Tricyclic compounds as inhibitors of KRAS

Abstract

Disclosed are compounds of formula (I), methods of using the compounds to inhibit KRAS activity, and pharmaceutical compositions containing such compounds, which are useful for treating, preventing, or ameliorating diseases or disorders associated with KRAS activity, such as cancer. TIFF2024529347000223.tif53164

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 221,595, filed July 14, 2021, the contents of which are incorporated herein 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; G12 and Q61 mutations are predominant 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 predominant 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 are prevalent in non-small cell lung cancer (NSCLC), including 11–16% of lung adenocarcinomas, and in 2–5% of pancreatic and colorectal adenocarcinomas, respectively (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 harboring 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; 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 an 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 a 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 aspect, provided herein is a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein [ka] is -NR 5 -C(=O)-, -N=N-, and -N=CR 6 -Selected from; R 1 H, D, C 1-2 Alkyl, and C 1-2 haloalkyl; 1-2 Alkyl is optional, R 11 substituted by 1 or 2 substituents independently selected from: Cy 1 is C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, and 6-10 membered heteroaryl; the 4-10 membered heterocycloalkyl and the 6-10 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; the ring-forming carbon atoms of the 6-10 membered heteroaryl and the 4-10 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 optional, and R 10 substituted by 1, 2, or 3 substituents independently selected from R 4 is H, C 1-3 Alkyl, C 1-3 Haloalkyl, 5-10 membered heteroaryl, OR a3 , and NR c3 R j3 C is selected from 1-3 The alkyl and 5- to 10-membered heteroaryl are each optional. 30or R 4 teeth, [ka] Selected from; R 5 is H, C 1-2 Alkyl and C 1-2 haloalkyl; R 7 is H, C 1-3 Alkyl, C 1-3 Haloalkyl, phenyl, 5-6 membered heteroaryl, F, Cl, D, CN, OR a7 , and NR c7 R d7 wherein the phenyl and 5-6 membered heteroaryl are each optionally selected from R 70 substituted by 1 or 2 substituents independently selected from: Cy 2 teeth, [ka] Selected from; Cy 2 Cy 2 -a, and [ka] -N=CR 6 -If R 6 H, D, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-10 membered heteroaryl; 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-10 membered heteroaryl are each optional; R 60 substituted by 1 or 2 substituents independently selected from: Cy 2 Cy 2 -If a, R2 is H, C 1-2 Alkyl, C 1-2 selected from haloalkyl, F, Cl, and —CH2CH2CN; Cy 2 Cy 2 -b, and [ka] -N=CR 6 -If R 6 is C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-10 membered heteroaryl; 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-10 membered heteroaryl are each optional; R 60 substituted by 1 or 2 substituents independently selected from: Cy 2 Cy 2 -b, then R 2 is H, C 1-2 Alkyl, C 1-2 Haloalkyl, F, -CH2CH2CN, [ka] Selected from; Each R 10 independently, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, halo, D, CN, OR a10 , C(O)NR c10 R d10 , N.R. c10 C(O)OR a10 , N.R. c10 C(O)NR c10 R d10 , and NR c10 R d10 C is selected from 1-3 Alkyl and C 3-6 Each cycloalkyl is optional, Rg substituted by 1 or 2 substituents independently selected from: Each R 11 independently, C 1-2 Alkyl, C 1-2 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, halo, D, CN, OR a11 and NR c11 R d11 C is selected from 1-2 Alkyl, C 3-6 Cycloalkyl and 4- to 6-membered heterocycloalkyl are each optional, and R g substituted by 1 or 2 substituents independently selected from: Each R 21 independently, C 1-3 Alkyl, C 1-3 Haloalkyl, Halo, D, CN, OR a21 , and NR c21 R d21 Selected from; Each R 30 independently, C 1-3 Alkyl, C 1-3 Haloalkyl, 4-10 membered heterocycloalkyl, halo, D, CN, OR a30 , C(O)NR c30 R d30 , N.R. c30 C(O)OR a30 , N.R. c30 C(O)NR c30 R d30 , and NR c30 R d30 C is selected from 1-3 The alkyl and 4- to 6-membered heterocycloalkyl are each optional. 31 substituted by 1 or 2 substituents independently selected from: Each R 31 independently, C 1-3 Alkyl, C 1-3 selected from haloalkyl, halo, D, and CN; Each R 60 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 a60 , C(O)R b60 , C(O)NR c60 R d60 , and NR c60 R d60 C is selected from 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are each optional; R 61 substituted by 1 or 2 substituents independently selected from: Each R 61 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 a61 , C(O)R b61 , and NR c61 R d61 Selected from; Each R 70 independently, C 1-3 Alkyl, C 1-3 Haloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, CN, OR a70 , and NR c70 R d70 Selected from; Each R a3 and R c3 are independently H, C 1-3 Alkyl, C 1-3 selected from haloalkyl, 5-6 membered heteroaryl, and phenyl; C 1-3 Alkyl, 5-6 membered heteroaryl, and phenyl are each optional; R 30 substituted by 1 or 2 substituents independently selected from: Each R j3 independently, C 1-3 Alkyl and C 1-3 haloalkyl; Each R a7 , R c7 , and R d7are independently H, C 1-3 Alkyl, and C 1-3 haloalkyl; 1-3 Alkyl is optional, R 70 substituted by 1 or 2 substituents independently selected from: Each R a10 , R c10 and R d10 are independently H, C 1-3 Alkyl and C 1-3 haloalkyl; Each R a11 , R c11 and R d11 are independently H, C 1-3 Alkyl and C 1-3 haloalkyl; R b20 is NH2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl; 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are each optional; R 21 substituted by 1 or 2 substituents independently selected from: Each R a21 , R c21 and R d21 are independently H, 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 a60 , R b60 , R c60 and R d60 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, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are each optional; R 61 substituted by 1 or 2 substituents independently 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, R 61 forming a 4-, 5-, 6-, 7-, 8-, or 9-membered heterocycloalkyl group optionally substituted with 1 or 2 substituents independently selected from: Each R a61 , R b61 , R c61 and R d61 are independently H, C 1-3 Alkyl and C 1-3 haloalkyl; Each R a70 , R c70 , and R d70 are independently H, C 1-3 Alkyl, and C 1-3 haloalkyl; Each R g are independently D, OH, CN, halo, C 1-2 Alkyl, amino and C 1-2 haloalkyl; provided that the compound of formula I is 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-dimethylpropanamide, 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-2-ethyl-6-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile, 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-((3-oxomorpholino)methyl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile, 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-2-yl)-N-methyl-N-(pyridin-2-ylmethyl)propanamide, and 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(2-(piperazin-1-yl)thiazol-4-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile There is a condition other than

[0011] In some embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, [ka] is -NR 5 -C(=O)-, -N=N-, and -N=CR 6 -Selected from; R 1 H, D, C 1-2 Alkyl, and C 1-2 haloalkyl; 1-2 Alkyl is optional, R 11substituted by 1 or 2 substituents independently selected from: Cy 1 is C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, and 6-10 membered heteroaryl; the 4-10 membered heterocycloalkyl and the 6-10 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; the ring-forming carbon atoms of the 6-10 membered heteroaryl and the 4-10 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 optional, and R 10 substituted by 1, 2, or 3 substituents independently selected from R 4 is OR a3 Selected from; R 5 is H, C 1-2 Alkyl and C 1-2 haloalkyl; R 7 is H, C 1-3 Alkyl, C 1-3 Haloalkyl, phenyl, 5-6 membered heteroaryl, F, Cl, D, CN, OR a7 , and NR c7 R d7 wherein each of the phenyl and 5- to 6-membered heteroaryl is optionally selected from R 70 substituted by 1 or 2 substituents independently selected from: Cy 2 teeth [ka] Selected from; Cy 2 Cy 2 -a, and [ka] -N=CR 6 -If R 6 H, D, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-10 membered heteroaryl; 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-10 membered heteroaryl are each optional; R 60 substituted by 1 or 2 substituents independently selected from: Cy 2 Cy 2 -If a, R 2 is H, C 1-2 Alkyl, C 1-2 selected from haloalkyl, F, Cl, and —CH2CH2CN; Cy 2 Cy 2 -b, and [ka] -N=CR 6 -If R 6 is C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-10 membered heteroaryl; 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-10 membered heteroaryl are each optional; R 60 substituted by 1 or 2 substituents independently selected from: Cy 2 Cy 2 -b, then R 2 is H, C 1-2 Alkyl, C 1-2 Haloalkyl, F, -CH2CH2CN, [ka] Selected from; Each R 10 independently, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, halo, D, CN, OR a10 , C(O)NR c10 R d10 , N.R. c10 C(O)OR a10 , N.R. c10 C(O)NR c10 R d10 , and NR c10 R d10 C is selected from 1-3 Alkyl and C 3-6 Each cycloalkyl is optional, R g substituted by 1 or 2 substituents independently selected from: Each R 11 independently, C 1-2 Alkyl, C 1-2 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, halo, D, CN, OR a11 and NR c11 R d11 C is selected from 1-2 Alkyl, C 3-6 Cycloalkyl and 4- to 6-membered heterocycloalkyl are each optional, and R g substituted by 1 or 2 substituents independently selected from: Each R 21 independently, C 1-3 Alkyl, C 1-3 Haloalkyl, Halo, D, CN, OR a21 , and NR c21 R d21 Selected from; Each R 30 independently, C 1-3 Alkyl, C 1-3 Haloalkyl, 4-10 membered heterocycloalkyl, halo, D, CN, OR a30 , C(O)NR c30 R d30 , N.R. c30 C(O)OR a30 , N.R.c30 C(O)NR c30 R d30 , and NR c30 R d30 C is selected from 1-3 The alkyl and 4- to 6-membered heterocycloalkyl are each optional. 31 substituted by 1 or 2 substituents independently selected from: Each R 31 is independently C 1-3 Alkyl, C 1-3 selected from haloalkyl, halo, D, and CN; Each R 60 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 a60 , C(O)R b60 , C(O)NR c60 R d60 , and NR c60 R d60 C is selected from 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are each optional; R 61 substituted by 1 or 2 substituents independently selected from: Each R 61 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 a61 , C(O)R b61 , and NR c61 R d61 Selected from; Each R 70 independently, C 1-3 Alkyl, C 1-3 Haloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, CN, OR a70 , and NR c70 R d70 Selected from; Each R a3 are independently H, C 1-3 Alkyl, C 1-3 haloalkyl, 5-6 membered heteroaryl, and phenyl; 1-3 Alkyl, 5-6 membered heteroaryl, and phenyl are each optional; R 30 substituted by 1 or 2 substituents independently selected from: Each R a7 , R c7 , and R d7 are independently H, C 1-3 Alkyl, and C 1-3 haloalkyl; 1-3 Alkyl is optional, R 70 substituted by 1 or 2 substituents independently selected from: Each R a10 , R c10 and R d10 are independently H, C 1-3 Alkyl and C 1-3 haloalkyl; Each R a11 , R c11 and R d11 are independently H, C 1-3 Alkyl and C 1-3 haloalkyl; R b20 is NH2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl; 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are each optional; R 21 substituted by 1 or 2 substituents independently selected from: Each R a21 , R c21 and R d21 are independently H, C 1-3 Alkyl, and C 1-3 haloalkyl; Each Ra30 , R c30 and R d30 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, phenyl, and 5- to 6-membered heteroaryl; 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are each optional; R 61 substituted by 1 or 2 substituents independently 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, R 61 forming a 4-, 5-, 6-, 7-, 8-, or 9-membered heterocycloalkyl group optionally substituted with 1 or 2 substituents independently selected from: Each R a61 , R b61 , R c61 and R d61 are independently H, C 1-3 Alkyl and C 1-3 haloalkyl; Each R a70 , R c70 , and R d70 are independently H, C 1-3 Alkyl and C 1-3 haloalkyl; and Each R g are independently D, OH, CN, halo, C 1-2 Alkyl, amino and C 1-2 haloalkyl.

