Quinoline compounds as inhibitors of KRAS

Abstract

Disclosed are compounds of formula I, methods of using the compounds to inhibit KRAS activity, and pharmaceutical compositions comprising such compounds, which are useful for treating, preventing, or ameliorating diseases or disorders associated with KRAS activity, such as cancer.

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 63 / 255,610, filed October 14, 2021, U.S. Provisional Application No. 63 / 279,464, filed November 15, 2021, U.S. Provisional Application No. 63 / 363,270, filed April 20, 2022, and U.S. Provisional Application No. 63 / 368,563, filed July 15, 2022, the contents of which are incorporated herein by reference in their entirety.

[0002] The present disclosure provides compounds, as well as compositions and methods of use thereof, that 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 that are activated by growth factors and various extracellular stimuli. The Ras family regulates intracellular signaling pathways involved in cell proliferation, migration, survival, and differentiation. Activation of RAS proteins at the cell membrane leads to the binding of key effectors and the initiation of a cascade of intracellular signaling pathways, including the RAF and PI3K kinase pathways. While somatic mutations in RAS can result in uncontrolled cell proliferation and malignant transformation, activation of RAS proteins is tightly regulated in normal cells (Simanshu, D. et al. Cell 170.1(2017):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 are mutated in 12% and 3% of all Ras-mutated cancers, respectively (Simanshu, D. et al. Cell 170.1 (2017): 17-33). KRAS mutations are prevalent among the top three most lethal cancer types: pancreatic (97%), colon (44%), and lung (30%) (Cox, AD et al. Nat Rev Drug Discov (2014) 13:828-51). The majority of RAS mutations occur at amino acid residues 12, 13, and 61. The frequency of specific mutations varies between RAS gene isoforms, with G12 and Q61 mutations prevalent in KRAS and NRAS, respectively, while G12, G13, and Q61 mutations are most frequent in HRAS. Furthermore, the spectrum of mutations in RAS isoforms differs between cancer types. For example, KRAS G12D mutations are prevalent 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%) (Cox, AD et al. Nat Rev Drug Discov (2014) 13:828-51). In contrast, KRAS G12C mutations predominate in non-small cell lung cancer (NSCLC), including 11–16% of lung adenocarcinomas, and 2–5% of pancreatic and colorectal adenocarcinomas (Cox, AD et al. Nat. Rev. Drug Discov. (2014) 13:828–51). Genomic studies across hundreds of cancer cell lines have demonstrated that cancer cells with KRAS mutations are highly dependent on KRAS function for cell proliferation and survival (McDonald, R. et al. Cell 170 (2017):577–592).The role of mutant KRAS as an oncogenic driver is further supported by extensive in vivo experimental evidence showing that mutant KRAS is required for the development and maintenance of primary tumors in animal models (Cox, AD et al. Nat Rev Drug Discov (2014) 13:828-51).

[0005] Taken together, these findings suggest that KRAS mutations play an important role in human cancer and, therefore, the development of inhibitors targeting mutant KRAS may be useful in the clinical treatment of diseases characterized by KRAS mutations. Summary of the Invention

[0006] The present disclosure is particularly directed to compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein the constituent variables are defined herein.

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

[0008] The present disclosure further provides a method for inhibiting KRAS activity, comprising administering to individual the compound of the present disclosure or its pharmaceutically acceptable salt.The present disclosure also provides the use of the compound described herein in the manufacture of the drug for use in treatment.The present disclosure also provides the compound described herein for use in treatment.

[0009] The present disclosure further provides a method of treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE INVENTION

[0010] compound In one embodiment, a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein Y is N or CR 6 and R 1 But H, C 1~3 Alkyl, C 1~3 Haloalkyl, cyclopropyl, halo, D, CN, and OR a1 C is selected from 1~3 alkyl and cyclopropyl are each independently R g optionally substituted with 1 or 2 substituents selected from R 2 But H, C 1~3 Alkyl, C 1~3 Haloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene, 5-6 membered heteroaryl-C 1~3 Alkylene, halo, D, CN, and OR a2 C is selected from 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene, 5-6 membered heteroaryl-C 1~3 Each alkylene is independently R g optionally substituted with 1 or 2 substituents selected from Cy 1 But C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10aryl, and 6- to 10-membered heteroaryl, wherein the 4- to 10-membered heterocycloalkyl and the 6- to 10-membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, and the ring-forming carbon atoms of the 6- to 10-membered heteroaryl and the 4- to 10-membered heterocycloalkyl are optionally substituted by oxo to form a carbonyl group; C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 aryl, and 6- to 10-membered heteroaryl are each independently R 10 optionally substituted with 1, 2, 3, or 4 substituents selected from R 3 But H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1~3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene, 5-6 membered heteroaryl-C 1~3 Alkylene, Halo, D, CN, OR f3 , C(O)NR c3 R d3 , N.R. c3 R j3 , and NR c3 C(O)R b3 C is selected from 1~3 Alkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1~3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Each alkylene is independently R 30 optionally substituted with 1, 2, or 3 substituents selected from R 5 But H, C1~3 Alkyl, C 1~3 Haloalkyl, cyclopropyl, halo, D, CN, and OR a5 C is selected from 1~3 alkyl and cyclopropyl are each independently R g optionally substituted with 1 or 2 substituents selected from R 6 But H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4-9 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1~3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene, 5-6 membered heteroaryl-C 1~3 Alkylene, Halo, D, CN, OR a6 , and C(O)NR c6 R d6 C is selected from 1~3 Alkyl, C 3~6 Cycloalkyl, 4-9 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1~3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Each alkylene is independently R 60 optionally substituted with 1 or 2 substituents selected from R 7 But H, C 1~3 Alkyl, C 1~3 Haloalkyl, cyclopropyl, halo, D, CN, and OR a7 C is selected from 1~3 alkyl and cyclopropyl are each independently R g optionally substituted with 1 or 2 substituents selected from Cy 2 is selected from the following: [ka] wherein n is 0, 1, or 2; Each R 10 But independently, C 1~3 Alkyl, C 1~3 Haloalkyl, Halo, D, CN, OR a10 , C(O)R b10 , C(O)NR c10 R d10 , C(O)OR a10 , N.R. c10 R d10 , and S(O)2R b10 is selected from Each R 20 But independently, C 1~3 Alkyl, C 1~3 Haloalkyl, halo, D, CN, and OR a20 is selected from Each R 30 But independently, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, CN, OR a30 , C(O)R b30 , C(O)NR c30 R d30 , C(O)OR a30 , N.R. c30 R d30 , and S(O)2R b30 C is selected from 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 31 optionally substituted with 1 or 2 substituents selected from Each R 31 But independently, C 1~3 Alkyl, C 1~3 Haloalkyl, Halo, D, CN, OR a31 , C(O)R b31 , C(O)NR c31 R d31 , C(O)OR a31 , N.R. c31 Rd31 , and S(O)2R b31 is selected from Each R 33 But independently, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl, halo, D, CN, OR a30 , C(O)NR c30 R d30 , and NR c30 R d30 C is selected from 1~3 Alkyl, C 3~6 Cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl, and 5-6-membered heteroaryl are each independently R 31 optionally substituted with 1 or 2 substituents selected from Each R 60 But independently, C 1~3 Alkyl, C 1~3 Haloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halo, D, CN, OR a60 , C(O)R b60 , C(O)NR c60 R d60 , N.R. c60 C(O)R b60 , C(O)OR a60 , N.R. c60 C(O)OR a60 , N.R. c60 R d60 , N.R. c60 S(O)2R b60 , and S(O)2R b60 C is selected from 1~3 alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 61 optionally substituted with 1 or 2 substituents selected from Each R 61 But independently, C 1~3 Alkyl, C 1~3 Haloalkyl, Halo, D, CN, OR a61 , and NR c61 Rd61 is selected from R a1 But H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a2 However, independently, H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R b3 , R c3 , and R d3 However, independently, H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 30 optionally substituted with 1, 2, or 3 substituents selected from or R bonded to the same N atom c3 and R d3 together with the N atom to which they are attached, independently R 30 forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents selected from R j3 But C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 30 optionally substituted with 1, 2, or 3 substituents selected from or R bonded to the same N atom c3 and R j3 together with the N atom to which they are attached, independently R 30forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents selected from R f3 But C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 30 or R f3 is selected from the following: [ka] In the formula, R x But H or C 1~2 alkyl, and R y But C 1~2 Is it alkyl? or R x and R y together with the C atom to which they are attached form a 3- or 4-membered cycloalkyl group, R a5 But H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a6 , R c6 , and R d6 However, independently, H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 60 optionally substituted with 1 or 2 substituents selected from R a7 But H, C1~3 Alkyl, and C 1~3 haloalkyl; Each R a10 , R b10 , R c10 , and R d10 However, independently, H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a20 However, independently, H, C 1~3 Alkyl, and C 1~3 haloalkyl; R b20 But NH2, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a30 , R b30 , R c30 , and R d30 However, independently, H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a31 , R b31 , R c31 , and R d31 However, independently, H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a60 , R b60 , R c60 , and R d60 However, independently, H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 61 or optionally substituted with one or two substituents selected from or any R bonded to the same N atom c60 and R d60 together with the N atom to which they are attached, independently R61 forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with one or two substituents selected from Each R a61 , R c61 , and R d61 However, independently, H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R g However, independently, D, OH, CN, halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, Amino, C 1~3 Alkylamino and di(C 1~3 alkyl)amino; provided that the compound of formula I is Provided herein are compounds other than 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-4-ethoxy-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N-dimethylpropanamide, or a pharmaceutically acceptable salt thereof.

[0011] In one embodiment of Formula I, or a pharmaceutically acceptable salt thereof, Y is N or CR 6 and R 1 is H, C 1~3 Alkyl, C 1~3 Haloalkyl, cyclopropyl, halo, D, CN, and OR a1 C is selected from 1~3 Alkyl and cyclopropyl are each independently R g optionally substituted with 1 or 2 substituents selected from R 2 is H, C 1~3 Alkyl, C 1~3 Haloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl-C1~3 Alkylene, Phenyl-C 1~3 Alkylene, 5-6 membered heteroaryl-C 1~3 Alkylene, halo, D, CN, and OR a2 C is selected from 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene, 5-6 membered heteroaryl-C 1~3 Each alkylene is independently R g optionally substituted with 1 or 2 substituents selected from Cy 1 is C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 aryl, and 6- to 10-membered heteroaryl, wherein the 4- to 10-membered heterocycloalkyl and the 6- to 10-membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, and the ring-forming carbon atoms of the 6- to 10-membered heteroaryl and the 4- to 10-membered heterocycloalkyl are optionally substituted by oxo to form a carbonyl group; C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl and 6- to 10-membered heteroaryl are each independently R 10 optionally substituted with 1, 2, 3, or 4 substituents selected from R 3 is H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1~3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene, 5-6 membered heteroaryl-C 1~3 Alkylene, Halo, D, CN, OR f3 , C(O)NR c3R d3 , N.R. c3 R j3 , and NR c3 C(O)R b3 C is selected from 1~3 Alkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1~3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Each alkylene is independently R 30 optionally substituted with 1, 2, or 3 substituents selected from R 5 is H, C 1~3 Alkyl, C 1~3 Haloalkyl, cyclopropyl, halo, D, CN, and OR a5 C is selected from 1~3 Alkyl and cyclopropyl are each independently R g optionally substituted with 1 or 2 substituents selected from R 6 is H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1~3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene, 5-6 membered heteroaryl-C 1~3 Alkylene, Halo, D, CN, OR a6 , and C(O)NR c6 R d6 C is selected from 1~3 Alkyl, C 3~6 Cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1~3 Alkylene, 4-6 membered heterocycloalkyl-C1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Each alkylene is independently R 60 optionally substituted with 1 or 2 substituents selected from R 7 is H, C 1~3 Alkyl, C 1~3 Haloalkyl, cyclopropyl, halo, D, CN, and OR a7 C is selected from 1~3 Alkyl and cyclopropyl are each independently R g optionally substituted with 1 or 2 substituents selected from Cy 2 is selected from: [ka] wherein n is 0, 1, or 2; Each R 10 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, Halo, D, CN, OR a10 , C(O)R b10 , C(O)NR c10 R d10 , C(O)OR a10 , N.R. c10 R d10 , and S(O)2R b10 is selected from Each R 20 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, halo, D, CN, and OR a20 is selected from Each R 30 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, CN, OR a30 , C(O)R b30 , C(O)NR c30 R d30 , C(O)ORa30 , N.R. c30 R d30 , and S(O)2R b30 C is selected from 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 31 optionally substituted with 1 or 2 substituents selected from Each R 31 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, Halo, D, CN, OR a31 , C(O)R b31 , C(O)NR c31 R d31 , C(O)OR a31 , N.R. c31 R d31 , and S(O)2R b31 is selected from Each R 33 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl, halo, D, CN, OR a30 , C(O)NR c30 R d30 , and NR c30 R d30 C is selected from 1~3 Alkyl, C 3~6 Cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl, and 5-6-membered heteroaryl are each independently R 31 optionally substituted with 1 or 2 substituents selected from Each R 60 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halo, D, CN, OR a60 , C(O)R b60 , C(O)NR c60 R d60 , N.R. c60 C(O)Rb60 , C(O)OR a60 , N.R. c60 C(O)OR a60 , N.R. c60 R d60 , N.R. c60 S(O)2R b60 , and S(O)2R b60 C is selected from 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 61 optionally substituted with 1 or 2 substituents selected from Each R 61 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, Halo, D, CN, OR a61 , and NR c61 R d61 is selected from R a1 is H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a2 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R b3 , R c3 , and R d3 are independently H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 30 optionally substituted with 1, 2, or 3 substituents selected from or R bonded to the same N atom c3 and R d3 are independently R together with the N atom to which they are attached. 30forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents selected from R j3 is C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 30 optionally substituted with 1, 2, or 3 substituents selected from or R bonded to the same N atom c3 and R j3 are independently R together with the N atom to which they are attached. 30 forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents selected from R f3 is C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 30 or R f3 is selected from: [ka] In the formula, R x is H or C 1~2 alkyl, and R y is C 1~2 Is it alkyl? or R x and R yform together with the C atom to which they are attached a 3- or 4-membered cycloalkyl group, R a5 is H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a6 , R c6 , and R d6 are independently H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 60 optionally substituted with 1 or 2 substituents selected from R a7 is H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a10 , R b10 , R c10 , and R d10 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a20 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl; R b20 is NH2, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a30 , R b30 , R c30 , and R d30 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a31 , R b31 , R c31 , and R d31are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a60 , R b60 , R c60 , and R d60 are independently H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 61 or optionally substituted with one or two substituents selected from or any R bonded to the same N atom c60 and R d60 are independently R together with the N atom to which they are attached. 61 forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with one or two substituents selected from Each R a61 , R c61 , and R d61 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R g are independently D, OH, CN, halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, Amino, C 1~3 Alkylamino and di(C 1~3 alkyl)amino; provided that the compound of formula I is provided that the compound is other than 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-4-ethoxy-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N-dimethylpropanamide.

[0012] In one embodiment of Formula I, or a pharmaceutically acceptable salt thereof, Y is CR 6 and R 1 is H, C 1~3 Alkyl, and C 1~3 haloalkyl; R 2 is H, C 1~3 Alkyl, C 1~3 Haloalkyl, halo, D, CN, and OR a2 C is selected from 1~3 Alkyl is independently R g optionally substituted with 1 or 2 substituents selected from Cy 1 is C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 aryl, and 6- to 10-membered heteroaryl, wherein the 4- to 10-membered heterocycloalkyl and the 6- to 10-membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, and the ring-forming carbon atoms of the 6- to 10-membered heteroaryl and the 4- to 10-membered heterocycloalkyl are optionally substituted by oxo to form a carbonyl group; C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl and 6- to 10-membered heteroaryl are each independently R 10 optionally substituted with 1, 2, 3, or 4 substituents selected from R 3 is H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, CN, C(O)NR c3 R d3 , and NR c3 C(O)R b3 C is selected from 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 30 optionally substituted with 1, 2, or 3 substituents selected from R 5 is H, C 1~3 Alkyl, C 1~3 selected from haloalkyl, and halo; R 6 is H, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, CN, OR a6 , and C(O)NR c6 R d6 C is selected from 3~6 Cycloalkyl, 4- to 8-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 60 or R 6 is C 1~3 alkyl, 1~3 Alkyl is independently R 60 is substituted with one or two substituents selected from R 7 is H, C 1~3 Alkyl, C 1~3 selected from haloalkyl, halo, and CN; Cy 2 is selected from: [ka] wherein n is 0, 1, or 2; Each R 10 independently, C 1~3Alkyl, C 1~3 Haloalkyl, Halo, D, CN, OR a10 , C(O)R b10 , C(O)NR c10 R d10 , C(O)OR a10 , N.R. c10 R d10 , and S(O)2R b10 is selected from Each R 20 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, halo, D, CN, and OR a20 is selected from Each R 30 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, CN, OR a30 , C(O)R b30 , C(O)NR c30 R d30 , C(O)OR a30 , N.R. c30 R d30 , and S(O)2R b30 C is selected from 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 31 optionally substituted with 1 or 2 substituents selected from Each R 31 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, Halo, D, CN, OR a31 , C(O)R b31 , C(O)NR c31 R d31 , C(O)OR a31 , N.R. c31 R d31 , and S(O)2R b31 is selected from Each R 60 independently, C 1~3 Alkyl, C 1~3Haloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halo, D, CN, OR a60 , C(O)R b60 , C(O)NR c60 R d60 , N.R. c60 C(O)R b60 , C(O)OR a60 , N.R. c60 C(O)OR a60 , N.R. c60 R d60 , N.R. c60 S(O)2R b60 , and S(O)2R b60 C is selected from 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 61 optionally substituted with 1 or 2 substituents selected from Each R 61 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, Halo, D, CN, OR a61 , and NR c61 R d61 is selected from Each R a2 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R b3 , R c3 , and R d3 are independently H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 30 optionally substituted with 1, 2, or 3 substituents selected from or R bonded to the same N atom c3 and R d3are independently R together with the N atom to which they are attached. 30 forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents selected from Each R a6 , R c6 , and R d6 are independently H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 60 optionally substituted with 1 or 2 substituents selected from Each R a10 , R b10 , R c10 , and R d10 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a20 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl; R b20 is NH2, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a30 , R b30 , R c30 , and R d30 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a31 , R b31 , R c31 , and R d31 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a60 , R b60, R c60 , and R d60 are independently H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 61 or optionally substituted with one or two substituents selected from or any R bonded to the same N atom c60 and R d60 are independently R together with the N atom to which they are attached. 61 forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with one or two substituents selected from Each R a61 , R c61 , and R d61 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R g are independently D, CN, halo, C 1~3 Alkyl, and C 1~3 haloalkyl.

[0013] In another embodiment of Formula I, or a pharmaceutically acceptable salt thereof, Y is CR 6 and R 1 is H, R 2 is C 1~3 Alkyl, C 1~3 selected from haloalkyl, halo, CN, and —CHCHCN; Cy 1 is C 3~10 Cycloalkyl, C 6~10aryl, and 6- to 10-membered heteroaryl, wherein the 6- to 10-membered heteroaryl has at least one ring-forming carbon atom and one ring-forming heteroatom independently selected from N and S; 3~10 Cycloalkyl, C 6~10 Aryl and 6- to 10-membered heteroaryl are each independently R 10 optionally substituted with 1 or 2 substituents selected from R 3 is H, C 1~3 Alkyl, C 1~3 haloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 30 optionally substituted with 1, 2, or 3 substituents selected from R 5 is selected from H and halo; R 6 is H, C 1~3 haloalkyl, 4- to 8-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, wherein the 4- to 8-membered heterocycloalkyl and the 5- to 6-membered heteroaryl are each independently selected from R 60 or R 6 is C 1~3 alkyl, 1~3 Alkyl is independently R 60 is substituted with one or two substituents selected from R 7 is a halo, Cy 2 is [ka] Each R 10 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, halo, D, CN, and OR a10 is selected from Each R30 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, 4-6 membered heterocycloalkyl, halo, D, CN, OR a30 , C(O)NR c30 R d30 , and NR c30 R d30 C is selected from 1~3 alkyl and 4- to 6-membered heterocycloalkyl are each independently R 31 optionally substituted with 1 or 2 substituents selected from Each R 31 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, Halo, CN, OR a31 , and NR c31 R d31 is selected from Each R 60 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halo, D, CN, OR a60 , C(O)R b60 , C(O)NR c60 R d60 , N.R. c60 C(O)R b60 , C(O)OR a60 , N.R. c60 C(O)OR a60 , N.R. c60 R d60 , N.R. c60 S(O)2R b60 , and S(O)2R b60 C is selected from 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 61 optionally substituted with 1 or 2 substituents selected from Each R 61 independently, C 1~3 Alkyl, C 1~3 selected from haloalkyl, halo, and CN; Each R a10 are independently H and C 1~3alkyl, Each R a30 , R c30 , and R d30 are independently H and C 1~3 alkyl, Each R a31 , R c31 , and R d31 are independently H and C 1~3 alkyl, Each R a60 , R b60 , R c60 , and R d60 are independently H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 61 or optionally substituted with one or two substituents selected from or any R bonded to the same N atom c60 and R d60 are independently R together with the N atom to which they are attached. 61 to form a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with one or two substituents selected from:

[0014] In yet another embodiment of Formula I, or a pharmaceutically acceptable salt thereof, Y is CR 6 and R 1 is H, R 2 is -CH2CH2CN, Cy 1 is phenyl, and the phenyl is independently R 10 optionally substituted with 1 or 2 substituents selected from R 3 is H, C 1~3alkyl, phenyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, phenyl, and 5- to 6-membered heteroaryl are each R 30 and optionally substituted with 1, 2, or 3 substituents independently selected from R 5 is selected from H and halo; R 6 is C 1~3 alkyl and 5- to 9-membered heterocycloalkyl, 1~3 The alkyl and 5- to 9-membered heterocycloalkyl are independently R 60 optionally substituted with 1 or 2 substituents selected from R 7 is a halo, Cy 2 is [ka] Each R 10 independently, C 1~3 selected from alkyl and halo; Each R 30 independently, C 1~3 Alkyl, halo, OH, and C(O)NR c30 R d30 C is selected from 1~3 Alkyl is independently R 31 and optionally substituted with one substituent selected from Each R 31 are independently OH, O(C 1~3 alkyl), and N(C 1~3 alkyl)2; Each R 60 independently, C 1~3 Alkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halo, C(O)R b60 , C(O)NR c60 R d60 , N.R. c60 C(O)R b60 , C(O)OR a60 , N.R. c60 C(O)OR a60 , and NRc60 S(O)2R b60 C is selected from 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 61 optionally substituted with 1 or 2 substituents selected from Each R 61 independently, C 1~3 selected from alkyl and halo; Each R c30 and R d30 are independently H and C 1~3 alkyl, Each R a60 , R b60 , R c60 , and R d60 are independently H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 61 or optionally substituted with one or two substituents selected from or any R bonded to the same N atom c60 and R d60 are independently R together with the N atom to which they are attached. 61 to form a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with one or two substituents selected from:

[0015] In yet another embodiment of Formula I, or a pharmaceutically acceptable salt thereof, Y is CR 6 and R 1 is H, R 2 is -CH2CH2CN, Cy 1 is phenyl, and the phenyl is independently R 10optionally substituted with 1 or 2 substituents selected from R 3 is H, C 1~3 alkyl, phenyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, phenyl, and 5- to 6-membered heteroaryl are each R 30 and optionally substituted with 1, 2, or 3 substituents independently selected from R 5 is selected from H and halo; R 6 is C 1~3 alkyl and 6- to 9-membered fused heterocycloalkyl, 1~3 The alkyl and 6- to 9-membered fused heterocycloalkyl are independently R 60 optionally substituted with 1 or 2 substituents selected from R 7 is a halo, Cy 2 is [ka] Each R 10 independently, C 1~3 selected from alkyl and halo; Each R 30 independently, C 1~3 Alkyl, halo, OH, and C(O)NR c30 R d30 C is selected from 1~3 Alkyl is independently R 31 and optionally substituted with one substituent selected from Each R 31 are independently OH, O(C 1~3 alkyl), and N(C 1~3 alkyl)2; Each R 60 independently, C 1~3 Alkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halo, C(O)R b60 , C(O)NR c60 R d60 , N.R. c60C(O)R b60 , C(O)OR a60 , N.R. c60 C(O)OR a60 , and NR c60 S(O)2R b60 C is selected from 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 61 optionally substituted with 1 or 2 substituents selected from Each R 61 independently, C 1~3 selected from alkyl and halo; Each R c30 and R d30 are independently H and C 1~3 alkyl, Each R a60 , R b60 , R c60 , and R d60 are independently H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 61 or optionally substituted with one or two substituents selected from or any R bonded to the same N atom c60 and R d60 are independently R together with the N atom to which they are attached. 61 to form a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with one or two substituents selected from:

[0016] In yet another embodiment of Formula I, or a pharmaceutically acceptable salt thereof, Y is CR 6 and R 1 is H, R 2is -CH2CH2CN, Cy 1 is phenyl, and the phenyl is independently R 10 optionally substituted with 1 or 2 substituents selected from R 3 is H, C 1~3 alkyl, phenyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, phenyl, and 5- to 6-membered heteroaryl are each R 30 and optionally substituted with 1, 2, or 3 substituents independently selected from R 5 is selected from H and halo; R 6 is selected from 4- to 8-membered heterocycloalkyl, and the 4- to 8-membered heterocycloalkyl is independently selected from R 60 or R 6 is C 1~3 alkyl, 1~3 Alkyl is independently R 60 is substituted with one or two substituents selected from R 7 is a halo, Cy 2 is [ka] Each R 10 independently, C 1~3 selected from alkyl and halo; Each R 30 independently, C 1~3 Alkyl, Halo, D, and C(O)NR c30 R d30 C is selected from 1~3 Alkyl is independently R 31 and optionally substituted with one substituent selected from Each R 31 is OR a31 and Each R 60 independently, C1~3 Alkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halo, C(O)R b60 , C(O)NR c60 R d60 , N.R. c60 C(O)R b60 , C(O)OR a60 , N.R. c60 C(O)OR a60 , and NR c60 S(O)2R b60 C is selected from 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 61 optionally substituted with 1 or 2 substituents selected from Each R 61 independently, C 1~3 selected from alkyl and halo; Each R c30 and R d30 are independently H and C 1~3 alkyl, Each R a31 are independently H and C 1~3 alkyl, Each R a60 , R b60 , R c60 , and R d60 are independently H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 61 or optionally substituted with one or two substituents selected from or any R bonded to the same N atom c60 and R d60 are independently R together with the N atom to which they are attached. 61 to form a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with one or two substituents selected from:

[0017] In yet another embodiment of Formula I, or a pharmaceutically acceptable salt thereof, Y is CR 6 and R 1 is H, R 2 is -CH2CH2CN, Cy 1 is phenyl, and the phenyl is independently R 10 optionally substituted with 1 or 2 substituents selected from R 3 is selected from H, methyl, phenyl, 1,2,4-triazolyl, pyrazyl, and pyridyl, and each of the methyl, phenyl, 1,2,4-triazolyl, pyrazyl, and pyridyl is independently selected from R 30 optionally substituted with 1, 2, or 3 substituents selected from R 5 is selected from H and chloro; R 6 is selected from pyrrolidinyl, 2-azabicyclo[3.1.0]hexanyl, and 5-oxo-1,2,3,5-tetrahydroindolizin-3-yl, and the pyrrolidinyl, 2-azabicyclo[3.1.0]hexanyl, and 5-oxo-1,2,3,5-tetrahydroindolizin-3-yl are independently selected from R 60 or R 6 is C 1~2 alkyl, 1~2 Alkyl is independently R 60 is substituted with one or two substituents selected from R 7 is fluoro, Cy 2 is [ka] Each R 10 is independently selected from methyl, fluoro, and chloro; Each R 30 are independently methyl, fluoro, D, and C(O)NR c30 R d30 and the methyl is independently selected from R 31 and optionally substituted with one substituent selected from Each R 31 is OR a31 and Each R 60 are independently methyl, fluoro, 3-oxomorpholinyl, 2-oxopyrazin-1(2H)-yl), C(O)R b60 , C(O)NR c60 R d60 , N.R. c60 C(O)R b60 , C(O)OR a60 , N.R. c60 C(O)OR a60 , and NR c60 S(O)2R b60 wherein the 3-oxomorpholinyl and 2-oxopyrazin-1(2H)-yl are each independently selected from R 61 optionally substituted with 1 or 2 substituents selected from Each R 61 is independently selected from methyl and fluoro; Each R c30 and R d30 is independently selected from H and methyl; Each R a31 is independently selected from H and methyl; Each R a60 , R b60 , R c60 , and R d60 are independently H, C 1~2 alkyl, C haloalkyl, cyclopropyl, tetrahydrofuranyl, and thiazolyl; 1~2 Alkyl, cyclopropyl, tetrahydrofuranyl, and thiazolyl are each independently R 61 or optionally substituted with one or two substituents selected from or any R bonded to the same N atom c60 and R d60are independently R together with the N atom to which they are attached. 61 to form an azetidinyl group optionally substituted with one or two substituents selected from:

[0018] In another embodiment of Formula I, or a pharmaceutically acceptable salt thereof, Y is N or CR 6 and R 1 is H, R 2 is -CH2CH2CN, Cy 1 is C 6~10 aryl or 6- to 10-membered heteroaryl, C 6~10 The aryl and 6- to 10-membered heteroaryl are independently R 10 optionally substituted with 1 or 2 substituents selected from R 3 is H, C 1~3 Alkyl, phenyl, 5-6 membered heteroaryl, and OR f3 C is selected from 1~3 Alkyl, phenyl, and 5- to 6-membered heteroaryl are each R 30 and optionally substituted with 1, 2, or 3 substituents independently selected from R 5 is selected from H and halo; R 6 is selected from H, pyridinyl, pyrrolidinyl, 2-azabicyclo[3.1.0]hexanyl, and 5-oxo-1,2,3,5-tetrahydroindolizin-3-yl, and the pyrrolidinyl, 2-azabicyclo[3.1.0]hexanyl, and 5-oxo-1,2,3,5-tetrahydroindolizin-3-yl are independently selected from R 60 or R 6 is C 1~2 alkyl, 1~2 Alkyl is independently R 60 is substituted with one or two substituents selected from R7 is a halo, Cy 2 is [ka] Each R 10 is independently selected from methyl and halo; Each R 30 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, halo, CN, OR a30 , C(O)R b30 , C(O)NR c30 R d30 , C(O)OR a30 , N.R. c30 R d30 , and S(O)2R b30 C is selected from 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 31 optionally substituted with 1 or 2 substituents selected from Each R 31 is OR a31 and Each R 60 are independently methyl, halo, 3-oxomorpholinyl, 2-oxopyrazin-1(2H)-yl), C(O)R b60 , C(O)NR c60 R d60 , N.R. c60 C(O)R b60 , C(O)OR a60 , N.R. c60 C(O)OR a60 , and NR c60 S(O)2R b60 wherein the 3-oxomorpholinyl and 2-oxopyrazin-1(2H)-yl are each independently selected from R 61 optionally substituted with 1 or 2 substituents selected from Each R 61is independently selected from methyl and halo; R f3 is R f3 -a, Each R c30 and R d30 is independently selected from H and methyl; Each R a31 is independently selected from H and methyl; Each R a60 , R b60 , R c60 , and R d60 are independently H, C 1~2 alkyl, C haloalkyl, cyclopropyl, tetrahydrofuranyl, and thiazolyl; 1~2 Alkyl, cyclopropyl, tetrahydrofuranyl, and thiazolyl are each independently R 61 or optionally substituted with one or two substituents selected from or any R bonded to the same N atom c60 and R d60 are independently R together with the N atom to which they are attached. 61 to form an azetidinyl group optionally substituted with one or two substituents selected from:

[0019] In another embodiment, the compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein: Y is N or CR 6 and R 1 But H, C 1~3 Alkyl, C 1~3 Haloalkyl, cyclopropyl, halo, D, CN, and OR a1 C is selected from 1~3 alkyl and cyclopropyl are each independently R g optionally substituted with 1 or 2 substituents selected from R 2 But H, C 1~3 Alkyl, C1~3 Haloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene, 5-6 membered heteroaryl-C 1~3 Alkylene, halo, D, CN, and OR a2 C is selected from 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene, 5-6 membered heteroaryl-C 1~3 Each alkylene is independently R g optionally substituted with 1 or 2 substituents selected from Cy 1 But C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 aryl, and 6- to 10-membered heteroaryl, wherein the 4- to 10-membered heterocycloalkyl and the 6- to 10-membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, and the ring-forming carbon atoms of the 6- to 10-membered heteroaryl and the 4- to 10-membered heterocycloalkyl are optionally substituted by oxo to form a carbonyl group; C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 aryl, and 6- to 10-membered heteroaryl are each independently R 10 optionally substituted with 1, 2, 3, or 4 substituents selected from R 3 But H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1~3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3Alkylene, 5-6 membered heteroaryl-C 1~3 Alkylene, Halo, D, CN, OR f3 , C(O)NR c3 R d3 , N.R. c3 R j3 , and NR c3 C(O)R b3 C is selected from 1~3 Alkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1~3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Each alkylene is independently R 30 optionally substituted with 1, 2, or 3 substituents selected from R 5 But H, C 1~3 Alkyl, C 1~3 Haloalkyl, cyclopropyl, halo, D, CN, and OR a5 C is selected from 1~3 alkyl and cyclopropyl are each independently R g optionally substituted with 1 or 2 substituents selected from R 6 But H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1~3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene, 5-6 membered heteroaryl-C 1~3 Alkylene, Halo, D, CN, OR a6 , and C(O)NR c6 R d6 C is selected from 1~3 Alkyl, C 3~6Cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1~3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Each alkylene is independently R 60 optionally substituted with 1 or 2 substituents selected from R 7 But H, C 1~3 Alkyl, C 1~3 Haloalkyl, cyclopropyl, halo, D, CN, and OR a7 C is selected from 1~3 alkyl and cyclopropyl are each independently R g optionally substituted with 1 or 2 substituents selected from Cy 2 is selected from the following: [ka] wherein n is 0, 1, or 2; Each R 10 But independently, C 1~3 Alkyl, C 1~3 Haloalkyl, Halo, D, CN, OR a10 , C(O)R b10 , C(O)NR c10 R d10 , C(O)OR a10 , N.R. c10 R d10 , and S(O)2R b10 is selected from Each R 20 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, halo, D, CN, and OR a20 is selected from Each R 30 But independently, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, CN, OR a30 , C(O)R b30 , C(O)NR c30 R d30 , C(O)OR a30 , N.R. c30 R d30 , and S(O)2R b30 C is selected from 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 31 optionally substituted with 1 or 2 substituents selected from Each R 31 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, Halo, D, CN, OR a31 , C(O)R b31 , C(O)NR c31 R d31 , C(O)OR a31 , N.R. c31 R d31 , and S(O)2R b31 is selected from Each R 33 But independently, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl, halo, D, CN, OR a30 , C(O)NR c30 R d30 , and NR c30 R d30 C is selected from 1~3 Alkyl, C 3~6 Cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl, and 5-6-membered heteroaryl are each independently R 31 optionally substituted with 1 or 2 substituents selected from Each R 60 But independently, C 1~3 Alkyl, C 1~3Haloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halo, D, CN, OR a60 , C(O)R b60 , C(O)NR c60 R d60 , C(O)OR a60 , N.R. c60 R d60 , and S(O)2R b60 C is selected from 1~3 alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 61 optionally substituted with 1 or 2 substituents selected from Each R 61 But independently, C 1~3 Alkyl, C 1~3 Haloalkyl, Halo, D, CN, OR a61 , and NR c61 R d61 is selected from R a1 But H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a2 However, independently, H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R b3 , R c3 , and R d3 However, independently, H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 30 optionally substituted with 1, 2, or 3 substituents selected from or R bonded to the same N atom c3 and R d3 together with the N atom to which they are attached, independently R 30forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents selected from R j3 But C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 30 optionally substituted with 1, 2, or 3 substituents selected from or R bonded to the same N atom c3 and R j3 together with the N atom to which they are attached, independently R 30 forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents selected from R f3 But C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 30 or R f3 is selected from the following: [ka] In the formula, R x But H or C 1~2 alkyl, and R y But C 1~2 Is it alkyl? or R x and R ytogether with the C atom to which they are attached form a 3- or 4-membered cycloalkyl group, R a5 But H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a6 , R c6 , and R d6 However, independently, H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 60 optionally substituted with 1 or 2 substituents selected from R a7 But H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a10 , R b10 , R c10 , and R d10 However, independently, H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a20 However, independently, H, C 1~3 Alkyl, and C 1~3 haloalkyl; R b20 But NH2, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a30 , R b30 , R c30 , and R d30 However, independently, H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a31 , R b31 , R c31 , and R d31However, independently, H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a60 , R b60 , R c60 , and R d60 However, independently, H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 61 or optionally substituted with one or two substituents selected from or any R bonded to the same N atom c60 and R d60 together with the N atom to which they are attached, independently R 61 forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with one or two substituents selected from Each R a61 , R c61 , and R d61 However, independently, H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R g However, independently, D, OH, CN, halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, Amino, C 1~3 Alkylamino and di(C 1~3 alkyl)amino; provided that the compound of formula I is Provided herein is a compound or a pharmaceutically acceptable salt thereof, provided that the compound is other than 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-4-ethoxy-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N-dimethylpropanamide.

[0020] In one embodiment of Formula I, or a pharmaceutically acceptable salt thereof, Y is CR 6 and R 1 is H, C 1~3 Alkyl, C 1~3 Haloalkyl, cyclopropyl, halo, D, CN, and OR a1 C is selected from 1~3 Alkyl and cyclopropyl are each independently R g optionally substituted with 1 or 2 substituents selected from R 2 is H, C 1~3 Alkyl, C 1~3 Haloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene, 5-6 membered heteroaryl-C 1~3 Alkylene, halo, D, CN, and OR a2 C is selected from 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene, 5-6 membered heteroaryl-C 1~3 Each alkylene is independently R g optionally substituted with 1 or 2 substituents selected from Cy 1 is C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10aryl, and 6- to 10-membered heteroaryl, wherein the 4- to 10-membered heterocycloalkyl and the 6- to 10-membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, and the ring-forming carbon atoms of the 6- to 10-membered heteroaryl and the 4- to 10-membered heterocycloalkyl are optionally substituted by oxo to form a carbonyl group; C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl and 6- to 10-membered heteroaryl are each independently R 10 optionally substituted with 1, 2, 3, or 4 substituents selected from R 3 is H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1~3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene, 5-6 membered heteroaryl-C 1~3 Alkylene, Halo, D, CN, C(O)NR c3 R d3 , and NR c3 C(O)R b3 C is selected from 1~3 Alkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1~3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Each alkylene is independently R 30 optionally substituted with 1, 2, or 3 substituents selected from R 5 is H, C 1~3 Alkyl, C 1~3Haloalkyl, cyclopropyl, halo, D, CN, and OR a5 C is selected from 1~3 Alkyl and cyclopropyl are each independently R g optionally substituted with 1 or 2 substituents selected from R 6 is H, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1~3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene, 5-6 membered heteroaryl-C 1~3 Alkylene, Halo, D, CN, OR a6 , and C(O)NR c6 R d6 C is selected from 3~6 Cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1~3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Each alkylene is independently R 60 or R 6 is C 1~3 alkyl, 1~3 Alkyl is independently R 60 is substituted with one or two substituents selected from R 7 is H, C 1~3 Alkyl, C 1~3 Haloalkyl, cyclopropyl, halo, D, CN, and OR a7 C is selected from 1~3 Alkyl and cyclopropyl are each independently R g optionally substituted with 1 or 2 substituents selected from Cy 2 is selected from: [ka] wherein n is 0, 1, or 2; Each R 10 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, Halo, D, CN, OR a10 , C(O)R b10 , C(O)NR c10 R d10 , C(O)OR a10 , N.R. c10 R d10 , and S(O)2R b10 is selected from Each R 20 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, halo, D, CN, and OR a20 is selected from Each R 30 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, CN, OR a30 , C(O)R b30 , C(O)NR c30 R d30 , C(O)OR a30 , N.R. c30 R d30 , and S(O)2R b30 C is selected from 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 31 optionally substituted with 1 or 2 substituents selected from Each R 31 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, Halo, D, CN, OR a31 , C(O)R b31 , C(O)NR c31 Rd31 , C(O)OR a31 , N.R. c31 R d31 , and S(O)2R b31 is selected from Each R 60 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halo, D, CN, OR a60 , C(O)R b60 , C(O)NR c60 R d60 , C(O)OR a60 , N.R. c60 R d60 , and S(O)2R b60 C is selected from 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 61 optionally substituted with 1 or 2 substituents selected from Each R 61 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, Halo, D, CN, OR a61 , and NR c61 R d61 is selected from R a1 is H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a2 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R b3 , R c3 , and R d3 are independently H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, C 3~6Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 30 optionally substituted with 1, 2, or 3 substituents selected from or R bonded to the same N atom c3 and R d3 are independently R together with the N atom to which they are attached. 30 forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents selected from R a5 is H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a6 , R c6 , and R d6 are independently H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 60 optionally substituted with 1 or 2 substituents selected from R a7 is H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a10 , R b10 , R c10 , and R d10 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a20 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl; R b20 is NH2, C 1~3 Alkyl, and C 1~3haloalkyl; Each R a30 , R b30 , R c30 , and R d30 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a31 , R b31 , R c31 , and R d31 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a60 , R b60 , R c60 , and R d60 are independently H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 61 or optionally substituted with one or two substituents selected from or any R bonded to the same N atom c60 and R d60 are independently R together with the N atom to which they are attached. 61 forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with one or two substituents selected from Each R a61 , R c61 , and R d61 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R g are independently D, OH, CN, halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, Amino, C 1~3Alkylamino and di(C 1~3 alkyl)amino.

[0021] In another embodiment of Formula I, or a pharmaceutically acceptable salt thereof, Y is CR 6 and R 1 is H, R 2 is C 1~3 Alkyl, C 1~3 selected from haloalkyl, halo, CN, and —CHCHCN; Cy 1 is C 3~10 Cycloalkyl, C 6~10 aryl, and 6- to 10-membered heteroaryl, wherein the 6- to 10-membered heteroaryl has at least one ring-forming carbon atom and one ring-forming heteroatom independently selected from N and S; 3~10 Cycloalkyl, C 6~10 Aryl and 6- to 10-membered heteroaryl are each independently R 10 optionally substituted with 1 or 2 substituents selected from R 3 is H, C 1~3 Alkyl, C 1~3 haloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 30 optionally substituted with 1 or 2 substituents selected from R 5 is H, R 6 is H, C 1~3 haloalkyl, 4- to 8-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, wherein the 4- to 8-membered heterocycloalkyl and the 5- to 6-membered heteroaryl are each independently selected from R 60 or R 6 is C 1~3alkyl, 1~3 Alkyl is independently R 60 is substituted with one or two substituents selected from R 7 is a halo, Cy 2 is [ka] Each R 10 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, halo, CN, and OR a10 is selected from Each R 30 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, 4-6 membered heterocycloalkyl, halo, D, CN, OR a30 , C(O)NR c30 R d30 , and NR c30 R d30 C is selected from 1~3 alkyl and 4- to 6-membered heterocycloalkyl are each independently R 31 optionally substituted with 1 or 2 substituents selected from Each R 31 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, Halo, CN, OR a31 , and NR c31 R d31 is selected from Each R 60 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halo, CN, OR a60 , C(O)R b60 , C(O)NR c60 R d60 , C(O)OR a60 , and NR c60 R d60 C is selected from 1~3Alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 61 optionally substituted with 1 or 2 substituents selected from Each R 61 independently, C 1~3 Alkyl, C 1~3 selected from haloalkyl, halo, and CN; Each R a10 are independently H and C 1~3 alkyl, Each R a30 , R c30 , and R d30 are independently H and C 1~3 alkyl, Each R a31 , R c31 , and R d31 are independently H and C 1~3 alkyl, Each R a60 , R b60 , R c60 , and R d60 are independently H, C 1~3 Alkyl, C 1~3 Haloalkyl, and C 3~6 cycloalkyl, wherein C 1~3 Alkyl and C 3~6 Each cycloalkyl is independently R 61 or optionally substituted with one or two substituents selected from or any R bonded to the same N atom c60 and R d60 are independently R together with the N atom to which they are attached. 61 to form a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with one or two substituents selected from:

[0022] In yet another embodiment of Formula I, or a pharmaceutically acceptable salt thereof, Y is CR 6 and R 1 is H, R 2is -CH2CH2CN, Cy 1 is phenyl, and the phenyl is independently R 10 optionally substituted with 1 or 2 substituents selected from R 3 is selected from 5- to 6-membered heteroaryl, and the 5- to 6-membered heteroaryl is independently selected from R 30 optionally substituted with 1 or 2 substituents selected from R 5 is H, R 6 is selected from 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl, and each of the 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl is independently R 60 or R 6 is C 1~3 alkyl, 1~3 Alkyl is independently R 60 is substituted with one or two substituents selected from R 7 is a halo, Cy 2 is [ka] Each R 10 independently, C 1~3 selected from alkyl and halo; Each R 30 independently, C 1~3 Alkyl, Halo, and C(O)NR c30 R d30 C is selected from 1~3 Alkyl is R 31 and optionally substituted with one substituent selected from Each R 31 is OR a31 and Each R 60 are independently 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C(O)R b60, C(O)NR c60 R d60 , and C(O)OR a60 wherein the 4- to 6-membered heterocycloalkyl and the 5- to 6-membered heteroaryl are each independently selected from R 61 optionally substituted with 1 or 2 substituents selected from Each R 61 independently, C 1~3 selected from alkyl and halo; Each R c30 and R d30 are independently H and C 1~3 alkyl, Each R a31 are independently H and C 1~3 alkyl, Each R a60 , R b60 , R c60 , and R d60 are independently H, C 1~3 Alkyl, and C 3~6 cycloalkyl, wherein C 1~3 Alkyl and C 3~6 Each cycloalkyl is independently R 61 or optionally substituted with one or two substituents selected from or any R bonded to the same N atom c60 and R d60 are independently R together with the N atom to which they are attached. 61 to form a 4-membered heterocycloalkyl group optionally substituted with one or two substituents selected from:

[0023] In another embodiment of Formula I, or a pharmaceutically acceptable salt thereof, Y is CR 6 and R 1 is H, R 2 is -CH2CH2CN, Cy 1 is phenyl, and the phenyl is independently R 10 optionally substituted with 1 or 2 substituents selected from R 3 is C 1~3 alkyl and 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is independently selected from R 30 optionally substituted with 1 or 2 substituents selected from R 5 is H, R 6 is selected from 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl, and each of the 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl is independently R 60 or R 6 is C 1~3 alkyl, and the C 1~3 Alkyl is independently R 60 is substituted with one or two substituents selected from R 7 is a halo, Cy 2 is [ka] Each R 10 independently, C 1~3 selected from alkyl and halo; Each R 30 independently, C 1~3 Alkyl, Halo, and C(O)NR c30 R d30 C is selected from 1~3 Alkyl is R 31 and optionally substituted with one substituent selected from Each R 31 is OR a31 and Each R 60 are independently 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C(O)R b60 , C(O)NR c60 R d60 , and C(O)OR a60wherein the 4- to 6-membered heterocycloalkyl and the 5- to 6-membered heteroaryl are each independently selected from R 61 optionally substituted with 1 or 2 substituents selected from Each R 61 independently, C 1~3 selected from alkyl and halo; Each R c30 and R d30 are independently H and C 1~3 alkyl, Each R a31 are independently H and C 1~3 alkyl, Each R a60 , R b60 , R c60 , and R d60 are independently H, C 1~3 Alkyl, and C 3~6 cycloalkyl, wherein C 1~3 Alkyl and C 3~6 Each cycloalkyl is independently R 61 or optionally substituted with one or two substituents selected from or any R bonded to the same N atom c60 and R d60 are independently R together with the N atom to which they are attached. 61 to form a 4-membered heterocycloalkyl group optionally substituted with one or two substituents selected from:

[0024] In yet another embodiment of Formula I, or a pharmaceutically acceptable salt thereof, Y is CR 6 and R 1 is H, R 2 is -CH2CH2CN, Cy 1 is phenyl or naphthyl, and each of phenyl and naphthyl is independently R 10 optionally substituted with 1 or 2 substituents selected from R 3is selected from H and 5- to 6-membered heteroaryl, and the 5- to 6-membered heteroaryl is independently R 30 optionally substituted with 1 or 2 substituents selected from R 5 is H, R 6 is selected from 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl, and each of the 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl is independently R 60 or R 6 is C 1~3 alkyl, 1~3 Alkyl is independently R 60 is substituted with one or two substituents selected from R 7 is a halo, Cy 2 is [ka] Each R 10 independently, C 1~3 selected from alkyl and halo; Each R 30 independently, C 1~3 Alkyl and C(O)NR c30 R d30 C is selected from 1~3 Alkyl is R 31 and optionally substituted with one substituent selected from Each R 31 is OR a31 and Each R 60 are independently 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C(O)R b60 , C(O)NR c60 R d60 , and C(O)OR a60 wherein the 4- to 6-membered heterocycloalkyl and the 5- to 6-membered heteroaryl are each independently selected from R 61optionally substituted with 1 or 2 substituents selected from Each R 61 independently, C 1~3 selected from alkyl and halo; Each R c30 and R d30 are independently H and C 1~3 alkyl, Each R a31 are independently H and C 1~3 alkyl, Each R a60 , R b60 , R c60 , and R d60 are independently H, C 1~3 Alkyl, and C 3~6 cycloalkyl, wherein C 1~3 Alkyl and C 3~6 Each cycloalkyl is independently R 61 or optionally substituted with one or two substituents selected from or any R bonded to the same N atom c60 and R d60 are independently R together with the N atom to which they are attached. 61 to form a 4-membered heterocycloalkyl group optionally substituted with one or two substituents selected from:

[0025] In one aspect, Formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein Y is N or CR 6 and R 1 But H, C 1~3 Alkyl, C 1~3 Haloalkyl, cyclopropyl, halo, D, CN, and OR a1 C is selected from 1~3 alkyl and cyclopropyl are each independently R g optionally substituted with 1 or 2 substituents selected from R 2 But H, C 1~3 Alkyl, C 1~3 Haloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene, 5-6 membered heteroaryl-C 1~3 Alkylene, halo, D, CN, and OR a2 C is selected from 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene, 5-6 membered heteroaryl-C 1~3 Each alkylene is independently R g optionally substituted with 1 or 2 substituents selected from Cy 1 But C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 aryl, and 6- to 10-membered heteroaryl, wherein the 4- to 10-membered heterocycloalkyl and the 6- to 10-membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, and the ring-forming carbon atoms of the 6- to 10-membered heteroaryl and the 4- to 10-membered heterocycloalkyl are optionally substituted by oxo to form a carbonyl group; C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 aryl, and 6- to 10-membered heteroaryl are each independently R 10 optionally substituted with 1, 2, 3, or 4 substituents selected from R 3 But H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1~3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3Alkylene, Phenyl-C 1~3 Alkylene, 5-6 membered heteroaryl-C 1~3 Alkylene, Halo, D, CN, OR f3 , C(O)NR c3 R d3 , N.R. c3 R j3 , and NR c3 C(O)R b3 C is selected from 1~3 Alkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1~3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Each alkylene is independently R 30 optionally substituted with 1, 2, or 3 substituents selected from R 5 But H, C 1~3 Alkyl, C 1~3 Haloalkyl, cyclopropyl, halo, D, CN, and OR a5 C is selected from 1~3 alkyl and cyclopropyl are each independently R g optionally substituted with 1 or 2 substituents selected from R 6 But H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1~3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene, 5-6 membered heteroaryl-C 1~3 Alkylene, Halo, D, CN, OR a6 , and C(O)NR c6 R d6 C is selected from 1~3 Alkyl, C3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1~3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Each alkylene is independently R 60 optionally substituted with 1 or 2 substituents selected from R 7 But H, C 1~3 Alkyl, C 1~3 Haloalkyl, cyclopropyl, halo, D, CN, and OR a7 C is selected from 1~3 alkyl and cyclopropyl are each independently R g optionally substituted with 1 or 2 substituents selected from Cy 2 is selected from the following: [ka] wherein n is 0, 1, or 2; Each R 10 But independently, C 1~3 Alkyl, C 1~3 Haloalkyl, Halo, D, CN, OR a10 , C(O)R b10 , C(O)NR c10 R d10 , C(O)OR a10 , N.R. c10 R d10 , and S(O)2R b10 is selected from Each R 20 But independently, C 1~3 Alkyl, C 1~3 Haloalkyl, halo, D, CN, and OR a20 is selected from Each R 30 But independently, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, CN, OR a30 , C(O)R b30 , C(O)NR c30 R d30 , C(O)OR a30 , N.R. c30 R d30 , and S(O)2R b30 C is selected from 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 31 optionally substituted with 1 or 2 substituents selected from Each R 31 But independently, C 1~3 Alkyl, C 1~3 Haloalkyl, Halo, D, CN, OR a31 , C(O)R b31 , C(O)NR c31 R d31 , C(O)OR a31 , N.R. c31 R d31 , and S(O)2R b31 is selected from Each R 33 But independently, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl, halo, D, CN, OR a30 , C(O)NR c30 R d30 , and NR c30 R d30 C is selected from 1~3 Alkyl, C 3~6 Cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl, and 5-6-membered heteroaryl are each independently R 31 optionally substituted with 1 or 2 substituents selected from Each R 60 But independently, C 1~3 Alkyl, C 1~3Haloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halo, D, CN, OR a60 , C(O)R b60 , C(O)NR c60 R d60 , C(O)OR a60 , N.R. c60 R d60 , and S(O)2R b60 C is selected from 1~3 alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 61 optionally substituted with 1 or 2 substituents selected from Each R 61 But independently, C 1~3 Alkyl, C 1~3 Haloalkyl, Halo, D, CN, OR a61 , and NR c61 R d61 is selected from R a1 But H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a2 However, independently, H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R b3 , R c3 , and R d3 However, independently, H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 30 optionally substituted with 1, 2, or 3 substituents selected from or R bonded to the same N atom c3 and R d3 together with the N atom to which they are attached, independently R 30forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents selected from R j3 But C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 30 optionally substituted with 1, 2, or 3 substituents selected from or R bonded to the same N atom c3 and R j3 together with the N atom to which they are attached, independently R 30 forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents selected from R f3 But C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 30 or R f3 is selected from the following: [ka] In the formula, R x But H or C 1~2 alkyl, and R y But C 1~2 Is it alkyl? or R x and R ytogether with the C atom to which they are attached form a 3- or 4-membered cycloalkyl group, R a5 But H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a6 , R c6 , and R d6 However, independently, H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 60 optionally substituted with 1 or 2 substituents selected from R a7 But H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a10 , R b10 , R c10 , and R d10 However, independently, H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a20 However, independently, H, C 1~3 Alkyl, and C 1~3 haloalkyl; R b20 But NH2, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a30 , R b30 , R c30 , and R d30 However, independently, H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a31 , R b31 , R c31 , and R d31However, independently, H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a60 , R b60 , R c60 , and R d60 However, independently, H, C 1~3 Alkyl, C 1~3 haloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; 1~3 alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 61 or optionally substituted with one or two substituents selected from or any R bonded to the same N atom c60 and R d60 together with the N atom to which they are attached, independently R 61 forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with one or two substituents selected from Each R a61 , R c61 , and R d61 However, independently, H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R g However, independently, D, OH, CN, halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, Amino, C 1~3 Alkylamino and di(C 1~3 alkyl)amino; provided that the compound of formula I is Provided herein are compounds other than 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-4-ethoxy-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N-dimethylpropanamide, or a pharmaceutically acceptable salt thereof.

[0026] In one embodiment of Formula I, or a pharmaceutically acceptable salt thereof, Y is N or CR 6 and R 1 is H, C 1~3 Alkyl, C 1~3 Haloalkyl, cyclopropyl, halo, D, CN, and OR a1 C is selected from 1~3 Alkyl and cyclopropyl are each independently R g optionally substituted with 1 or 2 substituents selected from R 2 is H, C 1~3 Alkyl, C 1~3 Haloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene, 5-6 membered heteroaryl-C 1~3 Alkylene, halo, D, CN, and OR a2 C is selected from 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene, 5-6 membered heteroaryl-C 1~3 Each alkylene is independently R g optionally substituted with 1 or 2 substituents selected from Cy 1 is C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 aryl, and 6- to 10-membered heteroaryl, wherein the 4- to 10-membered heterocycloalkyl and the 6- to 10-membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, and the ring-forming carbon atoms of the 6- to 10-membered heteroaryl and the 4- to 10-membered heterocycloalkyl are optionally substituted by oxo to form a carbonyl group; C 3~10Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl and 6- to 10-membered heteroaryl are each independently R 10 optionally substituted with 1, 2, 3, or 4 substituents selected from R 3 is H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1~3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene, 5-6 membered heteroaryl-C 1~3 Alkylene, Halo, D, CN, OR f3 , C(O)NR c3 R d3 , N.R. c3 R j3 , and NR c3 C(O)R b3 C is selected from 1~3 Alkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1~3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Each alkylene is independently R 30 optionally substituted with 1, 2, or 3 substituents selected from R 5 is H, C 1~3 Alkyl, C 1~3 Haloalkyl, cyclopropyl, halo, D, CN, and OR a5 C is selected from 1~3 Alkyl and cyclopropyl are each independently R g optionally substituted with 1 or 2 substituents selected from R 6 is H, C 1~3Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1~3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene, 5-6 membered heteroaryl-C 1~3 Alkylene, Halo, D, CN, OR a6 , and C(O)NR c6 R d6 C is selected from 1~3 Alkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1~3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Each alkylene is independently R 60 optionally substituted with 1 or 2 substituents selected from R 7 is H, C 1~3 Alkyl, C 1~3 Haloalkyl, cyclopropyl, halo, D, CN, and OR a7 C is selected from 1~3 Alkyl and cyclopropyl are each independently R g optionally substituted with 1 or 2 substituents selected from Cy 2 is selected from: [ka] wherein n is 0, 1, or 2; Each R 10 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, Halo, D, CN, OR a10 , C(O)R b10 , C(O)NR c10 Rd10 , C(O)OR a10 , N.R. c10 R d10 , and S(O)2R b10 is selected from Each R 20 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, halo, D, CN, and OR a20 is selected from Each R 30 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, CN, OR a30 , C(O)R b30 , C(O)NR c30 R d30 , C(O)OR a30 , N.R. c30 R d30 , and S(O)2R b30 C is selected from 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 31 optionally substituted with 1 or 2 substituents selected from Each R 31 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, Halo, D, CN, OR a31 , C(O)R b31 , C(O)NR c31 R d31 , C(O)OR a31 , N.R. c31 R d31 , and S(O)2R b31 is selected from R 33 is C 2~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl, halo, D, CN, OR a30, C(O)NR c30 R d30 , and NR c30 R d30 C is selected from 2~3 Alkyl, C 3~6 Cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl, and 5-6-membered heteroaryl are each independently R 31 optionally substituted with 1 or 2 substituents selected from Each R 60 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halo, D, CN, OR a60 , C(O)R b60 , C(O)NR c60 R d60 , C(O)OR a60 , N.R. c60 R d60 , and S(O)2R b60 C is selected from 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 61 optionally substituted with 1 or 2 substituents selected from Each R 61 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, Halo, D, CN, OR a61 , and NR c61 R d61 is selected from R a1 is H, C 1~3 Alkyl, and C 1~3 haloalkyl; R a2 is H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R b3 , R c3 , and R d3 are independently H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 30 optionally substituted with 1, 2, or 3 substituents selected from or R bonded to the same N atom c3 and R d3 are independently R together with the N atom to which they are attached. 30 forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents selected from R j3 is C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 30 optionally substituted with 1, 2, or 3 substituents selected from or R bonded to the same N atom c3 and R j3 are independently R together with the N atom to which they are attached. 30 forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents selected from R f3 is C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 30 or R f3 is selected from: [ka] In the formula, R x is H or C 1~2 alkyl, and R y is C 1~2 Is it alkyl? or R x and R y form together with the C atom to which they are attached a 3- or 4-membered cycloalkyl group, R a5 is H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a6 , R c6 , and R d6 are independently H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 60 optionally substituted with 1 or 2 substituents selected from R a7 is H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a10 , R b10 , R c10 , and R d10 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a20 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl; R b20 is NH2, C 1~3 Alkyl, and C1~3 haloalkyl; Each R a30 , R b30 , R c30 , and R d30 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a31 , R b31 , R c31 , and R d31 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a60 , R b60 , R c60 , and R d60 are independently H, C 1~3 Alkyl, C 1~3 haloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 61 or optionally substituted with one or two substituents selected from or any R bonded to the same N atom c60 and R d60 are independently R together with the N atom to which they are attached. 61 forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with one or two substituents selected from Each R a61 , R c61 , and R d61 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R g are independently D, OH, CN, halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, Amino, C 1~3 Alkylamino and di(C 1~3alkyl)amino.

[0027] In another embodiment of Formula I, or a pharmaceutically acceptable salt thereof, Y is N or CR 6 and R 1 is H, C 1~3 Alkyl, C 1~3 Haloalkyl, cyclopropyl, halo, D, CN, and OR a1 C is selected from 1~3 Alkyl and cyclopropyl are each independently R g optionally substituted with 1 or 2 substituents selected from R 2 is H, C 1~3 Alkyl, C 1~3 Haloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene, 5-6 membered heteroaryl-C 1~3 Alkylene, halo, D, CN, and OR a2 C is selected from 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Each alkylene is independently R g optionally substituted with 1 or 2 substituents selected from Cy 1 is C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10aryl, and 6- to 10-membered heteroaryl, wherein the 4- to 10-membered heterocycloalkyl and the 6- to 10-membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, and the ring-forming carbon atoms of the 6- to 10-membered heteroaryl and the 4- to 10-membered heterocycloalkyl are optionally substituted by oxo to form a carbonyl group; C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl and 6- to 10-membered heteroaryl are each independently R 10 optionally substituted with 1, 2, 3, or 4 substituents selected from R 3 is H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1~3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene, 5-6 membered heteroaryl-C 1~3 Alkylene, Halo, D, CN, OR f3 , C(O)NR c3 R d3 , N.R. c3 R j3 , and NR c3 C(O)R b3 C is selected from 1~3 Alkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1~3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Each alkylene is independently R 30 optionally substituted with 1, 2, or 3 substituents selected from R 5 is H, C1~3 Alkyl, C 1~3 Haloalkyl, cyclopropyl, halo, D, CN, and OR a5 C is selected from 1~3 Alkyl and cyclopropyl are each independently R g optionally substituted with 1 or 2 substituents selected from R 6 is H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1~3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene, 5-6 membered heteroaryl-C 1~3 Alkylene, Halo, D, CN, OR a6 , and C(O)NR c6 R d6 C is selected from 1~3 Alkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1~3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Each alkylene is independently R 60 optionally substituted with 1 or 2 substituents selected from R 7 is H, C 1~3 Alkyl, C 1~3 Haloalkyl, cyclopropyl, halo, D, CN, and OR a7 C is selected from 1~3 Alkyl and cyclopropyl are each independently R g optionally substituted with 1 or 2 substituents selected from Cy 2 is selected from: [ka] wherein n is 0, 1, or 2; Each R 10 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, Halo, D, CN, OR a10 , C(O)R b10 , C(O)NR c10 R d10 , C(O)OR a10 , N.R. c10 R d10 , and S(O)2R b10 is selected from Each R 20 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, halo, D, CN, and OR a20 is selected from Each R 30 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, CN, OR a30 , C(O)R b30 , C(O)NR c30 R d30 , C(O)OR a30 , N.R. c30 R d30 , and S(O)2R b30 C is selected from 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 31 optionally substituted with 1 or 2 substituents selected from Each R 31 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, Halo, D, CN, OR a31 , C(O)R b31 , C(O)NR c31 R d31 , C(O)OR a31 , N.R. c31 Rd31 , and S(O)2R b31 is selected from Each R 33 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl, halo, D, CN, OR a30 , C(O)NR c30 R d30 , and NR c30 R d30 C is selected from 1~3 Alkyl, C 3~6 Cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl, and 5-6-membered heteroaryl are each independently R 31 optionally substituted with 1 or 2 substituents selected from Each R 60 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halo, D, CN, OR a60 , C(O)R b60 , C(O)NR c60 R d60 , C(O)OR a60 , N.R. c60 R d60 , and S(O)2R b60 C is selected from 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 61 optionally substituted with 1 or 2 substituents selected from Each R 61 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, Halo, D, CN, OR a61 , and NR c61 R d61 is selected from R a1 is H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a2 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R b3 , R c3 , and R d3 are independently H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 30 optionally substituted with 1, 2, or 3 substituents selected from or R bonded to the same N atom c3 and R d3 are independently R together with the N atom to which they are attached. 30 forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents selected from R j3 is C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 30 optionally substituted with 1, 2, or 3 substituents selected from or R bonded to the same N atom c3 and R j3 are independently R together with the N atom to which they are attached. 30 forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents selected from R f3 is C 1~3Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 30 or R f3 is selected from: [ka] In the formula, R x is H or C 1~2 alkyl, and R y is C 1~2 Is it alkyl? or R x and R y form together with the C atom to which they are attached a 3- or 4-membered cycloalkyl group, R a5 is H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a6 , R c6 , and R d6 are independently H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 60 optionally substituted with 1 or 2 substituents selected from R a7 is H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a10 , R b10 , R c10, and R d10 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a20 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl; R b20 is NH2, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a30 , R b30 , R c30 , and R d30 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a31 , R b31 , R c31 , and R d31 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a60 and R b60 are independently H, C 1~3 Alkyl, C 1~3 haloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 61 optionally substituted with 1 or 2 substituents selected from Each R c60 and R d60 are independently H, C 2~3 Alkyl, C 1~3 haloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; 2~3 Alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 61 optionally substituted with 1 or 2 substituents selected from or any R bonded to the same N atomc60 and R d60 are independently R together with the N atom to which they are attached. 61 forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with one or two substituents selected from Each R a61 , R c61 , and R d61 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R g are independently D, OH, CN, halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, Amino, C 1~3 Alkylamino and di(C 1~3 alkyl)amino.

[0028] In yet another embodiment of Formula I, or a pharmaceutically acceptable salt thereof, Y is N or CR 6 and R 1 is H, C 1~3 Alkyl, C 1~3 haloalkyl, and D; R 2 is H, C 1~3 Alkyl, C 1~3 Haloalkyl, halo, D, CN, and OR a2 C is selected from 1~3 Alkyl is independently R g optionally substituted with 1 or 2 substituents selected from Cy 1 is C 6~10 selected from aryl and 6- to 10-membered heteroaryl, wherein the 6- to 10-membered heteroaryl has at least one ring-forming carbon atom and 1, 2, or 3 ring-forming heteroatoms independently selected from N, O, and S, and wherein the ring-forming carbon atoms of the 6- to 10-membered heteroaryl are optionally substituted by oxo to form a carbonyl group; C 6~10The aryl and the 6- to 10-membered heteroaryl are each independently R 10 optionally substituted with 1, 2, or 3 substituents selected from R 3 is H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, CN, OR f3 , and NR c3 R j3 C is selected from 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 30 optionally substituted with 1, 2, or 3 substituents selected from R 5 is H, C 1~3 Alkyl, C 1~3 haloalkyl, and D; R 6 is H, C 1~3 Alkyl, C 1~3 haloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, halo, D, and CN; 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 60 optionally substituted with 1 or 2 substituents selected from R 7 is H, C 1~3 Alkyl, C 1~3 selected from haloalkyl, halo, D, and CN; Cy 2 is selected from: [ka] In the formula, n is 0 or 1, Each R 10 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, Halo, D, CN, OR a10 , and NRc10 R d10 is selected from Each R 20 independently, C 1~3 Alkyl, C 1~3 selected from haloalkyl, halo, D, and CN; Each R 30 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halo, D, CN, OR a30 , and NR c30 R d30 C is selected from 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 31 optionally substituted with 1 or 2 substituents selected from Each R 31 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, Halo, D, CN, OR a31 , and NR c31 R d31 is selected from R 33 is C 2~3 Alkyl, C 1~3 Haloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, 5-6-membered heteroaryl, halo, D, CN, OR a30 , and NR c30 R d30 C is selected from 2~3 Alkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, and 5-6-membered heteroaryl are each independently R 31 optionally substituted with 1 or 2 substituents selected from Each R 60 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halo, D, CN, OR a60 , C(O)NR c60 R d60 , and NR c60 R d60C is selected from 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 61 optionally substituted with 1 or 2 substituents selected from Each R 61 independently, C 1~3 Alkyl, C 1~3 selected from haloalkyl, halo, D, and CN; R a2 is H, C 1~3 Alkyl, and C 1~3 haloalkyl; R c3 is H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 30 optionally substituted with 1, 2, or 3 substituents selected from R j3 is C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 30 optionally substituted with 1, 2, or 3 substituents selected from or R bonded to the same N atom c3 and R j3 are independently R together with the N atom to which they are attached. 30 forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents selected from R f3 is C1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 30 or R f3 is selected from: [ka] In the formula, R x is H or C 1~2 alkyl, and R y is C 1~2 Is it alkyl? or R x and R y form together with the C atom to which they are attached a 3- or 4-membered cycloalkyl group, Each R a10 , R c10 , and R d10 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl; R b20 is NH2, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a30 , R c30 , and R d30 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a31 , R c31 , and R d31 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a60 , R c60 , and R d60 are independently H, C 1~3 Alkyl, C1~3 haloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 61 or optionally substituted with one or two substituents selected from or any R bonded to the same N atom c60 and R d60 are independently R together with the N atom to which they are attached. 61 forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with one or two substituents selected from Each R g are independently D, CN, halo, C 1~3 Alkyl, and C 1~3 haloalkyl.

[0029] In yet another embodiment of Formula I, or a pharmaceutically acceptable salt thereof, Y is N or CR 6 and R 1 is H, R 2 is H, C 1~3 Alkyl, C 1~3 selected from haloalkyl, halo, D, CN, and —CHCHCN; Cy 1 is C 6~10 aryl and 6- to 10-membered heteroaryl, wherein the 6- to 10-membered heteroaryl has at least one ring-forming carbon atom and 1 or 2 ring-forming heteroatoms independently selected from N, O, and S; 6~10 The aryl and the 6- to 10-membered heteroaryl are each independently R 10 optionally substituted with 1, 2, or 3 substituents selected from R 3 is H, C 1~3 Alkyl, C 1~3 haloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halo, D, CN, and OR f3C is selected from 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 30 optionally substituted with 1 or 2 substituents selected from R 5 is H, R 6 is H, C 1~3 Alkyl, C 1~3 haloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, halo, D, and CN; 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 60 optionally substituted with 1 or 2 substituents selected from R 7 is a halo, Cy 2 is selected from: [ka] Each R 10 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, halo, D, CN, and OR a10 is selected from Each R 30 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, 4-6 membered heterocycloalkyl, halo, D, CN, OR a30 , and NR c30 R d30 C is selected from 1~3 alkyl and 4- to 6-membered heterocycloalkyl are each independently R 31 optionally substituted with 1 or 2 substituents selected from Each R 31 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, Halo, D, CN, OR a31 , and NR c31 R d31 is selected from R 33 is C2~3 Alkyl, C 1~3 Haloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, halo, D, CN, OR a30 , and NR c30 R d30 C is selected from 2~3 Alkyl, 4-membered heterocycloalkyl, and 6-membered heterocycloalkyl are each independently R 31 optionally substituted with 1 or 2 substituents selected from Each R 60 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, 4-6 membered heterocycloalkyl, halo, D, CN, OR a60 , C(O)NR c60 R d60 , and NR c60 R d60 C is selected from 1~3 alkyl and 4- to 6-membered heterocycloalkyl are each independently R 61 optionally substituted with 1 or 2 substituents selected from Each R 61 independently, C 1~3 Alkyl, C 1~3 selected from haloalkyl, halo, D, and CN; R f3 is C 1~3 haloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, wherein the 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are each independently selected from R 30 or R f3 is selected from: [ka] In the formula, R x is H or C 1~2 alkyl, and R y is C 1~2 is alkyl, Each R a10 are independently H, C 1~3Alkyl, and C 1~3 haloalkyl; R b20 is C 1~3 Alkyl and C 1~3 haloalkyl; Each R a30 , R c30 , and R d30 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a31 , R c31 , and R d31 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a60 , R c60 , and R d60 are independently H, C 1~3 Alkyl, C 1~3 haloalkyl, and 4- to 6-membered heterocycloalkyl, 1~3 alkyl and 4- to 6-membered heterocycloalkyl are each independently R 61 or optionally substituted with one or two substituents selected from or any R bonded to the same N atom c60 and R d60 are independently R together with the N atom to which they are attached. 61 to form a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with one or two substituents selected from:

[0030] In one embodiment of Formula I, or a pharmaceutically acceptable salt thereof, Y is N or CR 6 and R 1 is H, R 2 is C 1~3 Alkyl, C 1~3 selected from haloalkyl, halo, CN, and —CHCHCN; Cy 1 is C 6~10aryl and 6- to 10-membered heteroaryl, wherein the 6- to 10-membered heteroaryl has at least one ring-forming carbon atom and one ring-forming heteroatom independently selected from N and S; 6~10 The aryl and the 6- to 10-membered heteroaryl are each independently R 10 optionally substituted with 1, 2, or 3 substituents selected from R 3 is C 1~3 Alkyl, C 1~3 haloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and OR f3 C is selected from 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 30 optionally substituted with 1 or 2 substituents selected from R 5 is H, R 6 is H, C 1~3 Alkyl, C 1~3 haloalkyl, and 5- to 6-membered heteroaryl, 1~3 The alkyl and the 5- to 6-membered heteroaryl are each independently R 60 optionally substituted with 1 or 2 substituents selected from R 7 is a halo, Cy 2 is selected from: [ka] Each R 10 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, halo, CN, and OR a10 is selected from Each R 30 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, 4-6 membered heterocycloalkyl, halo, and NR c30 R d30 C is selected from 1~3alkyl and 4- to 6-membered heterocycloalkyl are each independently R 31 optionally substituted with 1 or 2 substituents selected from Each R 31 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, halo, and NR c31 R d31 is selected from R 33 is C 2~3 Alkyl, C 1~3 haloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, halo, and CN; 2~3 Alkyl, 4-membered heterocycloalkyl, and 6-membered heterocycloalkyl are each independently R 31 optionally substituted with 1 or 2 substituents selected from Each R 60 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, 4-6 membered heterocycloalkyl, halo, and C(O)NR c60 R d60 C is selected from 1~3 alkyl and 4- to 6-membered heterocycloalkyl are each independently R 61 optionally substituted with 1 or 2 substituents selected from Each R 61 independently, C 1~3 Alkyl, C 1~3 selected from haloalkyl, and halo; R f3 is C 1~3 haloalkyl, or R f3 is selected from: [ka] In the formula, R x is H or C 1~2 alkyl, and R y is C 1~2 is alkyl, Each R a10 are independently H, C 1~3Alkyl, and C 1~3 haloalkyl; R b20 is C 1~3 Alkyl and C 1~3 haloalkyl; Each R c30 and R d30 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R c31 and R d31 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R c60 and R d60 are independently H, C 1~3 Alkyl, C 1~3 haloalkyl, and 4- to 6-membered heterocycloalkyl, 1~3 alkyl and 4- to 6-membered heterocycloalkyl are each independently R 61 or optionally substituted with one or two substituents selected from or any R bonded to the same N atom c60 and R d60 are independently R together with the N atom to which they are attached. 61 to form a 4- or 5-membered heterocycloalkyl group optionally substituted with one or two substituents selected from:

[0031] In one embodiment, Y is N or CR 6 and R 1 is H, R 2 is C 1~3 selected from alkyl, halo, CN, and —CHCHCN; Cy 1 are phenyl, naphthyl, indolyl, benzothiophenyl, and isoquinolinyl, all of which are each independently R 10 optionally substituted with 1, 2, or 3 substituents selected from R 3 is C 1~3 alkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and OR f3 C is selected from 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 30 optionally substituted with 1 or 2 substituents selected from R 5 is H, R 6 is H, C 1~3 alkyl, and 5- to 6-membered heteroaryl, 1~3 The alkyl and the 5- to 6-membered heteroaryl are each independently R 60 optionally substituted with 1 or 2 substituents selected from R 7 is a halo, Cy 2 is selected from: [ka] Each R 10 independently, C 1~3 Alkyl, C 1~3 selected from haloalkyl, halo, CN, and OH; Each R 30 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, 4-6 membered heterocycloalkyl, halo, and N(C 1~3 alkyl)2, and 1~3 alkyl and 4- to 6-membered heterocycloalkyl are each independently R 31 optionally substituted with 1 or 2 substituents selected from Each R 31 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, halo, and N(C 1~3 alkyl)2; R 33 is C 2~3 Alkyl, C 1~3haloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, halo, and CN; 2~3 Alkyl, 4-membered heterocycloalkyl, and 6-membered heterocycloalkyl are each independently R 31 optionally substituted with 1 or 2 substituents selected from Each R 60 are independently 4- to 6-membered heterocycloalkyl and C(O)NR c60 R d60 wherein each 4- to 6-membered heterocycloalkyl is optionally selected from R 61 and is substituted with 1 or 2 substituents independently selected from Each R 61 independently, C 1~3 Alkyl, C 1~3 selected from haloalkyl, and halo; R f3 is selected from: [ka] In the formula, R x is H or C 1~2 alkyl, and R y is C 1~2 is alkyl, R b20 is C 1~3 is alkyl, Each R c60 and R d60 are independently H and C 1~3 alkyl; or any R bonded to the same N atom c60 and R d60 are independently R together with the N atom to which they are attached. 61 to form a 4- or 5-membered heterocycloalkyl group optionally substituted with one or two substituents selected from:

[0032] In yet another embodiment, the compound of formula I is a compound of formula Ia: [ka] or a pharmaceutically acceptable salt thereof.

[0033] In yet another embodiment, the compound of formula I is a compound of formula Ib: [ka] or a pharmaceutically acceptable salt thereof.

[0034] In one embodiment, Y is N. In another embodiment, Y is CR 6 is.

[0035] In yet another embodiment, R 1 is H, C 1~3 Alkyl, C 1~3 Haloalkyl, cyclopropyl, halo, D, CN, and OR a1 In yet another embodiment, R 1 is H, C 1~3 Alkyl, C 1~3 haloalkyl, and D. In one embodiment, R 1 is H. In one embodiment, R 1 is H, C 1~3 Alkyl, and C 1~3 haloalkyl.

[0036] In another embodiment, R 2 is H, C 1~3 Alkyl, C 1~3 Haloalkyl, halo, D, CN, and OR a2 C is selected from 1~3 Alkyl is independently R g In yet another embodiment, R 2 is H, C 1~3 Alkyl, C 1~3 In yet another embodiment, R is selected from haloalkyl, halo, D, CN, and —CHCHCN. 2 is C 1~3 Alkyl, C 1~3 In one embodiment, R is selected from haloalkyl, halo, CN, and —CHCHCN.2 is -CH2CH2CN.

[0037] In one embodiment, Cy 1 is C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 aryl, and 6- to 10-membered heteroaryl, wherein the 4- to 10-membered heterocycloalkyl and the 6- to 10-membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, and the ring-forming carbon atoms of the 6- to 10-membered heteroaryl and the 4- to 10-membered heterocycloalkyl are optionally substituted by oxo to form a carbonyl group; C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl and 6- to 10-membered heteroaryl are each independently R 10 is optionally substituted with 1, 2, or 3 substituents selected from:

[0038] In one embodiment, Cy 1 is C 3~10 Cycloalkyl, C 6~10 aryl, and 6- to 10-membered heteroaryl, wherein the 6- to 10-membered heteroaryl has at least one ring-forming carbon atom and one ring-forming heteroatom independently selected from N and S; 3~10 Cycloalkyl, C 6~10 Aryl and 6- to 10-membered heteroaryl are each independently R 10 is optionally substituted with one or two substituents selected from:

[0039] In another embodiment, Cy 1 is C 6~10 selected from aryl and 6- to 10-membered heteroaryl, wherein the 6- to 10-membered heteroaryl has at least one ring-forming carbon atom and 1, 2, or 3 ring-forming heteroatoms independently selected from N, O, and S, and wherein the ring-forming carbon atoms of the 6- to 10-membered heteroaryl are optionally substituted by oxo to form a carbonyl group; C 6~10The aryl and the 6- to 10-membered heteroaryl are each independently R 10 is optionally substituted with 1, 2, or 3 substituents selected from:

[0040] In yet another embodiment, Cy 1 is C 6~10 aryl and 6- to 10-membered heteroaryl, wherein the 6- to 10-membered heteroaryl has at least one ring-forming carbon atom and one ring-forming heteroatom independently selected from N and S; 6~10 The aryl and the 6- to 10-membered heteroaryl are each independently R 10 is optionally substituted with 1, 2, or 3 substituents selected from:

[0041] In one embodiment, Cy 1 is phenyl, and the phenyl is independently R 10 In another embodiment, Cy is optionally substituted with one or two substituents selected from 1 is 2,3-dichlorophenyl.

[0042] In yet another embodiment, Cy 1 are phenyl, naphthyl, indole, benzothiophene, and isoquinoline, all of which are each independently R 10 is optionally substituted with 1, 2, or 3 substituents selected from:

[0043] In one embodiment, Cy 1 is independently R 10 In another embodiment, Cy is phenyl optionally substituted with 1, 2, or 3 substituents selected from 1 is independently R 10 In another embodiment, Cy is naphthyl optionally substituted with 1, 2, or 3 substituents selected from 1 is independently R 10 In yet another embodiment, Cy is an indolyl optionally substituted with 1, 2, or 3 substituents selected from 1 is independently R 10In one embodiment, Cy is benzothiophenyl optionally substituted with 1, 2, or 3 substituents selected from 1 is independently R 10 isoquinolinyl optionally substituted with 1, 2, or 3 substituents selected from:

[0044] In yet another embodiment, R 3 is H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, CN, OR f3 , and NR c3 R j3 C is selected from 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 30 is optionally substituted with 1, 2, or 3 substituents selected from:

[0045] In one embodiment, R 3 is H, C 1~3 Alkyl, C 1~3 haloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halo, D, CN, and OR f3 C is selected from 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 30 is optionally substituted with one or two substituents selected from:

[0046] In another embodiment, R 3 is C 1~3 Alkyl, C 1~3 haloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and OR f3 C is selected from 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 30is optionally substituted with one or two substituents selected from:

[0047] In one embodiment, R 3 is H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, CN, C(O)NR c3 R d3 , and NR c3 C(O)R b3 C is selected from 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 30 is optionally substituted with 1, 2, or 3 substituents selected from:

[0048] In another embodiment, R 3 is H, C 1~3 Alkyl, C 1~3 haloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 30 is optionally substituted with 1, 2, or 3 substituents selected from:

[0049] In one embodiment, R 3 is H, C 1~3 Alkyl, C 1~3 haloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 30 In another embodiment, R 3 is H, C 1~3 alkyl, phenyl, and 5- to 6-membered heteroaryl, 1~3Alkyl, phenyl, and 5- to 6-membered heteroaryl are each R 30 In yet another embodiment, R 3 is selected from H, methyl, phenyl, 1,2,4-triazolyl, pyrazyl, and pyridyl, and each of the methyl, phenyl, 1,2,4-triazolyl, pyrazyl, and pyridyl is independently selected from R 30 is optionally substituted with 1, 2, or 3 substituents selected from:

[0050] In one embodiment, R 3 is a 5- to 6-membered heteroaryl, and the 5- to 6-membered heteroaryl is independently R 30 In one embodiment, R 3 is a 6-membered heteroaryl, and the 6-membered heteroaryl is independently R 30 is optionally substituted with one or two substituents selected from:

[0051] In another embodiment, R 3 is C 1~3 In yet another embodiment, R 3 is methyl.

[0052] In yet another embodiment, R 5 is H, C 1~3 Alkyl, C 1~3 Haloalkyl, cyclopropyl, halo, D, CN, and OR a5 In yet another embodiment, R 5 is H, C 1~3 Alkyl, C 1~3 haloalkyl, and D. In one embodiment, R 5 is H, C 1~3 Alkyl, C 1~3 In another embodiment, R 5 is selected from H and halo. In yet another embodiment, R 5 is selected from H and chloro. In one embodiment, R5 is H. In another embodiment, R 5 is chloro.

[0053] In another embodiment, R 6 is H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, CN, OR a6 , and C(O)NR c6 R d6 C is selected from 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 60 is optionally substituted with one or two substituents selected from:

[0054] In yet another embodiment, R 6 is H, C 1~3 Alkyl, C 1~3 haloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, halo, D, and CN; 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 60 is optionally substituted with one or two substituents selected from:

[0055] In yet another embodiment, R 6 is H, C 1~3 Alkyl, C 1~3 haloalkyl, 4- to 6-membered heterocycloalkyl, halo, D, and CN; 1~3 alkyl and 4- to 6-membered heterocycloalkyl are each independently R 60 is optionally substituted with one or two substituents selected from:

[0056] In yet another embodiment, R 6 is H, C 1~3 Alkyl, C 1~3haloalkyl, and 5- to 6-membered heteroaryl, 1~3 The alkyl and the 5- to 6-membered heteroaryl are each independently R 60 is optionally substituted with one or two substituents selected from:

[0057] In one embodiment, R 6 is H, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, CN, OR a6 , and C(O)NR c6 R d6 C is selected from 3~6 Cycloalkyl, 4- to 8-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 60 or R 6 is C 1~3 alkyl, and the C 1~3 Alkyl is independently R 60 is substituted with one or two substituents selected from:

[0058] In one embodiment, R 6 is H, C 1~3 haloalkyl, 4- to 8-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, wherein the 4- to 8-membered heterocycloalkyl and the 5- to 6-membered heteroaryl are each independently selected from R 60 or R 6 is C 1~3 alkyl, 1~3 Alkyl is independently R 60 is substituted with one or two substituents selected from:

[0059] In one embodiment, R 6is selected from 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl, and each of the 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl is independently R 60 or R 6 is C 1~3 alkyl, 1~3 Alkyl is independently R 60 is substituted with one or two substituents selected from:

[0060] In one embodiment, R 6 is selected from pyrrolidinyl, 2-azabicyclo[3.1.0]hexanyl, and 5-oxo-1,2,3,5-tetrahydroindolizin-3-yl, and the pyrrolidinyl, 2-azabicyclo[3.1.0]hexanyl, and 5-oxo-1,2,3,5-tetrahydroindolizin-3-yl are independently selected from R 60 or R 6 is C 1~2 alkyl, and the C 1~2 Alkyl is independently R 60 is substituted with one or two substituents selected from:

[0061] In one embodiment, R 7 is H, C 1~3 Alkyl, C 1~3 Haloalkyl, cyclopropyl, halo, D, CN, and OR a7 In another embodiment, R 7 is H, C 1~3 Alkyl, C 1~3 In another embodiment, R is selected from haloalkyl, halo, D, and CN. 7 is H, C 1~3 Alkyl, C 1~3 In yet another embodiment, R is selected from haloalkyl, halo, and CN. 7 is halo. In one embodiment, R 7 is F.

[0062] In yet another embodiment, Cy 2 is selected from: [ka] In the formula, n is 0 or 1.

[0063] In one embodiment, Cy 2 is selected from: [ka] In the formula, n is 0 or 1.

[0064] In another embodiment, Cy 2 is selected from the following: [ka]

[0065] In one embodiment, Cy 2 Cy 2 -a and Cy 2 -b, and n is 0. In one embodiment, Cy 2 Cy 2 -b and n is 0. In one embodiment, Cy 2 Cy 2 -a, and n is 0. In another embodiment, Cy 2 Cy 2 In yet another embodiment, Cy 2 Cy 2 -b.

[0066] In yet another embodiment, n is 0 or 1. In one embodiment, n is 0. In another embodiment, n is 1. In yet another embodiment, n is 2.

[0067] In yet another embodiment, each R 10 independently, C 1~3 Alkyl, C 1~3Haloalkyl, Halo, D, CN, OR a10 , and NR c10 R d10 In one embodiment, each R 10 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, halo, D, CN, and OR a10 In another embodiment, each R 10 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, halo, CN, and OR a10 In one embodiment, each R 10 independently, C 1~3 In another embodiment, each R 10 is independently selected from methyl, fluoro, and chloro. 10 is chloro.

[0068] In yet another embodiment, each R 20 independently, C 1~3 Alkyl, C 1~3 It is selected from haloalkyl, halo, D, and CN.

[0069] In yet another embodiment, each R 30 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halo, D, CN, OR a30 , and NR c30 R d30 C is selected from 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 31 is optionally substituted with one or two substituents selected from:

[0070] In one embodiment, each R 30 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, 4-6 membered heterocycloalkyl, halo, D, CN, OR a30, and NR c30 R d30 C is selected from 1~3 alkyl and 4- to 6-membered heterocycloalkyl are each independently R 31 is optionally substituted with one or two substituents selected from:

[0071] In one embodiment, each R 30 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, 4-6 membered heterocycloalkyl, halo, D, CN, OR a30 , C(O)NR c30 R d30 , and NR c30 R d30 C is selected from 1~3 alkyl and 4- to 6-membered heterocycloalkyl are each independently R 31 In one embodiment, each R 30 independently, C 1~3 Alkyl, Halo, and C(O)NR c30 R d30 C is selected from 1~3 Alkyl is R 31 is optionally substituted with one substituent selected from:

[0072] In one embodiment, each R 30 independently, C 1~3 Alkyl, Halo, D, and C(O)NR c30 R d30 C is selected from 1~3 Alkyl is R 31 In one embodiment, each R 30 are independently methyl, fluoro, D, and C(O)NR c30 R d30 and the methyl is selected from R 31 is optionally substituted with one substituent selected from:

[0073] In another embodiment, each R 30 independently, C 1~3Alkyl, C 1~3 Haloalkyl, 4-6 membered heterocycloalkyl, halo, and NR c30 R d30 C is selected from 1~3 alkyl and 4- to 6-membered heterocycloalkyl are each independently R 31 is optionally substituted with one or two substituents selected from:

[0074] In one embodiment, each R 31 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, Halo, D, CN, OR a31 , and NR c31 R d31 In another embodiment, each R 31 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, halo, and NR c31 R d31 In one embodiment, each R 31 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, Halo, CN, OR a31 , and NR c31 R d31 In one embodiment, each R 31 are independently OR a31 is selected from.

[0075] In another embodiment, R 33 is C 2~3 Alkyl, C 1~3 Haloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, halo, D, CN, OR a30 , and NR c30 R d30 C is selected from 2~3 Alkyl, 4-membered heterocycloalkyl, and 6-membered heterocycloalkyl are each independently R 31 is optionally substituted with one or two substituents selected from:

[0076] In yet another embodiment, R 33 is C2~3 Alkyl, C 1~3 haloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, halo, and CN; 2~3 Alkyl, 4-membered heterocycloalkyl, and 6-membered heterocycloalkyl are each independently R 31 is optionally substituted with one or two substituents selected from:

[0077] In one embodiment, each R 60 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halo, CN, OR a60 , C(O)R b60 , C(O)NR c60 R d60 , C(O)OR a60 , and NR c60 R d60 C is selected from 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 61 In one embodiment, each R 60 are independently 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C(O)R b60 , C(O)NR c60 R d60 , and C(O)OR a60 wherein the 4- to 6-membered heterocycloalkyl and the 5- to 6-membered heteroaryl are each independently selected from R 61 is optionally substituted with one or two substituents selected from:

[0078] In yet another embodiment, each R 60 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halo, D, CN, OR a60 , C(O)NR c60 R d60 , and NR c60 R d60C is selected from 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 61 is optionally substituted with one or two substituents selected from:

[0079] In one embodiment, each R 60 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, 4-6 membered heterocycloalkyl, halo, D, CN, OR a60 , C(O)NR c60 R d60 , and NR c60 R d60 C is selected from 1~3 alkyl and 4- to 6-membered heterocycloalkyl are each independently R 61 is optionally substituted with one or two substituents selected from:

[0080] In another embodiment, each R 60 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, 4-6 membered heterocycloalkyl, halo, and C(O)NR c60 R d60 C is selected from 1~3 alkyl and 4- to 6-membered heterocycloalkyl are each independently R 61 is optionally substituted with one or two substituents selected from:

[0081] In another embodiment, each R 60 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, 4-6 membered heterocycloalkyl, halo, C(O)OR a60 , and C(O)NR c60 R d60 C is selected from 1~3 alkyl and 4- to 6-membered heterocycloalkyl are each independently R 61 is optionally substituted with one or two substituents selected from:

[0082] In one embodiment, each R60 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halo, D, CN, OR a60 , C(O)R b60 , C(O)NR c60 R d60 , N.R. c60 C(O)R b60 , C(O)OR a60 , N.R. c60 C(O)OR a60 , N.R. c60 R d60 , N.R. c60 S(O)2R b60 , and S(O)2R b60 C is selected from 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 61 is optionally substituted with one or two substituents selected from:

[0083] In another embodiment, each R 60 independently, C 1~3 Alkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halo, C(O)R b60 , C(O)NR c60 R d60 , N.R. c60 C(O)R b60 , C(O)OR a60 , N.R. c60 C(O)OR a60 , and NR c60 S(O)2R b60 C is selected from 1~3 Alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 61 In another embodiment, each R 60 are independently methyl, fluoro, 3-oxomorpholinyl, 2-oxopyrazin-1(2H)-yl), C(O)R b60 , C(O)NR c60 R d60 , N.R. c60 C(O)Rb60 , C(O)OR a60 , N.R. c60 C(O)OR a60 , and NR c60 S(O)2R b60 wherein the 3-oxomorpholinyl and 2-oxopyrazin-1(2H)-yl are each independently selected from R 61 is optionally substituted with one or two substituents selected from:

[0084] In yet another embodiment, each R 61 independently, C 1~3 Alkyl, C 1~3 In yet another embodiment, each R 61 independently, C 1~3 Alkyl, C 1~3 In one embodiment, each R 61 independently, C 1~3 Alkyl, C 1~3 In one embodiment, each R 61 independently, C 1~3 In one embodiment, each R 61 is independently selected from methyl and fluoro.

[0085] In one embodiment, R f3 is C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently R 30 or R f3 is selected from: [ka] In the formula, R x is H or C1~2 is alkyl, R y is C 1~2 It is alkyl.

[0086] In another embodiment, R f3 is C 1~3 haloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, wherein the 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are each independently selected from R 30 or R f3 is R f3 -a and R f3 -b is selected from R x is H or C 1~2 is alkyl, R y is C 1~2 It is alkyl.

[0087] In yet another embodiment, R f3 is C 1~3 haloalkyl or R f3 is R f3 -a and R f3 -b is selected from R x is H or C 1~2 alkyl, and R y is C 1~2 It is alkyl.

[0088] In yet another embodiment, R f3 is R f3 In one embodiment, R f3 is R f3 -b.

[0089] In another embodiment, R x is H. In yet another embodiment, R x is C 1~2 It is alkyl.

[0090] In one embodiment, each R a30 , Rb30 , R c30 , and R d30 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl.

[0091] In one embodiment, each R a30 , R c30 , and R d30 are independently H, C 1~3 Alkyl, and C 1~3 In one embodiment, each R a30 , R c30 , and R d30 are independently H and C 1~3 In another embodiment, each R c30 and R d30 are independently H and C 1~3 In yet another embodiment, each R c30 and R d30 is independently selected from H and methyl.

[0092] In one embodiment, each R a31 , R b31 , R c31 , and R d31 are independently H, C 1~3 Alkyl, and C 1~3 In another embodiment, each R a31 , R c31 , and R d31 are independently H and C 1~3 In yet another embodiment, each R a31 is independently selected from H and methyl.

[0093] In one embodiment, each R a60 , R c60 , and R d60 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl or any R bonded to the same N atom c60 and R d60together with the N atom to which they are attached form a 4-membered heterocycloalkyl group.

[0094] In another embodiment, each R c60 and R d60 are independently H, C 1~3 Alkyl, and C 1~3 haloalkyl or any R bonded to the same N atom c60 and R d60 together with the N atom to which they are attached form a 4-membered heterocycloalkyl group. c60 and R d60 are independently H, C 2~3 Alkyl, and C 1~3 haloalkyl or any R bonded to the same N atom c60 and R d60 together with the N atom to which they are attached form a 4-membered heterocycloalkyl group.

[0095] In one embodiment, each R a60 , R b60 , R c60 , and R d60 are independently H, C 1~3 Alkyl, C 1~3 Haloalkyl, and C 3~6 cycloalkyl, wherein C 1~3 Alkyl and C 3~6 Each cycloalkyl is independently R 61 or optionally substituted with one or two substituents selected from or any R bonded to the same N atom c60 and R d60 are independently R together with the N atom to which they are attached. 61 to form a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with one or two substituents selected from:

[0096] In one embodiment, each R a60 , R b60 , R c60 , and Rd60 are independently H, C 1~3 Alkyl, and C 3~6 cycloalkyl, wherein C 1~3 Alkyl and C 3~6 Each cycloalkyl is independently R 61 or optionally substituted with one or two substituents selected from or any R bonded to the same N atom c60 and R d60 are independently R together with the N atom to which they are attached. 61 to form a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with one or two substituents selected from:

[0097] In one embodiment, each R a60 , R b60 , R c60 , and R d60 are independently H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently R 61 or optionally substituted with one or two substituents selected from or any R bonded to the same N atom c60 and R d60 are independently R together with the N atom to which they are attached. 61 to form a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with one or two substituents selected from:

[0098] In another embodiment, each R a60 , R b60 , R c60 , and R d60 are independently H, C 1~2alkyl, C haloalkyl, cyclopropyl, tetrahydrofuranyl, and thiazolyl; 1~2 Alkyl, cyclopropyl, tetrahydrofuranyl, and thiazolyl are each independently R 61 or optionally substituted with one or two substituents selected from or any R bonded to the same N atom c60 and R d60 are independently R together with the N atom to which they are attached. 61 to form an azetidinyl group optionally substituted with one or two substituents selected from:

[0099] In one embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is deuterated.

[0100] In yet another embodiment, the compound of Formula I is other than 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-4-ethoxy-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N-dimethylpropanamide.

