,5H), 2.72-2.63(m,2H), 2.36(d,J=9.1Hz,1H), 2.11(m,2H), 1.69-1.52(m,4H), 0.95-0.82(m,3H), 0.79-0.73(m,1H).

[0361] Alternative atropisomer 3-((S a)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-methoxy-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile is tert-butyl(1R,4R,5S)-5-(((R a )-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-3-iodo-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate is replaced with tert-butyl(1R,4R,5S)-5-(((S a Starting from )-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-3-iodo-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate, it can be prepared by a similar route by carrying out a process similar to the steps described above.

[0362] Example 2.3-((R a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-fluoro-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile [ka] Step 1. ((1R,3R,4R,5R)-5-((tert-butyldiphenylsilyl)oxy)-3-ethynyl-2-azabicyclo[2.2.1]heptan-2-yl)(cyclopropyl)methanone [ka] The subtitle compound was prepared in a manner similar to that of Example 1, Step 1, using tert-butyl(1R,3R,4R,5S)-5-((tert-butyldiphenylsilyl)oxy)-3-ethynyl-2-azabicyclo[2.2.1]heptane-2-carboxylate (intermediate 6) instead of tert-butyl(1R,3R,4R,5R)-5-((tert-butyldiphenylsilyl)oxy)-3-ethynyl-2-azabicyclo[2.2.1]heptane-2-carboxylate (intermediate 6) instead of tert-butyl(1R,3R,4R,5S). 28 H 34 NO2Si(M+H) + LC-MS calculated value for this: m / z = 444.2; measured value 444.2.

[0363] Step 2. tert-butyl(1R,4R,5S)-5-((R a )-8-(2-cyanoethyl)-2-((1R,3R,4R,5R)-2-(cyclopropanecarbonyl)-5-hydroxy-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] The subtitle compound was prepared in a manner similar to that of Example 1, Step 2, using ((1R,3R,4R,5S)-5-((tert-butyldiphenylsilyl)oxy)-3-ethynyl-2-azabicyclo[2.2.1]heptan-2-yl)(cyclopropyl)methane instead of ((1R,3R,4R,5R)-5-((tert-butyldiphenylsilyl)oxy)-3-ethynyl-2-azabicyclo[2.2.1]heptan-2-yl)(cyclopropyl)methane. 41 H 43 Cl2FN5O4(M+H) + LC-MS calculated value for this: m / z = 758.3; measured value: 758.2.

[0364] Step 3. tert-butyl(1R,4R,5S)-5-((R a)-8-(2-cyanoethyl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-fluoro-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] tert-butyl(1R,4R,5S)-5-((R) in DCM (0.2 mL) a To a solution of )-8-(2-cyanoethyl)-2-((1R,3R,4R,5R)-2-(cyclopropanecarbonyl)-5-hydroxy-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (0.015 g, 0.020 mmol), diethylaminosulfur trifluoride (6.4 mg, 0.040 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 hours and quenched with saturated NaHCO3 solution at 0°C. The resulting mixture was diluted with ELISA, washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was used in the next step without further purification. 41 H 42 Cl2F2N5O3(M+H) + LC-MS calculated value for this: m / z = 760.3; measured value: 760.4.

[0365] Step 4.3-((R a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-fluoro-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile The title compound should be changed from tert-butyl(1R,4R,5S)-5-((R)-8-(2-cyanoethyl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-methoxy-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate to tert-butyl(1R,4R,5S)-5-((R a A preparation was made using )-8-(2-cyanoethyl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-fluoro-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate in a manner similar to that of Example 1, Step 4. 36 H 34 Cl2F2N5O(M+H) + LC-MS calculated value for this: m / z = 660.2; measured value 660.2.

[0366] Alternative atropisomer 3-((S a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-fluoro-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile is tert-butyl(1R,4R,5S)-5-(((R a )-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-3-iodo-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate is replaced with tert-butyl(1R,4R,5S)-5-(((S aStarting from )-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-3-iodo-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate, it can be prepared by a similar route by carrying out a process similar to the steps described above.

[0367] Example 3.3-((R a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1S,2S,4R,5R,7R)-6-(cyclopropanecarbonyl)-6-azatricyclo[3.2.1.0 2,4 ]Octane-7-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile [ka] Step 1. Cyclopropyl((1S,2S,4R,5R,7R)-7-ethynyl-6-azatricyclo[3.2.1.0 2,4 Octane-6-yl)methanone [ka] The subtitle compound is changed from tert-butyl(1R,3R,4R,5S)-5-((tert-butyldiphenylsilyl)oxy)-3-ethynyl-2-azabicyclo[2.2.1]heptane-2-carboxylate (intermediate 5) to tert-butyl(1S,2S,4R,5R,7R)-7-ethynyl-6-azatricyclo[3.2.1.0 2,4 Octane-6-carboxylate (intermediate 7) was used to prepare the mixture in a manner similar to that of Example 1, Step 1. 13 H 16 NO(M+H) + LC-MS calculated value for this: m / z = 202.1; measured value 202.1.

[0368] Step 2. tert-butyl(1R,4R,5S)-5-((R a)-8-(2-cyanoethyl)-2-((1S,2S,4R,5R,7R)-6-(cyclopropanecarbonyl)-6-azatricyclo[3.2.1.0 2,4 Octane-7-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] tert-butyl(1R,4R,5S)-5-(((R in DMF (0.2 mL) a )-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-3-iodo-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate 2, 0.015g, 0.022mmol), cyclopropyl((1S,2S,4R,5R,7R)-7-ethynyl-6-azabicyclo[3.2.1.0 2,4 A mixture of octan-6-yl)methanone (0.009 g, 0.044 mmol), copper(I) iodide (0.002 g, 0.009 mmol), Pd(PPh3)4 (0.005 g, 0.004 mmol), and DIPEA (39 μL, 0.220 mmol) was spurged with N2 and heated at 70°C for 1 hour. Then, Cs2CO3 (0.022 g, 0.066 mmol) was added to the reaction mixture. The resulting slurry was stirred at 90°C for a further 18 hours. Once complete, the mixture was cooled to room temperature and poured into water. The solution was extracted twice with ELISA. The combined organic layer was then washed five times with brine, dried over Na2SO4, filtered, and concentrated. The crude product was used in the next step without further purification. 42 H 43 Cl2FN5O3(M+H) + LC-MS calculated value for this: m / z = 754.3; measured value: 754.3.

[0369] Step 3.3-((R a)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1S,2S,4R,5R,7R)-6-(cyclopropanecarbonyl)-6-azatricyclo[3.2.1.0 2,4 ]Octane-7-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile The title compound is tert-butyl(1R,4R,5S)-5-((R a )-8-(2-cyanoethyl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-methoxy-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate is replaced with tert-butyl(1R,4R,5S)-5-((R a )-8-(2-cyanoethyl)-2-((1S,2S,4R,5R,7R)-6-(cyclopropanecarbonyl)-6-azatricyclo[3.2.1.0 2,4 [Octane-7-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate was used and prepared in a manner similar to that of Example 1, Step 4. 37 H 35 Cl2F2N5O(M+H) + LC-MS calculated value for this: m / z = 654.2; measured value 654.2.

[0370] Alternative atropisomer 3-((S a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1S,2S,4R,5R,7R)-6-(cyclopropanecarbonyl)-6-azatricyclo[3.2.1.0 2,4Octane-7-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile is tert-butyl(1R,4R,5S)-5-(((R a )-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-3-iodo-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate is replaced with tert-butyl(1R,4R,5S)-5-(((S a Starting from )-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-3-iodo-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate, it can be prepared by a similar route by carrying out a process similar to the steps described above.

[0371] Example 4.3-((R a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-(methoxy-d3)-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile [ka] Step 1. tert-butyl(1R,4R,5S)-5-((R a )-8-(2-cyanoethyl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-(methoxy-d3)-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] The subtitle compound was prepared using iodomethane-d3 instead of iodomethane, in a manner similar to that of Example 1, Step 3. 42 H 42 D3Cl2FN5O4(M+H) + LC-MS calculated value for this: m / z = 775.3; measured value: 775.2.

[0372] Step 2.3-((R a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-(methoxy-d3)-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile The title compound should be changed from tert-butyl(1R,4R,5S)-5-((R)-8-(2-cyanoethyl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-methoxy-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate to tert-butyl(1R,4R,5S)-5-((R a A preparation was made using )-8-(2-cyanoethyl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-(methoxy-d3)-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate in a manner similar to that of Example 1, Step 4. 37 H 34 D3Cl2F2N5O2(M+H) + LC-MS calculated value for this: m / z = 675.2; measured value: 675.3.

[0373] Alternative atropisomer 3-((S a)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-(methoxy-d3)-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile is tert-butyl(1R,4R,5S)-5-((R a )-8-(2-cyanoethyl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-hydroxy-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate is replaced with tert-butyl(1R,4R,5S)-5-((S a Starting from )-8-(2-cyanoethyl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-hydroxy-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate, it can be prepared by a similar route by carrying out a process similar to the steps described above.

[0374] Example 5.3-((R a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-(pyridine-3-yloxy)-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile [ka] Step 1. tert-butyl(1R,4R,5S)-5-((R a)-8-(2-cyanoethyl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-(pyridine-3-yloxy)-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] tert-butyl(1R,4R,5S)-5-((R) in toluene (0.5 mL) a )-8-(2-cyanoethyl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-hydroxy-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Example 1, Step A mixture of 2 (0.035 g, 0.046 mmol), copper(I) iodide (0.007 g, 0.035 mmol), 3,4,7,8-tetramethyl-1,10-phenanthroline (0.016 g, 0.069 mmol), Cs2CO3 (0.113 g, 0.346 mmol), and 3-iodopyridine (0.047 g, 0.231 mmol) was spurged with N2 and heated at 130°C for 18 hours. After completion, the mixture was cooled to room temperature and diluted with siRNA and saturated NH4Cl solution. The organic layer was separated. The aqueous solution was extracted twice with siRNA. The combined organic layer was then washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was used in the next step without further purification. 46 H 46 Cl2FN6O4(M+H) + LC-MS calculated value for this: m / z = 835.3; measured value: 835.2.

[0375] Step 2.3-((R a)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-(pyridine-3-yloxy)-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile The title compound is tert-butyl(1R,4R,5S)-5-((R a )-8-(2-cyanoethyl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-methoxy-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate is replaced with tert-butyl(1R,4R,5S)-5-((R a A preparation was made using )-8-(2-cyanoethyl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-(pyridine-3-yloxy)-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate in a manner similar to that of Example 1, Step 4. 41 H 38 Cl2FN6O2(M+H) + LC-MS calculated value for this: m / z = 735.2; measured value 735.2.

[0376] Alternative atropisomer 3-((S a)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-(pyridine-3-yloxy)-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile is tert-butyl(1R,4R,5S)-5-((R a )-8-(2-cyanoethyl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-hydroxy-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate is replaced with tert-butyl(1R,4R,5S)-5-((S a Starting from )-8-(2-cyanoethyl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-hydroxy-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate, it can be prepared by a similar route by carrying out a process similar to the steps described above.

[0377] Example 6.3-((R a )-2-((1R,3R,4R,5S)-5-(benzyloxy)-2-(cyclopropanecarbonyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile [ka] Step 1. tert-butyl(1R,4R,5S)-5-((R a)-2-((1R,3R,4R,5S)-5-(benzyloxy)-2-(cyclopropanecarbonyl)-2-azabicyclo[2.2.1]heptan-3-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] The subtitle compound was prepared in a manner similar to that of Example 1, Step 3, using benzyl bromide instead of iodomethane. 48 H 49 Cl2FN5O4(M+H) + LC-MS calculated value for this: m / z = 848.3; measured value: 848.2.

[0378] Step 2.3-((R a )-2-((1R,3R,4R,5S)-5-(benzyloxy)-2-(cyclopropanecarbonyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile The title compound is tert-butyl(1R,4R,5S)-5-((R a )-8-(2-cyanoethyl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-methoxy-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate is replaced with tert-butyl(1R,4R,5S)-5-((R aA preparation was made using )-2-((1R,3R,4R,5S)-5-(benzyloxy)-2-(cyclopropanecarbonyl)-2-azabicyclo[2.2.1]heptan-3-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate in a manner similar to that of Example 1, Step 4. 43 H 41 Cl2FN5O2(M+H) + LC-MS calculated value for this: m / z = 748.3; measured value: 748.2.