[0012] In another embodiment of Formula I, or a pharmaceutically acceptable salt thereof, [ka] is -NR 5 -C(=O)-, -N=N-, and -N=CR 6 -Selected from; R 1 H, D, C 1-2 Alkyl, and C 1-2 haloalkyl; 1-2 Alkyl is optional, R 11 substituted by 1 or 2 substituents independently selected from: Cy 1 is C 3-10 selected from cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, and 6-10 membered heteroaryl; the 4-10 membered heterocycloalkyl and 6-10 membered heteroaryl each having at least one ring-forming carbon atom and one or two ring-forming heteroatoms independently selected from N, O, and S; C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, phenyl and 6-10 membered heteroaryl are each optional; R 10 or Cy 1 teeth, [ka] Selected from; R 4 is H, C 1-3 Alkyl, C 1-3 Haloalkyl, 5-10 membered heteroaryl, OR a3 , and NR c3 R j3 C is selected from 1-3 The alkyl and 5- to 10-membered heteroaryl are each optional. 30 or R 4 teeth, [ka] Selected from; R 5 is H, C 1-2 Alkyl and C 1-2 haloalkyl; R 7 is H, C 1-3 Alkyl, C 1-3 Haloalkyl, phenyl, 5-6 membered heteroaryl, F, Cl, D, CN, OR a7 , and NR c7 R d7 wherein each of the phenyl and 5- to 6-membered heteroaryl is optionally selected from R 70 substituted by 1 or 2 substituents independently selected from: Cy 2 teeth, [ka] Selected from; Cy 2 Cy 2 -a, and [ka] -N=CR 6 -If R 6 is H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-10 membered heteroaryl, D; 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-10 membered heteroaryl are each optional; R 60 substituted by 1 or 2 substituents independently selected from: Cy 2 Cy 2 -If a, R 2 is H, C 1-2 Alkyl, C 1-2 selected from haloalkyl, F, Cl, -CH2CH2CN; Cy 2 Cy 2-b, and [ka] -N=CR 6 -If R 6 is C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, -CH2CH2NHMe, -CH2CH2C(O)NMe2, [ka] Selected from; Cy 2 Cy 2 -b, then R 2 is H, C 1-2 Alkyl, C 1-2 Haloalkyl, F, -CH2CH2CN, [ka] Selected from; Each R 10 independently, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, halo, D, CN, OR a10 , C(O)NR c10 R d10 , N.R. c10 C(O)OR a10 , N.R. c10 C(O)NR c10 R d10 , and NR c10 R d10 C is selected from 1-3 Alkyl and C 3-6 Each cycloalkyl is optional, R g substituted by 1 or 2 substituents independently selected from: Each R 11 independently, C 1-2 Alkyl, C 1-2 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, halo, D, CN, OR a11 and NR c11R d11 C is selected from 1-2 Alkyl, C 3-6 Cycloalkyl and 4- to 6-membered heterocycloalkyl are each optional, and R g substituted by 1 or 2 substituents independently selected from: Each R 21 independently, C 1-3 Alkyl, C 1-3 Haloalkyl, Halo, D, CN, OR a21 , and NR c21 R d21 Selected from; Each R 30 independently, C 1-3 Alkyl, C 1-3 Haloalkyl, 4-10 membered heterocycloalkyl, halo, D, CN, OR a30 , C(O)NR c30 R d30 , N.R. c30 C(O)OR a30 , N.R. c30 C(O)NR c30 R d30 , 5-6 membered heteroaryl, and NR c30 R d30 C is selected from 1-3 The alkyl and 4- to 6-membered heterocycloalkyl are each optional. 31 substituted by 1 or 2 substituents independently selected from: Each R 31 is independently C 1-3 Alkyl, C 1-3 selected from haloalkyl, halo, D, and CN; Each R 60 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 a60 , C(O)R b60 , C(O)NR c60 R d60 , and NR c60 R d60 C is selected from 1-3 Alkyl, C3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are each optional; R 61 substituted by 1 or 2 substituents independently selected from: Each R 61 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 a61 , C(O)R b61 , and NR c61 R d61 Selected from; Each R 70 independently, C 1-3 Alkyl, C 1-3 Haloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, CN, OR a70 , and NR c70 R d70 Selected from; Each R a3 and R c3 are independently H, C 1-3 Alkyl, C 1-3 haloalkyl, 5-6 membered heteroaryl, and phenyl; 1-3 Alkyl, 5-6 membered heteroaryl, and phenyl are each optional; R 30 substituted by 1 or 2 substituents independently selected from: Each R j3 independently, C 1-3 Alkyl and C 1-3 haloalkyl; Each R a7 , R c7 , and R d7 are independently H, C 1-3 Alkyl, and C 1-3 haloalkyl; 1-3 Alkyl is optional, R 70 substituted by 1 or 2 substituents independently selected from: Each R a10 , R c10 and Rd10 are independently H, C 1-3 Alkyl and C 1-3 haloalkyl; Each R a11 , R c11 and R d11 are independently H, C 1-3 Alkyl and C 1-3 haloalkyl; R b20 is NH2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl; 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are each optional; R 21 substituted by 1 or 2 substituents independently selected from: Each R a21 , R c21 and R d21 are independently H, 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 a60 , R b60 , R c60 and R d60 are independently H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl; 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are each optional; R 61 substituted by 1 or 2 substituents independently 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, R 61 forming a 4-, 5-, 6-, 7-, 8-, or 9-membered heterocycloalkyl group optionally substituted with 1 or 2 substituents independently selected from: Each R a61 , R b61 , R c61 and R d61 are independently H, C 1-3 Alkyl and C 1-3 haloalkyl; Each R a70 , R c70 , and R d70 are independently H, C 1-3 Alkyl and C 1-3 haloalkyl; and Each R g are independently D, OH, CN, halo, C 1-2 Alkyl, amino and C 1-2 haloalkyl.

[0013] In yet another embodiment of Formula I, or a pharmaceutically acceptable salt thereof, [ka] is -NR 5 -C(=O)-, -N=N-, and -N=CR 6 -Selected from; R 1 H, D, C 1-2 Alkyl, and C 1-2 haloalkyl; 1-2 Alkyl is optional, R 11 substituted by 1 or 2 substituents independently selected from: Cy 1 is C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10aryl, and 6-10 membered heteroaryl; the 4-10 membered heterocycloalkyl and the 6-10 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; the ring-forming carbon atoms of the 6-10 membered heteroaryl and the 4-10 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 optional, and R 10 substituted by 1, 2, or 3 substituents independently selected from R 4 is OR a3 Selected from; R 5 is H, C 1-2 Alkyl and C 1-2 haloalkyl; R 7 is H, C 1-3 Alkyl, C 1-3 Haloalkyl, phenyl, 5-6 membered heteroaryl, F, Cl, D, CN, OR a7 , and NR c7 R d7 wherein each of the phenyl and 5- to 6-membered heteroaryl is optionally selected from R 70 substituted by 1 or 2 substituents independently selected from: Cy 2 teeth, [ka] Selected from; Cy 2 Cy 2 -a, and [ka] -N=CR 6 -If R 6 H, D, C 1-3 Alkyl and C 1-3 haloalkyl; 1-3Alkyl is optional, R 60 substituted by 1 or 2 substituents independently selected from: Cy 2 Cy 2 -If a, R 2 is H, C 1-2 Alkyl, C 1-2 selected from haloalkyl, F, Cl, and —CH2CH2CN; Cy 2 Cy 2 -b, and [ka] -N=CR 6 -If R 6 is C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-10 membered heteroaryl; 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-10 membered heteroaryl are each optional; R 60 substituted by 1 or 2 substituents independently selected from: Cy 2 Cy 2 -b, then R 2 is H,C 1-2 Alkyl, C 1-2 Haloalkyl, F, -CH2CH2CN, [ka] Selected from; Each R 10 independently, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, halo, D, CN, OR a10 , C(O)NR c10 R d10 , and NR c10 R d10 C is selected from 1-3 Alkyl and C3-6 Each cycloalkyl is optional, R g substituted by 1 or 2 substituents independently selected from: Each R 11 independently, C 1-2 Alkyl, C 1-2 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, halo, D, CN, OR a11 and NR c11 R d11 C is selected from 1-2 Alkyl, C 3-6 Cycloalkyl and 4- to 6-membered heterocycloalkyl are each optional, and R g substituted by 1 or 2 substituents independently selected from: Each R 21 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, 4-10 membered heterocycloalkyl, halo, D, CN, OR a30 , C(O)NR c30 R d30 , and NR c30 R d30 C is selected from 1-3 The alkyl and 4- to 6-membered heterocycloalkyl are each optional. 31 substituted by 1 or 2 substituents independently selected from: Each R 31 is independently C 1-3 Alkyl, C 1-3 selected from haloalkyl, halo, D, and CN; Each R 60 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 a60 , C(O)R b60 , C(O)NR c60R d60 , and NR c60 R d60 C is selected from 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are each optional; R 61 substituted by 1 or 2 substituents independently selected from: Each R 61 independently, C 1-3 Alkyl, C 1-3 Haloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, CN, OR a61 , C(O)R b61 , and NR c61 R d61 Selected from; Each R 70 independently, C 1-3 Alkyl, C 1-3 selected from haloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, and CN; Each R a3 are independently H, C 1-3 Alkyl, C 1-3 haloalkyl, 5-6 membered heteroaryl, and phenyl; 1-3 Alkyl, 5-6 membered heteroaryl, and phenyl are each optional; R 30 substituted by 1 or 2 substituents independently selected from: Each R a7 , R c7 , and R d7 are independently H, C 1-3 Alkyl, and C 1-3 haloalkyl; 1-3 Alkyl is optional, R 70 substituted by 1 or 2 substituents independently selected from: Each R a10 , R c10 and R d10 are independently H, C 1-3 Alkyl and C 1-3 haloalkyl; Each R a11 , R c11 and Rd11 are independently H, C 1-3 Alkyl and C 1-3 haloalkyl; R b20 is NH2, 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, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are each optional; R 21 substituted by 1 or 2 substituents independently selected from: Each R a21 , R c21 and R d21 are independently H, 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 a60 , R b60 , R c60 and R d60 are independently H, C 1-3 Alkyl, and C 1-3 haloalkyl; 1-3 Alkyl is optional, R 61 substituted by 1 or 2 substituents independently 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, R 61 forming a 4-, 5-, 6-, or 9-membered heterocycloalkyl group optionally substituted with 1 or 2 substituents independently selected from: Each R a61 , R b61 , R c61 and R d61are independently H, C 1-3 Alkyl and C 1-3 haloalkyl; and Each R g are independently D, OH, CN, halo, C 1-2 Alkyl, amino and C 1-2 haloalkyl.