[0101] In some embodiments, Y is CR 6 and R 1 is H, R 2 is replaced by CN 1~3 is alkyl, Cy 1 is independently R 10 and each R is phenyl substituted with one or two substituents selected from 10 are independently haloes, R 3 is selected from 6-membered heteroaryl substituted with -CH, -CH(CH)-OH, and -C(CH)OH; R 5 is H, R 6is -6-membered heterocycloalkyl-C(O)R b60 , -CH(CH3)-R 60 , and -CH(CH3)-NHC(O)R b60 is selected from R 7 is a halo, Cy 2 teeth, [ka] and R 60 is a 6-membered heterocycloalkyl; R b60 is R 61 C is replaced by 3~4 is cycloalkyl, R 61 is a halo.

[0102] In a further embodiment, R 2 is CH2CH2CN.

[0103] In another embodiment, R 10 is Cl.

[0104] In another embodiment, Cy 1 is 2,3-dichlorophenyl.

[0105] In a further embodiment, R 3 is -CH3. In another embodiment, R 3 is —CH(CH)—OH. In a further embodiment, R 3 is a 6-membered heteroaryl substituted with —C(CH)OH. In a further embodiment, R 3 is a pyridine substituted with -C(CH3)2OH.

[0106] In another embodiment, R 6 is -CH(CH3)-R 60 In a further embodiment, R 6 is -CH(CH3)-NHC(O)R b60 In another embodiment, R6 is a 6-membered heterocycloalkyl-C(O)R b60 In a further embodiment, R 6 is -CH(CH3)-R 60 where R 60 teeth, [ka] In another embodiment, R 6 is --CH(CH3)-NHC(O)R b60 where R b60 is 1-fluorocycloalkyl. In a further embodiment, R 6 teeth, [ka] In another embodiment, R 6 teeth, [ka] where R b60 is 1-fluorocycloalkyl.

[0107] In a further embodiment, R 7 is F.

[0108] In yet another embodiment, the compound of formula I is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(7-chloro-3-hydroxynaphthalen-1-yl)-6-fluoro-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(5,7-difluoro-1H-indol-3-yl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(6-fluoro-5-methyl-1H-indol-3-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(2-(3-(azetidin-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-((1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-2-yl)methyl)oxazolidin-2-one, 8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-2,8-dimethyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthonitrile, 1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-7-(8-cyanonaphthalen-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinoline-8-carbonitrile, 8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-((3-oxomorpholino)methyl)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthonitrile, 3-(7-(benzo[b]thiophen-3-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(((S)-1-(dimethylamino)propan-2-yl)oxy)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthonitrile, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichloro-5-hydroxyphenyl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-6-fluoro-4-((3-fluoro-1-methylazetidin-3-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N-dimethylpropanamide, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-methyl-4-(5-methylpyrazin-2-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-methyl-2-((4-methyl-2-oxopiperazin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichloro-5-hydroxyphenyl)-4-ethoxy-6-fluoro-2-((4-isopropyl-2-oxopiperazin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-((3-oxomorpholino)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-4-ethoxy-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-(pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(2-(3-(azetidin-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(7,8-difluoronaphthalen-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(2-(3-(azetidin-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(6,7-difluoronaphthalen-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 1-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)isoquinoline-8-carbonitrile, 8-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthonitrile, 8-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)-1-naphthonitrile, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, and 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, or a pharmaceutically acceptable salt thereof.

[0109] In another embodiment, the compound of formula I is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(7-chloro-3-hydroxynaphthalen-1-yl)-6-fluoro-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(5,7-difluoro-1H-indol-3-yl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(6-fluoro-5-methyl-1H-indol-3-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(2-(3-(azetidin-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-((1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-2-yl)methyl)oxazolidin-2-one, 8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-2,8-dimethyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthonitrile, 1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-7-(8-cyanonaphthalen-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinoline-8-carbonitrile, 8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-((3-oxomorpholino)methyl)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthonitrile, 3-(7-(benzo[b]thiophen-3-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(((S)-1-(dimethylamino)propan-2-yl)oxy)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthonitrile, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichloro-5-hydroxyphenyl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-6-fluoro-4-((3-fluoro-1-methylazetidin-3-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N-dimethylpropanamide, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-methyl-4-(5-methylpyrazin-2-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-methyl-2-((4-methyl-2-oxopiperazin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-((3-oxomorpholino)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-(pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(2-(3-(azetidin-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(7,8-difluoronaphthalen-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(2-(3-(azetidin-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(6,7-difluoronaphthalen-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 1-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)isoquinoline-8-carbonitrile, 8-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthonitrile, 8-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)-1-naphthonitrile, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, and 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, or a pharmaceutically acceptable salt thereof.

[0110] In another embodiment, the compound of formula I is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(7-chloro-3-hydroxynaphthalen-1-yl)-6-fluoro-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(5,7-difluoro-1H-indol-3-yl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(6-fluoro-5-methyl-1H-indol-3-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(2-(3-(azetidin-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-((1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-2-yl)methyl)oxazolidin-2-one, 8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-2,8-dimethyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthonitrile, 1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-7-(8-cyanonaphthalen-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinoline-8-carbonitrile, 8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-((3-oxomorpholino)methyl)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthonitrile, 3-(7-(benzo[b]thiophen-3-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(((S)-1-(dimethylamino)propan-2-yl)oxy)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthonitrile, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichloro-5-hydroxyphenyl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-methyl-4-(5-methylpyrazin-2-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-methyl-2-((4-methyl-2-oxopiperazin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(1-(2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichloro-5-hydroxyphenyl)-4-ethoxy-6-fluoro-2-((4-isopropyl-2-oxopiperazin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-((3-oxomorpholino)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(1-(2-azabicyclo[2.1.1]hexan-5-yl)-4-ethoxy-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-(pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(2-(3-(azetidin-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(7,8-difluoronaphthalen-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(2-(3-(azetidin-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(6,7-difluoronaphthalen-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 1-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)isoquinoline-8-carbonitrile, 8-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthonitrile, 8-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)-1-naphthonitrile, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, and 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, or a pharmaceutically acceptable salt thereof.

[0111] In yet another embodiment, the compound of formula I is (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N-dimethylpyrrolidine-1-carboxamide, and methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2-chloro-3-methylphenyl)-8-(2-cyanoethyl)-6-fluoro-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate, or a pharmaceutically acceptable salt thereof.

[0112] In another embodiment, the compound of formula I is methyl (1S,3R,5S)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-2-(5-oxo-1,2,3,5-tetrahydroindolizin-3-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate, methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(methylcarbamoyl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2-chloro-3-fluorophenyl)-2-((R)-1-(cyclopropanecarbonyl)pyrrolidin-2-yl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 8-(2-((R)-1-acetylpyrrolidin-2-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-8-methyl-4-(2-methylpyridin-4-yl)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1,2,3,4-tetrahydronaphthalene-1-carbonitrile, 5-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(3-chloro-2-methylphenyl)-8-(2-cyanoethyl)-6-fluoro-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-4-yl)-N-methylpicolinamide, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(3-chloro-2-methylphenyl)-6-fluoro-4-(5-methylpyrazin-2-yl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(5-fluoro-6-(methylcarbamoyl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate, methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate, ethyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-2-((R)-1-(3,3-difluoroazetidine-1-carbonyl)pyrrolidin-2-yl)-6-fluoro-4-(methyl-d3)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-2-((R)-1-(3,3-difluoroazetidine-1-carbonyl)pyrrolidin-2-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(3-chloro-2-methylphenyl)-6-fluoro-4-(5-methylpyrazin-2-yl)-2-((R)-1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 5-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-((R)-1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinolin-4-yl)-N-methylpicolinamide, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-((R)-1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-(5-methylpyrazin-2-yl)-2-((R)-1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, methyl (1R,3R,5R)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, and 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, or a pharmaceutically acceptable salt thereof.

[0113] In yet another embodiment, the compound of formula I is 5-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(3-chloro-2-methylphenyl)-8-(2-cyanoethyl)-6-fluoro-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-4-yl)-N-methylpicolinamide, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(3-chloro-2-methylphenyl)-6-fluoro-4-(5-methylpyrazin-2-yl)-2-((R)-1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, and 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, or a pharmaceutically acceptable salt thereof.

[0114] In yet another embodiment, the compound of formula I is methyl (2R,4S)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-4-fluoropyrrolidine-1-carboxylate, methyl (2R,5R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-5-methylpyrrolidine-1-carboxylate, methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-3-chloro-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate, 4-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-4-yl)-2-fluoro-N-methylbenzamide, methyl ((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)carbamate, N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-2,2-difluoroacetamide, N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-2,2-difluoroacetamide, (2S)—N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)tetrahydrofuran-2-carboxamide, N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)cyclopropanesulfonamide, N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)thiazole-4-carboxamide, and N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-N-methylcyclopropanecarboxamide, or a pharmaceutically acceptable salt thereof.

[0115] In another embodiment, the compound of formula I is N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-1-methylcyclopropane-1-carboxamide, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-2-((1R,3R,5R)-2-(1-methylcyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-1-fluorocyclopropane-1-carboxamide, N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-1-fluorocyclobutane-1-carboxamide, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(3-chloro-2-methylphenyl)-2-(1-(2,6-dimethyl-3-oxo-2,3-dihydropyridazin-4-yl)ethyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)pyrimidine-4-carboxamide, N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)pyridazine-3-carboxamide, N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-3,3-difluoroazetidine-1-carboxamide, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-2-((R)-1-((1-methyl-1H-pyrazol-4-yl)amino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile, 5-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(1-fluorocyclopropane-1-carbonyl)pyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-4-yl)-N,N-dimethylpicolinamide, and methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(4-((dimethylamino)methyl)-2,3-difluorophenyl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate, or a pharmaceutically acceptable salt thereof.

[0116] In another embodiment, the compound of formula I is a pharmaceutically acceptable salt.

[0117] In another aspect, provided herein is a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0118] It will be further understood that certain features of the invention that are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment (the embodiments are intended to be combined as if written in multiple sub-embodiments). Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. Accordingly, it is contemplated that the features described in the embodiments of the compounds of Formula I can be combined in any suitable combination.

[0119] At various places in the present specification, certain characteristics of compounds are disclosed in groups or ranges. It is specifically intended that such disclosures include any and all individual subcombinations of the members of such groups and ranges. For example, "C 1~6 The term "alkyl" is specifically intended to individually (and without limitation) disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0120] The term "n-membered," where n is an integer, generally refers to the number of ring-forming atoms in the moiety where n is the number of ring-forming atoms. 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-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[0121] At various places in this specification, variables defining divalent linking groups may be described. Specifically, each linking substituent is intended to include both the forward and backward forms of the linking substituent. For example, -NR(CR'R'') n -NR(CR'R'') n -and-(CR'R'') n It is intended that both NR- and NR- are included and that each form is disclosed individually. If a structure requires a linking group, the Markush variable listed in that group is understood to be the linking group. For example, if a structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it is understood that "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively.

[0122] The term "substituted" formally means that an atom or group of atoms replaces hydrogen as a "substituent" attached to another group. The term "substituted" refers to any level of substitution, for example, mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted, unless otherwise specified. Substituents are independently selected, and substitution may occur at any chemically accessible position. It should be understood that substitution at a given atom is limited by valence. It should be understood that substitution at a given atom results in a chemically stable molecule. The phrase "optionally substituted" means unsubstituted or substituted. The term "substituted" means that a hydrogen atom has been removed and replaced with a substituent. A single divalent substituent, for example, oxo, can replace two hydrogen atoms.

[0123] "C n~m " denotes an inclusive range where n and m are integers and indicate the number of carbons. Examples include C 1~4 , C 1~6 Examples include:

[0124] The term "alkyl," employed alone or in combination with other terms, refers to a saturated hydrocarbon group which may be straight-chained or branched. n~m The term "alkyl" refers to an alkyl group having n to m carbon atoms. An alkyl group formally corresponds to an alkane with one C-H bond replaced by the point of attachment of the alkyl group to the remainder 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, sec-butyl, and higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, etc.

[0125] The term "alkylene," used alone or in combination with other terms, refers to a divalent alkyl linking group. An alkylene group formally corresponds to an alkane in which two C-H bonds are replaced by points of attachment of the alkylene group to the remainder 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, 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, 2-methyl-propane-1,3-diyl, and the like.

[0126] The term "alkoxy", employed alone or in combination with other terms, refers to a radical of the formula -O-alkyl, wherein the alkyl radical is as defined above. n~m The term "alkoxy" refers to an alkoxy group, where the alkyl group has n to m carbon atoms. Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. "C n~m The term "dialkoxy" refers to a group of the formula -O-(C n~m Dialkoxy groups refer to the linking group -O-. Exemplary dialkyoxy groups include -OCH2CH2O- and OCH2CH2CH2O-. In some embodiments, C n~m Two O atoms of a dialkoxy group may be attached to the same B atom to form a 5- or 6-membered heterocycloalkyl group.

[0127] The term "amino," employed alone or in combination with other terms, refers to a group of formula -NH, where the hydrogen atom can be substituted with a substituent described herein. For example, "alkylamino" can refer to both -NH(alkyl) and -N(alkyl).

[0128] The terms "halo" or "halogen," employed alone or in combination with other terms, refer to fluoro, chloro, bromo, and iodo. In some embodiments, "halo" refers to a halogen atom selected from F, Cl, or Br. In some embodiments, the halo group is F.

[0129] The term "haloalkyl," as used herein, refers to an alkyl group in which one or more of the hydrogen atoms is replaced by a halogen atom. n~m The term "haloalkyl" refers to a C alkyl group having n to m carbon atoms and at least 1 and at most {2(n to m)+1} halogen atoms, which may be the same or different. n~m 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 CF, C2F5, CHF2, CH2F, CCl3, CHCl2, C2Cl5, and the like. In some embodiments, the haloalkyl group is a fluoroalkyl group.

[0130] The term "haloalkoxy," employed alone or in combination with other terms, refers to a radical of the formula -O-haloalkyl, wherein haloalkyl group is as defined above. n~m The term "haloalkoxy" refers to a haloalkoxy group where the haloalkyl group has n to m carbon atoms. Exemplary haloalkoxy groups include trifluoromethoxy, and the like. In some embodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0131] The term "oxo" or "oxy" refers to a divalent oxygen atom that forms a carbonyl group when attached to a carbon, or a sulfoxide or sulfone group, or an N-oxide group when attached to a heteroatom. In some embodiments, heterocyclic groups can be optionally substituted with one or two oxo (=O) substituents.

[0132] The term "oxidized" in reference to a ring-forming N atom refers to a ring-forming N-oxide.

[0133] The term "oxidized" with respect to a ring-forming S atom refers to a ring-forming sulfonyl or ring-forming sulfinyl.

[0134] The term "aromatic" refers to a carbocyclic or heterocyclic ring having one or more polyunsaturated rings that have aromatic character (i.e., have (4n+2) delocalized π (pi) electrons, where n is an integer).

[0135] The term "aryl," employed alone or in combination with other terms, refers to an aromatic hydrocarbon group that can 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. Aryl groups include, for example, phenyl, naphthyl, and the like. In some embodiments, an aryl group has 6 to about 10 carbon atoms. In some embodiments, an aryl group has 6 carbon atoms. In some embodiments, an aryl group has 10 carbon atoms. In some embodiments, an aryl group is phenyl. In some embodiments, an aryl group is naphthyl.

[0136] The terms "heteroaryl" or "heteroaromatic," employed alone or in combination with other terms, refer to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, any ring-forming N in the heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl has 5 to 14 ring atoms, including carbon atoms, and 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl has 5 to 10 ring atoms, including carbon atoms, and 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl has 5 to 6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a 5- or 6-membered heteroaryl ring. In other embodiments, the heteroaryl is an 8-, 9-, or 10-membered fused bicyclic heteroaryl ring. Exemplary heteroaryl groups include, but are not limited to, pyridinyl (pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, azolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl, quinolinyl, isoquinolinyl, naphthyridinyl (including 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3-, and 2,6-naphthyridine), indolyl, isoindolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, purinyl, and the like. In some embodiments, the heteroaryl group is a pyridone (e.g., 2-pyridone).

[0137] A 5-membered heteroaryl ring is a heteroaryl group having 5 ring atoms, wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary 5-membered heteroaryls 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.

[0138] A 6-membered heteroaryl ring is a heteroaryl group having 6 ring atoms, wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary 6-membered heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, isoindolyl, and pyridazinyl.

[0139] The term "cycloalkyl," employed 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 having n to m ring carbon atoms. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spirocycles. Cycloalkyl groups can have 3, 4, 5, 6, or 7 ring carbon atoms (C 3~7 In some embodiments, the cycloalkyl group has 3 to 6 ring members, 3 to 5 ring members, or 3 to 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 3~6Monocyclic cycloalkyl groups. The ring-forming carbon atoms of a cycloalkyl group can be optionally oxidized to form oxo or sulfide groups. Cycloalkyl groups also include cycloalkylidenes. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The definition of cycloalkyl also includes moieties having one or more aromatic rings fused (i.e., having a common bond) to the cycloalkyl ring, such as benzo or thienyl derivatives of cyclopentane and cyclohexane. Cycloalkyl groups containing fused aromatic rings can be bonded through any ring-forming atom, including the ring-forming atoms of the fused aromatic ring. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like. 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).

[0140] The term "heterocycloalkyl," employed alone or in combination with other terms, refers to a non-aromatic ring or ring system, which optionally has at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen, and phosphorus, and may include one or more alkenylene groups as part of the ring structure, having 4 to 10 ring members, 4 to 7 ring members, or 4 to 6 ring members. Included within the term "heterocycloalkyl" are monocyclic 4-, 5-, 6-, and 7-membered heterocycloalkyl groups. Heterocycloalkyl groups can include monocyclic or bicyclic (e.g., having two fused or bridged rings) or spiro ring systems. In some embodiments, heterocycloalkyl groups are monocyclic groups 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 be optionally oxidized to form oxo or sulfido groups or other oxidized bonds (e.g., C(O), S(O), C(S), or S(O), N-oxide, etc.), or the nitrogen atom can be quaternized. A heterocycloalkyl group can be bonded through a ring-forming carbon atom or ring-forming heteroatom. In some embodiments, a heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, a heterocycloalkyl group contains 0 to 2 double bonds. Also included within the definition of heterocycloalkyl are moieties having one or more aromatic rings fused (i.e., having a common bond) to the heterocycloalkyl ring, e.g., benzo or thienyl derivatives such as piperidine, morpholine, azepine, etc. Heterocycloalkyl groups containing fused aromatic rings can be bonded through any ring-forming atom, including a ring-forming atom of the fused aromatic ring. Examples of heterocycloalkyl groups include 2,5-diazobicyclo[2.2.1]heptanyl, pyrrolidinyl, hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl, 1,6-dihydropyridinyl, morpholinyl, azetidinyl, piperazinyl, and 4,7-diazaspiro[2.5]octan-7-yl.

[0141] In certain places, definitions or embodiments refer to specific rings (e.g., azetidine ring, pyridine ring, etc.). Unless otherwise specified, these rings can be bonded to any ring member, provided that the valence of the atom is not exceeded. For example, an azetidine ring can be bonded at any position on the ring, while an azetidin-3-yl ring is bonded at the 3-position.

[0142] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise specified, all stereoisomers, such as enantiomers and diastereomers, are intended. Compounds of the present invention containing asymmetrically substituted carbon atoms may be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like, may also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.

[0143] Resolution 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 a chiral resolving acid, which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are optically active acids, such as the D and L forms of various optically active camphorsulfonic acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms (e.g., S and R forms, or diastereomerically pure forms) of α-methylbenzylamine, 2-phenylglycinol, norephedrine, ephedrine, N-methylphedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

[0144] Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by one skilled in the art.

[0145] In some embodiments, the compounds of the invention have the (R)-configuration. In other embodiments, the compounds have the (S)-configuration. In compounds with more than one chiral center, each of the chiral centers in the compound may independently be (R) or (S), unless otherwise indicated.

[0146] The compounds of the present invention also include tautomeric forms. Tautomeric forms arise when a single bond and an adjacent double bond swap positions, resulting in the migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy more than one position in a heterocyclic ring system, such as 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.

[0147] The compounds of the present invention may also include all isotopes of atoms occurring in intermediates or final compounds. Isotopes include atoms with 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 can be replaced or substituted with an isotope of the atom in natural or non-natural abundance. In some embodiments, the compounds contain at least one deuterium atom. For example, one or more hydrogen atoms in the compounds of the present disclosure can be replaced or substituted with deuterium. In some embodiments, the compounds contain two or more deuterium atoms. In some embodiments, the compounds contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 deuterium atoms. Synthetic methods for incorporating isotopes into organic compounds are known in the art (see, for example, "Deuterium Labeling in Organic Chemistry" by Alan F. Thomas (New York, NY, Appleton-Century-Crofts, 1971); "The Renaissance of H / D Exchange" by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; "The Organic Chemistry of Isotopic Labelling" by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can be used in a variety of studies, such as NMR spectroscopy, metabolic studies, and / or assays.

[0148] Substitution with heavier isotopes, such as deuterium, may confer certain therapeutic advantages, such as increased in vivo half-life or reduced dosage requirements, due to greater metabolic stability and may therefore be 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).

[0149] The term "compound," as used herein, is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structures. This term is also meant to refer to compounds of the present invention regardless of how they are prepared, for example, whether they are prepared synthetically, via a biological process (e.g., metabolic or enzymatic transformation), or a combination thereof.

[0150] All compounds and their pharmaceutically acceptable salts may be found together with other substances such as water and solvents (e.g., hydrates and solvates) or may be isolated. When in the solid state, the compounds described herein and their salts may occur in various forms, for example, they may take the form of solvates, including hydrates. The compounds may be in any solid form, such as polymorphs or solvates, and therefore, unless expressly indicated otherwise, references herein to compounds and their salts should be understood to encompass any solid form of the compound.

[0151] In some embodiments, the compound of the present invention or a salt thereof is 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 separation can include, for example, a composition enriched for the compound of the present invention. Substantial separation can include a composition containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound of the present invention or a salt thereof.

[0152] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0153] The expressions "ambient temperature" and "room temperature" as used herein are understood in the art and generally refer to a temperature, e.g., a reaction temperature, i.e., about the temperature of the room in which the reaction is carried out, e.g., a temperature of about 20°C to about 30°C.

[0154] The present invention also includes pharmaceutically acceptable salts of the compounds described herein. The term "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds, where the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, etc. The pharmaceutically acceptable salts of the present invention include non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, alcohol (e.g., methanol, ethanol, isopropanol, or butanol), or acetonitrile (MeCN) are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17 thEd., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19, and Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). In some embodiments, the compounds described herein include N-oxide forms.

[0155] synthesis The compounds of the present invention, including their salts, can be prepared using known organic synthesis techniques, or can be synthesized according to any of a number of possible synthetic routes, such as those in the following schemes.

[0156] The reaction for preparing the compound of the present invention can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis.Suitable solvents can be substantially non-reactive with starting materials (reactants), intermediates or products at the temperature at which the reaction is carried out, for example, a temperature that can range from the freezing temperature of the solvent to the boiling temperature of the solvent.A given reaction can be carried out in one solvent or a mixture of more than one solvent.Depending on the specific reaction step, suitable solvents for specific reaction steps can be selected by those skilled in the art.

[0157] The preparation of compounds of the present invention can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be easily determined by one 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); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6 thEd. (Wiley, 2007), Peturssion et al., "Protective Groups in Carbohydrate Chemistry," J. Chem. Educ., 1997, 74(11), 1297, and Wuts et al., Protective Groups in Organic Synthesis, 4th Ed., (Wiley, 2006).

[0158] 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), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).

[0159] The following schemes provide general guidance relating to the preparation of compounds of the present invention. Those skilled in the art will understand that the preparations shown in the schemes can be modified or optimized using general knowledge of organic chemistry to prepare various compounds of the present invention.

[0160] [ka] Compounds of formula 1-12 can be prepared via the synthetic route outlined in Scheme 1. Halogenation of commercially available starting material 1-1 with an appropriate reagent, such as N-chlorosuccinimide (NCS), yields intermediate 1-2 (where Hal is a halide such as F, Cl, Br, or I). Intermediate 1-4 can then be prepared by condensation of intermediate 1-2 with diethyl 2-(ethoxymethylene)malonate (1-3), followed by cyclization by heating in a suitable high-boiling solvent (e.g., PhO) to yield quinolone 1-5. Treatment of intermediate 1-5 with POCl3 yields intermediate 1-6. Reduction of the ethyl ester with a reducing reagent (e.g., DIBAL), followed by oxidation of the alcohol with an appropriate reagent, such as Dess-Martin periodinane, yields intermediate 1-7. Cyclization with hydrazine 1-8 (PG is a suitable protecting group such as Boc) yields tricyclic adduct 1-9. Compound 1-11 can then be prepared by coupling 1-9 with an adduct of formula 1-10, where M is a boronic acid, boronic ester, or appropriately substituted metal (e.g., M is B(OR)2, Sn(alkyl)3, or Zn-Hal), under standard Suzuki cross-coupling conditions (e.g., in the presence of a palladium catalyst and a suitable base), or standard Stille cross-coupling conditions (e.g., in the presence of a palladium catalyst), or standard Negishi cross-coupling conditions (e.g., in the presence of a palladium catalyst). Removal of the protecting group in 1-11 and subsequent functionalization of the resulting adduct (such as coupling with an acid chloride, e.g., acryloyl chloride) affords the desired product 1-12.