[0379] Alternative atropisomer 3-((S a )-2-((1R,3R,4R,5S)-5-(benzyloxy)-2-(cyclopropanecarbonyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile is tert-butyl(1R,4R,5S)-5-((R a )-8-(2-cyanoethyl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-hydroxy-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate is replaced with tert-butyl(1R,4R,5S)-5-((S a Starting from )-8-(2-cyanoethyl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-hydroxy-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate, it can be prepared by a similar route by carrying out a process similar to the steps described above.

[0380] Example 7.3-((R a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-(difluoromethoxy)-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile [ka] Step 1. tert-butyl(1R,4R,5S)-5-((R a )-8-(2-cyanoethyl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-(difluoromethoxy)-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] tert-butyl(1R,4R,5S)-5-((R) in MeCN (0.1 mL) heated at 50°C aA mixture of )-8-(2-cyanoethyl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-hydroxy-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Example 1, Step 2, 0.014 g, 0.018 mmol) and copper iodide (0.001 g, 0.005 mmol) was mixed with a MeCN solution (0.1 mL) of 2,2-difluoro-2-(fluorosulfonyl)acetic acid (0.005 g, 0.027 mmol). The mixture was stirred at the same temperature for 1 hour. Once complete, the mixture was cooled to room temperature and diluted with RINKAN and saturated NH4Cl solution. The organic layer was separated. The aqueous solution was extracted twice with RINKAN. The combined organic layers were then washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was used in the next step without further purification. 42 H 43 Cl2F3N5O4(M+H) + LC-MS calculated value for this: m / z = 808.3; measured value: 808.2.

[0381] Step 2.3-((R a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-(difluoromethoxy)-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile The subject compound is tert-butyl(1R,4R,5S)-5-((R a)-8-(2-cyanoethyl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-methoxy-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate is replaced with tert-butyl(1R,4R,5S)-5-((R a A preparation was made using )-8-(2-cyanoethyl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-(difluoromethoxy)-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate in a manner similar to that of Example 1, Step 4. 37 H 35 Cl2F3N5O2(M+H) + LC-MS calculated value for this: m / z = 708.2; measured value 708.2.

[0382] Alternative atropisomer 3-((S a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-(difluoromethoxy)-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile is tert-butyl(1R,4R,5S)-5-((R a )-8-(2-cyanoethyl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-hydroxy-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate is replaced with tert-butyl(1R,4R,5S)-5-((S aStarting from )-8-(2-cyanoethyl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-hydroxy-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate, it can be prepared by a similar route by carrying out a process similar to the steps described above.

[0383] Example 8.3-((R a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,4R,5S)-5-fluoro-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[2.2.1]heptan-3-yl)-4-((R)-1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile [ka] Step 1. ((1R,3R,4R,5R)-5-((tert-butyldiphenylsilyl)oxy)-3-ethynyl-2-azabicyclo[2.2.1]heptan-2-yl)(1-fluorocyclopropyl)methanone [ka] To a solution of tert-butyl(1R,3R,4R,5R)-5-((tert-butyldiphenylsilyl)oxy)-3-ethynyl-2-azabicyclo[2.2.1]heptane-2-carboxylate (intermediate 6, 0.250 g, 0.53 mmol) in 1,4-dioxane (2 mL), 4N HCl in 1,4-dioxane (2 mL) was added. The reaction mixture was stirred at room temperature for 0.5 hours. After completion, volatile substances were evaporated under reduced pressure. The residue was dissolved in DMF (0.5 mL).

[0384] In a separate container containing 1-fluorocyclopropane-1-carboxylic acid (0.129 g, 1.05 mmol) in DMF (2 mL), DIPEA (0.46 mL, 2.63 mmol), followed by HATU (0.400 g, 1.05 mmol), was added. The mixture was stirred for 15 minutes, after which the aforementioned residue was added as a DMF solution. The resulting mixture was stirred for 0.5 hours. Upon completion, the reaction mixture was diluted with siRNA, washed five times with brine, dried over Na2SO4, filtered, and concentrated. The crude product was further purified with FCC (0-40% siRNA / hexane) to obtain the subtitle compound. 28 H 33 FNO2Si(M+H) + LC-MS calculated value for this: m / z = 462.2; measured value 462.2.

[0385] Step 2. tert-butyl(1R,4R,5S)-5-(4-((R a )-1-(benzyloxy)ethyl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,4R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-5-hydroxy-2-azabicyclo[2.2.1]heptan-3-yl)-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] The subtitle compound is ((1R,3R,4R,5S)-5-((tert-butyldiphenylsilyl)oxy)-3-ethynyl-2-azabicyclo[2.2.1]heptan-2-yl)(cyclopropyl)methanone instead of ((1R,3R,4R,5R)-5-((tert-butyldiphenylsilyl)oxy)-3-ethynyl-2-azabicyclo[2.2.1]heptan-2-yl)(1-fluorocyclopropyl)methanone, and tert-butyl(1R,4R,5S)-5-(((R a)-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-3-iodo-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate 2) is replaced with tert-butyl(1R,4R,5S)-5-((2-((R a A preparation was made using )-1-(benzyloxy)ethyl)-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-3-iodoquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate 8) in a manner similar to that of Example 1, Step 2. 49 H 50 Cl2F2N5O5(M+H) + LC-MS calculated value for this: m / z = 896.3; measured value: 896.2.

[0386] Step 3. tert-butyl(1R,4R,5S)-5-(4-((R a )-1-(benzyloxy)ethyl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,4R,5S)-5-fluoro-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] The subtitle compound is tert-butyl(1R,4R,5S)-5-((R a )-8-(2-cyanoethyl)-2-((1R,3R,4R,5R)-2-(cyclopropanecarbonyl)-5-hydroxy-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate is replaced with tert-butyl(1R,4R,5S)-5-(4-((R aA preparation was made using )-1-(benzyloxy)ethyl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,4R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-5-hydroxy-2-azabicyclo[2.2.1]heptan-3-yl)-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate in a manner similar to that of Example 3, Step 3. 49 H 49 Cl2F3N5O4(M+H) + LC-MS calculated value for this: m / z = 898.3; measured value: 898.2.

[0387] Step 4.3-((R a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,4R,5S)-5-fluoro-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[2.2.1]heptan-3-yl)-4-((R)-1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile tert-butyl(1R,4R,5S)-5-(4-((R in DCM (1.4 mL) cooled to -78°C) aTo a solution of )-1-(benzyloxy)ethyl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,4R,5S)-5-fluoro-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (0.060 g, 0.067 mmol), BCl3 (1N in DCM, 0.34 mL, 0.34 mmol) was added dropwise. The reaction mixture was stirred at -78°C for 1 hour, then warmed to room temperature. After completion, the mixture was cooled to 0°C and saturated NaHCO3 solution (2 mL) was added. The mixture was extracted three times with DCM and concentrated. Dissolve the residue in MeCN (4 mL) and water (1 mL), and perform preparative LC-MS (XBRIDGE® C 18 The compound was purified by column chromatography (using a MeCN / water gradient containing 0.1% TFA, eluting at a flow rate of 60 mL / min) to obtain a pair of atrop isomers. The title compound was isolated as peak 1 of the two atrop isomers. 37 H 35 Cl2F3N5O2(M+H) + LC-MS calculated value for this: m / z = 708.2; measured value 708.2.

[0388] Alternative atropisomer 3-((S a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,4R,5S)-5-fluoro-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[2.2.1]heptan-3-yl)-4-((R)-1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile is tert-butyl(1R,4R,5S)-5-((2-((R a)-1-(benzyloxy)ethyl)-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-3-iodoquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate is replaced with tert-butyl(1R,4R,5S)-5-((2-((S a Starting from )-1-(benzyloxy)ethyl)-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-3-iodoquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate, it can be prepared by a similar route by carrying out a process similar to the steps described above.

[0389] Example 9.3-((R a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,4S,5S)-2-(cyclopropanecarbonyl)-5-(difluoromethyl)-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile [ka] Step 1. Cyclopropyl((1R,3R,4S,5S)-5-(difluoromethyl)-3-ethynyl-2-azabicyclo[2.2.1]heptan-2-yl)methanone [ka] The subtitle compound was prepared in a manner similar to that of Example 1, Step 1, using tert-butyl(1R,3R,4S,5S)-5-(difluoromethyl)-3-ethynyl-2-azabicyclo[2.2.1]heptane-2-carboxylate (intermediate 9) instead ofR,5S)-5-((tert-butyldiphenylsilyl)oxy)-3-ethynyl-2-azabicyclo[2.2.1]heptane-2-carboxylate (intermediate 9) instead of tert-butyl(1R,3R,4S,5S)-5-((tert-butyldiphenylsilyl)oxy)-3-ethynyl-2-azabicyclo[2.2.1]heptane-2-carboxylate (intermediate 9). 13 H 16F2NO(M+H) + LC-MS calculated value for this: m / z = 240.1; measured value 240.1.

[0390] Step 2. tert-butyl(1R,4R,5S)-5-((R a )-8-(2-cyanoethyl)-2-((1R,3R,4S,5S)-2-(cyclopropanecarbonyl)-5-(difluoromethyl)-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] The subtitle compound was prepared in a manner similar to that of Example 1, Step 2, using cyclopropyl((1R,3R,4S,5S)-5-(difluoromethyl)-3-ethynyl-2-azabicyclo[2.2.1]heptan-2-yl)methane instead of ((1R,3R,4R,5S)-5-((tert-butyldiphenylsilyl)oxy)-3-ethynyl-2-azabicyclo[2.2.1]heptan-2-yl)methane. 42 H 43 Cl2F3N5O3(M+H) + LC-MS calculated value for this: m / z = 792.3; measured value: 792.2.

[0391] Step 3.3-((R a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,4S,5S)-2-(cyclopropanecarbonyl)-5-(difluoromethyl)-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile The subject compound is tert-butyl(1R,4R,5S)-5-((R a)-8-(2-cyanoethyl)-2-((1R,3R,4R,5S)-2-(cyclopropanecarbonyl)-5-methoxy-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate is replaced with tert-butyl(1R,4R,5S)-5-((R a A preparation was made using )-8-(2-cyanoethyl)-2-((1R,3R,4S,5S)-2-(cyclopropanecarbonyl)-5-(difluoromethyl)-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate in a manner similar to that of Example 1, Step 4. 37 H 35 Cl2F3N5O(M+H) + LC-MS calculated value for this: m / z = 692.2; measured value: 692.1.

[0392] Alternative atropisomer 3-((S a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,4S,5S)-2-(cyclopropanecarbonyl)-5-(difluoromethyl)-2-azabicyclo[2.2.1]heptan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile is tert-butyl(1R,4R,5S)-5-(((R a )-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-3-iodo-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate is replaced with tert-butyl(1R,4R,5S)-5-(((S aStarting from )-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-3-iodo-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate, it can be prepared by a similar route by carrying out a process similar to the steps described above.

[0393] Example 10.3-((R a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-2-((1R,3R,4R,5S)-5-(difluoromethoxy)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[2.2.1]heptan-3-yl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile [ka] Step 1. ((1R,3R,4R,5S)-5-((tert-butyldiphenylsilyl)oxy)-3-ethynyl-2-azabicyclo[2.2.1]heptan-2-yl)(1-fluorocyclopropyl)methanone [ka] To a solution of tert-butyl(1R,3R,4R,5S)-5-((tert-butyldiphenylsilyl)oxy)-3-ethynyl-2-azabicyclo[2.2.1]heptane-2-carboxylate (intermediate 5, 0.17 g, 0.36 mmol) in 1,4-dioxane (2 mL), 4N HCl in 1,4-dioxane (2 mL) was added. The reaction mixture was stirred at room temperature for 0.5 hours. After completion, volatile substances were evaporated under reduced pressure. The residue was dissolved in DMF (0.5 mL).