[0014] In yet another embodiment of Formula I, or a pharmaceutically acceptable salt thereof, [ka] is -NR 5 -C(=O)-, -N=N-, and -N=CR 6 -Selected from; R 1 H, and C 1-2 alkyl; 1-2 Alkyl is optional, R 11 substituted by 1 or 2 substituents independently selected from: Cy 1 is C 3-10 Cycloalkyl, C 6-10 aryl, and 6- to 10-membered heteroaryl; each 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; a ring-forming carbon atom of the 6- to 10-membered heteroaryl is optionally substituted by oxo to form a carbonyl group; C 3-10 Cycloalkyl, C 6-10 Aryl and 6- to 10-membered heteroaryl are each optional, and R 10 substituted by 1, 2, or 3 substituents independently selected from R 4 is OR a3 Selected from; R 5 is H, R 7 is phenyl, 5-6 membered heteroaryl, F, and OR a7 wherein each of the phenyl and 5- to 6-membered heteroaryl is optionally selected from R 70substituted by 1 or 2 substituents independently selected from: Cy 2 teeth [ka] Selected from; Cy 2 Cy 2 -a, and [ka] -N=CR 6 -If R 6 is H; Cy 2 Cy 2 -If a, R 2 is Cl; Cy 2 Cy 2 -b, and [ka] -N=CR 6 -If R 6 is C 1-3 Alkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl; 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl are each optional; R 60 substituted by 1 or 2 substituents independently selected from: Cy 2 Cy 2 -b, then R 2 is H, C 1-2 Alkyl, -CH2CH2CN, [ka] Selected from; Each R 10 independently, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6Cycloalkyl, halo, CN, OR a10 , and NR c10 R d10 C is selected from 1-3 Alkyl and C 3-6 Each cycloalkyl is optional, R g substituted by 1 or 2 substituents independently selected from: Each R 11 are independently 4-6 membered heterocycloalkyl, and OR a11 wherein said 4-6 membered heterocycloalkyl is optionally selected from R g substituted by 1 or 2 substituents independently selected from: Each R 21 is CN; Each R 30 are independently 4-10 membered heterocycloalkyl, and C(O)NR c30 R d30 wherein said 4-6 membered heterocycloalkyl is optionally selected from R 31 substituted by 1 or 2 substituents independently selected from: Each R 31 independently, C 1-3 alkyl; Each R 60 independently, C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C(O)R b60 , C(O)NR c60 R d60 , and NR c60 R d60 C is selected from 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are each optional; R 61 substituted by 1 or 2 substituents independently selected from: Each R 61 are independently phenyl, 5- to 6-membered heteroaryl, and C(O)R b61 Selected from; Each R 70is selected from phenyl, 5-6 membered heteroaryl, and CN; Each R a3 independently, C 1-3 alkyl, and phenyl; 1-3 Alkyl and phenyl are each optional, R 30 substituted by 1 or 2 substituents independently selected from: Each R a7 is C 1-3 alkyl; 1-3 Alkyl is optional, R 70 substituted by 1 or 2 substituents independently selected from: Each R a10 , R c10 and R d10 is H; Each R a11 is H; R b20 is NH2, C 1-3 Alkyl, C 3-6 cycloalkyl, and 5-6 membered heteroaryl; 1-3 Alkyl, C 3-6 Cycloalkyl and 5-6 membered heteroaryl are each optional, and R 21 substituted by 1 or 2 substituents independently selected from: Each R c30 and R d30 are independently H and C 1-3 alkyl; Each R b60 , R c60 and R d60 are independently H and C 1-3 alkyl; 1-3 Alkyl is optional, R 61 substituted by 1 or 2 substituents independently 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, R 61 forming a 6- or 9-membered heterocycloalkyl group optionally substituted with 1 or 2 substituents independently selected from: Each R b61 is C 1-3 is alkyl; and Each R g is CN.

[0015] In one embodiment, [ka] Ha-NR 5 In another embodiment, [ka] is -N=N-. In yet another embodiment, [ka] is -N=CR 6 -It is.

[0016] In one embodiment, R 1 is H and C 1-2 alkyl; 1-2 Alkyl is optional, R 11 In another embodiment, R 1 is H and C 1-2 In yet another embodiment, R 1 is H.

[0017] In one embodiment, Cy 1 is C 3-10 Cycloalkyl, C 6-10 selected from aryl and 6-10 membered heteroaryl; the 6-10 membered heteroaryl having at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; the ring-forming carbon atoms of the 6-10 membered heteroaryl are optionally substituted by oxo to form a carbonyl group; C 3-10 Cycloalkyl, C 6-10 The aryl and 6- to 10-membered heteroaryl are each optional, and R 10is substituted with 1, 2, or 3 substituents independently selected from

[0018] In another embodiment, Cy 1 is C 6-10 selected from aryl and 6-10 membered heteroaryl; the 6-10 membered heteroaryl having at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; the ring-forming carbon atoms of the 6-10 membered heteroaryl are optionally substituted by oxo to form a carbonyl group; C 6-10 The aryl and 6- to 10-membered heteroaryl are each optional, and R 10 is substituted with 1, 2, or 3 substituents independently selected from

[0019] In yet another embodiment, Cy 1 is C 3-10 is selected from cycloalkyl, phenyl, and 6-10 membered heteroaryl; the 6-10 membered heteroaryl has at least one ring-forming carbon atom and one or two ring-forming heteroatoms independently selected from N, O, and S; 3-10 Cycloalkyl, phenyl and 6-10 membered heteroaryl are each optional; R 10 is substituted with 1, 2 or 3 substituents independently selected from:

[0020] In yet another embodiment, Cy 1 is selected from phenyl or 6-10 membered heteroaryl; the 6-10 membered heteroaryl has at least one ring-forming carbon atom and one or two ring-forming heteroatoms independently selected from N, O, and S; each phenyl or 6-10 membered heteroaryl is optionally selected from R 10 is substituted with 1, 2 or 3 substituents independently selected from:

[0021] In one embodiment, Cy 1 teeth, [ka] is selected from.

[0022] In another embodiment, Cy 1 Cy 1 -a and Cy 1 In yet another embodiment, Cy 1 Cy 1 In yet another embodiment, Cy 1 Cy 1 In one embodiment, Cy 1 Cy 1 -c.

[0023] In another embodiment, R 4 is C 1-3 Alkyl, C 1-3 Haloalkyl, 5-10 membered heteroaryl, and OR a3 C is selected from 1-3 The alkyl and 5- to 10-membered heteroaryl are each optional. 30 or R 4 teeth, [ka] is selected from.

[0024] In another embodiment, R 4 is H, C 1-3 Alkyl, C 1-3 haloalkyl, and 5-10 membered heteroaryl; 1-3 The alkyl and 5- to 10-membered heteroaryl are each optional. 30 or R 4 is R 4 -a, R 4 -b and R 4 -c is selected.

[0025] In yet another embodiment, R 4 is H, C 1-3 Alkyl, C 1-3 Haloalkyl, 5-10 membered heteroaryl, OR a3, and NR c3 R j3 C is selected from 1-3 The alkyl and 5- to 10-membered heteroaryl are each optional, and R 30 is substituted with one or two substituents independently selected from

[0026] In yet another embodiment, R 4 is C 1-3 Alkyl, 5-10 membered heteroaryl, and OR a3 C is selected from 1-3 The alkyl and 5- to 10-membered heteroaryl are each optional. 30 is substituted with one or two substituents independently selected from

[0027] In one embodiment, R 4 is C 1-3 alkyl and 5-10 membered heteroaryl; 1-3 The alkyl and 5- to 10-membered heteroaryl are each optional. 30 In another embodiment, R 4 is OR a3 is.

[0028] In yet another embodiment, R 4 teeth, [ka] is selected from.

[0029] In one embodiment, R 4 is R 4 -c.

[0030] In another embodiment, R 7 is phenyl, 5-6 membered heteroaryl, F, Cl, CN, OR a7 , and NR c7 R d7 wherein each of the phenyl and 5- to 6-membered heteroaryl is optionally selected from R 70is substituted with one or two substituents independently selected from

[0031] In yet another embodiment, R 7 is phenyl, 5-6 membered heteroaryl, F, and OR a7 wherein each of the phenyl and 5- to 6-membered heteroaryl is optionally selected from R 70 In yet another embodiment, R 7 is F.

[0032] In another embodiment, Cy 2 Cy 2 In one embodiment, Cy 2 Cy 2 -b.

[0033] In one embodiment, Cy 2 Cy 2 -a, and [ka] -N=CR 6 -If R 6 is selected from 4-6 membered heterocycloalkyl, phenyl, and 5-10 membered heteroaryl; 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-10 membered heteroaryl are each optional; R 60 In another embodiment, Cy is substituted with one or two substituents independently selected from 2 Cy 2 -a, and [ka] -N=CR 6 -If R 6 H, D, C 1-3 Alkyl and C 1-3 haloalkyl; 1-3 Alkyl is optional, R 60 is substituted by one or two substituents independently selected from:

[0034] In yet another embodiment, Cy 2 Cy 2 -a, and [ka] -N=CR 6 -If R 6 is H and C 1-3 alkyl; 1-3 Alkyl is optional, R 60 In yet another embodiment, Cy is substituted with one or two substituents independently selected from 2 Cy 2 -a, [ka] -N=CR 6 -If R 6 is H.