[0161] [ka] Compounds of formula 2-13 can be prepared via the synthetic route outlined in Scheme 2. Halogenation of commercially available starting material 2-1 with an appropriate reagent, such as N-chlorosuccinimide (NCS), provides intermediate 2-2 (Hal is a halide such as F, Cl, Br, or I). Compound 2-4 can be prepared by treating 2-2 with a reagent such as 2,2-dimethyl-1,3-dioxane-4,6-dione (2-3). Intermediate 2-4 can undergo a cyclization reaction (in polyphosphoric acid under thermal conditions) to give compound 2-5, which can be treated with an appropriate reagent (e.g., POCl) to give compound 2-6. Intermediate 2-6 can be treated with an appropriate reagent (e.g., LDA in THF followed by DMF) to give compound 2-7. Condensation of intermediate 2-7 with hydrazine 2-8 (PG is a suitable protecting group such as Boc) can be carried out to give compound 2-9. Next, R in 2-10 3 The group is S N The intermediate 2-10 can be incorporated via a suitable transformation, such as an Ar reaction or a coupling reaction. Intermediate 2-10 can first undergo deprotection of the protecting group PG, followed by functionalization of the resulting amine (e.g., coupling with an acid chloride, e.g., acryloyl chloride), which then affords compound 2-11. The desired product 2-13 can be prepared by a cross-coupling reaction between 2-11 and an adduct of formula 2-12, where M is a boronic acid, a boronic ester, or an appropriately substituted metal (e.g., M is B(OR)2, Sn(alkyl)3, or Zn-Hal), under standard Suzuki cross-coupling conditions (e.g., in the presence of a palladium catalyst and a suitable base), or standard Stille cross-coupling conditions (e.g., in the presence of a palladium catalyst), or standard Negishi cross-coupling conditions (e.g., in the presence of a palladium catalyst). The above chemical reaction sequence can be rearranged as appropriate to accommodate the preparation of different analogs.

[0162] [ka] Compounds of formula 3-16 can be prepared via the synthetic route outlined in Scheme 3. Esterification of commercially available starting material 3-1 with H2SO4 in ethanol. Halogenation of compound 3-2 with an appropriate reagent, such as N-chlorosuccinimide (NCS), yields intermediate 3-3 (Hal is a halide such as F, Cl, Br, or I). Compound 3-5 can be prepared by treating 3-3 with a reagent such as ethyl malonyl chloride (3-4). Intermediate 3-5 can undergo a cyclization reaction (sodium ethoxide in ethanol) to yield compound 3-6, which can be treated with an appropriate reagent (e.g., POCl3) to yield compound 3-7. Condensation of intermediate 3-7 with amine 3-8 (PG is a suitable protecting group, such as Boc) can be carried out to produce compound 3-9. Reduction of the ester with a reducing reagent (such as DIBAL), followed by oxidation of the intermediate with an oxidizing reagent (such as Dess-Martin periodinane) affords the aldehyde 3-10. Treatment of intermediate 3-10 with hydroxylamine hydrochloride and pyridine affords compound 3-11. Intermediate 3-11 can undergo a cyclization reaction (e.g., methanesulfonyl chloride, aminopyridine, etc. in DCM) to afford compound 3-12. The R in 3-13 can then be removed. 3 The group is S NThe intermediate 3-13 can be incorporated via a suitable transformation, such as an Ar reaction or a coupling reaction. Intermediate 3-13 can first undergo deprotection of the protecting group PG, followed by functionalization of the resulting amine (e.g., coupling with an acid chloride, e.g., acryloyl chloride), to give compound 3-14. The desired product 3-16 can then be prepared by a cross-coupling reaction between 3-14 and an adduct of formula 3-15, where M is a boronic acid, a boronic ester, or an appropriately substituted metal (e.g., M is B(OR)2, Sn(alkyl)3, or Zn-Hal), under standard Suzuki cross-coupling conditions (e.g., in the presence of a palladium catalyst and a suitable base), or standard Stille cross-coupling conditions (e.g., in the presence of a palladium catalyst), or standard Negishi cross-coupling conditions (e.g., in the presence of a palladium catalyst). The above chemical reaction sequence can be rearranged as needed to accommodate the preparation of different analogs.

[0163] [ka] Compounds of formula 4-6 can be prepared via the synthetic route outlined in Scheme 4. Intermediate 3-10 can be prepared by reacting S NThe intermediate 4-1 can be converted to compound 4-1 via a suitable transformation, such as an Ar reaction or a coupling reaction. A Wittig reaction of aldehyde 4-1 with (methoxymethyl)triphenylphosphonium chloride and potassium tert-butoxide in THF affords compound 4-2. Intermediate 4-2 can undergo a cyclization reaction (e.g., TFA in DCM) to give compound 4-3. Intermediate 4-5 can be prepared by a cross-coupling reaction between 4-3 and an adduct of formula 4-4, where M is a boronic acid, boronic ester, or appropriately substituted metal (e.g., M is B(OR)2, Sn(alkyl)3, or Zn-Hal), under standard Suzuki cross-coupling conditions (e.g., in the presence of a palladium catalyst and a suitable base), or standard Stille cross-coupling conditions (e.g., in the presence of a palladium catalyst), or standard Negishi cross-coupling conditions (e.g., in the presence of a palladium catalyst). Compound 4-5 can first undergo deprotection of the protecting group PG, followed by functionalization of the resulting amine (e.g., coupling with an acid chloride, such as acryloyl chloride), to then afford compound 4-6. The above chemical reaction sequence can be rearranged as appropriate to accommodate the preparation of different analogs.

[0164] [ka] Compounds of formula 5-18 can be prepared via the synthetic route outlined in Scheme 5. Halogenation of starting material 5-1 with an appropriate reagent, such as N-chlorosuccinimide (NCS), provides intermediate 5-2 (Hal is a halide such as F, Cl, Br, or I). Compound 5-3 can be prepared by treating 5-2 with a reagent such as triphosgene. Intermediate 5-3 can then be reacted with ester 5-4 to give nitro compound 5-5, which can be treated with an appropriate reagent (e.g., POCl) to provide compound 5-6. Scheme 5 of intermediate 5-6 with amine 5-7 N An Ar reaction (PG is a suitable protecting group such as Boc) can be carried out to produce compound 5-8. R in 5-9 can then be 3The group is S N The amine can be incorporated via a suitable transformation, such as an Ar reaction or a coupling reaction. Protection of the amino group leads to intermediate 5-10, which can be reduced in the presence of a reducing agent (e.g., Fe in acetic acid) to provide 5-11. The halogen (Hal) in 5-11 can optionally be converted to R via transition metal-mediated coupling or other suitable methods. 2 to give 5-12. Diazotization and reduction of the amino group in 5-12 gives intermediate 5-13, which after protecting group (PG) removal provides 5-14. Coupling of the bromo in 5-14 gives 5-15, which can be halogenated to give intermediate 5-16. Sonogashira coupling gives 5-17, which after cyclization and deprotection provides compounds of formula 5-18.

[0165] [ka] Compounds of formula 6-6 can be prepared via the synthetic route outlined in Scheme 6. Coupling of 5-16 with M (B, Sn, Si, Zn)-substituted vinyl ether 6-1 provides intermediate 6-2, which upon treatment under acidic conditions (e.g., TFA) affords 6-3. Halogenation of 6-3 provides 6-4, which can be converted to derivative 6-5 via coupling or other suitable transformations. Deprotection of 6-5 then affords compounds of formula 6-6.

[0166] KRAS protein 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 in human cancers, with 85% of all RAS mutations occurring in KRAS, 12% in NRAS, and 3% in HRAS (Simanshu, D. et al. Cell 170.1 (2017): 17-33). KRAS mutations are prevalent among the top three most lethal cancer types: pancreatic cancer (97%), colorectal cancer (44%), and lung cancer (30%) (Cox, AD et al. Nat Rev Drug Discov (2014) 13:828-51). 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 between RAS genes and G12D mutations is most prevalent in KRAS, while Q61R and G12R mutations are most frequent in NRAS and HRAS. Furthermore, the spectrum of mutations in RAS isoforms differs between cancer types. For example, G12D mutations in KRAS are prevalent in pancreatic cancer (51%), followed by colorectal adenocarcinoma (45%) and lung cancer (17%) (Cox, AD et al. Nat Rev Drug Discov (2014) 13:828-51). In contrast, KRAS G12C mutations are prevalent in non-small cell lung cancer (NSCLC), including 11–16% of lung adenocarcinomas (nearly half of mutant KRAS are G12C), as well as in 2–5% of pancreatic and colorectal adenocarcinomas, respectively (Cox, AD et al. Nat. Rev. Drug Discov. (2014) 13:828–51). 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 proliferation (McDonald, R. et al. Cell 170 (2017):577–592). Collectively, these findings suggest that KRAS mutations play an important role in human cancer, and therefore, the development of inhibitors targeting mutant KRAS may be useful in the clinical treatment of diseases characterized by KRAS mutations.

[0167] How to use Cancer types involving KRAS with G12C, G12V, and G12D mutations include, but are not limited to, carcinomas (e.g., pancreatic, colon, lung, bladder, stomach, esophagus, breast, head and neck, cervix, skin, thyroid), hematopoietic malignancies (e.g., myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), chronic and juvenile myelomonocytic leukemia (CMML and JMML), acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and multiple myeloma (MM)), and 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), which are caused by somatic mutations in KRAS or NRAS (Fernandez-Medarde, A. et al. Genes & Cancer, (2011): 344-358).

[0168] The compound of the present disclosure can inhibit the activity of KRAS protein.For example, the compound of the present disclosure can be used to inhibit the activity of KRAS in cells or individuals or patients that need enzyme inhibition by administering to cells, individuals or patients one or more compounds of the present disclosure that inhibit the activity of KRAS.

[0169] As KRAS inhibitors, the compounds of the present disclosure are useful for treating various diseases associated with abnormal expression or activity of KRAS. Compounds that inhibit KRAS will be useful for preventing proliferation or inducing apoptosis in tumors, or by inhibiting angiogenesis.Therefore, it is expected that the compounds of the present disclosure will prove useful for treating or preventing proliferative disorders such as cancer.In particular, tumors with activated mutant forms of receptor tyrosine kinases or upregulated receptor tyrosine kinases may be particularly sensitive to inhibitors.

[0170] In one aspect, provided herein is a method of inhibiting KRAS activity, comprising contacting KRAS with a compound of the present disclosure. In one embodiment, the contacting comprises administering the compound to a patient.

[0171] In one aspect, provided herein is a method of inhibiting a KRAS protein having a G12C mutation, the method comprising contacting KRAS with a compound of the disclosure.

[0172] In one aspect, provided herein is a method of inhibiting a KRAS protein having a G12D mutation, the method comprising contacting KRAS with a compound of the present disclosure.

[0173] In one aspect, provided herein is a method of inhibiting a KRAS protein having a G12V mutation, the method comprising contacting KRAS with a compound of the present disclosure.

[0174] In another aspect, provided herein is a method for treating a disease or disorder associated with inhibition of KRAS interaction, comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of any of the formulas disclosed herein, or a pharmaceutically acceptable salt thereof.

[0175] In one embodiment, the disease or disorder is an immunological or inflammatory disorder. In another embodiment, the immunological or inflammatory disorder is a Ras-associated lymphoproliferative disorder caused by somatic mutations in KRAS and juvenile myelomonocytic leukemia.

[0176] In yet another aspect, provided herein is a method for treating a disease or disorder associated with inhibiting a KRAS protein having a G12D mutation, comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of any of the formulas disclosed herein, or a pharmaceutically acceptable salt thereof.

[0177] In another aspect, provided herein is a method for treating a disease or disorder associated with inhibiting a KRAS protein having a G12V mutation, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of any of the formulas disclosed herein, or a pharmaceutically acceptable salt thereof.

[0178] In another aspect, also provided herein is a method of treating cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound disclosed herein.

[0179] In yet another aspect, also provided herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, wherein the cancer is characterized by interaction with a KRAS protein having a G12D mutation.

[0180] In another aspect, also provided herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, wherein the cancer is characterized by interaction with a KRAS protein having a G12V mutation.

[0181] In yet another aspect, provided herein is a method of 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.

[0182] In one embodiment, the cancer is selected from carcinoma, hematological cancer, sarcoma, and glioblastoma. In another embodiment, the hematological cancer is selected from myeloproliferative neoplasm, myelodysplastic syndrome, chronic and juvenile myelomonocytic leukemia, acute myeloid leukemia, acute lymphocytic leukemia, and multiple myeloma. In yet another embodiment, the carcinoma is selected from carcinoma of the pancreas, colon, lung, bladder, stomach, esophagus, breast, head and neck, cervix, skin, and thyroid.

[0183] In one aspect, provided herein is a method for treating a disease or disorder associated with inhibition of KRAS interaction or a mutant form thereof in a patient in need of such treatment, comprising administering to the patient a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof, in combination with another therapy or therapeutic agent described herein.

[0184] In one embodiment, the cancer is selected from hematological cancer, sarcoma, lung cancer, gastrointestinal cancer, genitourinary tract cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer, and skin cancer.

[0185] In another embodiment, the lung cancer is selected from non-small cell lung cancer (NSCLC), small cell lung carcinoma, bronchogenic carcinoma, squamous cell bronchogenic carcinoma, undifferentiated small cell bronchogenic carcinoma, undifferentiated large cell bronchogenic carcinoma, adenocarcinoma, bronchogenic carcinoma, alveolar carcinoma, bronchogenic carcinoma, bronchial adenoma, chondromatous hamartoma, mesothelioma, pavicellular and non-pavicellular carcinoma, bronchial adenoma, and pleuropulmonary blastoma.

[0186] In yet another embodiment, the lung cancer is non-small cell lung cancer (NSCLC). In yet another embodiment, the lung cancer is adenocarcinoma.

[0187] In one embodiment, the gastrointestinal cancer is selected from esophageal squamous cell carcinoma, esophageal adenocarcinoma, esophageal leiomyosarcoma, esophageal lymphoma, gastric carcinoma, gastric lymphoma, gastric leiomyosarcoma, exocrine pancreatic carcinoma, 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, colon adenocarcinoma, colon ductal adenoma, colon villous adenoma, colon hamartoma, colon leiomyoma, colon carcinoma, gallbladder carcinoma, and anal carcinoma.

[0188] In one embodiment, the gastrointestinal cancer is colon cancer.

[0189] In another embodiment, the cancer is a carcinoma. In yet another embodiment, the carcinoma is selected from pancreatic cancer, colon cancer, lung cancer, bladder cancer, gastric cancer, esophageal cancer, breast cancer, head and neck cancer, cervical skin cancer, and thyroid cancer.

[0190] 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 neoplasms.

[0191] In another embodiment, the cancer is a neoplasm. In yet another embodiment, the neoplasm is a glioblastoma or a sarcoma.

[0192] In certain embodiments, the present disclosure provides a method for treating a KRAS-mediated disorder in a patient in need thereof, comprising administering to the patient a compound according to the present invention or a pharmaceutically acceptable composition thereof.

[0193] In some embodiments, diseases and indications treatable using compounds of the present disclosure include, but are not limited to, hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.

[0194] Exemplary hematological cancers include lymphomas and leukemias, such as 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's lymphoma (including relapsed or refractory NHL and relapsed follicular), Hodgkin's lymphoma, myeloproliferative disorders (e.g., Examples include primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET), 8p11 myeloproliferative syndrome, myelodysplastic syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-cell lymphoma, adult T-cell lymphoma, Waldenstrom's macroglobulinemia, hairy cell lymphoma, marginal zone lymphoma, chronic myeloid lymphoma, and Burkitt's lymphoma.

[0195] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdomyosarcoma, fibroma, lipoma, hamartoma, lymphosarcoma, leiomyosarcoma, and teratoma.

[0196] Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer, bronchial carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchial) carcinoma, bronchial adenoma, chondromatous hamartoma, mesothelioma, small cell (pavicellular) and non-small cell (non-pavicellular) carcinoma, bronchial adenoma, and pleuropulmonary blastoma.

[0197] Exemplary gastrointestinal cancers include cancer of the esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), cancer of the stomach (carcinoma, lymphoma, leiomyosarcoma), cancer of the pancreas (exocrine pancreatic carcinoma, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), cancer of the small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), cancer of the large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colorectal carcinoma, gallbladder carcinoma, and anal carcinoma.

[0198] Exemplary genitourinary tract cancers include cancer of the kidney (adenocarcinoma, Wilms' tumor [nephroblastoma], renal cell carcinoma), cancer of the bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), cancer of the prostate (adenocarcinoma, sarcoma), cancer of the testes (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma), and urothelial carcinoma.

[0199] Exemplary liver cancers include hepatocarcinoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0200] Exemplary bone cancers include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exostosis), benign cartilage tumor, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor.

[0201] Exemplary nervous system cancers include cancers of the skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), cancers of the meninges (meningioma, meningeal sarcoma, gliomatosis), cancers of the brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, neuroectodermal tumors), and cancers of the spinal cord (neurofibroma, meningioma, glioma, sarcoma), neuroblastoma, Lhermitte-Dacros disease, and pineal tumors.

[0202] Exemplary gynecological cancers include cancer of the breast (ductal carcinoma, lobular carcinoma, breast sarcoma, triple-negative breast cancer, HER2-positive breast cancer, inflammatory breast cancer, papillary carcinoma), cancer of the uterus (endometrial carcinoma), cancer of the cervix (cervical carcinoma, preneoplastic cervical dysplasia), cancer of the ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulo-squamous cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), cancer of the vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), cancer of the vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma)), and cancer of the fallopian tubes (carcinoma).

[0203] Exemplary skin cancers include melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, lenticular dysplastic nevi, lipoma, hemangioma, dermatofibroma, and keloids.

[0204] Exemplary head and neck cancers include glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinoma, adenocarcinoma, oral cancer, laryngeal cancer, nasopharyngeal cancer, nasal cavity and paranasal sinus cancer, thyroid and parathyroid cancer, eye tumors, lip and oral cavity tumors, and head and neck squamous cell carcinoma.

[0205] Compounds of the present disclosure may also be useful in inhibiting tumor metastasis.

[0206] In addition to oncogenic neoplasms, the compounds of the present invention are useful for treating skeletal and chondrocyte disorders, including, but not limited to, achondroplasia, hypochondroplasia, dwarfism, thanatophoric dysplasia (TD) (clinical forms TD I and TD II), Apert syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Behle-Stevenson gyriform scalp syndrome, Pfeiffer syndrome, and craniosynostosis syndrome. In some embodiments, the present disclosure provides methods for treating patients suffering from skeletal and chondrocyte disorders.

[0207] In some embodiments, the compounds described herein can be used to treat Alzheimer's disease, HIV, or tuberculosis.

[0208] As used herein, the term "8p11 myeloproliferative syndrome" is meant to refer to myeloid / lymphoid neoplasms associated with eosinophilia and FGFR1 abnormalities.

[0209] As used herein, the term "cell" is meant to refer to a cell that is in vitro, ex vivo, or in vivo. In some embodiments, an ex vivo cell may be part of a tissue sample excised from an organism, such as a mammal. In some embodiments, an in vitro cell may be a cell in cell culture. In some embodiments, an in vivo cell is a cell that is living in an organism, such as a mammal.

[0210] As used herein, the term " contacting " refers to bringing together the indicated components in vitro or in vivo.For example, " contacting " KRAS with the compound described herein includes administering the compound described herein to an individual or patient, such as a human, who has KRAS, as well as introducing the compound described herein into the sample that contains the cell preparation or purified preparation that contains KRAS.

[0211] As used herein, the terms "individual," "subject," or "patient," used interchangeably, refer to any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, most preferably a human.

[0212] As used herein, the phrase "therapeutically effective amount" refers to an amount of an active compound or pharmaceutical agent, such as an amount of any of the solid forms disclosed herein or salts thereof, that elicits the biological or medicinal response in a tissue, system, animal, individual, or human that is being sought by a researcher, veterinarian, physician, or other clinician. An appropriate "effective" amount in any individual case can be determined using techniques known to those of ordinary skill in the art.

[0213] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, immunogenicity, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0214] As used herein, 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 are generally safe, non-toxic, and not biologically or otherwise undesirable, and include excipients or carriers that are acceptable for veterinary use as well as human pharmaceutical use. In one embodiment, each component is "pharmaceutically acceptable" as defined herein. For example, Remington: The Science and Practice of Pharmacy, 21st ed., Lippincott Williams & Wilkins: Philadelphia, Pa., 2005, Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009, Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007, Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, Fla., 2009.

[0215] As used herein, the term "treating" or "treatment" refers to inhibiting a disease, e.g., inhibiting a disease, condition, or disorder (i.e., halting further development of the pathology and / or symptoms) in an individual experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder, or ameliorating a disease, e.g., ameliorating a disease, condition, or disorder (i.e., reversing the pathology and / or symptoms) in an individual experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder, e.g., reducing the severity of the disease.

[0216] The terms "prevent," "preventing," or "prevention," as used herein, include the prevention of at least one symptom associated with or caused by the condition, disease, or disorder being prevented.

[0217] It is understood that certain features of the invention that are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment (while those embodiments are intended to be combined as if described in multiple dependent forms). Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0218] Combination therapy I. Cancer Therapy Cancer cell growth and survival can be affected by the dysfunction of multiple signal transduction pathways.Therefore, to treat such conditions, it is useful to combine different enzyme / protein / receptor inhibitors that have different preferences in the target that regulates their activity.Targeting more than one signal transduction pathway (or more than one biomolecule involved in a given signal transduction pathway) can reduce the possibility of drug resistance occurring in cell populations and / or reduce the toxicity of treatment.

[0219] For example, one or more additional pharmaceutical agents, such as chemotherapeutic agents, anti-inflammatory agents, steroids, immunosuppressants, cancer immunotherapeutic agents, metabolic enzyme inhibitors, chemokine receptor inhibitors, and phosphatase inhibitors, as well as targeted therapies, such as Bcr-Abl, Flt-3, EGFR, HER2, JAK, c-MET, VEGFR, PDGFR, c-Kit, IGF-1R, RAF, FAK, and CDK4 / 6 kinase inhibitors, e.g., those described in WO 2006 / 056399, can be used in combination with the compounds of the present disclosure for the treatment of CDK2-related diseases, disorders, or conditions. Other agents, such as therapeutic antibodies, can be used in combination with the compounds of the present disclosure for the treatment of CDK2-related diseases, disorders, or conditions. The one or more additional pharmaceutical agents can be administered to a patient simultaneously or sequentially.

[0220] In some embodiments, a CDK2 inhibitor is administered or used in combination with a BCL2 inhibitor or a CDK4 / 6 inhibitor.

[0221] 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 include those described herein. Examples of cancer include solid tumors and non-solid tumors, such as liquid tumors and hematological cancers. Examples of infectious diseases include viral infections, bacterial infections, fungal infections, or parasitic infections. For example, the compounds of the present disclosure can be combined with inhibitors of one or more 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 kinases). ), CSF1R, KIT, FLK-II, KDR / FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, PARP, Ron, Sea, TRKA, TRKB, TRKC, TAM kinases (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 infectious diseases. Non-limiting examples of inhibitors that may be combined with compounds of the present 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, orsimertinib, cetuximab, necitumumab, 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 INCB052794), CB054707), 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., palsaclisib (INCB50465) or INCB50797), PI3K-gamma inhibitors, e.g., PI3K-gamma selective inhibitors, Pim inhibitors agents (e.g., INCB53914), CSF1R inhibitors, TAM receptor tyrosine kinase (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), e.g., 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., tafasitamab), ALK2 inhibitors (e.g., INCB00928), or combinations thereof.

[0222] 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 selective over JAK2.

[0223] Examples of antibodies for use in combination therapy include, but are not limited to, 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 antibodies against c-MET.

[0224] One or more of the following agents may be used in combination with the compounds of the present disclosure, and are presented as a non-limiting list: cytostatic agents, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptosar, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, IRESSA™ (gefitinib), TARCEVA™ (erlotinib), antibodies to EGFR, Intron, ara-C, adriamycin, cytoxan, gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN™ (oxaliplatin), pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mithramycin, deoxycoformycin, mitomycin C, L-asparaginase, teniposide 17 alpha.Ethinyl estradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, 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™ (trastuzumab) (ibritumomab), BEXXAR™ (tositumomab), VELCADE™ (bortezomib), ZEVALIN™ (ibritumomab tiuxetan), TRISENOX™ (arsenic trioxide), XELODA™ (capecitabine), vinorelbine, porfimer, ERBITUX™ (cetuximab), thiotepa, altretamine, melphalan, trastuzumab, lerozole, fulvestra Cetuximab, C225 (cetuximab), Cambus (alemtuzumab), clofarabine, cladribine, aphidicolon, Rituxan, sunitinib, dasatinib, tezacitabine, Sml1, fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP, and MDL-101,731.