[0394] In a separate reaction vessel containing 1-fluorocyclopropane-1-carboxylic acid (0.074 g, 0.72 mmol) in DMF (2 mL), DIPEA (0.31 mL, 1.79 mmol), followed by HATU (0.27 g, 0.72 mmol), was added. After stirring the mixture for 15 minutes, the aforementioned residue was added as a DMF solution. The resulting mixture was stirred for 0.5 hours. Upon completion, the reaction mixture was diluted with siRNA, washed five times with brine, dried over Na₂SO₄, filtered, and concentrated. The crude product was purified with FCC (0-40% siRNA / hexane) to obtain the subtitle compound (0.073 g, 54% yield). 28 H 33 FNO2Si(M+H) + LC-MS calculated value for this: m / z = 462.2; measured value 462.2.

[0395] Step 2. tert-butyl(1R,4R,5S)-5-((R a )-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,4R,5S)-2-(1-fluorocyclopropane-1-carbonyl)-5-hydroxy-2-azabicyclo[2.2.1]heptan-3-yl)-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] tert-butyl(1R,4R,5S)-5-(((R in DMF (0.5 mL) a)-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-3-iodo-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate 2, 0.070g, 0.103mmol), ((1R,3R,4R,5S)-5-((tert-butyldiphenylsilyl)oxy)-3-ethynyl-2-azabicyclo[2.2 A mixture of [1]heptan-2-yl)(1-fluorocyclopropyl)methanone (0.071 g, 0.154 mmol), copper(I) iodide (0.008 g, 0.041 mmol), Pd(PPh3)4 (0.024 g, 0.021 mmol), CsF (0.047 g, 0.308 mmol), and DIPEA (0.18 mL, 1.03 mmol) was spurged with N2 and heated at 70°C for 1 hour. Then Cs2CO3 (0.100 g, 0.308 mmol) was added to the reaction mixture. The resulting slurry was stirred for a further 18 hours at 90°C. After completion, the mixture was cooled to room temperature and poured into water. The solution was extracted twice with SiO2. The combined organic layer was then washed five times with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by FCC (0-100% alkylammonium hexane) to obtain the subtitle compound (0.073 g, 70% yield). 41 H 42 Cl2F2N5O4(M+H) + LC-MS calculated value for this: m / z = 776.3; measured value: 776.2.

[0396] Step 3. tert-butyl(1R,4R,5S)-5-((R a )-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-2-((1R,3R,4R,5S)-5-(difluoromethoxy)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[2.2.1]heptan-3-yl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] tert-butyl(1R,4R,5S)-5-((R) in MeCN (0.1 mL) heated at 50°C a A mixture of )-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,4R,5S)-2-(1-fluorocyclopropane-1-carbonyl)-5-hydroxy-2-azabicyclo[2.2.1]heptan-3-yl)-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (0.035 g, 0.045 mmol) and copper iodide (0.002 g, 0.009 mmol) was mixed with a MeCN solution (0.1 mL) of 2,2-difluoro-2-(fluorosulfonyl)acetic acid (0.012 g, 0.068 mmol). The mixture was stirred at the same temperature for 1 hour. Once complete, the mixture was cooled to room temperature and diluted with RINKAN and saturated NH4Cl solution. The organic layer was separated. The aqueous solution was extracted twice with RINKAN. The combined organic layers were then washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was used in the next step without further purification. 42 H 42 Cl2F4N5O4(M+H) + LC-MS calculated value for this: m / z = 826.3; measured value: 826.2.

[0397] Step 4.3-((R a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-2-((1R,3R,4R,5S)-5-(difluoromethoxy)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[2.2.1]heptan-3-yl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile tert-butyl(1R,4R,5S)-5-((R) in DCM (1 mL) aTo a solution of )-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-2-((1R,3R,4R,5S)-5-(difluoromethoxy)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[2.2.1]heptan-3-yl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (0.037 g, 0.045 mmol), MeCN (0.1 mL) and TFA (1.1 mL) were added. The reaction mixture was stirred at room temperature for 0.5 hours. After completion, volatile substances were removed under reduced pressure, and the residue was dissolved in MeCN (4 mL) and water (1 mL) and preparative LC-MS (XBRIDGE® C 18 The title compound was obtained by purification using a column with a MeCN / water gradient containing 0.1% TFA at a flow rate of 60 mL / min. 37 H 34 Cl2F4N5O2(M+H) + LC-MS calculated value for this: m / z = 726.2; measured value 726.2.

[0398] Alternative atropisomer 3-((S a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-2-((1R,3R,4R,5S)-5-(difluoromethoxy)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[2.2.1]heptan-3-yl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile is tert-butyl(1R,4R,5S)-5-(((R a )-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-3-iodo-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate is replaced with tert-butyl(1R,4R,5S)-5-(((S aStarting from )-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-3-iodo-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate, it can be prepared by a similar route by carrying out a process similar to the steps described above.

[0399] Further example compounds within the scope of this disclosure have also been prepared and are listed in Table B below. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5]

[0400] The alternative atropisomers of the compounds in the table above are the alternative atropisomers (S a Starting from an intermediate of ), it can be prepared via a similar route by carrying out a process similar to the steps described above.

[0401] Example 35.3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-2-((1R,3R,4R,5S)-5-(difluoromethoxy)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[2.2.1]heptan-3-yl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile [ka] Step 1. tert-buty...