[0035] In one embodiment, Cy 2 Cy 2 -b, and [ka] -N=CR 6 -If R 6 is C 1-3 Alkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl; 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl are each optional; R 60 is substituted with one or two substituents independently selected from

[0036] In another embodiment, Cy 2 Cy 2 -b, and [ka] -N=CR 6 -If R 6 is C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-10 membered heteroaryl; 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-10 membered heteroaryl are each optional; R 60 is substituted with one or two substituents independently selected from

[0037] In yet another embodiment, Cy 2 Cy 2 -b, and [ka] -N=CR 6 -If R 6 is C 1-3 Alkyl and C 1-3 haloalkyl; 1-3 Alkyl is optional, R 60 is substituted with one or two substituents independently selected from

[0038] In yet another embodiment, Cy 2 Cy 2 -b, and [ka] -N=CR 6 -If R 6 is C 1-3 alkyl; 1-3 Alkyl is optional, R 60か and substituted with one or two substituents independently selected from:

[0039] In one embodiment, Cy 2 Cy 2 -b, and [ka] -N=CR 6-If R 6 is selected from -CH2CH2C(O)NMe2 and -CH2CH3. In another embodiment, Cy 2 Cy 2 -If a, R 2 is H, C 1-2 Alkyl, C 1-2 In yet another embodiment, Cy is selected from haloalkyl, F, Cl, and —CH2CH2CN. 2 Cy 2 -If a, R 2 is H, C 1-2 In yet another embodiment, Cy is selected from alkyl, and -CH2CH2CN. 2 Cy 2 -If a, R 2 is C 1-2 is selected from haloalkyl, F, and Cl.

[0040] In one embodiment, Cy 2 Cy 2 -If a, R 2 is selected from F and Cl. In another embodiment, Cy 2 Cy 2 -If a, R 2 is Cl.

[0041] In yet another embodiment, Cy 2 Cy 2 -b, then R 2 is H, C 1-2 Alkyl, -CH2CH2CN, [ka] is selected from.

[0042] In one embodiment, Cy 2 Cy 2 -b, then R 2 is R 2 -a, R 2 -b, R 2 -c, R 2 -d, and R 2 In another embodiment, Cy2 Cy 2 -b, then R 2 is H, C 1-2 Alkyl, -CH2CH2CN, R 2 -a, R 2 -b and R 2 In yet another embodiment, Cy 2 Cy 2 -b, then R 2 is H, C 1-2 In yet another embodiment, Cy is selected from alkyl, and -CH2CH2CN. 2 Cy 2 -b, then R 2 is -CH2CH2CN.

[0043] In one embodiment, each R 10 independently, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, halo, D, CN, OR a10 , C(O)NR c10 R d10 , N.R. c10 C(O)OR a10 , N.R. c10 C(O)NR c10 R d10 , and NR c10 R d10 C is selected from 1-3 Alkyl and C 3-6 Each cycloalkyl is optional, R g In another embodiment, each R 10 independently, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, halo, CN, OR a10 , C(O)NR c10 R d10 , and NR c10 R d10 C is selected from 1-3 Alkyl and C 3-6 Each cycloalkyl is optional, R gis substituted with one or two substituents independently selected from

[0044] In yet another embodiment, each R 10 independently, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, halo, CN, OR a10 , and NR c10 R d10 C is selected from 1-3 Alkyl and C 3-6 Each cycloalkyl is optional, R g is substituted with one or two substituents independently selected from

[0045] In yet another embodiment, each R 11 are independently 4-6 membered heterocycloalkyl, halo, CN, and OR a11 wherein said 4-6 membered heterocycloalkyl is optionally selected from R g is substituted with one or two substituents independently selected from

[0046] In one embodiment, each R 11 are independently 4-6 membered heterocycloalkyl and OR a11 wherein said 4-6 membered heterocycloalkyl is optionally selected from R g is substituted with one or two substituents independently selected from

[0047] In another embodiment, each R 21 independently, C 1-3 Alkyl, C 1-3 Haloalkyl, Halo, CN, OR a21 , and NR c21 R d21 In yet another embodiment, each R 21 are independently halo, CN, and OR a21 In yet another embodiment, each R 21 is independently selected from halo, and CN. In one embodiment, each R 21 is CN.

[0048] In one embodiment, each R 30 independently, C 1-3 Alkyl, C 1-3 Haloalkyl, 4-10 membered heterocycloalkyl, halo, CN, OR a30 , C(O)NR c30 R d30 , and NR c30 R d30 C is selected from 1-3 The alkyl and 4- to 6-membered heterocycloalkyl are each optional. 31 In another embodiment, each R 30 are independently 4-10 membered heterocycloalkyl, and C(O)NR c30 R d30 wherein said 4-6 membered heterocycloalkyl is optionally selected from R 31 is substituted with one or two substituents independently selected from

[0049] In yet another embodiment, each R 31 independently, C 1-3 Alkyl, C 1-3 In yet another embodiment, each R is selected from haloalkyl, halo, and CN. 31 independently, C 1-3 Alkyl, and C 1-3 haloalkyl.

[0050] In one embodiment, each R 60 independently, C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C(O)R b60 , C(O)NR c60 R d60 , and NR c60 R d60 C is selected from 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are each optional; R 61 is substituted with one or two substituents independently selected from

[0051] In another embodiment, each R 60 independently, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl; 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are each optional; R 61 is substituted with one or two substituents independently selected from

[0052] In yet another embodiment, each R 60 independently, C 1-3 Alkyl, C 1-3 Haloalkyl, Halo, D, CN, OR a60 , C(O)R b60 , C(O)NR c60 R d60 , and NR c60 R d60 C is selected from 1-3 Alkyl is optional, R 61 is substituted with one or two substituents independently selected from

[0053] In yet another embodiment, each R 60 independently, C 1-3 Alkyl, C(O)NR c60 R d60 , and NR c60 R d60 C is selected from 1-3 Alkyl is optional, R 61 is substituted with one or two substituents independently selected from

[0054] In one embodiment, each R 61 independently, C 1-3 Alkyl, C 1-3 Haloalkyl, phenyl, 5-6 membered heteroaryl, halo, CN, OR a61 , C(O)R b61 , and NR c61 R d61 In another embodiment, each R 61are independently phenyl, 5- to 6-membered heteroaryl, and C(O)R b61 is selected from.

[0055] In yet another embodiment, each R 70 independently, C 1-3 Alkyl, C 1-3 In yet another embodiment, each R is selected from haloalkyl, phenyl, 5-6 membered heteroaryl, halo, and CN. 70 is independently selected from phenyl, 5-6 membered heteroaryl, and CN.

[0056] In one embodiment, each R g are independently OH, CN, halo, and C 1-2 In one embodiment, each R g is independently selected from OH, CN, and halo. g is CN.

[0057] In yet another embodiment, each R a3 are independently H, C 1-3 Alkyl, C 1-3 haloalkyl, 5-6 membered heteroaryl, and phenyl; 1-3 Alkyl, 5-6 membered heteroaryl, and phenyl are each optional; R 30 is substituted with one or two substituents independently selected from

[0058] In yet another embodiment, each R a3 are independently H, C 1-3 Alkyl, and C 1-3 haloalkyl; 1-3 Alkyl is optional, R 30 is substituted with one or two substituents independently selected from

[0059] In one embodiment, each R a3 independently, C 1-3 alkyl; 1-3 Alkyl is optional, R 30is substituted with one or two substituents independently selected from

[0060] In another embodiment, R b20 is NH2, C 1-3 Alkyl, C 3-6 cycloalkyl, and 5-6 membered heteroaryl; 1-3 Alkyl, C 3-6 Cycloalkyl and 5-6 membered heteroaryl are each optional, and R 21 In yet another embodiment, R b20 is NH2, C 1-3 Alkyl and C 1-3 haloalkyl; 1-3 Alkyl is optional, R 21 In yet another embodiment, R b20 is NH2 and C 1-3 alkyl; 1-3 Alkyl is optional, R 21 is substituted with one or two substituents independently selected from

[0061] In one embodiment, each R b60 , R c60 and R d60 are independently H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl; 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are each optional; R 61 or any R bonded to the same N atom c60 and R d60 together with the N atom to which they are attached, R 61and forming a 4-, 5-, 6-, 7-, 8-, or 9-membered heterocycloalkyl group optionally substituted with 1 or 2 substituents independently selected from:

[0062] In another embodiment, each R b60 , R c60 , and R d60 are independently H, C 1-3 Alkyl, and C 1-3 haloalkyl; 1-3 Alkyl is optional, R 61 or any R bonded to the same N atom c60 and R d60 together with the N atom to which they are attached, R 61 and forming a 4-, 5-, 6-, or 9-membered heterocycloalkyl group optionally substituted with 1 or 2 substituents independently selected from:

[0063] In yet another embodiment, each R b60 , R c60 , and R d60 are independently H and C 1-3 alkyl; 1-3 Alkyl is optional, R 61 or any R bonded to the same N atom c60 and R d60 together with the N atom to which they are attached, R 61 and forming a 6- or 9-membered heterocycloalkyl group optionally substituted with 1 or 2 substituents independently selected from:

[0064] In yet another embodiment, the compound of formula I is: 1-(3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-8-methyl-1H-imidazo[4,5-c]quinolin-2-yl)piperidin-1-yl)ethan-1-one; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-8-methyl-1H-imidazo[4,5-c]quinolin-2-yl)-1-(4-(pyrimidin-2-yl)piperazin-1-yl)propan-1-one; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(3-oxo-3-(7-oxa-2-azaspiro[3.5]nonan-2-yl)propyl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 3-(2-(3-(4-acetylpiperazin-1-yl)-3-oxopropyl)-1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 4-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-2-ethyl-6-fluoro-8-(oxazol-5-yl)-1H-imidazo[4,5-c]quinolin-7-yl)naphthalen-2-ol; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-8-yl)-3-(1H-pyrazol-1-yl)propanenitrile; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-8-yl)-3-(4-(hydroxymethyl)-1H-pyrazol-1-yl)propanenitrile; 3-(8-((1H-pyrazol-1-yl)methyl)-1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-dimethylpropanamide; 3-(1-(2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichloro-6-hydroxyphenyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-dimethylpropanamide; 3-(1-(2-azabicyclo[2.1.1]hexan-5-yl)-7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-dimethylpropanamide; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-6-(3-cyanophenyl)-4-(3-(dimethylamino)azetidin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-dimethylpropanamide; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-4-(3-(dimethylamino)azetidin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-6-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-dimethylpropanamide; 3-(6-(benzyloxy)-1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-4-(3-(dimethylamino)azetidin-1-yl)-7-(7-fluoronaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-dimethylpropanamide; 3-(1-((endo)2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-9-(hydroxymethyl)-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-dimethylpropanamide; 3-(1-((endo)2-azabicyclo[2.1.1]hexan-5-yl)-9-((3-cyanopyrrolidin-1-yl)methyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-dimethylpropanamide; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-4-yl)-4-fluoro-N-methylbenzamide; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-ethyl-4-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 5-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-4-yl)-N-methylpicolinamide; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-4-(oxazol-2-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 3-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-4-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-4-methyl-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-4-phenoxy-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-cyclopropyl-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-(1-cyclobutyl-1H-1,2,3-triazol-4-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-4-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 3-(1-(2-azabicyclo[2.1.1]hexan-5-yl)-2-ethyl-6-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(5-methyl-1H-indol-3-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 4-((1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(2-(methylamino)ethyl)-1H-imidazo[4,5-c]quinolin-8-yl)methyl)benzonitrile; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-ethyl-6-fluoro-7-(5-fluoro-1H-indol-3-yl)-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 3-(7-(3-aminoisoquinolin-1-yl)-1-endo-(2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-dimethylpropanamide; 3-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-1-endo-(2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-dimethylpropanamide; 3-(1-endo-(2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(7,7-difluoro-5,6,7,8-tetrahydronaphthalen-1-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-dimethylpropanamide; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(1-phenyl-1H-pyrazol-3-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-2-(1-ethyl-1H-pyrazol-3-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 3-(2-(1-benzyl-1H-pyrazol-3-yl)-1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(2-(pyrimidin-2-yl)ethyl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; (3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(1H-indazol-5-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 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-imidazo[4,5-c]quinolin-7-yl)-1-naphthonitrile; 8-(8-chloro-1-((2S,4S)-1-(2-cyanoacetyl)-2-(cyanomethyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-imidazo[4,5-c]quinolin-7-yl)-1-naphthonitrile; 8-(8-chloro-1-((2S,4S)-2-(cyanomethyl)-1-(1H-1,2,4-triazole-3-carbonyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-imidazo[4,5-c]quinolin-7-yl)-1-naphthonitrile; (2S,4S)-4-(8-chloro-7-(8-cyanonaphthalen-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-imidazo[4,5-c]quinolin-1-yl)-2-(cyanomethyl)piperidine-1-carboxamide; 8-(8-chloro-1-((2S,4S)-2-(cyanomethyl)-1-(cyclopropanecarbonyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-imidazo[4,5-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-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-1-naphthonitrile; and 8-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-7-yl)-1-naphthonitrile; or a pharmaceutically acceptable salt thereof.

[0065] In another embodiment, the compound of formula I is: 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-4-phenoxy-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-(1-cyclobutyl-1H-1,2,3-triazol-4-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-4-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 3-(1-(2-azabicyclo[2.1.1]hexan-5-yl)-2-ethyl-6-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(5-methyl-1H-indol-3-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-ethyl-6-fluoro-7-(5-fluoro-1H-indol-3-yl)-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 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-imidazo[4,5-c]quinolin-7-yl)-1-naphthonitrile; 8-(8-chloro-1-((2S,4S)-1-(2-cyanoacetyl)-2-(cyanomethyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-imidazo[4,5-c]quinolin-7-yl)-1-naphthonitrile; 8-(8-chloro-1-((2S,4S)-2-(cyanomethyl)-1-(1H-1,2,4-triazole-3-carbonyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-imidazo[4,5-c]quinolin-7-yl)-1-naphthonitrile; (2S,4S)-4-(8-chloro-7-(8-cyanonaphthalen-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-imidazo[4,5-c]quinolin-1-yl)-2-(cyanomethyl)piperidine-1-carboxamide; 8-(8-chloro-1-((2S,4S)-2-(cyanomethyl)-1-(cyclopropanecarbonyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-imidazo[4,5-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-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-1-naphthonitrile; and 8-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-7-yl)-1-naphthonitrile; or a pharmaceutically acceptable salt thereof.

[0066] 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 embodiments of compounds of Formula I, as described features, can be combined in any suitable combination.

[0067] At various places in the present specification, certain features 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 (without limitation) disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0068] The term "n-membered ring," 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.

[0069] At various places herein, 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 - is -NR(CR'R") n -and-(CR'R") n It is intended that both NR- and NR- are included, and each form is disclosed individually. If a structure requires a linking group, the Markush variable listed for 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 includes "alkyl" or "aryl," it is understood that "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively.

[0070] 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, if 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.

[0071] "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:

[0072] 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 substituted at the point where the alkyl group is attached 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, and 1,2,2-trimethylpropyl.

[0073] The term "alkenyl," employed alone or in combination with other terms, refers to a straight- or branched-chain hydrocarbon group corresponding to an alkyl group having one or more double carbon-carbon bonds. An alkenyl group formally corresponds to an alkene in which one C-H bond is replaced at the point where the alkenyl group is attached to the remainder of the compound. n-m The term "alkenyl" refers to an alkenyl group having n to m carbons. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Exemplary alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

[0074] The term "alkynyl," employed alone or in combination with other terms, refers to a straight- or branched-chain hydrocarbon group corresponding to an alkyl group having one or more triple carbon-carbon bonds. An alkynyl group formally corresponds to an alkyne in which one C-H bond is replaced at the point where the alkyl group is attached to the remainder of the compound. n-m The term "alkynyl" refers to an alkynyl group having n to m carbons. Exemplary alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0075] 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 with two C-H bonds substituted at the points where the alkylene group is attached 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.

[0076] 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, the alkyl group of which 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 Dialkyloxy 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 bonded to the same B atom to form a 5- or 6-membered heterocycloalkyl group.

[0077] The term "alkylthio", employed alone or in combination with other terms, refers to a radical of the formula --S-alkyl, wherein the alkyl radical is as defined above.

[0078] The term "amino," employed alone or in combination with other terms, refers to a group of formula -NH, wherein the hydrogen atom may be replaced with a substituent described herein. For example, "alkylamino" can refer to both -NH(alkyl) and -N(alkyl).

[0079] The term "carbonyl," employed alone or in combination with other terms, refers to a -C(=O)- group, which may also be written as C(O).

[0080] The term "cyano" or "nitrile" refers to a group of formula -C≡N, which may also be written as -CN.

[0081] The term "carbamyl," as used herein, refers to the group -NHC(O)O- or -OC(O)NH- in which the carbon atom is double-bonded to one oxygen atom and single-bonded to the nitrogen and second oxygen atoms.

[0082] 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.

[0083] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms has been replaced with 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. Exemplary haloalkyl groups include CF, C2F5, CHF2, CH2F, CCl3, CHCl2, C2Cl5, and the like. In some embodiments, the haloalkyl group is a fluoroalkyl group.

[0084] The term "haloalkoxy," employed alone or in combination with other terms, refers to a radical of the formula -O-haloalkyl, wherein the 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.

[0085] The terms "oxo" or "oxy" refer to a divalent oxygen atom that forms a carbonyl group when attached to 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.

[0086] The term "sulfide" refers to a divalent sulfur atom which, when attached to carbon, forms a thiocarbonyl group (C=S).

[0087] The term "sulfonyl" refers to the group -SO2- in which the sulfur atom is double bonded to two oxygen atoms.

[0088] The term "oxidized" in reference to a ring-forming N atom refers to a ring-forming N-oxide.

[0089] The term "oxidized" with respect to a ring-forming S atom refers to a ring-forming sulfonyl or ring-forming sulfinyl.

[0090] The term "aromatic" refers to a carbocyclic or heterocyclic ring having one or more polyunsaturated rings with aromatic character (i.e., having (4n+2) delocalized (pi) electrons, where n is an integer).

[0091] The term "aryl," employed alone or in combination with other terms, refers to an aromatic hydrocarbon group that may be monocyclic or polycyclic (e.g., having two fused rings). n-m The term "aryl" refers to an aryl group having n to m ring carbon atoms. Examples of aryl groups include phenyl, 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.

[0092] 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 5-14 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 5-10 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 5-6 ring atoms independently selected from nitrogen, sulfur, and oxygen and 1 or 2 heteroatom ring members. In some embodiments, heteroaryl is a 5- or 6-membered heteroaryl ring. In other embodiments, heteroaryl is an 8-, 9-, or 10-membered fused bicyclic heteroaryl ring. Examples of 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 (eg, 2-pyridone).

[0093] 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.

[0094] A 6-membered heteroaryl ring is a heteroaryl group having 6 ring atoms, where one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary 6-membered heteroaryls include pyridyl, pyrazinyl, pyrimidinyl, triazinyl, isoindolyl, and pyridazinyl.

[0095] 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 3-6 ring members, 3-5 ring members, or 3-4 ring members. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is C 3-6Monocyclic 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, cyclohexane, etc. 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.

[0096] The term "heterocycloalkyl," employed alone or in combination with other terms, refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene groups as part of the ring structure, has at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen, and phosphorus, and has 4-10 ring members, 4-7 ring members, or 4-6 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 linkages (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 zero to three double bonds. In some embodiments, a heterocycloalkyl group contains zero to two 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.

[0097] 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.

[0098] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise specified. 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.

[0099] 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 are optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or the D- and L-forms of various optically active camphorsulfonic acids, such as -camphorsulfonic acid. Other resolving agents suitable for fractional crystallization include stereomerically pure forms (e.g., S- and R-forms, or diastereomerically pure forms) of -methylbenzylamine, 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

[0100] 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.

[0101] 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.

[0102] 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. Exemplary 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 on 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 fixed into one form by appropriate substitution.

[0103] 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 that atom at 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 (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.

[0104] Substitution with heavier isotopes, such as deuterium, may confer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, 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).

[0105] The term "compound," as used herein, is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. This term is also meant to refer to compounds of the present invention regardless of how they are prepared, for example, synthetically, through a biological process (e.g., metabolic or enzymatic transformation), or through a combination thereof.

[0106] All compounds and pharmaceutically acceptable salts thereof 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 and salts thereof described herein 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 salts thereof should be understood to encompass any solid form of the compound.

[0107] 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.

[0108] The phrase "pharmaceutically acceptable" is employed 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, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0109] The expressions "ambient temperature" and "room temperature" as used herein are understood in the art and generally refer to a temperature approaching the temperature of the room in which the reaction is carried out, e.g., from about 20°C to about 30°C, e.g., the reaction temperature.