[0225] The compounds of the present disclosure can also be used in combination with other methods of treating cancer, such as chemotherapy, radiation therapy, tumor-targeted therapy, adjuvant therapy, immunotherapy, or surgery. Examples of immunotherapy 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 virotherapy, and immunomodulatory small molecules, including thalidomide or JAK1 / 2 inhibitors, PI3Kδ inhibitors, etc. The compounds can be administered in combination with one or more anti-cancer drugs, such as chemotherapeutic agents. Examples of chemotherapy drugs include abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib, bleomycin, bortezomib, intravenous busulfan, oral busulfan, calcitonin, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, and dromostanoate. Lon, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, 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, levamisole, lomustine, mechlorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane,Mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib, streptomycin, Tozocine, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronate.

[0226] Additional examples of chemotherapeutic agents include proteasome inhibitors (e.g., bortezomib), thalidomide, revlimid, and DNA damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine, and the like.

[0227] Exemplary steroids include corticosteroids such as dexamethasone or prednisone.

[0228] Exemplary Bcr-Abl inhibitors include imatinib mesylate (GLEEVAC™), nilotinib, dasatinib, bosutinib, and ponatinib, and pharmaceutically acceptable salts. Other exemplary suitable Bcr-Abl inhibitors include compounds of the genera and species disclosed in U.S. Pat. No. 5,521,184, WO 04 / 005281, and U.S. Ser. No. 60 / 578,491, and pharmaceutically acceptable salts thereof.

[0229] Exemplary suitable Flt-3 inhibitors include midostaurin, lestaurtinib, linifanib, sunitinib, sunitinib, maleic acid, sorafenib, quizartinib, crenolanib, pacritinib, tanzutinib, PLX3397, and ASP2215, and pharmaceutically acceptable salts thereof. Other exemplary suitable Flt-3 inhibitors include the compounds disclosed in WO03 / 037347, WO03 / 099771, and WO04 / 046120, and pharmaceutically acceptable salts thereof.

[0230] Exemplary suitable RAF inhibitors include dabrafenib, sorafenib, and vemurafenib, and pharmaceutically acceptable salts thereof. Other exemplary suitable RAF inhibitors include the compounds disclosed in WO00 / 09495 and WO05 / 028444, and pharmaceutically acceptable salts thereof.

[0231] Exemplary suitable FAK inhibitors include VS-4718, VS-5095, VS-6062, VS-6063, BI853520, and GSK2256098, and pharmaceutically acceptable salts thereof. Other exemplary suitable FAK inhibitors include compounds disclosed in WO04 / 080980, WO04 / 056786, WO03 / 024967, WO01 / 064655, WO00 / 053595, and WO01 / 014402, and pharmaceutically acceptable salts thereof.

[0232] Exemplary suitable CDK4 / 6 inhibitors include palbociclib, ribociclib, trilaciclib, relociclib, and abemaciclib, and pharmaceutically acceptable salts thereof. Other exemplary suitable CDK4 / 6 inhibitors include the compounds disclosed in WO09 / 085185, WO12 / 129344, WO11 / 101409, WO03 / 062236, WO10 / 075074, and WO12 / 061156, and pharmaceutically acceptable salts thereof.

[0233] In some embodiments, compounds of the present disclosure can be used in combination with one or more other kinase inhibitors, including imatinib, particularly to treat patients who are resistant to imatinib or other kinase inhibitors.

[0234] In some embodiments, compounds of the present disclosure can be used in combination with chemotherapeutic agents in the treatment of cancer, and can improve therapeutic responses compared to the response to the chemotherapeutic agent alone without exacerbating its toxic effects. In some embodiments, compounds of the present disclosure can be used in combination with the chemotherapeutic agents provided herein. For example, additional pharmaceutical agents used in the treatment of multiple myeloma can include, without limitation, melphalan, melphalan and 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 immunomodulatory agent. 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 immunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM). Additive or synergistic effects are desirable results of combining a CDK2 inhibitor of the present disclosure with an additional agent.

[0235] The agents can be combined with the compound in a single or continuous dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.

[0236] The compounds of the present disclosure can be used in combination with one or more other inhibitors or one or more therapies for the treatment of infectious diseases, including viral, bacterial, fungal, or parasitic infections.

[0237] In some embodiments, a corticosteroid such as dexamethasone is administered to a patient in combination with a compound of the present disclosure, and the dexamethasone is administered intermittently as opposed to continuously.

[0238] A compound of Formula (I) or any of the formulae described herein, a compound recited in any of the claims and described herein, or a salt thereof, can be combined with another immunogenic agent, such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune-stimulating cytokines. Non-limiting examples of tumor vaccines that can be used include peptides of melanoma antigens, such as peptides of gp100, MAGE antigens, Trp-2, MARTI, and / or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF.

[0239] A compound of Formula (I) or any of the formulas described herein, a compound listed in any of the claims and described herein, or a salt 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 implicated in human cancers, such as human papillomavirus (HPV), hepatitis viruses (HBV and HCV), and Kaposi's herpes sarcoma virus (KHSV). In some embodiments, compounds of the present disclosure can be used in combination with tumor-specific antigens, such as heat shock proteins isolated from the tumor tissue itself. In some embodiments, a compound of Formula (I) or any of the formulas described herein, a compound listed in any of the claims and described herein, or a salt thereof, can be combined with dendritic cell immunization to activate a potent anti-tumor response.

[0240] The compounds of the present 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 the present disclosure can also be combined with macrocyclic peptides that activate host immune responsiveness.

[0241] In some further embodiments, the combination of the disclosed compounds and other therapeutic agents can be administered to patients before, during, and / or after bone marrow or stem cell transplantation. The disclosed compounds can be used in combination with bone marrow transplantation to treat various tumors of hematopoietic origin.

[0242] A compound of formula (I) or any of the formulae described herein, a compound listed in any of the claims and described herein, or a salt 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 those for which there is currently no effective vaccine or for which conventional vaccines are not fully 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.

[0243] Viruses causing infectious diseases treatable by the methods of the present disclosure include, but are not limited to, human papillomavirus, influenza, hepatitis A, B, C, or D virus, 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, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus, and arboviral encephalitis virus.

[0244] Pathogenic bacteria causing infections treatable by the methods of the present disclosure include, but are not limited to, chlamydia, rickettsia bacteria, mycobacteria, staphylococci, streptococci, pneumococci, meningococci and conococci, klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria, salmonella, bacillus, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and lyme disease bacteria.

[0245] Pathogenic fungi that cause infections treatable by the methods of the present disclosure include, but are not limited to, Candida (e.g., albicans, krusei, glabrata, tropicalis), Cryptococcus neoformans, Aspergillus (e.g., fumigatus, niger), Genus Mucorales (e.g., mucor, absidia, rhizophus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis, and Histoplasma capsulatum.

[0246] Pathogenic parasites that cause infections treatable by the methods of the present 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.

[0247] When more than one pharmaceutical agent is administered to a patient, they may be administered simultaneously, separately, sequentially, or in combination (eg, in the case of more than two agents).

[0248] Methods for safely and effectively administering most of these chemotherapeutic agents are known to those skilled in the art. In addition, 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), the disclosure of which is incorporated herein by reference as if set forth in its entirety.

[0249] II. Immune checkpoint therapy The compounds of the present 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 of 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 stimulatory 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 a KIR inhibitor, a TIGIT inhibitor, a LAIR1 inhibitor, a CD160 inhibitor, a 2B4 inhibitor, and a TGFRbeta inhibitor.

[0250] 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).

[0251] In some embodiments, the inhibitor of an immune checkpoint molecule is an anti-PD1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

[0252] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1 or PD-L1, e.g., an anti-PD-1 or anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-1 or anti-PD-L1 antibody is selected from the group consisting of nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, cemiplimab, atezolizumab, avelumab, tislelizumab, spartalizumab (PDR001), cetrelimab (JNJ-63723283), toripalimab (JS001), camrelizumab (SHR-1210), sintilimab (IBI308), AB122 (GLS-010), AMP-224, AMP-514 / MEDI- 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, the PD-1 or PD-L1 inhibitor is a compound described in U.S. Pat. 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; 2017 / 0174679; Same No. 2017 / 0320875, No. 2017 / 0342060, No. 2017 / 0362253, No. 2018 / 0016260, No. 2018 / 0057486, No. 20 18 / 0177784, 2018 / 0177870, 2018 / 0179179, 2018 / 0179201, 2018 / 0179202, 2018 / 0 273519, 2019 / 0040082, 2019 / 0062345, 2019 / 0071439, 2019 / 0127467, 2019 / 0144439, 2019 / 0202824, 2019 / 0225601, 2019 / 0300524, or 2019 / 0345170, or PCT Publication No. WO and / or WO2011161699, each of which is incorporated by reference in its entirety. In some embodiments, the PD-L1 inhibitor is INCB086550.

[0253] In some embodiments, the PD-L1 inhibitor is selected from the compounds of Table A or a pharmaceutically acceptable salt thereof. [Table 1-1] [Table 1-2] [Table 1-3]

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

[0254] In some embodiments, the antibody is an anti-PD-1 antibody, e.g., an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab, cemiplimab, spartalizumab, camrelizumab, cetrelimab, toripalimab, sintilimab, 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, cemiplimab, spartalizumab, camrelizumab, cetrelimab, toripalimab, or sintilimab. 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 cemiplimab. 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 toripalimab. In some embodiments, the anti-PD-1 antibody is sintilimab. 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-PD1 antibody is SHR-1210.Other anti-cancer agent(s) include antibody therapeutics such as 4-1BB (e.g., urelumab, utomilumab). In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is atezolizumab, avelumab, durvalumab, tislelizumab, 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 tislelizumab. 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 tislelizumab. 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.

[0255] In some embodiments, the inhibitor of an immune checkpoint molecule is a small molecule that binds to PD-L1, or a pharmaceutically acceptable salt thereof. In some embodiments, the inhibitor of an immune checkpoint molecule is a small molecule that binds to and internalizes PD-L1, or a pharmaceutically acceptable salt thereof. In some embodiments, the inhibitor of an immune checkpoint molecule is a compound selected from those described in US2018 / 0179201, US2018 / 0179197, US2018 / 0179179, US2018 / 0179202, US2018 / 0177784, US2018 / 0177870, US Ser. No. 16 / 369,654 (filed March 29, 2019), and US Ser. No. 62 / 688,164 (each of which is incorporated by reference in its entirety).

[0256] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of KIR, TIGIT, LAIR1, CD160, 2B4, and TGFRbeta.

[0257] In some embodiments, the inhibitor is MCLA-145.

[0258] In some embodiments, the inhibitor of an 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.

[0259] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, such as an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016, LAG525, INCAGN2385, or eftiragimode alpha (IMP321).

[0260] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD73. In some embodiments, the inhibitor of CD73 is oleclumab.

[0261] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of TIGIT. In some embodiments, the inhibitor of TIGIT is OMP-31M32.

[0262] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of VISTA, hi some embodiments, the inhibitor of VISTA is JNJ-61610588 or CA-170.

[0263] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of B7-H3. In some embodiments, the inhibitor of B7-H3 is enoblituzumab, MGD009, or 8H9.

[0264] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of a KIR. In some embodiments, the inhibitor of a KIR is lirilumab or IPH4102.

[0265] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of A2aR, hi some embodiments, the inhibitor of A2aR is CPI-444.

[0266] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of TGF-beta, hi some embodiments, the inhibitor of TGF-beta is travedelsen, galcertinib, or M7824.

[0267] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PI3K-gamma. In some embodiments, the inhibitor of PI3K-gamma is IPI-549.

[0268] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD47. In some embodiments, the inhibitor of CD47 is Hu5F9-G4 or TTI-621.

[0269] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD73. In some embodiments, the inhibitor of CD73 is MEDI9447.

[0270] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD70. In some embodiments, the inhibitor of CD70 is cusatuzumab or BMS-936561.

[0271] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of TIM3, such as an anti-TIM3 antibody. In some embodiments, the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

[0272] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD20, e.g., an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is obinutuzumab or rituximab.

[0273] In some embodiments, the agonist of an immune checkpoint molecule is an agonist of OX40, CD27, CD28, GITR, ICOS, CD40, TLR7 / 8, and CD137 (also known as 4-1BB).

[0274] In some embodiments, the agonist of CD137 is urelumab. In some embodiments, the agonist of CD137 is utomilumab.

[0275] In some embodiments, the agonist of the immune checkpoint molecule is an inhibitor of GITR. In some embodiments, the agonist of GITR 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.

[0276] In some embodiments, the agonist of an immune checkpoint molecule is an agonist of CD40, hi some embodiments, the CD40 agonist is CP-870893, ADC-1013, CDX-1140, SEA-CD40, RO7009789, JNJ-64457107, APX-005M, or Chi Lob 7 / 4.

[0277] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of ICOS, hi some embodiments, the agonist of ICOS is GSK-3359609, JTX-2011, or MEDI-570.

[0278] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of CD28, hi some embodiments, the agonist of CD28 is celalizumab.

[0279] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of CD27, hi some embodiments, the agonist of CD27 is varlilumab.

[0280] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of TLR7 / 8, hi some embodiments, the agonist of TLR7 / 8 is MEDI9197.

[0281] The compounds of the present 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 a 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.

[0282] In some embodiments, the compounds of the present disclosure can be used in combination with one or more metabolic enzyme inhibitors. In some embodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1, TDO, or arginase. Examples of IDO1 inhibitors include epacadostat, NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099, and LY338196. Examples of arginase inhibitor inhibitors include INCB1158.

[0283] As provided throughout, the additional compounds, inhibitors, drugs, etc. can be combined with the compounds of the present invention in a single or sequential dosage form, or they can be administered simultaneously or sequentially as separate dosage forms.

[0284] Formulation, Dosage Form, and Administration When employed as a pharmaceutical, the compounds of the present disclosure can be administered in the form of a pharmaceutical composition. Accordingly, the present disclosure provides compositions comprising a compound of Formula I, a compound listed in any of the claims and described herein, or a pharmaceutically acceptable salt thereof, or any of its embodiments, and at least one pharmaceutically acceptable carrier or excipient. These compositions can be prepared by methods well known in the pharmaceutical arts and can be administered by various routes, depending on whether local or systemic treatment is indicated and on the area to be treated. Administration can be topical (including transdermal, epidermal, ophthalmic, and mucosal, including intranasal, intravaginal, and rectal delivery), pulmonary (e.g., intratracheal or intranasal, by inhalation or insufflation of powders or aerosols, including by nebulizer), oral, or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, or injection or infusion, or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose or, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder, or oily bases, thickeners, and the like may be necessary or desirable.

[0285] The present invention also includes pharmaceutical compositions containing the compounds of the present disclosure or their pharmaceutically acceptable salts as an active ingredient in combination with one or more pharmaceutically acceptable carriers or excipients.In some embodiments, the compositions are suitable for topical administration.When preparing the compositions of the present invention, the active ingredient is typically mixed with an excipient, diluted by an excipient, or enclosed in such a carrier, for example, in the form of a capsule, a sachet, paper, or other container.When the excipient functions as a diluent, it can be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient.Thus, the composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), for example, ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injection solutions, and sterile packaged powders.

[0286] When preparing formulations, active compound can be milled to obtain suitable particle size before being combined with other components.If active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh.If active compound is substantially water-soluble, its particle size can be adjusted by, for example, milling to about 40 mesh to provide substantially uniform distribution in formulations.

[0287] The compounds of the present invention can be milled using known milling procedures, such as wet milling, to obtain a particle size suitable for tablet formation and other formulation types. Finely divided (nanoparticulate) preparations of the compounds of the present invention can be prepared by processes known in the art (see, for example, WO2002 / 000196).

[0288] 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.Preparation can also include lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preservatives such as methyl benzoate and propylhydroxybenzoate, sweeteners, and flavoring agents.The composition of the present invention can be formulated to provide quick, sustained, or delayed release of active ingredients after administration to patients by adopting procedures known in the art.

[0289] In some embodiments, the pharmaceutical composition comprises silicified microcrystalline cellulose (SMCC) and at least one compound described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the silicified microcrystalline cellulose comprises about 98% w / w microcrystalline cellulose and about 2% w / w silicon dioxide.

[0290] 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, 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, 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, the 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, the polyethylene oxide is polyethylene oxide WSR 1105 (e.g., Polyox WSR 1105™).

[0291] In some embodiments, the compositions are manufactured using a wet granulation process. In some embodiments, the compositions are manufactured using a dry granulation process.

[0292] The compositions can be formulated in unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g), more usually about 100 mg to about 500 mg, of the active ingredient. In some embodiments, each dosage contains about 10 mg of the active ingredient. In some embodiments, each dosage contains about 50 mg of the active ingredient. In some embodiments, each dosage contains about 25 mg of the active ingredient. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dosage for human subjects and other mammals, each unit containing a predetermined quantity of the active agent calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0293] Ingredients 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 regulations, as defined in applicable U.S. Food and Drug Administration regulations. For example, suitable formulations may be sterile and / or substantially isotonic and / or in full compliance with all U.S. Food and Drug Administration Good Manufacturing Practice regulations.

[0294] The active compound can be effective over a wide dosage range and is generally administered in a therapeutically effective amount. However, it will be understood that the amount of compound actually administered will usually be determined by the physician according to the relevant circumstances, including the condition being treated, the selected route of administration, the actual compound being administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0295] Therapeutic dosages of the compounds of the invention can vary according to, for example, the particular application for which the treatment is being administered, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending on many factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, for parenteral administration, the compounds of the invention can be provided in an aqueous physiological buffer containing about 0.1 to about 10% w / v of the compound. Some typical dosage ranges are about 1 μg / kg to about 1 g / kg of body weight per day. In some embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg of body weight per day. The dosage can depend on variables such as the type and progression of the disease or disorder, the overall health of the particular patient, the relative bioefficacy of the selected compound, the formulation of excipients, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0296] To prepare solid compositions such as tablets, the primary active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of the compounds of the present invention. When these preformulation compositions are referred to as homogeneous, the active ingredient is typically dispersed evenly throughout the composition, allowing the composition to be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above, containing, for example, about 0.1 to about 1000 mg of the active ingredient of the present invention.

[0297] The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form that offers the advantage of prolonged action. For example, the tablet or pill can contain an inner and outer component, the latter in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, including a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0298] Liquid forms into which the compounds and compositions of the present invention may 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.

[0299] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions can be nebulized by use of inert gases. Nebulized solutions can be inhaled directly from the nebulizing device, or the nebulizing device can be attached to a face mask, tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices that deliver the formulation in an appropriate manner.

[0300] Topical formulations can contain one or more conventional carriers. In some embodiments, ointments can contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white petrolatum, etc. Cream carrier compositions can be based on water combined with glycerol and one or more other ingredients, such as glycerol monostearate, PEG-glycerol monostearate, and cetylstearyl alcohol. Gels can be suitably formulated using isopropyl alcohol and water in combination with other ingredients, such as glycerol and hydroxyethylcellulose. In some embodiments, topical formulations 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 a compound of the present invention. Topical formulations can be suitably packaged, for example, in 100g tubes, optionally with instructions for the treatment of a selected indication, such as psoriasis or other skin conditions.

[0301] The amount of compound or composition administered to a patient will vary depending on what is being administered, the purpose of the administration, such as prophylaxis or treatment, the condition of the patient, the mode of administration, etc. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dose will depend on the condition being treated and the judgment of the attending physician, depending on factors such as the severity of the disease, the age, weight, and general condition of the patient, etc.

[0302] The compositions administered to patients may be in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques or may be sterile filtered. Aqueous solutions may be packaged for immediate use or lyophilized, with the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations will typically be 3-11, more preferably 5-9, and most preferably 7-8. It is understood that the use of some of the aforementioned excipients, carriers, or stabilizers may result in the formation of pharmaceutical salts.

[0303] Therapeutic dosages of the compounds of the invention can vary according to, for example, the particular application for which the treatment is being administered, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending on many factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, for parenteral administration, the compounds of the invention can be provided in an aqueous physiological buffer containing about 0.1 to about 10% w / v of the compound. Some typical dosage ranges are about 1 μg / kg to about 1 g / kg of body weight per day. In some embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg of body weight per day. The dosage can depend on variables such as the type and progression of the disease or disorder, the overall health of the particular patient, the relative bioefficacy of the selected compound, the formulation of excipients, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0304] Labeled Compounds and Assay Methods Another aspect of the present invention relates to the labeled compounds (radiolabeled, fluorescently labeled, etc.) of the present disclosure, which may be useful in both in vitro and in vivo assays, as well as imaging techniques, for localizing and quantifying KRAS protein in tissue samples, including human tissues, and for identifying KRAS ligands, through the inhibitory binding of the labeled compounds. Substitution of one or more atoms of the compounds of the present disclosure may also be useful for generating differentiated ADME (adsorption, distribution, metabolism, and excretion). Thus, the present invention includes KRAS binding assays containing such labeled or substituted compounds.

[0305] The present disclosure further includes isotopically labeled compounds of the present disclosure. An "isotopically labeled" or "radiolabeled" compound is a compound of the present disclosure in which one or more atoms have been replaced or substituted by an atom having an atomic mass or mass number different from that typically found in nature (i.e., naturally occurring). Suitable radionuclides that can be incorporated into compounds of the present disclosure include: 2 H (also written as D for deuterium), 3 H (also written as T for 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 For example, one or more hydrogen atoms in the compounds of the present disclosure can be replaced by a deuterium atom (e.g., C of Formula I). 1~6One or more hydrogen atoms of an alkyl group can be optionally replaced with a deuterium atom, such as -CD3 substituted for -CH3.) In some embodiments, the alkyl group of formula I can be perdeuterated.

[0306] One or more constituent atoms of the compounds presented herein can be replaced or substituted with a natural or non-naturally abundant isotope of that atom. 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 to 2, 1 to 3, 1 to 4, 1 to 5, or 1 to 6 deuterium atoms. In some embodiments, all hydrogen atoms in the compounds can be replaced or substituted with deuterium atoms.

[0307] Synthetic methods for incorporating isotopes into organic compounds are known in the art (see, for example, "Deuterium Labeling in Organic Chemistry" by Alan F. Thomas (New York, NY, Appleton-Century-Crofts, 1971); "The Renaissance of H / D Exchange" by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; "The Organic Chemistry of Isotopic Labelling" by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can be used in a variety of studies, such as NMR spectroscopy, metabolic studies, and / or assays.

[0308] Substitution with heavier isotopes, such as deuterium, can provide certain therapeutic advantages, such as increased in vivo half-life or reduced dosage requirements, due to higher metabolic stability, and therefore may be preferable in some situations (see, for example, A. Kerekes et al. J. Med. Chem. 2011, 54, 201-210; R. Xu et al. J. Label Compd. Radiopharm. 2015, 58, 308-312). In particular, substitution at one or more metabolic sites can provide one or more therapeutic advantages.

[0309] The radionuclide that is incorporated into the present radiolabeled compounds will depend on the specific use of that radiolabeled compound. For example, for in vitro adenosine receptor labeling and competition assays: 3 H, 14 C. 82 Br, 125 I, 131 I, or 35 Compounds incorporating S may be useful. For radioimaging applications, 11 C. 18 F, 125 I, 123 I, 124 I, 131 I, 75 Br, 76 Br, or 77 Br may be useful.

[0310] A "radiolabel" or "labeled compound" is understood to be a compound that incorporates at least one radionuclide. In some embodiments, the radionuclide is 3 H, 14 C. 125 I, 35 S, and 82 Br.

[0311] The present disclosure further includes synthetic methods for incorporating radioisotopes into the compounds of the present disclosure. Synthetic methods for incorporating radioisotopes into organic compounds are well known in the art, and one of ordinary skill in the art will readily recognize methods applicable to the compounds of the present disclosure.

[0312] The labeled compounds of the present invention can be used in screening assays to identify and / or evaluate compounds.For example, a labeled newly synthesized or identified compound (i.e., test compound) can be evaluated for its ability to bind to KRAS protein by monitoring its concentration change upon contact with KRAS through label tracking.For example, a (labeled) test compound can be evaluated for its ability to reduce the binding of another compound known to bind to KRAS protein (i.e., standard compound).Therefore, the ability of a test compound to compete with a standard compound for binding to KRAS protein is directly correlated with its binding affinity.Conversely, in some other screening assays, the standard compound is labeled, and the test compound is not labeled.Therefore, the concentration of the labeled standard compound is monitored to evaluate the competition between the standard compound and the test compound, and thus the relative binding affinity of the test compound is confirmed.