Claims

1. Equation (I): 【Chemistry 1】 A compound having, or a pharmaceutically acceptable salt thereof, wherein, Cy １ However, D and C respectively １－３ Alkyl, C １－３ Haloalkyl, C ２－３ Alkenil, C ２－３ Alkinyl, Halo, OH, C １－３ Alkoxy, and C １－３ A phenyl molecule optionally substituted with one, two, three, or four substituents selected from haloalkoxys. R １ However, it is a halogen, R ２ where R is H, D, C １－３ alkyl, C ２－３ alkenyl, C ２－３ alkynyl, C １－３ haloalkyl, C ３－５ cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, C ３－６ cycloalkyl-C １－３ alkylene, 4- to 6-membered heterocycloalkyl-C １－３ alkylene, phenyl-C １－３ alkylene, 5- to 6-membered heteroaryl-C １－３ alkylene, halo, CN, OR ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , NR ｃ２ R ｅ２ , and NR ｃ２ C(O)R ｂ２ and is selected from R ２ The C forming R ３－５ cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, C ３－６ cycloalkyl-C １－３ alkylene, 4- to 6-membered heterocycloalkyl-C １－３ alkylene, phenyl-C １－３ alkylene, and 5- to 6-membered heteroaryl-C １－３ alkylene are each independently optionally substituted with 1, 2, or 3 substituents selected from R ２Ａ The ring-forming atoms of the 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ２ forming R cycloalkyl-C ３－６ alkylene, and 4- to 6-membered heterocycloalkyl-C １－３ alkylene consist of at least 1 carbon atom and 1, 2, 3, or 4 heteroatoms selected from O, N, and S, and R １－３ The 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ２ forming R cycloalkyl-C ３－６ alkylene, and 4- to 6-membered heterocycloalkyl-C １－３ alkylene １－３ The ring-forming carbon atoms of the alkylene are optionally substituted with oxo atoms to form a carbonyl group, R ２ The C that forms １－３ Alkyl, C ２－３ Alkenyl and C ２－３ Each alkinyl independently, R ２Ｂ Optionally substituted with one, two, or three substituents selected from, Each R ａ２ However, independently, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－３ Haloalkyl, C ３－６ Selected from cycloalkyl, 4-6 member heterocycloalkyl, phenyl, and 5-6 member heteroaryl, R ａ２ The C that forms ３－６ Cycloalkyl, 4-6 member heterocycloalkyl, phenyl, and 5-6 member heteroaryl are each independently R ２Ａ Optionally substituted with one, two, or three substituents selected from R ａ２ The ring-forming atoms of the 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl that form the ring consist of at least one carbon atom and 1, 2, 3, or 4 heteroatoms selected from O, N, and S, R ａ２ The ring-forming carbon atoms of the 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl groups that form the ring are optionally substituted with oxo to form a carbonyl group, R ａ２ The C that forms １－６ Alkyl, C ２－６ Alkenyl and C ２－６ Each alkinyl independently, R ２Ｂ Optionally substituted with one, two, or three substituents selected from, Each R ｂ２ 、R ｃ２ 、and R ｄ２ is independently selected from H, C １－３ alkyl, C ２－３ alkenyl, C ２－３ alkynyl, C １－３ haloalkyl, C ３－６ cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, and the C ｂ２ 、R ｃ２ 、and R ｄ２ cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl forming R ３－６ are each independently optionally substituted with 1, 2, or 3 substituents selected from R ２Ａ 、and the ring-forming atoms of the 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl forming R ｂ２ 、R ｃ２ 、and R ｄ２ consist of at least 1 carbon atom and 1, 2, 3, or 4 heteroatoms selected from O, N, and S, and the ring-forming carbon atoms of the 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl forming R ｂ２ 、R ｃ２ 、and R ｄ２ are optionally substituted with oxo to form a carbonyl group, and the C ｂ２ alkyl, C ｃ２ alkenyl, and C ｄ２ alkynyl forming R １－３ are each independently optionally substituted with 1, 2, or 3 substituents selected from R ２－３ 、or ２－３ is optionally substituted with 1, 2, or 3 substituents selected from R ２Ｂ 、or Any R that bonds with the same N atom ｃ２ and R ｄ２ However, together with the N atom to which they are bonded, R ２Ｂ Form a 4, 5, or 6-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents selected from the above, Each R ｅ２ is independently selected from C １－３ alkyl, C ２－３ alkenyl, C ２－３ alkynyl, C １－３ haloalkyl, C ３－６ cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, and the C ｅ２ forming R ３－６ cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently optionally substituted with 1, 2, or 3 substituents selected from R ２Ａ , and the ring-forming atoms of the 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl forming R ｅ２ consist of at least 1 carbon atom and 1, 2, 3, or 4 heteroatoms selected from O, N, and S, and the ring-forming carbon atoms of the 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl forming R ｅ２ are optionally substituted with oxo to form a carbonyl group, and the C ｅ２ forming R １－３ alkyl, C ２－３ alkenyl, and C ２－３ alkynyl are each independently optionally substituted with 1, 2, or 3 substituents selected from R ２Ｂ or R bonded to the same N atom ｃ２ and R ｅ２ However, together with the N atom to which they are bonded, R ２Ｂ Form a 4, 5, or 6-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents selected from the above, Each R ２Ａ However, independently, C １－３ Alkyl, C ２－３ Alkenil, C ２－３ Alkinyl, C １－３ Haloalkyl and R ２Ｂ Selected from, R ２Ａ The C that forms １－３ Alkyl, C ２－３ Alkenyl and C ２－３ Each alkinyl independently, R ２Ｂ Optionally substituted with one, two, or three substituents selected from, Each R ２Ｂ However, independently, C ３－６ Cycloalkyl, 4-10 member heterocycloalkyl, phenyl, 5-6 member heteroaryl, halo, D, CN, OR ａ２Ｂ , C(O)R ｂ２Ｂ , C(O)NR ｃ２Ｂ R ｄ２Ｂ , C(O)OR ａ２Ｂ , NR ｃ２Ｂ R ｄ２Ｂ , and S(O) ２ R ｂ２Ｂ Selected from, C １－３ Alkyl, C ３－６ Cycloalkyl, 4-6 member heterocycloalkyl, phenyl, and 5-6 member heteroaryl are each independently R ２Ｃ Optionally substituted with one, two, or three substituents selected from, Each R ２Ｃ However, independently, C １－３ Alkyl, C ２－３ Alkenil, C ２－３ Alkinyl, C １－３ Haloalkyl, C ３－６ Cycloalkyl, 4-6 member heterocycloalkyl, phenyl, 5-6 member heteroaryl, halo, D, CN, OR ａ２Ｃ , C(O)R ｂ２Ｃ , C(O)NR ｃ２Ｃ R ｄ２Ｃ , C(O)OR ａ２Ｃ , NR ｃ２Ｃ R ｄ２Ｃ , and S(O) ２ R ｂ２Ｃ Selected from, Each R ａ２Ｂ , R ｂ２Ｂ , R ｃ２Ｂ , and R ｄ２Ｂ However, independently, H and C １－３ Alkyl and C １－３ Selected from haloalkyl groups, Each R ａ２Ｃ , R ｂ２Ｃ , R ｃ２Ｃ , and R ｄ２Ｃ However, independently, H and C １－３ Alkyl and C １－３ Selected from haloalkyl groups, R ３ However, C １－３ Alkyl, C ２－３ Alkenil, C ２－３ Alkinyl, C ３－１０ Cycloalkyl, 4-10 member heterocycloalkyl, C ６－１０ Aryl, 5-10 member heteroaryl, OR ３Ａ , and NR ３Ｂ R ３Ｃ Selected from, R ３ The C that forms ３－１０ Cycloalkyl, 4-10 member heterocycloalkyl, C ６－１０ Aryl and 5-10 member heteroaryl C １－３ Each alkyl group independently, R ３Ｄ Optionally substituted with one, two, or three substituents selected from R ３ The ring-forming atoms of the 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl that form the ring consist of at least one carbon atom and 1, 2, 3, or 4 heteroatoms selected from O, N, and S, R ３ The ring-forming carbon atoms of the 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl groups that form the R are optionally substituted with oxo to form a carbonyl group, ３ The C that forms １－３ Alkyl, C ２－３ Alkenyl and C ２－３ Each alkinyl independently, R ３Ｅ Optionally substituted with one, two, or three substituents selected from, R ３Ａ However, C １－３ Alkyl, C ２－３ Alkenil, C ２－３ Alkinyl, C ３－１０ Cycloalkyl, 4-10 member heterocycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, R ３Ａ The C that forms ３－１０ Cycloalkyl, 4-10 member heterocycloalkyl, C ６－１０ Aryl and 5-10 member heteroaryl C １－３ Each alkyl group independently, R ３Ｄ Optionally substituted with one, two, or three substituents selected from R ３Ａ The ring-forming atoms of the 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl that form the ring consist of at least one carbon atom and 1, 2, 3, or 4 heteroatoms selected from O, N, and S, R ３Ａ The ring-forming carbon atoms of the 4-10 membered heterocycloalkyl or 5-10 membered heteroaryl that form the ring are optionally substituted with oxo to form a carbonyl group, R ３Ａ The C that forms １－３ Alkyl, C ２－３ Alkenyl and C ２－３ Each alkinyl independently, R ３Ｅ Optionally substituted with one, two, or three substituents selected from, R ３Ｂ However, H, C １－３ Alkyl, C ２－３ Alkenil, C ２－３ Alkinyl, C ３－１０ Cycloalkyl, 4-10 member heterocycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, R ３Ｂ The C that forms ３－１０ Cycloalkyl, 4-10 member heterocycloalkyl, C ６－１０ Aryl and 5-10 membered heteroaryls are each independently, R ３Ｄ Optionally substituted with one, two, or three substituents selected from R ３Ｂ The ring-forming atoms of the 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl that form the ring consist of at least one carbon atom and 1, 2, 3, or 4 heteroatoms selected from O, N, and S, R ３Ｂ The ring-forming carbon atoms of the 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl groups that form the R are optionally substituted with oxo to form a carbonyl group, ３Ｂ The C that forms １－３ Alkyl, C ２－３ Alkenyl and C ２－３ Each alkinyl independently, R ３Ｅ Optionally substituted with one, two, or three substituents selected from, R ３Ｂ and R ３Ｃ However, together with the N atom to which they are bonded, R ３Ｄ Optionally, a 4, 5, 6, or 7-membered heterocycloalkyl group is formed by independently selecting from the following, and optionally substituted with 1, 2, or 3 substituents: R ３Ｃ However, H, C １－３ Alkyl, C ２－３ Alkenyl and C ２－３ Selected from Alkinil, R ３Ｃ The C that forms １－３ Alkyl, C ２－３ Alkenyl and C ２－３ Each alkinyl independently, R ３Ｅ Optionally substituted with one, two, or three substituents selected from, Each R ３Ｄ However, independently, C １－３ Alkyl, C １－３ Haloalkyl, C ２－３ Alkenil, C ２－３ Alkinyl and R ３Ｅ Selected from, R ３Ｄ The C that forms １－３ Alkyl, C ２－３ Alkenyl and C ２－３ Each of the alkinyls is independent, R ３Ｅ Optionally substituted with one, two, or three substituents selected from, Each R ３Ｅ However, independently, D, Halo, CN, OR ａ３ , SR ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ OC(O)R ｂ３ , OC(O)NR ｃ３ R ｄ３ , NR ｃ３ R ｄ３ , NR ｃ３ C(O)R ｂ３ , NR ｃ３ C(O)NR ｃ３ R ｄ３ , NR ｃ３ C(O)OR ａ３ , C(=NR ｅ３ ) NR ｃ３ R ｄ３ , NR ｃ３ C (=NR ｅ３ ) NR ｃ３ R ｄ３ S(O)R ｂ３ S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , NR ｃ３ S(O) ２ R ｂ３ , and S(O) ２ NR ｃ３ R ｄ３ Selected from, R ａ３ , R ｂ３ , R ｃ３ , and R ｄ３ However, each is independent of H and C. １－３ Alkyl, C ２－３ Alkenil, C ２－３ Alkinyl, C ６－１０ Ariel, C ３－７ Cycloalkyl, 5-10 member heteroaryl, 4-10 member heterocycloalkyl, C ６－１０ Aryl-C １－３ Alkyl, 5-10 member heteroaryl-C １－３ Alkyl, C ３－７ Cycloalkyl-C １－３ Alkyl and 4-10 member heterocycloalkyl-C １－３ Selected from alkyl groups, R ａ３ , R ｂ３ , R ｃ３ , and R ｄ３ The C that forms ６－１０ Aryl-C １－３ Alkyl, 5-10 member heteroaryl-C １－３ Alkyl, C ３－７ Cycloalkyl-C １－３ Alkyl and 4-10 member heterocycloalkyl-C １－３ Each alkyl group is independently C １－３ Alkyl, C １－３ Haloalkyl, C ２－３ Alkenil, C ２－３ Alkinyl, Halo, CN, OR ａ３Ａ , SR ａ３Ａ , C(O)R ｂ３Ａ , C(O)NR ｃ３Ａ R ｄ３Ａ , C(O)OR ａ３Ａ OC(O)R ｂ３Ａ , OC(O)NR ｃ３Ａ R ｄ３Ａ , NR ｃ３Ａ R ｄ３Ａ , NR ｃ３Ａ C(O)R ｂ３Ａ , NR ｃ３Ａ C(O)NR ｃ３Ａ R ｄ３Ａ , NR ｃ３Ａ C(O)OR ａ３Ａ , C(=NR ｅ３Ａ ) NR ｃ３Ａ R ｄ３Ａ , NR ｃ３Ａ C (=NR ｅ３Ａ ) NR ｃ３Ａ R ｄ３Ａ S(O)R ｂ３Ａ S(O)NR ｃ３Ａ R ｄ３Ａ , S(O) ２ R ｂ３Ａ , NR ｃ３Ａ S(O) ２ R ｂ３Ａ , and S(O) ２ NR ｃ３Ａ R ｄ３Ａ R is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from the above. ａ３ , R ｂ３ , R ｃ３ , and R ｄ３ The 4-10 member heterocycloalkyl, 5-10 member heteroaryl, and 5-10 member heteroaryl-C that form the aforementioned C １－３ Alkyl and 4-10 member heterocycloalkyl-C １－３ The alkyl ring-forming atoms consist of at least one carbon atom and one, two, three, or four heteroatoms selected from O, N, and S, R ａ３ , R ｂ３ , R ｃ３ , and R ｄ３ The 4-10 member heterocycloalkyl, 5-10 member heteroaryl, and 5-10 member heteroaryl-C that form the aforementioned C １－３ Alkyl and 4-10 member heterocycloalkyl-C １－３ The ring-forming carbon atoms of the alkyl group are optionally substituted with oxo atoms to form a carbonyl group, or R bonded to the same N atom ｃ３ and R ｄ３ However, together with the N atom to which both are bonded, they form a 4, 5, 6, or 7-membered heterocycloalkyl