[0110] 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, and the like. 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.

[0111] synthesis The compounds of the present invention (including salts thereof) may be prepared using known organic synthesis techniques, or may be synthesized according to any of a number of possible synthetic routes, such as those in the following schemes.

[0112] 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.A suitable solvent can be substantially non-reactive with the starting material (reactant), intermediate or product 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, a suitable solvent for a specific reaction step can be selected by those skilled in the art.

[0113] The preparation of the 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 those skilled in the art. The chemistry of protecting groups is described, 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, 6th Ed. (Wiley, 2007); Peturssion et al., "Protecting Groups in Carbohydrate Chemistry," J. Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groups in Organic Synthesis, 4th Ed. (Wiley, 2006).

[0114] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as 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).

[0115] 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.

[0116] Scheme 1 [ka] Compounds of formulas 1-16 can be prepared via the synthetic route outlined in Scheme 1. Starting material 1-1 (Hal is a halide such as F, Cl, Br, or I) can be halogenated with a suitable reagent such as N-chlorosuccinimide (NCS) to give intermediate 1-2 (Hal is a halide such as F, Cl, Br, or I). Compound 1-3 can be prepared by treating 1-2 with a reagent such as triphosgene. Intermediate 1-3 can then be reacted with ester 1-4 to give nitro compound 1-5, which can be treated with a suitable reagent (e.g., POCl) to give compound 1-6. Scheme 14 of intermediate 1-6 can be prepared by Scheme 14 of amine 1-7 (PG is a suitable protecting group such as Boc). N Ar reaction to give compounds 1-8, followed by S NAr reaction can be carried out to give 1-9. The nitro group in 1-9 can be reduced to NH in the presence of a reducing agent (e.g., Fe in acetic acid or sodium dithionite). Cross-coupling reaction with 1-11, where M is a boronic acid, boronic ester, or appropriately substituted metal or metalloid (e.g., M is B(OR)2, Sn(alkyl)3, Zn-Hal, or CF3TMS), under standard Suzuki cross-coupling conditions (e.g., in the presence of a palladium catalyst and a suitable base), or under standard Stille cross-coupling conditions (e.g., in the presence of a palladium catalyst), or under standard Negishi cross-coupling conditions (e.g., in the presence of a palladium catalyst), or under trifluoromethylation conditions (e.g., in the presence of a copper catalyst), generates 1-12. Intermediate 1-14 can be prepared by a cross-coupling reaction between 1-12 and an adduct of formula 1-13 (wherein 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 under standard Stille cross-coupling conditions (e.g., in the presence of a palladium catalyst), or under standard Negishi cross-coupling conditions (e.g., in the presence of a palladium catalyst). Intermediate 1-14 can then undergo a cyclization reaction (e.g., using triethyl orthoformate) to yield intermediate 1-15. Removal of the protecting group in 1-15 affords the desired product 1-16. The sequence of the above chemical reactions can be rearranged or omitted as appropriate to prepare different analogs.

[0117] Scheme 2 [ka] Compounds of formula 2-6 can be prepared via the synthetic route outlined in Scheme 2. Cyclization of starting material 1-14 with an appropriate ester bearing aldehyde 2-1 gives intermediate 2-2, which can be converted to acid 2-3 by saponification. Coupling with amine 2-4 under standard amide coupling conditions (e.g., in the presence of HATU and a suitable base) gives 2-5. Removal of the protecting group on 2-5 gives the desired product 2-6. The above chemical reaction sequence can be rearranged or omitted as appropriate to suit the preparation of different analogs.

[0118] Scheme 3 [ka] Alternatively, compounds of formula 3-5 can be prepared via the synthetic route outlined in Scheme 3. Condensation of starting material 1-14 with a suitable leaving group-substituted triethyl orthoformate 3-1 (e.g., 2-chloro-1,1,1-triethoxyethane) provides intermediate 3-2. Displacement of the leaving group in 3-2 with nucleophile 3-3 in the presence of a suitable base provides 3-4. Removal of the protecting group in 3-4 provides the desired product 3-5. The sequence of the above chemical reactions can be rearranged or omitted as appropriate to prepare different analogs.

[0119] Scheme 4 [ka] Compounds of formula 4-7 can be prepared via the synthetic route outlined in Scheme 4. Coupling of starting material 1-10 with acrylonitrile under standard Heck reaction conditions (e.g., in the presence of a palladium catalyst and a suitable base) provides intermediate 4-1. Cross-coupling with 4-2, 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 under standard Stille cross-coupling conditions (e.g., in the presence of a palladium catalyst), or under standard Negishi cross-coupling conditions (e.g., in the presence of a palladium catalyst) provides 4-3. Intermediate 4-3 can then undergo a cyclization reaction (e.g., using triethyl orthoformate) to give intermediate 4-4. Michael addition of nucleophile 4-5 to the olefin in 4-4 with the aid of a suitable base can provide 4-6. Removal of the protecting groups in 1-15 gives the desired products 1-16. The sequence of the chemical reactions described above can be rearranged or omitted as appropriate to suit the preparation of different analogs.

[0120] Scheme 5 [ka] Compounds of formula 5-17 can be prepared according to the synthetic route in Scheme 5. Starting material 5-1 can be acylated with ethyl malonyl chloride, followed by hydrolysis of the ester group in the presence of a suitable base such as LiOH, to produce intermediate 5-2. Compound 5-3 can be prepared by treating 5-2 with a dehydrating reagent, such as Eaton's reagent or polyphosphoric acid (PPA). Nitration of 5-3 with nitric acid in acetic acid can give the nitro-containing compound 5-4, which can be treated with a suitable reagent (e.g., POCl3) to give compound 5-5. Scheme 5 shows the reaction of intermediate 5-5 with amine 5-6 (PG is a suitable protecting group such as Boc). N Ar reaction to give compounds 5-7, followed by a second SN An Ar reaction can be carried out to give 5-8. Compound 5-10 can be prepared by cross-coupling with a vinylmetal reagent of formula 5-9, where M is a hydrogen atom, a boronic acid, a boronate ester, or an appropriately substituted metal or metalloid (e.g., M is B(OR)2, Sn(alkyl)3, or Zn-Hal), under standard Heck reaction conditions (e.g., in the presence of a palladium catalyst), or 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 nitro group in 5-10 can be reduced to NH2 in the presence of a reducing agent (e.g., Fe or sodium dithionite) to give intermediate 5-11, which can undergo cyclization with aldehyde 5-12 or a suitable surrogate (e.g., triethyl orthoformate) to give intermediate 5-13. Cross-coupling reaction between 5-13 and an adduct of formula 5-14, 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 under standard Stille cross-coupling conditions (e.g., in the presence of a palladium catalyst), or under standard Negishi cross-coupling conditions (e.g., in the presence of a palladium catalyst), can produce compound 5-15. The double bond in 5-15 can be reduced with a reducing agent (e.g., palladium on carbon under a hydrogen atmosphere or lithium borohydride) or oxidatively cleaved with an oxidizing agent (e.g., NaIO4 with a catalytic amount of OsO4) to the aldehyde, followed by reduction to the alcohol or conversion to the amine under standard reductive amination conditions, gives compound 5-16. Removal of the protecting group in 5-16 gives the desired product 5-17. The sequence of the chemical reactions described above may be rearranged or omitted as appropriate to suit the preparation of different analogs.

[0121] Scheme 6 [ka] Alternatively, compounds of formula 6-8 can be prepared via the synthetic route outlined in Scheme 6. Thioether 1-9a (as prepared in Scheme 1, R 4 where M is SMe) can undergo nitro reduction to NH in the presence of a reducing agent (e.g., Fe in acetic acid or sodium dithionite). Intermediate 6-1 can undergo cyclization (e.g., using triethyl orthoformate or an appropriate aldehyde) to provide tricycle 6-2. Subsequent coupling with an adduct of formula 1-11, 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 under standard Stille cross-coupling conditions (e.g., in the presence of a palladium catalyst), or under standard Negishi cross-coupling conditions (e.g., in the presence of a palladium catalyst), provides compounds of formula 6-4. Alternatively, the appropriate alkene R* can be reacted with an alkene R* under standard Heck conditions (e.g., in the presence of a palladium catalyst and a base) or reductive Heck conditions (e.g., in the presence of a palladium catalyst and a hydride source). 2 Coupling with (6-3) also provides compounds of formula 6-4. Intermediate 6-4 can then be cross-coupled to the adduct Cy, 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 under standard Stille cross-coupling conditions (e.g., in the presence of a palladium catalyst), or under standard Negishi cross-coupling conditions (e.g., in the presence of a palladium catalyst). 1The thioether moiety of compound 6-5 can then be coupled with methyl boronic acid ester (M(1-13)) under standard Liebeskind-Srogl conditions (in the presence of a palladium catalyst and a copper(I) source) to afford compounds of formula R, where M is a boronic acid, boronic ester, or appropriately substituted metal (e.g., M is B(OR)2, Sn(alkyl)3, Mg-Hal, or Zn-Hal). 4 Alternatively, the desired compounds 6-7 can be prepared by a two-step protocol, in which the aryl thioether 6-5 is oxidized to the corresponding sulfoxide or sulfone with a suitable oxidizing agent (e.g., m-CPBA), followed by S N In Ar reactions, the appropriate R 4 The -H is replaced by a nucleophile. Finally, the title compounds 6-8 can be prepared by removing the protecting groups. The above chemical reaction sequence can be rearranged as appropriate to prepare different analogs.

[0122] 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: 85% of all RAS mutations are 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 (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 / codons 12, 13, and 61; codon 12 mutations are most frequent in KRAS. The frequency of specific mutations that vary 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 expressing 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; therefore, the development of inhibitors targeting mutant KRAS may be useful in the clinical treatment of diseases characterized by KRAS mutations.

[0123] How to use Cancer types involving KRAS harboring G12C, G12V, and G12D mutations include, but are not limited to, carcinomas (e.g., pancreatic, colon, lung, bladder, stomach, esophagus, breast, head and neck, cervical skin, thyroid); hematopoietic malignancies (e.g., myeloproliferative neoplasms (MPNs), 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 are found in immunological and inflammatory disorders (Fernandez-Medarde, A. et al. Genes & Cancer, (2011): 344-358), such as Ras-associated lymphoproliferative disorder (RALD) or juvenile myelomonocytic leukemia (JMML), which are caused by somatic mutations in KRAS or NRAS.

[0124] The compounds of the present disclosure can inhibit the activity of KRAS protein.For example, the compounds of the present disclosure can be used to inhibit the activity of KRAS in cells or individuals or patients that require enzyme inhibition by administering an inhibitory amount of one or more compounds of the present disclosure to cells, individuals or patients.