[0313] kit The present disclosure also includes pharmaceutical kits useful for treating or preventing diseases or disorders associated with KRAS activity, such as cancer or infectious diseases, comprising 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 can further include one or more of a variety of conventional pharmaceutical kit components, such as, for example, a container containing one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to one of skill in the art. Instructions, either as an insert or label, indicating the amounts of components to be administered, guidelines for administration, and / or guidelines for mixing the components, can also be included in the kit.

[0314] The present invention will be further described in detail by specific examples.The following examples are provided for illustrative purposes and are not intended to limit the present invention in any way.Those skilled in the art will easily recognize various non-critical parameters that can be changed or modified to produce essentially the same results.The compound of example has been found to inhibit the activity of KRAS by at least one assay described herein. [Example]

[0315] The experimental procedures for the compounds of the present invention are provided below. Preparative LC-MS purification of some of the prepared compounds was carried out on a Waters mass fractionation system. The basic instrument setup, protocols, and control software for the operation of these systems are described in detail in the literature. See, for example, "Two-Pump At Column Dilution Configuration for Preparative LC-MS," K. Blom, J. Combi. Chem., 4, 295 (2002); "Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification," K. Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi. Chem., 5, 670 (2003); and "Preparative LC-MS Purification: Improved Compound Specific Method Optimization," K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem., 6, 874-883 (2004). Isolated compounds are typically subjected to analytical liquid chromatography-mass spectrometry (LCMS) for purity checks.

[0316] The isolated compounds were typically subjected to analytical liquid chromatography mass spectrometry (LCMS) for purity check under the following conditions: Instrument: Agilent 1100 series LC / MSD, Column: Waters Sunfire™ C 18 5 μm particle size, 2.1 x 5.0 mm, buffer: mobile phase A: 0.025% TFA in water and mobile phase B: acetonitrile; gradient 2% to 80% of B in 3 min at a flow rate of 2.0 mL / min.

[0317] Some of the prepared compounds were also separated on a preparative scale by reversed-phase high-performance liquid chromatography (RP-HPLC) or flash chromatography (silica gel) using the MS detectors indicated in the examples. Typical preparative reversed-phase high-performance liquid chromatography (RP-HPLC) column conditions are as follows:

[0318] pH=2 purification: Waters Sunfire(TM) C 18 The column was 5 μm in particle size, 19 × 100 mm, and eluted with mobile phase A: 0.1% TFA (trifluoroacetic acid) in water and mobile phase B: acetonitrile at a flow rate of 30 mL / min. The separation gradient was optimized for each compound using a Compound Specific Method Optimization protocol described in the literature [see "Preparative LCMS Purification: Improved Compound Specific Method Optimization," K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)]. Typically, the flow rate used with a 30 × 100 mm column was 60 mL / min.

[0319] pH=10 Purification: Waters XBridge C 18The 5 μm particle size, 19 × 100 mm column was eluted with mobile phase A: 0.15% NH OH in water and mobile phase B: acetonitrile at a flow rate of 30 mL / min. The separation gradient was optimized for each compound using a Compound Specific Method Optimization protocol described in the literature [see "Preparative LCMS Purification: Improved Compound Specific Method Optimization," K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)]. Typically, the flow rate used with a 30 × 100 mm column was 60 mL / min.

[0320] The following abbreviations may be used herein: AcOH (acetic acid); AcO (acetic anhydride); aq. (aqueous); atm. (atmosphere(s)); Boc (t-butoxycarbonyl); BOP ((benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate); br (broad area); Cbz (carboxybenzyl); calc. (calculated); d (doublet); dd (doublet of doublet); DBU (1,8-diazabicyclo[5.4.0]undeca-7 -ene); DCM (dichloromethane); DIAD (diisopropyl azidodicarboxylate N,N'); DIEA (N,N-diisopropylethylamine); DIPEA (N,N-diisopropylethylamine); DIBAL (diisobutylaluminum hydride); DMF (N,N-dimethylformamide); Et (ethyl acetate); EtOAc (ethyl acetate); FCC (flash column chromatography); g (gram(s)); h (hour(s)); HATU (N,N,N' N'-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate; HCl (hydrochloric acid); HPLC (high performance liquid chromatography); Hz (hertz); J (coupling constant); LCMS (liquid chromatography-mass spectrometry); LDA (lithium diisopropylamide); m (multiplet); M (mol); mCPBA (3-chloroperoxybenzoic acid); MS (mass spectrometry); Me (methyl); MeCN (acetonitrile); MeOH (methanol); mg (milligram(s)); min (minute(s)); mL (milliliter(s)); mmol (millimole(s)); N (normal); NCS (N-chlorosuccinimide); NEt3 (triethylamine); nM (nanomole); NMP (N-methylpyrrolidinone); NMR (nuclear magnetic resonance spectroscopy); OTf (trifluoromethanesulfonic acid); Ph (phenyl); pM (picomole); PPT (precipitate); RP-HPLC (reverse-phase high-performance liquid chromatography); rt(room temperature), s (singlet); t (triplet or tertiary); TBS (tert-butyldimethylsilyl); tert (tertiary); tt (triplet of triplets); TFA (trifluoroacetic acid); THF (tetrahydrofuran); μg (microgram(s)); μL (microliter(s)); μM (micromoles); wt% (weight percent). Brine is saturated aqueous sodium chloride solution. In vacuo is under vacuum.

[0321] Intermediate 1. 7-Bromo-2,4-dichloro-8-fluoro-6-iodo-3-nitroquinoline [ka] Step 1. 2-Amino-4-bromo-3-fluoro-5-iodobenzoic acid [ka] 1-Iodopyrrolidine-2,5-dione (21.15 g, 94 mmol) was added to a solution of 2-amino-4-bromo-3-fluorobenzoic acid (20 g, 85 mmol) in DMF (200 ml), and the reaction was stirred at 80° C. for 3 hours. The mixture was cooled with ice water, and then water (500 mL) was added. The precipitate was filtered, washed with water, and dried to provide the desired product as a solid. C7H5BrFINO2 + (M+H) + LC-MS calculated for: m / z = 359.9, 361.9; found 359.9, 361.9.

[0322] Step 2. 7-Bromo-8-fluoro-6-iodo-2H-benzo[d][1,3]oxazine 2,4(1H)-dione [ka] Triphosgene (9.07 g, 30.6 mmol) was added to a solution of 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (22 g, 61.1 mmol) in dioxane (200 ml), and the reaction was then stirred at 80° C. for 2 hours. The reaction mixture was cooled with ice water and then filtered. The solid was washed with ethyl acetate to provide the desired product as a solid. C8H3BrFINO3 + (M+H) + LC-MS calculated for: m / z = 385.8, 387.8; found 385.8, 387.8.

[0323] Step 3. 7-Bromo-8-fluoro-6-iodo-3-nitroquinoline-2,4-diol [ka] DIPEA (25.5 ml, 146 mmol) was added to a solution of ethyl 2-nitroacetate (16.33 ml, 146 mmol) and 7-bromo-8-fluoro-6-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (20 g, 73.0 mmol) in toluene (200 ml) at room temperature, and the reaction was stirred at 95 °C for 3 hours. The reaction was cooled and then filtered, then washed with a small amount of hexane to provide the desired product. C9H4BrFIN2O4 + (M+H) + LC-MS calculated for: m / z = 428.8, 430.8; observed 428.8, 430.8.

[0324] Step 4. 7-Bromo-2,4-dichloro-8-fluoro-6-iodo-3-nitroquinoline DIPEA (8.14 ml, 46.6 mmol) was added to a mixture of 7-bromo-8-fluoro-6-iodo-3-nitroquinoline-2,4-diol (10 g, 23.31 mmol) in POCl (10.86 ml, 117 mmol), and the reaction was stirred at 100° C. for 2 hours. The solvent was removed under vacuum and then azeotroped three times with toluene to provide the crude material, which was purified by flash column chromatography. + (M+H)+ LC-MS calculated for: m / z = 464.8, 466.8; found 464.8, 466.8.

[0325] Intermediate 2. tert-Butyl (1R,4R,5S)-5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-3-iodo-2-(methylthio)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] Step 1. tert-Butyl (1R,4R,5S)-5-((7-bromo-8-fluoro-6-iodo-2-(methylthio)-3-nitroquinolin-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 g, 53.7 mmol, Intermediate 1) and tert-butyl (1R,4R,5S)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylate (10.6 g, 53.7 mmol) in NMP (200 mL) was added Hunig's base (14.0 mL, 81 mmol), and the reaction mixture was heated to 60° C. for 1 hour. Ice chips and water (100 mL) were added, and the suspension was stirred for 15 minutes. The solid was filtered, rinsed with water, and air-dried under vacuum overnight to give the desired product.

[0326] The solid obtained above was suspended in MeCN (200 mL) and cooled to 0° C. 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 and air-dried. The filtrate was extracted with EtOAc and combined with the solid. This combined product was used without further purification. 20 H 22 BrFIN4O4S +(M+H) + LC-MS calculated for: m / z = 639.0; found 639.1.

[0327] Step 2. tert-Butyl (1R,4R,5S)-5-((7-bromo-8-fluoro-6-iodo-2-(methylthio)-3-nitroquinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] To a solution of tert-butyl (1R,4R,5S)-5-((7-bromo-8-fluoro-6-iodo-2-(methylthio)-3-nitroquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (34.3 g, 53.7 mmol) in THF (200 ml), triethylamine (18.7 ml, 134 mmol), DMAP (0.66 g, 5.37 mmol), and di-tert-butyl dicarbonate (23.4 g, 107 mmol) were added successively at room temperature, and the reaction mixture was heated to 50° C. for 3 hours. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO and brine. The organic layer was dried over MgSO, filtered, and concentrated. The product was used without further purification. 21 H 22 BrFIN4O6S + (M+H-C4H8) + LC-MS calculated for: m / z = 683.0; found 683.1.

[0328] Step 3. tert-Butyl (1R,4R,5S)-5-((3-amino-7-bromo-8-fluoro-6-iodo-2-(methylthio)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] A 1 L flask equipped with a mechanical stirrer was charged with tert-butyl (1R,4R,5S)-5-((7-bromo-8-fluoro-6-iodo-2-(methylthio)-3-nitroquinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (39.7 g, 53.7 mmol), MeOH (75 mL), water (75 mL), and THF (75 mL). Iron (15.0 g, 268 mmol) and ammonium chloride (14.4 g, 268 mmol) were added, and the reaction mixture was stirred at 70° C. overnight. The reaction mixture was diluted with EtOAc and filtered through a pad of Celite. The layers were separated, and 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 for: m / z = 709.0; found 709.1.

[0329] Step 4. tert-Butyl (1R,4R,5S)-5-((3-amino-7-bromo-6-(2-cyanoethyl)-8-fluoro-2-(methylthio)-quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] tert-Butyl (1R,4R,5S)-5-((3-amino-7-bromo-8-fluoro-6-iodo-2-(methylthio)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (36.7 g, 51.7 mmol), PdOAc (1.16 g, 5.17 mmol), and tri-o-tolylphosphine (3.15 g, 10.4 mmol) were dissolved in DMF (200 mL). Acrylonitrile (6.78 mL, 103 mmol) and triethylamine (14.3 mL, 103 mmol) were added to the reaction mixture in one portion. The headspace was purged with nitrogen, and the reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was cooled to room temperature, and water was added. The resulting precipitate was filtered, washed with water and air-dried.

[0330] The resulting solid was taken up in THF (200 ml) and cooled to 0° C. Superhydride (55.8 ml, 55.8 mmol) was added dropwise with LCMS monitoring. Upon completion, MeOH and water were added dropwise at 0° C., then the reaction mixture was warmed to room temperature and stirred for 15 minutes. The reaction mixture was extracted with EtOAc and the layers were separated. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The product was used without further purification. 28 H 36 BrFN5O4S + (M+H) + LC-MS calculated for: m / z = 636.2; found 636.3.

[0331] Step 5. tert-Butyl (1R,4R,5S)-5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-3-iodo-2-(methylthio)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate To a mixture of tert-butyl (1R,4R,5S)-5-((3-amino-7-bromo-6-(2-cyanoethyl)-8-fluoro-2-(methylthio)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (32 g, 50.3 mmol), potassium iodide (41.7 g, 251 mmol), and copper(I) iodide (12.45 g, 65.3 mmol), propionic acid (200 ml) and water (50 mL) were added, and the mixture was cooled to −10° C. t-BuONO (50 mL, 377 mmol) was added slowly over 15 minutes to control bubbling. After the addition, the reaction was stirred for 30 minutes. The reaction mixture was poured into cold sodium thiosulfate solution and then extracted with ethyl acetate. The organic layer was washed with NH4OH and saturated NaCl, dried over MgSO4, and concentrated. The product was purified by FCC (0-50% EtOAc / hexanes) to give the title compound as a brown solid (20 g, 53% over five steps). 24 H 26 BrFIN4O4S + (M+H-C4H8) + LC-MS calculated for: m / z = 691.0; found 691.1.

[0332] Intermediate 3. tert-Butyl 5,7-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate [ka] Step 1. tert-Butyl 3-bromo-5,7-difluoro-1H-indole-1-carboxylate [ka] To a solution of 5,7-difluoro-1H-indole (300 mg, 1.96 mmol) in DMF (8 mL) at 0 °C, NBS (384 mg, 2.16 mmol) was added, and the reaction mixture was stirred at this temperature for 30 minutes. Upon completion of bromination, triethylamine (410 μL, 2.94 mmol), Boc anhydride (641 mg, 2.94 mmol), and DMAP (24 mg, 0.2 mmol) were added sequentially, and the reaction mixture was allowed to warm to room temperature. After 30 minutes, the reaction was diluted with EtOAc and quenched with saturated NaHCO3. The reaction mixture was partitioned between water and EtOAc, and the layers were separated. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (0-10% hexane / EtOAc) to give the title compound (531 mg, 82%). CHBrFNO2 + (M+H-C4H8) + LC-MS calculated for: m / z = 276.0; found 276.0.

[0333] Step 2. tert-Butyl 5,7-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate A mixture of tert-butyl 3-bromo-5,7-difluoro-1H-indole-1-carboxylate (531 mg, 1.60 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.21 g, 4.80 mmol), potassium acetate (471 mg, 4.80 mmol), and PdCl(dppf)-CHCl adduct (131 mg, 0.16 mmol) in dioxane (10 mL) was sparged with N and heated to 95 °C overnight. The reaction mixture was diluted with EtOAc, filtered, and concentrated. The residue was purified by flash chromatography (0-10% EtOAc / hexanes). 15 H 17 BF2NO4 + (M+H-C4H8) + LC-MS calculated for: m / z = 324.1; found 324.2.

[0334] Intermediate 4. tert-Butyl 6-fluoro-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate [ka] Step 1. tert-Butyl 3-bromo-6-fluoro-5-methyl-1H-indole-1-carboxylate [ka] This compound was prepared by the same procedure as described for tert-butyl 3-bromo-5,7-difluoro-1H-indole-1-carboxylate (Intermediate 3, Step 1), utilizing 6-fluoro-5-methyl-1H-indole instead of 5,7-difluoro-1H-indole. 14 H 15 BrFNO2Na + (M+Na) + LC-MS calculated for: m / z = 350.0; found 350.0.

[0335] Step 2. tert-Butyl 6-fluoro-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate To a solution of tert-butyl 3-bromo-6-fluoro-5-methyl-1H-indole-1-carboxylate (187 mg, 0.57 mmol) in THF (4 ml) at -78 °C, sec-butyllithium (1.4 M / hexane, 0.61 ml, 0.86 mmol) was added and the reaction mixture was stirred at -78 °C for 15 minutes. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.29 ml, 1.43 mmol) was then added and the reaction mixture was allowed to warm to room temperature. The reaction was quenched with saturated NH4Cl and extracted with EtOAc. The layers were separated and the organic layer was dried over MgSO4, filtered, and concentrated. The product was used without further purification. C 20 H28 BFNO4 + (M+H) + LC-MS calculated for: m / z = 376.2; found 376.3.

[0336] Intermediate 5. tert-Butyl (1R,4R,5S)-5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-3-iodo-2-(methylthio)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] To a solution of tert-butyl (1R,4R,5S)-5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-3-iodo-2-(methylthio)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (10.0 g, 13.4 mmol, Intermediate 2) in DCM (134 mL) at room temperature, TFA (134 mL) was added and the reaction was stirred at room temperature for 2 hours. The reaction mixture was then concentrated and dissolved with THF (134 mL). Then, BocO (9.32 mL, 40.1 mmol) and TEA (5.59 mL, 40.1 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction was then concentrated and purified by flash chromatography (0-60% EtOAc / hexanes) to give the title compound (6.5 g, 75%). C 23 H 26 BrFIN4O2S + (M+H) + LC-MS calculated for: m / z = 647.0; found 647.0.

[0337] Intermediate 6: tert-butyl (1R,4R,5S)-5-((7-bromo-8-fluoro-3-iodo-6-methyl-2-(methylthio)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] Step 1: tert-butyl (1R,4R,5S)-5-((3-amino-7-bromo-8-fluoro-6-methyl-2-(methylthio)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] To a mixture of tert-butyl (1R,4R,5S)-5-((3-amino-7-bromo-8-fluoro-6-iodo-2-(methylthio)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (10.0 g, 14.1 mmol) (Intermediate 2, Step 3), methylboronic acid (4.22 g, 70.5 mmol), bis(triphenylphosphine)palladium(II) chloride (1.484 g, 2.114 mmol), and potassium phosphate (8.98 g, 42.3 mmol) was added 1,4-dioxane (100 ml) in water (10 ml), and the reaction flask was evacuated and backfilled with nitrogen, then stirred at 80° C. for 24 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by Biotage (0-50% ethyl acetate in hexanes) to provide the desired product. 26 H 35 BrFN4O4S(M+H) + LC-MS calculated for: m / z = 597.2; found 597.1.

[0338] Step 2: tert-butyl (1R,4R,5S)-5-((7-bromo-8-fluoro-3-iodo-6-methyl-2-(methylthio)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate This compound was prepared according to the procedure described in the synthesis of tert-butyl (1R,4R,5S)-5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-3-iodo-2-(methylthio)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Intermediate 2, Step 5). 26 H 33 BrFIN3O4S(M+H) + LC-MS calculated for: m / z = 708.0; found 708.2.

[0339] Intermediate 7. tert-Butyl (1R,4R,5S)-5-((7-bromo-8-fluoro-3-iodo-6-methyl-2-(methylthio)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] This compound was prepared according to the procedure described for Intermediate 5 using tert-butyl (1R,4R,5S)-5-((7-bromo-8-fluoro-3-iodo-6-methyl-2-(methylthio)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Intermediate 6). 21 H 25 BrFIN3O2S(M+H) + LC-MS calculated for: m / z = 608.0; found 608.2.

[0340] Intermediate 8. Ethyl 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinoline-3-carboxylate [ka] Step 1: Methyl 2-amino-4-bromo-3-fluorobenzoate [ka] Sulfuric acid (16.7 mL, 313 mmol) was slowly added to a solution of 2-amino-4-bromo-3-fluorobenzoic acid (36.6 g, 156 mmol) in MeOH (300 ml) at room temperature. The resulting mixture was heated to 80° C. overnight. The mixture was then cooled to room temperature and slowly quenched with 1 M aqueous NaOH (150 mL). The mixture was stirred at room temperature for 30 minutes, then filtered and dried under air...

Claims

1. A compound which is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile, or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein the compound is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile.

3. A pharmaceutically acceptable salt of the compound according to claim 1, which is a pharmaceutically acceptable salt of 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile.

4. A compound which is methyl(1S,3R,5S)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridine-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate, or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 4, wherein the compound is methyl(1S,3R,5S)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridine-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate.

6. A pharmaceutically acceptable salt of the compound according to claim 4, which is a pharmaceutically acceptable salt of methyl(1S,3R,5S)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridine-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate.

7. A compound which is methyl(1R,3R,5R)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridine-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate, or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 7, wherein the compound is methyl(1R,3R,5R)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridine-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate.

9. A pharmaceutically acceptable salt of the compound according to claim 7, which is a pharmaceutically acceptable salt of methyl(1R,3R,5R)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridine-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate.

10. A compound which is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-2-((1R,3R,5R)-2-(1-methylcyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile, or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 10, wherein the compound is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-2-((1R,3R,5R)-2-(1-methylcyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile.

12. A pharmaceutically acceptable salt of the compound according to claim 10, which is a pharmaceutically acceptable salt of 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-2-((1R,3R,5R)-2-(1-methylcyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile.

13. A compound which is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile, or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 13, wherein the compound is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile.

15. A pharmaceutically acceptable salt of the compound according to claim 13, which is a pharmaceutically acceptable salt of 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile.

16. A compound which is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile, or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 16, wherein the compound is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile.

18. A pharmaceutically acceptable salt of the compound according to claim 16, which is a pharmaceutically acceptable salt of 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile.

19. A pharmaceutical composition comprising the compound described in Claim 1 or a pharmaceutically acceptable salt thereof, the compound described in Claim 2 or a pharmaceutically acceptable salt of the compound described in Claim 3, and at least one pharmaceutically acceptable carrier or excipient.

20. A pharmaceutical composition comprising the compound described in claim 4 or a pharmaceutically acceptable salt thereof, the compound described in claim 5 or a pharmaceutically acceptable salt of the compound described in claim 6, and at least one pharmaceutically acceptable carrier or excipient.

21. A pharmaceutical composition comprising the compound according to claim 7 or a pharmaceutically acceptable salt thereof, the compound according to claim 8 or a pharmaceutically acceptable salt of the compound according to claim 9, and at least one pharmaceutically acceptable carrier or excipient.

22. A pharmaceutical composition comprising the compound according to claim 10 or a pharmaceutically acceptable salt thereof, the compound according to claim 11 or a pharmaceutically acceptable salt of the compound according to claim 12, and at least one pharmaceutically acceptable carrier or excipient.

23. A pharmaceutical composition comprising the compound according to claim 13 or a pharmaceutically acceptable salt thereof, the compound according to claim 14 or a pharmaceutically acceptable salt of the compound according to claim 15, and at least one pharmaceutically acceptable carrier or excipient.

24. A pharmaceutical composition comprising the compound according to claim 16 or a pharmaceutically acceptable salt thereof, the compound according to claim 17 or a pharmaceutically acceptable salt of the compound according to claim 18, and at least one pharmaceutically acceptable carrier or excipient.

25. A pharmaceutical agent for treating a disease or disorder related to the activity of KRAS, comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 4, 7, 10, 13, and 16, a compound according to any one of claims 2, 5, 8, 11, 14, and 17, or a pharmaceutically acceptable salt of a compound according to any one of claims 3, 6, 9, 12, 15, and 18.

26. A pharmaceutical agent for treating a disease or disorder related to the activity of a G12D mutation in the KRAS protein, comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 4, 7, 10, 13, and 16, the compound according to any one of claims 2, 5, 8, 11, 14, and 17, or a pharmaceutically acceptable salt of the compound according to any one of claims 3, 6, 9, 12, 15, and 18.

27. ​​The pharmaceutical product according to claim 26, wherein the disease or disorder is an immunological or inflammatory disorder.

28. The pharmaceutical product according to claim 27, wherein the immunological or inflammatory disorder is Ras-associated lymphoproliferative disorder or juvenile myelomonocytic leukemia caused by a somatic mutation of KRAS.

29. A pharmaceutical agent for treating cancer in a patient, comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 4, 7, 10, 13, and 16, a compound according to any one of claims 2, 5, 8, 11, 14, and 17, or a pharmaceutically acceptable salt of a compound according to any one of claims 3, 6, 9, 12, 15, and 18.

30. The pharmaceutical product according to claim 29, wherein the cancer is selected from carcinoma, hematological carcinoma, sarcoma, and glioblastoma.

31. The pharmaceutical product according to claim 29, wherein the cancer is a hematological cancer selected from myeloproliferative neoplasm, myelodysplastic syndrome, chronic and juvenile myelomonocytic leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, and multiple myeloma.

32. The pharmaceutical product according to claim 29, wherein the cancer is a carcinoma selected from carcinomas of the pancreas, colon, lung, bladder, stomach, esophagus, breast, head and neck, cervix, skin, and thyroid.

33. The pharmaceutical product according to claim 29, wherein the cancer is characterized by a KRAS protein having a G12D mutation.

34. The pharmaceutical product according to claim 29, wherein the cancer is pancreatic cancer.

35. The pharmaceutical product according to claim 29, wherein the cancer is pancreatic ductal adenocarcinoma.

36. The pharmaceutical product according to claim 29, wherein the cancer is colorectal cancer.

37. The pharmaceutical product according to claim 29, wherein the cancer is a type of colorectal cancer.

38. The pharmaceutical product according to claim 29, wherein the cancer is lung cancer.

39. The pharmaceutical product according to claim 29, wherein the cancer is non-small cell lung cancer.