group or a 5-membered heteroaryl group, each independently of C １－３ Alkyl, C １－３ Haloalkyl, C ２－３ Alkenil, C ２－３ Alkinyl, Halo, CN, OR ａ３Ａ , SR ａ３Ａ , C(O)R ｂ３Ａ , C(O)NR ｃ３Ａ R ｄ３Ａ , C(O)OR ａ３Ａ OC(O)R ｂ３Ａ , OC(O)NR ｃ３Ａ R ｄ３Ａ , NR ｃ３Ａ R ｄ３Ａ , NR ｃ３Ａ C(O)R ｂ３Ａ , NR ｃ３Ａ C(O)NR ｃ３Ａ R ｄ３Ａ , NR ｃ３Ａ C(O)OR ａ３Ａ , C(=NR ｅ３Ａ ) NR ｃ３Ａ R ｄ３Ａ , NR ｃ３Ａ C (=NR ｅ３Ａ ) NR ｃ３Ａ R ｄ３Ａ S(O)R ｂ３Ａ S(O)NR ｃ３Ａ R ｄ３Ａ , S(O) ２ R ｂ３Ａ , NR ｃ３Ａ S(O) ２ R ｂ３Ａ , and S(O) ２ NR ｃ３Ａ R ｄ３Ａ Optionally substituted with one, two, or three substituents selected from, R ａ３Ａ , R ｂ３Ａ , R ｃ３Ａ , and R ｄ３Ａ However, each is independent of H and C. １－３ Alkyl, C １－３ Haloalkyl, C ２－３ Alkenil, C ２－３ Alkinyl, aryl, C ６－１０ Aryl-C １－３ Alkyl, 5-10 member heteroaryl-C １－３ Alkyl, C ３－７ Cycloalkyl-C １－３ Alkyl and 4-10 member heterocycloalkyl-C １－３ Selected from alkyl groups, R ａ３Ａ , R ｂ３Ａ , R ｃ３Ａ , and R ｄ３Ａ C that forms １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenil, C ２－６ Alkinyl C ６－１０ Aryl-C １－３ Alkyl, 5-10 member heteroaryl-C １－３ Alkyl, C ３－７ Cycloalkyl-C １－３ Alkyl and 4-10 member heterocycloalkyl-C １－３ Each alkyl group independently consists of OH, CN, amino, and NH(C) １－６ Alkyl), N (C １－６ Alkyl) ２ Hello, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl and C １－６ R is optionally substituted with one, two, or three substituents selected from haloalkoxys. ａ３Ａ , R ｂ３Ａ , R ｃ３Ａ , and R ｄ３Ａ 4-10 member heterocycloalkyl, 5-10 member heteroaryl, 5-10 member heteroaryl-C １－３ Alkyl and 4-10 member heterocycloalkyl-C １－３ The alkyl ring-forming atoms consist of at least one carbon atom and one, two, three, or four heteroatoms selected from O, N, and S, R ａ３Ａ , R ｂ３Ａ , R ｃ３Ａ , and R ｄ３Ａ The 4-10 member heterocycloalkyl, 5-10 member heteroaryl, and 5-10 member heteroaryl-C that form the aforementioned C １－３ Alkyl and 4-10 member heterocycloalkyl-C １－３ The ring-forming carbon atoms of the alkyl group are optionally substituted with oxo atoms to form a carbonyl group, or R bonded to the same N atom ｃ３Ａ and R ｄ３Ａ However, together with the N atom to which they are both bonded, they form a 4, 5, 6, or 7-membered heterocycloalkyl group or a 5-membered heteroaryl group, each independently of OH, CN, amino, or NH(C) １－６ Alkyl), N (C １－６ Alkyl) ２ Hello, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl and C １－６ R is optionally substituted with one, two, or three substituents selected from haloalkoxys. ｅ３ and R ｅ３Ａ However, each is independent of H, CN, or NO. ２ And, Each R ４ However, independently, H, D, C １－３ Alkyl, C １－３ Haloalkyl, C ２－３ Alkenil, C ２－３ Alkinyl, Halo, and OR ａ４ Selected from, Each R ａ４ However, independently, H and C １－３ Alkyl and C １－３ Selected from haloalkyl groups, One R ５ However, R ５Ａ And each other R ５ However, independently, H, D, Halo, C １－３ Alkyl, OR ａ５ , C １－３ Haloalkyl, C ２－３ Alkenyl and C ２－３ Selected from alkynyls, or optionally, two other R atoms bonded to the same carbon atom. ５ However, together with the carbon atoms to which they are both bonded, D and C respectively １－３ SpiroC optionally substituted with 1, 2, 3, or 4 substituents selected from alkyl and halo ３－６ A cycloalkyl ring is formed, or optionally, two other R atoms bonded to adjacent carbon atoms. ５ However, together with the carbon atoms to which they are each bonded, D, C １－３ Condensed C is optionally substituted with 1, 2, 3, or 4 substituents selected from alkyl and halo groups. ３－６ Forming a cycloalkyl ring, R ５Ａ However, H, D, C １－３ Alkyl, C １－３ Haloalkyl, C ２－３ Alkenil, C ２－３ Alkinyl, Halo, OR ａ５Ａ , CN, or Cy ２ And R ５Ａ The C that forms １－３ Each alkyl group is R ５Ｂ Optionally substituted with 1, 2, 3, or 4 substituents selected from and Cy ２ However, R is either arbitrarily substituted or arbitrarily bonded to the same carbon atom. ５Ａ and R ５ However, together with the carbon atoms to which they are both bonded, D and C respectively １－３ SpiroC optionally substituted with 1, 2, 3, or 4 substituents selected from alkyl and halo ３－６ R that forms a cycloalkyl ring or, optionally, bonds to an adjacent carbon atom ５Ａ and R ５ However, together with the carbon atoms to which they are each bonded, D, C １－３ Condensed C is optionally substituted with 1, 2, 3, or 4 substituents selected from alkyl and halo groups. ３－６ Forming a cycloalkyl ring, Each R ５Ｂ However, independently, they are selected from D and Halo. Each R ａ５ However, independently, H and C １－３ Alkyl and C １－３ Selected from haloalkyl groups, R ａ５Ａ However, H, C １－３ Alkyl, C １－３ Haloalkyl and Cy ２ Selected from, R ａ５Ａ The C that forms １－３ Each alkyl group is R ５Ｂ Optionally substituted with 1, 2, 3, or 4 substituents selected from and Cy ２ However, it can be arbitrarily replaced, Cy ２ However, C ３－７ Cycloalkyl, 4-10 member heterocycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, Cy ２ The C that forms ３－７ Cycloalkyl, 4-10 member heterocycloalkyl, C ６－１０ Aryl, 5-10 member heteroaryl, C ６－１０ Aryl and 5- to 10-membered heteroaryls are independently R Ｃｙ２ Optionally substituted with 1, 2, 3, or 4 substituents selected from Cy ２ The ring-forming atoms of the 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl rings are at least one carbon atom and independently 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and Cy ２ The ring-forming carbon atoms of the 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl groups that form the carbon, are optionally substituted with oxo to form a carbonyl group. Each R Ｃｙ２ However, independently, D and C １－３ Alkyl, C １－３ Haloalkyl, C ２－３ Alkenil, C ２－３ Alkinyl, C ３－６ Cycloalkyl, 4-10 member heterocycloalkyl, C ６－１０ Aryl, 5-10 member heteroaryl, halo, CN, OR ａＣｙ２１ , SR ａＣｙ２１ , C(O)R ｂＣｙ２１ , C(O)NR ｃＣｙ２１ R ｄＣｙ２１ , C(O)OR ａＣｙ２１ OC(O)R ｂＣｙ２１ , OC(O)NR ｃＣｙ２１ R ｄＣｙ２１ , NR ｃＣｙ２１ R ｄＣｙ２１ , NR ｃＣｙ２１ C(O)R ｂＣｙ２１ , NR ｃＣｙ２１ C(O)NR ｃＣｙ２１ R ｄＣｙ２１ , NR ｃＣｙ２１ C(O)OR ａＣｙ２１ , C(=NR ｅＣｙ２１ ) NR ｃＣｙ２１ R ｄＣｙ２１ , NR ｃＣｙ２１ C (=NR ｅＣｙ２１ ) NR ｃＣｙ２１ R ｄＣｙ２１ S(O)R ｂＣｙ２１ S(O)NR ｃＣｙ２１ R ｄＣｙ２１ , S(O) ２ R ｂＣｙ２１ , NR ｃＣｙ２１ S(O) ２ R ｂＣｙ２１ , and S(O) ２ NR ｃＣｙ２１ R ｄＣｙ２１ Selected from, R Ｃｙ２ The C that forms ３－６ Cycloalkyl, 4-10 member heterocycloalkyl, C ６－１０ Aryl and 5-10 membered heteroaryls are each independently, R Ｃｙ２Ａ Optionally substituted with 1, 2, 3, or 4 substituents selected from R Ｃｙ２ The ring-forming atoms of the 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl that form the ring consist of at least one carbon atom and independently 1, 2, 3, or 4 heteroatoms selected from N, O, and S, R Ｃｙ２ The ring-forming carbon atoms of the 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl groups that form the R are optionally substituted with oxo to form a carbonyl group, Ｃｙ２ The C that forms １－３ Alkyl, C ２－３ Alkenyl and C ２－３ Each alkinyl independently, R Ｃｙ２Ｂ Optionally substituted with one, two, or three substituents selected from, Each R Ｃｙ２Ａ However, independently, C １－３ Alkyl, C １－３ Haloalkyl, C ２－３ Alkenil, C ２－３ Alkinyl and R Ｃｙ２Ｂ Selected from, R Ｃｙ２Ａ The C that forms １－３ Alkyl, C ２－３ Alkenyl and C ２－３ Each alkinyl independently, R Ｃｙ２Ｂ Optionally substituted with one, two, or three substituents selected from, Each R Ｃｙ２Ｂ However, independently, D, Halo, CN, OR ａＣｙ２１ , SR ａＣｙ２１ , C(O)R ｂＣｙ２１ , C(O)NR ｃＣｙ２１ R ｄＣｙ２１ , C(O)OR ａＣｙ２１ OC(O)R ｂＣｙ２１ , OC(O)NR ｃＣｙ２１ R ｄＣｙ２１ , NR ｃＣｙ２１ R ｄＣｙ２１ , NR ｃＣｙ２１ C(O)R ｂＣｙ２１ , NR ｃＣｙ２１ C(O)NR ｃＣｙ２１ R ｄＣｙ２１ , NR ｃＣｙ２１ C(O)OR ａＣｙ２１ , C(=NR ｅＣｙ２１ ) NR ｃＣｙ２１ R ｄＣｙ２１ , NR ｃＣｙ２１ C (=NR ｅＣｙ２１ ) NR ｃＣｙ２１ R ｄＣｙ２１ S(O)R ｂＣｙ２１ S(O)NR ｃＣｙ２１ R ｄＣｙ２１ , S(O) ２ R ｂＣｙ２１ , NR ｃＣｙ２１ S(O) ２ R ｂＣｙ２１ , and S(O) ２ NR ｃＣｙ２１ R ｄＣｙ２１ Selected from, R ａＣｙ２１ , R ｂＣｙ２１ , R ｃＣｙ２１ , and R ｄＣｙ２１ However, each is independent of H and C. １－３ Alkyl, C １－３ Haloalkyl, C ２－３ Alkenil, C ２－３ Alkinyl, C ６－１０ Ariel, C ３－７ Cycloalkyl, 5-10 member heteroaryl, 4-10 member heterocycloalkyl, C ６－１０ Aryl-C １－３ Alkyl, 5-10 member heteroaryl-C １－３ Alkyl, C ３－７ Cycloalkyl-C １－３ Alkyl and 4-10 member heterocycloalkyl-C １－３ Selected from alkyl groups, R ａＣｙ２１ , R ｂＣｙ２１ , R ｃＣｙ２１ , and R ｄＣｙ２１ The C that forms ６－１０ Aryl-C １－３ Alkyl, 5-10 member heteroaryl-C １－３ Alkyl, C ３－７ Cycloalkyl-C １－３ Alkyl and 4-10 member heterocycloalkyl-C １－３ Each alkyl group is independently C １－３ Alkyl, C １－３ Haloalkyl, C ２－３ Alkenil, C ２－３ Alkinyl, Halo, CN, OR ａＣｙ２２ , SR ａＣｙ２２ , C(O)R ｂＣｙ２２ , C(O)NR ｃＣｙ２２ R ｄＣｙ２２ , C(O)OR ａＣｙ２２ OC(O)R ｂＣｙ２２ , OC(O)NR ｃＣｙ２２ R ｄＣｙ２２ , NR ｃＣｙ２２ R ｄＣｙ２２ , NR ｃＣｙ２２ C(O)R ｂＣｙ２２ , NR ｃＣｙ２２ C(O)NR ｃＣｙ２２ R ｄＣｙ２２ , NR ｃＣｙ２２ C(O)OR ａＣｙ２２ , C(=NR ｅＣｙ２２ ) NR ｃＣｙ２２ R ｄＣｙ２２ , NR ｃＣｙ２２ C (=NR ｅＣｙ２２ ) NR ｃＣｙ２２ R ｄＣｙ２２ S(O)R ｂＣｙ２２ S(O)NR ｃＣｙ２２ R ｄＣｙ２２ , S(O) ２ R ｂＣｙ２２ , NR ｃＣｙ２２ S(O) ２ R ｂＣｙ２２ , and S(O) ２ NR ｃＣｙ２２ R ｄＣｙ２２ Optionally substituted with one, two, or three substituents selected from R ａＣｙ２１ , R ｂＣｙ２１ , R ｃＣｙ２１ , and R ｄＣｙ２１ The 5-10 member heteroaryl, 4-10 member heterocycloalkyl, and 5-10 member heteroaryl-C that form the above １－３ Alkyl and 4-10 member heterocycloalkyl-C １－３ Each ring-forming atom of the alkyl group consists of at least one carbon atom and, independently, one, two, three, or four heteroatoms selected from N, O, and S, R ａＣｙ２１ , R ｂＣｙ２１ , R ｃＣｙ２１ , and R ｄＣｙ２１ The 5-10 member heteroaryl, 4-10 member heterocycloalkyl, and 5-10 member heteroaryl-C that form the above １－３ Alkyl and 4-10 member heterocycloalkyl-C １－３ The ring-forming carbon atoms of the alkyl group are optionally substituted with oxo atoms to form a carbonyl group, Alternatively, R that bonds with the same N atom ｃＣｙ２１ and R ｄＣｙ２１ However, together with the N atom to which both are bonded, they form a 4, 5, 6, or 7-membered heterocycloalkyl group or a 5-membered heteroaryl group, each independently of C １－３ Alkyl, C １－３ Haloalkyl, C ２－３ Alkenil, C ２－３ Alkinyl, Halo, CN, OR ａＣｙ２２ , SR ａＣｙ２２ , C(O)R ｂＣｙ２２ , C(O)NR ｃＣｙ２２ R ｄＣｙ２２ , C(O)OR ａＣｙ２２ OC(O)R ｂＣｙ２２ , OC(O)NR ｃＣｙ２２ R ｄＣｙ２２ , NR ｃＣｙ２２ R ｄＣｙ２２ , NR ｃＣｙ２２ C(O)R ｂＣｙ２２ , NR ｃＣｙ２２ C(O)NR ｃＣｙ２２ R ｄＣｙ２２ , NR ｃＣｙ２２ C(O)OR ａＣｙ２２ , C(=NR ｅＣｙ２２ ) NR ｃＣｙ２２ R ｄＣｙ２２ , NR ｃＣｙ２２ C (=NR ｅＣｙ２２ ) NR ｃＣｙ２２ R ｄＣｙ２２ S(O)R ｂＣｙ２２ S(O)NR ｃＣｙ２２ R ｄＣｙ２２ , S(O) ２ R ｂＣｙ２２ , NR ｃＣｙ２２ S(O) ２ R ｂＣｙ２２ , and S(O) ２ NR ｃＣｙ２２ R ｄＣｙ２２ Optionally substituted with one, two, or three substituents selected from, R ａＣｙ２２ , R ｂＣｙ２２ , R ｃＣｙ２２ , and R ｄＣｙ２２ However, each is independent of H and C. １－３ Alkyl, C １－３ Haloalkyl, C ２－３ Alkenil, C ２－３ Alkinyl, aryl, C ６－１０ Aryl-C １－３ Alkyl, 5-10 member heteroaryl-C １－３ Alkyl, C ３－７ Cycloalkyl-C １－３ Alkyl and 4-10 member heterocycloalkyl-C １－３ Selected from alkyl groups, R ａＣｙ２２ , R ｂＣｙ２２ , R ｃＣｙ２２ , and R ｄＣｙ２２ The C that forms １－３ Alkyl, C ２－３ Alkenil, C ２－３ Alkinyl, C ６－１０ Aryl-C １－３ Alkyl, 5-10 member heteroaryl-C １－３ Alkyl, C ３－７ Cycloalkyl-C １－３ Alkyl and 4-10 member heterocycloalkyl-C １－３ Each alkyl group independently consists of OH, CN, amino, and NH(C) １－３ Alkyl), N (C １－３ Alkyl) ２ Hello, C １－３ Alkyl, C １－３ Alkoxy, C １－３ Haloalkyl and C １－３ R is optionally substituted with one, two, or three substituents selected from haloalkoxys. ａＣｙ２２ , R ｂＣｙ２２ , R ｃＣｙ２２ , and R ｄＣｙ２２ 5-10 member heteroaryl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl-C １－３ Alkyl and 4-10 member heterocycloalkyl-C １－３ Each ring-forming atom of the alkyl group consists of at least one carbon atom and, independently, one, two, three, or four heteroatoms selected from N, O, and S, R ａＣｙ２２ , R ｂＣｙ２２ , R ｃＣｙ２２ , and R ｄＣｙ２２ The 5-10 member heteroaryl, 4-10 member heterocycloalkyl, and 5-10 member heteroaryl-C that form the above １－３ Alkyl and 4-10 member heterocycloalkyl-C １－３ The ring-forming carbon atoms of the alkyl group are optionally substituted with oxo atoms to form a carbonyl group, or R bonded to the same N atom ｃＣｙ２２ and R ｄＣｙ２２ However, together with the N atom to which they are both bonded, they form a 4, 5, 6, or 7-membered heterocycloalkyl group or a 5-membered heteroaryl group, each independently of OH, CN, amino, or NH(C) １－６ Alkyl), N (C １－６ Alkyl) ２ Hello, C １－３ Alkyl, C １－３ Alkoxy, C １－３ Haloalkyl and C １－３ Optionally substituted with one, two, or three substituents selected from haloalkoxys, R ｅＣｙ２１ and R ｅＣｙ２２ However, each is independent of H, CN, or NO. ２ A compound, or a pharmaceutically acceptable salt thereof.