[0125] 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 may be useful for inhibiting angiogenesis, thereby providing a means of preventing tumor growth or inducing apoptosis. 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 activating mutations of receptor tyrosine kinases or upregulated receptor tyrosine kinases may be particularly sensitive to inhibitors.

[0126] In one aspect, provided herein is a method of inhibiting KRAS activity, the method comprising contacting KRAS with a compound of the present disclosure. In one embodiment, the contacting comprises administering the compound to a patient.

[0127] In one aspect, provided herein is a method of inhibiting a KRAS protein harboring a G12C mutation, said method comprising contacting KRAS with a compound of the present disclosure.

[0128] In one aspect, provided herein is a method of inhibiting a KRAS protein harboring a G12D mutation, said method comprising contacting KRAS with a compound of the present disclosure.

[0129] In one aspect, provided herein is a method of inhibiting a KRAS protein harboring a G12V mutation, said method comprising contacting KRAS with a compound of the present disclosure.

[0130] In another aspect, provided herein is a method of treating a disease or disorder associated with inhibition of KRAS interaction, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any of the formulas disclosed herein, or a pharmaceutically acceptable salt thereof.

[0131] In yet another aspect, provided herein is a method for treating a disease or disorder associated with inhibiting a KRAS protein harboring a G12D mutation, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any of the formulas disclosed herein, or a pharmaceutically acceptable salt thereof.

[0132] In yet another aspect, 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 harboring a G12D mutation.

[0133] 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.

[0134] In one aspect, provided herein is a method of treating a disease or disorder associated with inhibition of KRAS interaction or a mutant form thereof in a patient in need thereof, 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.

[0135] 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.

[0136] 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, bronchial carcinoma, bronchial adenoma, chondromatous hamartoma, mesothelioma, pavicellular and non-pavicellular carcinoma, bronchial adenoma, and pleuropulmonary blastoma.

[0137] In yet another embodiment, the lung cancer is non-small cell lung cancer (NSCLC). In yet another embodiment, the lung cancer is adenocarcinoma.

[0138] 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.

[0139] In one embodiment, the gastrointestinal cancer is colon cancer.

[0140] 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.

[0141] 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.

[0142] In another embodiment, the cancer is a neoplasm. In yet another embodiment, the neoplasm is a glioblastoma or a sarcoma.

[0143] In certain embodiments, the present disclosure provides a method of treating a KRAS-mediated disorder in a patient in need thereof, the method comprising administering to the patient a compound of the present invention or a pharmaceutically acceptable composition thereof.

[0144] 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.

[0145] 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., These 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.

[0146] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdomyosarcoma, fibroma, lipoma, hamartoma, lymphosarcoma, leiomyosarcoma, and teratoma.

[0147] 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, pavicellular and non-pavicellular carcinoma, bronchial adenoma, and pleuropulmonary blastoma.

[0148] 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), colon carcinoma, gallbladder carcinoma, and anal carcinoma.

[0149] 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 testicles (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma), and urothelial carcinoma.

[0150] Exemplary liver cancers include hepatocarcinoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0151] 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.

[0152] 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 and Lhermitte-Dacros disease and pineal tumor.

[0153] 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).

[0154] 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.

[0155] Exemplary head and neck cancers include glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinoma, adenocarcinoma, oral cancer, laryngeal cancer, nasopharyngeal cancer, nasal and paranasal sinus cancer, thyroid and parathyroid cancer, eye tumors, lip tumors, and mouth and squamous cell head and neck cancers.

[0156] Compounds of the present disclosure may also be useful in inhibiting tumor metastasis.

[0157] In addition to oncogenic neoplasms, the compounds of the present invention are useful in 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 of treating patients suffering from skeletal and chondrocyte disorders.

[0158] In some embodiments, the compounds described herein can be used to treat Alzheimer's disease, HIV, or tuberculosis.

[0159] As used herein, the term "8p11 myeloproliferative syndrome" is meant to refer to myeloid / lymphoid neoplasms associated with eosinophilia and FGFR1 abnormalities.

[0160] As used herein, the term "cell" is meant to refer to a cell that is in vitro, ex vivo, or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism, such as a mammal. In some embodiments, an in vitro cell can be a cell in cell culture. In some embodiments, an in vivo cell is a cell that is living in an organism, such as a mammal.

[0161] As used herein, the term "contacting" refers to bringing the indicated moieties together in an in vitro or in vivo system. For example, "contacting" KRAS with a compound described herein includes administering a compound described herein to an individual or patient, such as a human, who has KRAS, as well as, for example, introducing a compound described herein into a sample containing a cell preparation or purified preparation containing KRAS.

[0162] 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, and most preferably a human.

[0163] 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 or salts thereof disclosed herein, that elicits the biological or medicinal response in a tissue, system, animal, individual, or human that is desired by a researcher, veterinarian, physician, or other clinician. An appropriate "effective" amount in any individual case may be determined using techniques known to those of ordinary skill in the art.

[0164] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problem or complication, and that are within the scope of safe medical judgment and commensurate with a reasonable benefit / risk ratio.

[0165] 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 excipient, diluent, solvent, or encapsulating material. The excipient or carrier is generally safe, non-toxic, and not biologically or otherwise undesirable, and includes 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.

[0166] 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 symptomology) in an individual experiencing or exhibiting the pathology or symptomology 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 symptomology) in an individual experiencing or exhibiting the pathology or symptomology of the disease, condition, or disorder, e.g., reducing the severity of the disease.

[0167] As used herein, the terms "prevent," "preventing," or "prevention" include the prevention of at least one symptom associated with or caused by the condition, disease, or disorder being prevented.

[0168] 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.

[0169] Combination therapy I. Cancer Therapy Cancer cell growth and survival can be affected by the dysfunction of multiple signaling pathways. Therefore, to treat such conditions, it is useful to combine different enzyme / protein / receptor inhibitors that exhibit different preferences for the targets they regulate. Targeting two or more signaling pathways (or two or more biomolecules involved in a given signaling pathway) may reduce the likelihood of drug resistance developing in a cell population and / or reduce the toxicity of treatment.

[0170] 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, such as those described in WO 2006 / 056399, may be used in combination with the compounds of the present disclosure to treat CDK2-related diseases, disorders, or conditions. Other agents, such as therapeutic antibodies, may be used in combination with the compounds of the present disclosure to treat CDK2-related diseases, disorders, or conditions. One or more additional pharmaceutical agents may be administered to a patient simultaneously or sequentially.

[0171] In some embodiments, the CDK2 inhibitor is administered or used in combination with a BCL2 inhibitor or a CDK4 / 6 inhibitor.

[0172] The compounds disclosed herein can be used in combination with one or more other enzyme / protein / receptor inhibitor therapies to treat 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 blood cancers. Examples of infectious diseases include viral infections, bacterial infections, fungal infections, or parasitic infections. For example, compounds of the present disclosure may be used to inhibit the following kinases: 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 (α, β, γ, δ, and multiple or selective), CSF1R, KIT, FLK-II, KDR / FLK- In some embodiments, the compounds of the present disclosure can be combined with one or more inhibitors of the following: 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 to treat 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 INCB05 4707), IDO inhibitors (e.g., epacadostat, NLG919, or BMS-986205, MK7162), LSD1 inhibitors (e.g., GSK2979552, INCB59872 or 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), such as HDAC8 inhibitors, angiogenesis inhibitors, interleukin receptor inhibitors, bromo- and extra-terminal family member inhibitors (e.g., bromodomain inhibitors or BET inhibitors, e.g., INCB54329 and INCB57643), c-MET inhibitors (e.g., capmatinib), anti-CD19 antibodies (e.g., tafasitamab), ALK2 inhibitors (e.g., INCB00928), or combinations thereof.

[0173] In some embodiments, the compounds or salts described herein are administered with a PI3Kδ inhibitor. In some embodiments, the compounds or salts described herein are administered with a JAK inhibitor. In some embodiments, the compounds or salts described herein are administered with a JAK1 or JAK2 inhibitor (e.g., baricitinib or ruxolitinib). In some embodiments, the compounds or salts described herein are administered with a JAK1 inhibitor. In some embodiments, the compounds or salts described herein are administered with a JAK1 inhibitor that is selective over JAK2.

[0174] Exemplary 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 directed against c-MET.

[0175] One or more of the following agents may be used in combination with the compounds of the present disclosure, and are provided as a non-limiting list: the cytostatic agents cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptosar, topotecan, paclitaxel, docetaxel, epothilones, 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, leucovorin, 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, anastrazole, letrozole, capecitabine, reloxafine, droloxifene, hexamethylmelamine, Avastin, HERCEPTIN™ (trastuzumab), BEXXAR™ (trademark) (tositumomab), VELCADE™ (bortezomib), ZEVALIN™ (ibritumomab tiuxetan), TRISENOX™ (arsenic trioxide), XELODA™ (capecitabine), vinorelbine, porfimer, ERBITUX™ (cetuximab), thiotepa, altretamine, melphalan, trastuzumab, letrozole, fulvestrant, exonuclease inhibitors (e.g., rivaroxaban), rivaroxaban, ... Semestan, ifosfamide, rituximab, C225 (cetuximab), campath (alemtuzumab), clofarabine, cladribine, aphidicolin, rituxan, sunitinib, dasatinib, tezacitabine, Sml1, fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP, and MDL-101,731.

[0176] 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 immunotherapies include cytokine therapy (e.g., interferon, GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccines, monoclonal antibodies, bispecific or multispecific antibodies, antibody-drug conjugates, adoptive T cell transfer, Toll receptor agonists, RIG-I agonists, oncolytic virotherapy, and immunomodulatory small molecules, including thalidomide or JAK1 / 2 inhibitors, PI3Kδ inhibitors, and the like. 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, dromostanolone propionate, and exon 10. Lizumab, 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, streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronate.

[0177] 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.

[0178] Exemplary steroids include corticosteroids such as dexamethasone or prednisone.

[0179] 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.

[0180] Exemplary suitable Flt-3 inhibitors include midostaurin, lestaurtinib, linifanib, sunitinib, sunitinib maleate, sorafenib, quizartinib, crenolanib, pacritinib, tanzutinib, PLX3397, and ASP2215, and pharmaceutically acceptable salts thereof. Other exemplary suitable Flt-3 inhibitors include compounds such as those disclosed in WO03 / 037347, WO03 / 099771, and WO04 / 046120, and pharmaceutically acceptable salts thereof.