2. Formulas (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (IJ), (IK), (IL), and (IM): 【Chemistry 2-1】 【Chemistry 2-2】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, having any one of the following.

3. Cy １ However, D and C respectively １－３ Alkyl, C １－３ Haloalkyl, Halo, OH, and C １－３ A phenyl compound optionally substituted with one or two substituents selected from alkoxy compounds. R １ But it's a halo, R ２ However, C is arbitrarily substituted with OH. １－３ It is alkyl, R ３ However, C is arbitrarily replaced by a halo. ３－１０ It is a cycloalkyl, Each R ４ However, it is H, One R ５ However, R ５Ａ And each other R ５ However, independently, H, D, Halo, C １－３ Alkyl, OC １－３ Alkyl, C １－３ Selected from haloalkyl groups, or optionally, two other R groups bonded to adjacent carbon atoms. ５ However, together with the carbon atoms to which they are each bonded, D, C １－３ Condensed C optionally substituted with one or two substituents selected from alkyl and halo ３－６ Forming a cycloalkyl ring, R ５Ａ However, H, halo, or OR ａ５Ａ And, R ａ５Ａ However, C １－３ Alkyl, C １－３ Haloalkyl and Cy ２ Selected from, R ａ５Ａ The C that forms １－３ The alkyl group is optionally substituted with 1, 2, or 3 D atoms, and Cy ２ However, it can be arbitrarily replaced, Cy ２ However, C ６－１０ A compound according to claim 1 or 2, selected from aryls and 5- to 10-membered heteroaryls, or a pharmaceutically acceptable salt thereof.

4. Cy １ However, D and C respectively １－３ Alkyl, C １－３ Haloalkyl, Halo, OH, and C １－３ A phenyl compound optionally substituted with one or two substituents selected from alkoxy compounds. R １ But it's a halo, R ２ However, C is arbitrarily substituted with OH. １－３ It is alkyl, R ３ However, C is arbitrarily replaced by a halo. ３－１０ It is a cycloalkyl, Each R ４ However, it is H, One R ５ However, R ５Ａ And each other R ５ However, independently, H, D, Halo, C １－３ Alkyl, OC １－３ Alkyl, C １－３ Selected from haloalkyl groups, or optionally, two other R groups bonded to adjacent carbon atoms. ５ However, together with the carbon atoms to which they are each bonded, D, C １－３ Condensed C optionally substituted with one or two substituents selected from alkyl and halo ３－６ Forming a cycloalkyl ring, R ５Ａ However, H, halo, or OR ａ５Ａ And, R ａ５Ａ However, C １－３ Alkyl, C １－３ Haloalkyl and Cy ２ Selected from, R ａ５Ａ The C that forms １－３ The alkyl group is optionally substituted with 1, 2, or 3 D atoms, and Cy ２ However, it can be arbitrarily replaced, Cy ２ However, C ３－７ Cycloalkyl, C ６－１０ A compound according to claim 1 or 2, selected from aryls and 5- to 10-membered heteroaryls, or a pharmaceutically acceptable salt thereof.

5. Cy １ However, each is a phenyl molecule arbitrarily substituted with two substituents selected from the halo. R １ But it's a halo, R ２ However, C is arbitrarily substituted with OH. １－３ It is alkyl, R ３ However, it is a cyclopropyl arbitrarily substituted with a halo, Each R ４ However, it is H, One R ５ However, R ５Ａ And each other R ５ However, they became independent: H, Halo, C １－３ Alkyl, OC １－３ Alkyl, C １－３ Selected from haloalkyl groups, or optionally, two other R groups bonded to adjacent carbon atoms. ５ However, together with the carbon atoms to which they are each bonded, D, C １－３ A condensed cyclopropyl ring is formed which is optionally substituted with one or two substituents selected from alkyl and halo, R ５Ａ However, H, halo, or OR ａ５Ａ And, R ａ５Ａ However, C １－３ Alkyl, C １－３ Haloalkyl and Cy ２ Selected from, R ａ５Ａ The C that forms １－３ The alkyl group is optionally substituted with 1, 2, or 3 D atoms, and Cy ２ However, it can be arbitrarily replaced, Cy ２ The compound according to any one of claims 1 to 4, selected from phenyl and pyridinyl, or a pharmaceutically acceptable salt thereof.

6. Cy １ However, it is 2,3-dichlorophenyl, R １ But it's a halo, R ２ However, it is methyl or 1-hydroxyethyl, R ３ However, it is a cyclopropyl that is optionally substituted with a fluoropolymer. Each R ４ However, it is H, One R ５ is R ５Ａ and each other R ５ is independently selected from H, halo, C １－３ alkyl, OC １－３ alkyl, C １－３ haloalkyl, or optionally, two other Rs bonded to adjacent carbon atoms ５ together with the carbon atom to which they are each bonded form a fused cyclopropyl ring optionally substituted with one or two substituents each selected from D, C １－３ alkyl, and halo, R ５Ａ However, H, Halo, OC １－３ Alkyl, OC １－３ Haloalkyl, OCD ３ A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, comprising O-pyridinyl and O-benzyl.

7. Cy １ However, it is 2,3-dichlorophenyl, R １ But it's a halo, R ２ is methyl or 1-hydroxyethyl, and R ３ However, it is a cyclopropyl that is optionally substituted with a fluoropolymer. Each R ４ However, it is H, One R ５ However, R ５Ａ And each other R ５ However, they became independent: H, Halo, C １－３ Alkyl, OC １－３ Alkyl, C １－３ Selected from haloalkyl groups, or optionally, two other R groups bonded to adjacent carbon atoms. ５ However, together with the carbon atoms to which they are each bonded, D, C １－３ A condensed cyclopropyl ring is formed which is optionally substituted with one or two substituents selected from alkyl and halo, R ５Ａ However, H, Halo, OC １－３ Alkyl, OC １－３ Haloalkyl, OCD ３ A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the compound is O-cyclopropyl, O-pyridinyl, and O-benzyl.

8. Cy １ However, independently, C １－３ Alkyl (e.g., methyl), C １－３ Haloalkyl, C ２－３ Alkenil, C ２－３ Alkynyl, halo (e.g., fluoro, or e.g., chloro), OH, C １－３ Alkoxy, and C １－３ The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, which is a phenyl optionally substituted with one, two, or three substituents (or one or two substituents, or one substituent) selected from haloalkoxys.

9. Cy １ However, independently, C １－３ A compound according to any one of claims 1, 2, and 8, or a pharmaceutically acceptable salt thereof, which is a phenyl optionally substituted with one, two, or three substituents (or one or two substituents, or one substituent) selected from alkyl (e.g., methyl) and halo (e.g., fluoro, or e.g., chloro).

10. Cy １ The compound according to any one of claims 1 to 4, 8, and 9, wherein the compound is 2-chloro-3-methylphenyl, or a pharmaceutically acceptable salt thereof.

11. Cy １ The compound according to any one of claims 1 to 5, 8, and 9, wherein the compound is 2,3-dichlorophenyl, or a pharmaceutically acceptable salt thereof.

12. R １ The compound according to any one of claims 1, 2, and 8 to 11, or a pharmaceutically acceptable salt thereof, which is a halo.

13. R １ A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein the compound is fluoro.

14. R ４ The compound according to any one of claims 1, 2, and 8 to 13, wherein H is present, or a pharmaceutically acceptable salt thereof.

15. R ２ However, C １－３ Alkyl, C １－３ Haloalkyl, C ２－３ Alkenil, C ２－３ It is alkinyl, R ２ The C that forms １－３ Alkyl, C ２－３ Alkenyl and C ２－３ Each alkinyl independently, R ２Ｂ A compound according to any one of claims 1, 2, and 8-14, or a pharmaceutically acceptable salt thereof, optionally substituted with one, two, or three substituents (or one or two substituents, or one substituent) selected from the above.

16. R ２ However, R ２Ｂ C optionally substituted with one, two, or three substituents (or one or two substituents, or one substituent) selected from １－３ A compound according to any one of claims 1, 2, and 8 to 15, or a pharmaceutically acceptable salt thereof, wherein the compound is alkyl (e.g., methyl or ethyl).

17. R ２ However, R ２Ｂ A compound according to any one of claims 1, 2, and 8-16, or a pharmaceutically acceptable salt thereof, wherein the methyl compound is optionally substituted with one, two, or three substituents (or one or two substituents, or one substituent) selected from the above.

18. R ２ A compound according to any one of claims 1 to 17, wherein the compound is methyl, or a pharmaceutically acceptable salt thereof.

19. R ２ However, R ２Ｂ A compound according to any one of claims 1 to 5 and 8 to 16, or a pharmaceutically acceptable salt thereof, which is ethyl optionally substituted with one, two, or three substituents (or one or two substituents, or one substituent) selected from the above.

20. R ２ The compound according to any one of claims 1 to 5, 8 to 16, and 19, or a pharmaceutically acceptable salt thereof, wherein the compound is ethyl.

21. R ２ The compound according to any one of claims 1 to 5, 8 to 16, and 19, wherein the compound is 1-hydroxyethyl, or a pharmaceutically acceptable salt thereof.

22. R ２ However, R ２Ａ A compound according to any one of claims 1, 2, and 8-14, or a pharmaceutically acceptable salt thereof, which is a 4- to 6-membered heterocycloalkyl (or a 4-, 5-, or 6-membered heterocycloalkyl) optionally substituted with one, two, or three substituents (or one or two substituents, or one substituent) selected from the above.

23. R ２ However, R ２Ａ A compound according to any one of claims 1, 2, 8-14, and 22, or a pharmaceutically acceptable salt thereof, which is azetidine-1-yl optionally substituted with one, two, or three substituents (or one or two substituents, or one substituent) selected from the above.

24. R ２ The compound according to any one of claims 1, 2, 8 to 14, 22, and 23, wherein the compound is 2-methyl-2-(N,N-dimethylamino)-2-methylazetidine-1-yl, or a pharmaceutically acceptable salt thereof.

25. R ２ However, R ２Ａ A compound according to any one of claims 1, 2, and 8-14, or a pharmaceutically acceptable salt thereof, which is a 5- to 6-membered heteroaryl (or 5- or 6-membered heteroaryl) optionally substituted with one, two, or three substituents (or one or two substituents, or one substituent) selected from the above.

26. R ２ However, R ２Ａ A compound according to any one of claims 1, 2, 8-14, and 25, or a pharmaceutically acceptable salt thereof, which is a six-membered heteroaryl (e.g., pyridyl, e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl) optionally substituted with one, two, or three substituents (or one or two substituents, or one substituent) selected from the above.

27. R ２ However, 2-hydroxypropyl or C(O)NR ｃ２Ｂ R ｃ２Ｄ (For example, C(O)NH ２ , C(O)NHMe, or C(O)NMe ２ The compound according to any one of claims 1, 2, 8 to 14, 25, and 26, or a pharmaceutically acceptable salt thereof, which is a six-membered heteroaryl (e.g., pyridyl, e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl) optionally substituted with ).

28. R ２ is OR ａ２ The compound according to any one of claims 1, 2, and 8 to 14, or a pharmaceutically acceptable salt thereof.

29. Each R ２Ａ However, independently, C １－３ Alkyl, NR ｃ２Ｂ R ｃ２Ｄ (For example, NH ２ NHMe, or NMe ２ ), or C(O)NR ｃ２Ｂ R ｃ２Ｄ (For example, C(O)NH ２ , C(O)NHMe, or C(O)NMe ２ ) is selected from, R ２Ａ The C that forms １－３ Each alkyl group independently, R ２Ｂ A compound according to any one of claims 1, 2, 8-14, 22, 23, 25, and 26, or a pharmaceutically acceptable salt thereof, optionally substituted with one, two, or three substituents (or one or two substituents, or one substituent) selected from the above.

30. Each R ２Ａ They are independent, each independently, R ２Ｂ C optionally substituted with one, two, or three substituents (or one or two substituents, or one substituent) selected from １－３ A compound selected from alkyl groups, according to any one of claims 1, 2, 8-14, 22, 23, 25, 26, and 29, or a pharmaceutically acceptable salt thereof.

31. Each R ２Ａ However, R ２Ｂ The compound according to any one of claims 1, 2, 8-14, 22, 23, 25, and 26, or a pharmaceutically acceptable salt thereof.

32. R ３ However, R ３Ｅ C optionally substituted with one, two, or three substituents (or one or two substituents, or one substituent) selected from １－３ A compound according to any one of claims 1, 2, and 8 to 31, or a pharmaceutically acceptable salt thereof, wherein the compound is alkyl (e.g., methyl or ethyl).

33. R ３ However, R ３Ｅ C optionally substituted with one, two, or three substituents (or one or two substituents, or one substituent) selected from ３－１０ A compound according to any one of claims 1, 2, and 8 to 31, which is a cycloalkyl compound, or a pharmaceutically acceptable salt thereof.

34. R ３ However, R ３Ｅ C optionally substituted with one, two, or three substituents (or one or two substituents, or one substituent) selected from ３－７ A compound according to any one of claims 1, 2, 8 to 31, and 33, which is a cycloalkyl compound, or a pharmaceutically acceptable salt thereof.

35. R ３ However, R ３Ｅ C optionally substituted with one, two, or three substituents (or one or two substituents, or one substituent) selected from ３－６ A compound according to any one of claims 1, 2, 8 to 31, 33, and 34, or a pharmaceutically acceptable salt thereof, which is a cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).

36. R ３ However, R ３Ｅ A compound according to any one of claims 1, 2, 8-31, and 33-35, or a pharmaceutically acceptable salt thereof, which is cyclobutyl optionally substituted with one, two, or three substituents (or one or two substituents, or one substituent) selected from the above.

37. R ３ However, R ３Ｅ A compound according to any one of claims 1, 2, 8-31, and 33-35, or a pharmaceutically acceptable salt thereof, which is a cyclopropyl optionally substituted with one, two, or three substituents (or one or two substituents, or one substituent) selected from the above.

38. R ３ The compound according to any one of claims 1 to 31 and 33 to 37, or a pharmaceutically acceptable salt thereof, wherein the compound is cyclopropyl.

39. R ３ The compound according to any one of claims 1 to 31 and 33 to 377, wherein the compound is 1-fluorocyclopropane-1-yl, or a pharmaceutically acceptable salt thereof.

40. R ３ The compound according to any one of claims 1 to 31 and 33 to 37, wherein the compound is 1-methylcyclopropane-1-yl, or a pharmaceutically acceptable salt thereof.

41. R ３ However, R ３Ｅ C optionally substituted with one, two, or three substituents (or one or two substituents, or one substituent) selected from ６－１０ A compound according to any one of claims 1, 2, and 8-31, or a pharmaceutically acceptable salt thereof, wherein the compound is an aryl (e.g., phenyl).

42. R ３ However, R ３Ｅ A compound according to any one of claims 1, 2, and 8-31, or a pharmaceutically acceptable salt thereof, which is a 5- to 10-membered heteroaryl optionally substituted with one, two, or three substituents (or one or two substituents, or one substituent) selected from the above.

43. R ３ However, OR ３Ａ The compound according to any one of claims 1, 2, and 8 to 31, or a pharmaceutically acceptable salt thereof.

44. R ３ However, NR ３Ｂ R ３Ｃ The compound according to any one of claims 1, 2, and 8 to 31, or a pharmaceutically acceptable salt thereof.

45. Each R ４ However, independently, H, D, C １－３ Alkyl (e.g., methyl or ethyl), C １－３ A compound according to any one of claims 1, 2, 8-12, and 14-44, selected from haloalkyl (e.g., trifluoroalkyl) and halo (e.g., fluoro), or a pharmaceutically acceptable salt thereof.

46. Each R ４ However, independently, H, D, C １－３ A compound according to any one of claims 1, 2, 8-12, and 14-45, selected from alkyl (e.g., methyl or ethyl) and halo (e.g., fluoro), or a pharmaceutically acceptable salt thereof.

47. Each R ４ However, independently selected from H, methyl, and fluoro, the compounds according to any one of claims 1, 2, 8-12, and 14-46, or pharmaceutically acceptable salts thereof.

48. Each R ４ However, independently selected from H and methyl, the compound according to any one of claims 1, 2, 8-12, and 14-47, or a pharmaceutically acceptable salt thereof.

49. One R ４ However, H is and one R ４ The compound according to any one of claims 1, 2, 8-12, and 14-48, wherein the compound is methyl, or a pharmaceutically acceptable salt thereof.

50. Each R ４ A compound according to any one of claims 1, 2, 8-12, and 14-48, wherein H is present, or a pharmaceutically acceptable salt thereof.

51. Each R ４ The compound according to any one of claims 1, 2, 8-12, and 14-48, wherein the compound is methyl, or a pharmaceutically acceptable salt thereof.

52. One R ５ However, R ５Ａ And each other R ５ However, independently, two other R atoms may be selected from H, methyl, and fluoro, or optionally bonded to the same carbon atom. ５ However, both of these are bonded together with the carbon atoms to which the spiro C is optionally substituted with one, two, three, or four substituents (or one, two, or three substituents, or one or two substituents, or one substituent) selected from methyl and fluoro. ３－６ A cycloalkyl ring (e.g., cyclopropyl) is formed, or optionally, two other R atoms bonded to adjacent carbon atoms. ５ However, each of these condensed C atoms may be optionally substituted with one, two, three, or four substituents (or one, two, or three substituents, or one or two substituents, or one substituent) selected from methyl and fluoro atoms, along with the carbon atom to which they are bonded. ３－６ A compound according to any one of claims 1, 2, and 8 to 51, or a pharmaceutically acceptable salt thereof, which forms a cycloalkyl ring (e.g., cyclopropyl).

53. One R ５ However, R ５Ａ And each other R ５ However, independently selected from H, methyl, and fluoro, the compound according to any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof.

54. One R ５ However, R ５Ａ And each other R ５ However, independently, two other R atoms may be selected from H and methyl, or optionally bonded to the same carbon atom. ５ However, along with the carbon atoms to which both are bonded, each is optionally substituted with one, two, three, or four substituents (or one, two, or three substituents, or one or two substituents, or one substituent) selected from methyl, and the spiro C ３－６ A cycloalkyl ring (e.g., cyclopropyl) is formed, or optionally, two other R atoms bonded to adjacent carbon atoms. ５ However, each of these condensed C atoms is optionally substituted with one, two, three, or four substituents (or one, two, or three substituents, or one or two substituents, or one substituent) selected from methyl, along with the carbon atom to which they are bonded. ３－６ A compound according to any one of claims 1, 2, and 8 to 52, or a pharmaceutically acceptable salt thereof, which forms a cycloalkyl ring (e.g., cyclopropyl).

55. One R ５ However, R ５Ａ And each other R ５ However, independently selected from H and methyl, the compound according to any one of claims 1 to 54, or a pharmaceutically acceptable salt thereof.

56. One R ５ However, R ５Ａ And each other R ５ However, it is either H, or optionally, two other R atoms bonded to the same carbon atom. ５ However, along with the carbon atoms to which both are bonded, each is optionally substituted with one, two, three, or four substituents (or one, two, or three substituents, or one or two substituents, or one substituent) selected from methyl, and the spiro C ３－６ A cycloalkyl ring (e.g., cyclopropyl) is formed, or optionally, two other R atoms bonded to adjacent carbon atoms. ５ However, each of these condensed C atoms is optionally substituted with one, two, three, or four substituents (or one, two, or three substituents, or one or two substituents, or one substituent) selected from methyl, along with the carbon atom to which they are bonded. ３－６ A compound according to any one of claims 1 to 54, or a pharmaceutically acceptable salt thereof, which forms a cycloalkyl ring (e.g., cyclopropyl).

57. One R ５ However, R ５Ａ And each other R ５ A compound according to any one of claims 1 to 56, wherein H is present, or a pharmaceutically acceptable salt thereof.

58. R ５Ａ However, H, D, C １－３ Alkyl (e.g., methyl), C １－３ Haloalkyl (e.g., trifluoromethyl), C ２－３ Alkenil, C ２－３ Alkinyl, halo (e.g., fluoro), OR ａ５Ａ , and R which is CN or, optionally, bonded to the same carbon atom ５Ａ and R ５ However, together with the carbon atoms to which they are both bonded, D and C respectively １－３ SpiroC optionally substituted with one, two, three, or four substituents (or one, two, or three substituents, or one or two substituents, or one substituent) selected from alkyl (e.g., methyl) and halo (e.g., fluoro) ３－６ A cycloalkyl ring, for example, one that forms a cyclopropyl group, or optionally, one that is bonded to an adjacent carbon atom. ５Ａ and R ５ However, along with the carbon atoms to which they are bonded, D and C respectively １－３ Condensed C molecules optionally substituted with one, two, three, or four substituents (or one, two, or three substituents, or one or two substituents, or one substituent) selected from alkyl (e.g., methyl) and halo (e.g., fluoro) elements. ３－６ Forming a cycloalkyl ring (e.g., cyclopropyl), R ａ５Ａ However, H, C １－３ Alkyl and C １－３ Haloalkyl and Cy ２ Selected from, R ａ５Ａ The C that forms １－３ Each alkyl group is R ５Ｂ A compound according to any one of claims 1, 2, and 8 to 57, or a pharmaceutically acceptable salt thereof, optionally substituted with one, two, three, or four substituents (or one, two, or three substituents, or one or two substituents, or one substituent) selected from the above.

59. R ５Ａ However, H, C １－３ The R is alkyl (e.g., methyl), halo (e.g., fluoro), or optionally bonded to the same carbon atom. ５Ａ and R ５ However, together with the carbon atom to which they are both bonded, each, C １－３ SpiroC optionally substituted with 1, 2, 3, or 4 substituents (or 1, 2, or 3 substituents, or 1 or 2 substituents, or 1 substituent) selected from alkyl (e.g., methyl) and halo (e.g., fluoro) ３－６ A cycloalkyl ring, for example, one that forms a cyclopropyl group, or optionally, one that is bonded to an adjacent carbon atom. ５Ａ and R ５ However, along with the carbon atoms to which they are bonded, each of them is C １－３ Condensed C molecules optionally substituted with one, two, three, or four substituents (or one, two, or three substituents, or one or two substituents, or one substituent) selected from alkyl (e.g., methyl) and halo. ３－６ A compound according to any one of claims 1, 2, and 8 to 58, or a pharmaceutically acceptable salt thereof, which forms a cycloalkyl ring (e.g., cyclopropyl).

60. R ５Ａ However, H or C １－３ It is alkyl (e.g., methyl), or optionally, R bonded to the same carbon atom. ５Ａ and R ５ However, together with the carbon atom to which they are both bonded, each, C １－３ SpiroC optionally substituted with 1, 2, 3, or 4 substituents (or 1, 2, or 3 substituents, or 1 or 2 substituents, or 1 substituent) selected from alkyl (e.g., methyl) ３－６ A cycloalkyl ring, for example, one that forms a cyclopropyl group, or optionally, one that is bonded to an adjacent carbon atom. ５Ａ and R ５ However, along with the carbon atoms to which they are bonded, each of them is C １－３ Condensed C, optionally substituted with one, two, three, or four substituents (or one, two, or three substituents, or one or two substituents, or one substituent) selected from alkyl (e.g., methyl) ３－６ A compound according to any one of claims 1, 2, and 8 to 59, or a pharmaceutically acceptable salt thereof, which forms a cycloalkyl ring (e.g., cyclopropyl).

61. R ５Ａ However, H, D, C １－３ Alkyl (e.g., methyl), C １－３ Haloalkyl (e.g., trifluoromethyl), C ２－３ Alkenil, C ２－３ Alkinyl, halo (e.g., fluoro), OR ａ５Ａ , and CN, R ａ５Ａ However, H, C １－３ Alkyl and C １－３ Haloalkyl and Cy ２ Selected from, R ａ５Ａ The C that forms １－３ Each alkyl group is R ５Ｂ A compound according to any one of claims 1, 2, and 8-58, or a pharmaceutically acceptable salt thereof, optionally substituted with one, two, three, or four substituents (or one, two, or three substituents, or one or two substituents, or one substituent) selected from the above.

62. R ５Ａ However, H, C １－３ A compound according to any one of claims 1, 2, and 8-61, or a pharmaceutically acceptable salt thereof, which is alkyl (e.g., methyl) or halo (e.g., fluoro).

63. R ５Ａ However, H or C １－３ A compound according to any one of claims 1, 2, and 8 to 62, or a pharmaceutically acceptable salt thereof, wherein the compound is alkyl (e.g., methyl).

64. R ５Ａ A compound according to any one of claims 1 to 63, wherein H is present, or a pharmaceutically acceptable salt thereof.

65. R ５Ａ However, Cy ２ The compound according to any one of claims 1, 2, and 8 to 57, or a pharmaceutically acceptable salt thereof.

66. R ５Ａ However, C １－３ Alkyl (e.g., methyl or ethyl), R ５Ａ The C that forms １－３ Alkyl (or methyl or ethyl) ２ Replaced by, and each, R ５Ｂ The compound according to any one of claims 1, 2, and 8 to 57, or a pharmaceutically acceptable salt thereof, optionally substituted with one, two, three, or four substituents (or one, two, or three substituents, or one or two substituents, or one substituent) selected from the above.

67. R ５Ａ However, C １－３ Alkyl (e.g., methyl or ethyl), R ５Ａ The C that forms １－３ Alkyl (or methyl or ethyl) ２ A compound according to any one of claims 1, 2, and 8 to 57, or a pharmaceutically acceptable salt thereof, substituted with.

68. R ５Ａ However, CH ２ Cy ２ The compound according to any one of claims 1, 2, 8 to 57, and 67, or a pharmaceutically acceptable salt thereof.

69. R ５Ａ However, CH ２ CH ２ Cy ２ The compound according to any one of claims 1, 2, 8 to 57, and 67, or a pharmaceutically acceptable salt thereof.

70. R ５Ａ However, OR ａ５Ａ And R ａ５Ａ However, Cy ２ The compound according to any one of claims 1, 2, and 8 to 57, or a pharmaceutically acceptable salt thereof.

71. R ５Ａ However, C １－３ Alkyl (e.g., methyl or ethyl), R ａ５Ａ The C that forms １－３ Alkyl, Cy ２ Replaced by, and each, R ５Ｂ The compound according to any one of claims 1, 2, and 8-57, or a pharmaceutically acceptable salt thereof, optionally substituted with one, two, three, or four substituents selected from, or one, two, or three substituents, or one substituent.

72. R ５Ａ However, OCH ２ Cy ２ The compound according to any one of claims 1, 2, and 8 to 57, or a pharmaceutically acceptable salt thereof.

73. R ５Ａ However, OCH ２ CH ２ Cy ２ The compound according to any one of claims 1, 2, and 8 to 57, or a pharmaceutically acceptable salt thereof.

74. Cy ２ However, R Ｃｙ２ C is optionally substituted with one, two, three, or four substituents (or one, two, or three substituents, or one or two substituents, or one substituent) selected from the above. ６－１０ A compound according to any one of claims 1, 2, and 8 to 73, or a pharmaceutically acceptable salt thereof, wherein the compound is an aryl (e.g., phenyl).

75. Cy ２ However, R Ｃｙ２ A compound according to any one of claims 1, 2, and 8-74, or a pharmaceutically acceptable salt thereof, which is a phenyl optionally substituted with one, two, three, or four substituents selected from the above.

76. Cy ２ However, C ６－１０ A compound according to any one of claims 1, 2, and 8 to 75, which is an aryl compound, or a pharmaceutically acceptable salt thereof.

77. Cy ２ The compound according to any one of claims 1, 2, and 8 to 76, wherein the compound is phenyl, or a pharmaceutically acceptable salt thereof.

78. Cy ２ However, R Ｃｙ２ A compound according to any one of claims 1, 2, and 8-73, or a pharmaceutically acceptable salt thereof, which is a 5- to 10-membered heteroaryl optionally substituted with one, two, three, or four substituents (or one, two, or three substituents, or one or two substituents, or one substituent) selected from the above.

79. Cy ２ However, R Ｃｙ２ A compound according to any one of claims 1, 2, 8 to 73, and 78, or a pharmaceutically acceptable salt thereof, which is a six-membered heteroaryl optionally substituted with one, two, three, or four substituents selected from the above.

80. Cy ２ The compound according to any one of claims 1, 2, 8 to 73, 78, and 79, or a pharmaceutically acceptable salt thereof, wherein the compound is a six-membered heteroaryl.

81. Cy ２ However, R Ｃｙ２ A compound according to any one of claims 1, 2, 8-73, and 78-80, or a pharmaceutically acceptable salt thereof, which is a pyridinyl optionally substituted with one, two, three, or four substituents selected from the above.

82. Cy ２ The compound according to any one of claims 1, 2, 8-73, and 78-81, wherein the compound is pyridinyl, or a pharmaceutically acceptable salt thereof.

83. Cy ２ However, R Ｃｙ２ C is optionally substituted with one, two, three, or four substituents (or one, two, or three substituents, or one or two substituents, or one substituent) selected from the above. ３－７ A compound according to any one of claims 1, 2, and 8 to 73, which is a cycloalkyl compound, or a pharmaceutically acceptable salt thereof.

84. Cy ２ However, R Ｃｙ２ A compound according to any one of claims 1, 2, and 8-73, or a pharmaceutically acceptable salt thereof, which is a 4- to 10-membered heterocycloalkyl optionally substituted with one, two, three, or four substituents (or one, two, or three substituents, or one or two substituents, or one substituent) selected from the above.

85. Each R Ｃｙ２ However, independently, D and C １－３ Alkyl, C １－３ Haloalkyl, C ２－３ Alkenil, C ２－３ A compound according to any one of claims 1, 2, 8 to 75, 78, 79, 81, 83, and 84, selected from alkynyl and halo, or a pharmaceutically acceptable salt thereof.

86. Each R Ｃｙ２ A compound according to any one of claims 1, 2, 8-75, 78, 79, 81, and 83-85, or a pharmaceutically acceptable salt thereof, which is independently a halo.

87. Compounds selected from those listed in Tables 1 and 2, and their pharmaceutically acceptable salts.

88. A pharmaceutical composition comprising a compound according to any one of claims 1 to 87, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

89. A method for inhibiting KRAS activity, comprising contacting KRAS with a compound according to any one of claims 1 to 87, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition according to claim 88.

90. The method according to claim 89, wherein the contact includes administering the compound to a patient.

91. The method according to claim 89 or 90, characterized in that KRAS has a G12C somatic mutation.

92. The method according to claim 89 or 90, characterized in that KRAS has a G12D somatic mutation.

93. The method according to claim 89 or 90, characterized in that KRAS has a G12V somatic mutation.

94. A method for treating a disease or disorder related to the activity of KRAS, comprising administering to a patient in need a therapeutically effective amount of a compound according to any one of claims 1 to 87, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition according to claim 88.

95. A method for treating a disease or disorder related to the activity of a KRAS protein having a G12C mutation, comprising administering to a patient in need a therapeutically effective amount of a compound according to any one of claims 1 to 87, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition according to claim 88.

96. A method for treating a disease or disorder related to the activity of the KRAS protein having a G12D mutation, comprising administering to a patient in need a therapeutically effective amount of a compound according to any one of claims 1 to 87, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition according to claim 88.

97. A method for treating a disease or disorder related to the activity of a KRAS protein having a G12V mutation, comprising administering to a patient in need a therapeutically effective amount of a compound according to any one of claims 1 to 87, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition according to claim 88.

98. A method for treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 87, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 88.

99. The method according to claim 98, wherein the cancer is selected from carcinoma, hematological cancer, sarcoma, and glioblastoma.

100. The method according to claim 98, wherein the cancer is a hematological cancer selected from myeloproliferative disorders, myelodysplastic syndromes, chronic and juvenile myelomonocytic leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, and multiple myeloma.

101. The method according to claim 98, wherein the cancer is a carcinoma selected from pancreatic cancer, colorectal cancer, lung cancer, bladder cancer, stomach cancer, esophageal cancer, breast cancer, head and neck cancer, cervical cancer, skin cancer, and thyroid cancer.

102. The method according to any one of claims 98 to 101, wherein the abnormally proliferating cancer cells include KRAS having a G12C mutation.

103. The method according to any one of claims 98 to 101, wherein the abnormally proliferating cancer cells include KRAS having a G12D mutation.

104. The method according to any one of claims 98 to 101, wherein the abnormally proliferating cancer cells include KRAS having a G12V mutation.

105. A method for treating an immunological or inflammatory disorder, comprising administering to a patient in need a therapeutically effective amount of a compound according to any one of claims 1 to 87, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 88.

106. The method according to claim 105, wherein the immunological or inflammatory disorder is related to the activity of KRAS.

107. The method according to claim 105, wherein the immunological or inflammatory disorder is related to the activity of KRAS having a G12C mutation.

108. The method according to claim 105, wherein the immunological or inflammatory disorder is related to the activity of KRAS having the G12D mutation.

109. The method according to claim 105, wherein the immunological or inflammatory disorder is related to the activity of KRAS having the G12V mutation.

110. The method according to claim 105, wherein the immunological or inflammatory disorder is Ras-associated lymphoproliferative disorder or juvenile myelomonocytic leukemia caused by a somatic mutation in KRAS.

111. The method according to claim 110, wherein the somatic mutation of KRAS is G12C.

112. The method according to claim 110, wherein the somatic mutation of KRAS is G12D.

113. The method according to claim 110, wherein the somatic mutation of KRAS is G12V.

114. A method for treating cancer in patients, The patient required cancer treatment, and it was identified that the abnormally proliferating cancer cells contained KRAS with a G12C mutation. A method comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 87, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 88.

115. A method for treating cancer in patients, The patient requires cancer treatment, and it is identified that the abnormally proliferating cancer cells contain KRAS with the G12D mutation. A method comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 87, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 88.

116. A method for treating cancer in patients, The patient requires cancer treatment, and it is identified that the abnormally proliferating cancer cells contain KRAS with the G12V mutation. A method comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 87, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 88.

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