[0181] Exemplary suitable RAF inhibitors include dabrafenib, sorafenib, and vemurafenib, and pharmaceutically acceptable salts thereof. Other exemplary suitable RAF inhibitors include compounds such as those disclosed in WO00 / 09495 and WO05 / 028444, and pharmaceutically acceptable salts thereof.

[0182] 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 such as those disclosed in WO04 / 080980, WO04 / 056786, WO03 / 024967, WO01 / 064655, WO00 / 053595, and WO01 / 014402, and pharmaceutically acceptable salts thereof.

[0183] Exemplary suitable CDK4 / 6 inhibitors include palbociclib, ribociclib, trilaciclib, lerociclib, and abemaciclib, and pharmaceutically acceptable salts thereof. Other exemplary suitable CDK4 / 6 inhibitors include compounds such as those disclosed in WO09 / 085185, WO12 / 129344, WO11 / 101409, WO03 / 062236, WO10 / 075074, and WO12 / 061156, and pharmaceutically acceptable salts thereof.

[0184] In some embodiments, the compounds of the present disclosure can be used in combination with one or more other kinase inhibitors, including imatinib, particularly to treat patients who are resistant to imatinib or other kinase inhibitors.

[0185] In some embodiments, the compounds of the present disclosure can be used in combination with chemotherapeutic agents in the treatment of cancer, and may improve the therapeutic response compared to the response to the chemotherapeutic agent alone without exacerbating the toxic effects of the chemotherapeutic agents. In some embodiments, the 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 include, but are not limited to, 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 when combining a CDK2 inhibitor of the present disclosure with an additional agent.

[0186] The agents may be combined with the compound in a single or sequential dosage form, or the agents may be administered simultaneously or sequentially as separate dosage forms.

[0187] 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.

[0188] 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 rather than continuously.

[0189] 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 tumor cells transfected to express peptides of melanoma antigens, such as gp100, MAGE antigens, Trp-2, MARTI, and / or tyrosinase, or the cytokine GM-CSF.

[0190] 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 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, the 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 formulae described herein, a compound recited 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.

[0191] The compounds of the present disclosure can be used in combination with bispecific macrocyclic peptides that target tumor cells to Fe alpha or Fe gamma receptor-expressing effector cells. The compounds of the present disclosure can also be combined with macrocyclic peptides that activate host immune responsiveness.

[0192] In some further embodiments, the combination of the disclosed compounds and other therapeutic agents may be administered to a patient 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.

[0193] Compounds of formula (I) or any of the formulae described herein, compounds recited in any of the claims and described herein, or salts thereof, can be used in combination with vaccines to stimulate immune responses 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.

[0194] 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.

[0195] 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.

[0196] 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.

[0197] 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.

[0198] 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).

[0199] 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.

[0200] II. Immune checkpoint therapy The compounds of the present disclosure may be used in combination with one or more immune checkpoint inhibitors to treat diseases such as cancer or infectious diseases. Exemplary immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CBL-B, CD20, CD28, CD40, CD70, CD122, CD96, CD73, CD47, CDK2, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, HPK1, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, TLR (TLR7 / 8), TIGIT, CD112R, VISTA, PD-1, PD-L1, and PD-L2. In some embodiments, the immune checkpoint molecule is a 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 may 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 TGFR beta inhibitor.

[0201] In some embodiments, the compounds provided herein may 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).

[0202] 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.

[0203] 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. Patent Nos. 7,488,802, 7,943,743, 8,008,449, 8,168,757, 8,217,149, or 10,308,644; U.S. Patent Publication Nos. 2017 / 0145025, 2017 / 0174671, 2017 / 017 No. 4679, No. 2017 / 0320875, No. 2017 / 0342060, No. 2017 / 0362253, No. 2018 / 0016260, No. 2018 / 005748 6, 2018 / 0177784, 2018 / 0177870, 2018 / 0179179, 2018 / 0179201, 2018 / 0179202, No. 2018 / 0273519, No. 2019 / 0040082, No. 2019 / 0062345, No. 2019 / 0071439, No. 2019 / 0127467, No. 2019 / 0144439, No. 2019 / 0202824, No. 2019 / 0225601, No. 2019 / 0300524, or No. 2019 / 03451 70; or PCT Publication Nos. WO03042402, WO2008156712, WO2010089411, WO2010036959, WO2011066342, WO2011159877, WO2011082400, or WO2011161699, each of which is incorporated by reference herein in its entirety. In some embodiments, the inhibitor of PD-L1 is INCB086550.

[0204] 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, e.g., 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 (MPDL3280A; also known as 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.

[0205] 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 in US2018 / 0179201, US2018 / 0179197, US2018 / 0179179, US2018 / 0179202, US2018 / 0177784, US2018 / 0177870, US 16 / 369,654 (filed March 29, 2019), and US 62 / 688,164, each of which is incorporated by reference in its entirety.

[0206] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of KIR, TIGIT, LAIR1, CD160, 2B4, and TGFRbeta.

[0207] In some embodiments, the inhibitor is MCLA-145.

[0208] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab, AGEN1884, or CP-675,206.

[0209] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016, LAG525, INCAGN2385, or eftiragimode alfa (IMP321).

[0210] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD73. In some embodiments, the inhibitor of CD73 is oleclumab.

[0211] 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.

[0212] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of VISTA. In some embodiments, the inhibitor of VISTA is JNJ-61610588 or CA-170.

[0213] 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.

[0214] 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.

[0215] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of A2aR. In some embodiments, the inhibitor of A2aR is CPI-444.

[0216] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of TGF-beta. In some embodiments, the inhibitor of TGF-beta is travedersen, galcertinib, or M7824.

[0217] 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.

[0218] 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.

[0219] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD73. In some embodiments, the inhibitor of CD73 is MEDI9447.

[0220] 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.

[0221] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of TIM3, e.g., an anti-TIM3 antibody. In some embodiments, the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

[0222] 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.

[0223] 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).

[0224] In some embodiments, the CD137 agonist is urelumab. In some embodiments, the CD137 agonist is utomilumab.

[0225] 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, e.g., 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.

[0226] 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.

[0227] In some embodiments, the agonist of an immune checkpoint molecule is an agonist of ICOS, hi some embodiments, the agonist of ICOS is GSK-3359609, JTX-2011, or MEDI-570.

[0228] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of CD28. In some embodiments, the agonist of CD28 is celalizumab.

[0229] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of CD27. In some embodiments, the agonist of CD27 is varlilumab.

[0230] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of TLR7 / 8. In some embodiments, the agonist of TLR7 / 8 is MEDI9197.

[0231] The compounds of the present disclosure may be used in combination with bispecific antibodies. In some embodiments, one domain 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.

[0232] 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.

[0233] As provided throughout, the additional compounds, inhibitors, drugs, etc. can be combined with the present compounds in a single or sequential dosage form, or they can be administered simultaneously or sequentially as separate dosage forms.

[0234] Formulation, Dosage Form, and Administration When used 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, II, or any of the formulae described herein, a compound recited in any of the claims and described herein, or a pharmaceutically acceptable salt thereof, or any of the embodiments thereof, 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, ocular, and mucosal delivery, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral, or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular 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 may 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.

[0235] The present invention also includes pharmaceutical compositions containing the compounds of the present disclosure or pharmaceutically acceptable salts thereof as an active ingredient in combination with one or more pharmaceutically acceptable carriers or additives. In some embodiments, the compositions are suitable for topical administration. When preparing the compositions of the present invention, the active ingredient is usually mixed with an additive, diluted by an additive, or enclosed in such a carrier, for example, in the form of a capsule, sachet, paper, or other container. When the additive serves 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 compositions 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.

[0236] 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 formulation.

[0237] 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).

[0238] Some examples of suitable additives 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 propyl hydroxybenzoate; sweeteners; and flavoring agents.The composition of the present invention can be formulated to provide rapid, sustained, or delayed release of active ingredient after administration to patients by using procedures known in the art.

[0239] 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% by weight microcrystalline cellulose and about 2% by weight silicon dioxide.

[0240] 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™).

[0241] In some embodiments, the composition is manufactured using a wet granulation process. In some embodiments, the composition is manufactured using a dry granulation process.

[0242] 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 suitable pharmaceutical excipients.

[0243] The components used to formulate pharmaceutical compositions are of high purity and substantially free of potentially harmful contaminants (e.g., at least national food grade, generally at least analytical grade, and more usually at least pharmaceutical grade). For human consumption in particular, compositions are preferably manufactured or formulated in accordance with Good Manufacturing Practice standards as defined in applicable regulations of the U.S. Food and Drug Administration. 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.

[0244] The active compounds can be effective over a wide dosage range and are 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 to be treated, the selected route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0245] 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 solution 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 biological efficacy of the selected compound, excipient formulation, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0246] 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 easily 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.

[0247] 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 comprise an inner dose and an outer dose component, the latter being 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 delay 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.

[0248] 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.

[0249] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable additives as described above. In some embodiments, compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask, tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered orally or nasally from devices that deliver the formulation in an appropriate manner.

[0250] 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 components, such as glycerol monostearate, PEG-glycerol monostearate, and cetylstearyl alcohol. Gels can be formulated using isopropyl alcohol and water, preferably in combination with other components such as glycerol, hydroxyethylcellulose, etc. 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 treating a selected indication, such as psoriasis or other skin conditions.

[0251] 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, as well as 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.

[0252] The compositions administered to patients can be in the form of the pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques or can be sterile filtered. Aqueous solutions can 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 preparation will generally be 3 to 11, more preferably 5 to 9, and most preferably 7 to 8. It will be understood that the use of some of the additives, carriers, or stabilizers described above will result in the formation of pharmaceutical salts.

[0253] 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 solution 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 biological efficacy of the selected compound, excipient formulation, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0254] 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 humans, 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 can also be useful in generating differentiated ADME (adsorption, distribution, metabolism, and excretion). Thus, the present invention includes KRAS binding assays containing such labeled or substituted compounds.

[0255] 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, i.e., substituted, with an atom having an atomic mass or mass number different from that normally found in nature (i.e., naturally occurring). Suitable radionuclides that may 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 with a deuterium atom (e.g., C of Formula I, II, or any formula provided herein). 1-6One or more hydrogen atoms of an alkyl group can optionally be replaced with a deuterium atom, e.g., -CH can be replaced with -CD.) In some embodiments, the alkyl group in Formula I, II, or any formula provided herein can be perdeuterated.

[0256] One or more constituent atoms of the compounds presented herein can be replaced or substituted with an isotope of the atom at natural or non-natural abundance. In some embodiments, the compounds contain at least one deuterium atom. In some embodiments, the compounds contain two or more deuterium atoms. In some embodiments, the compounds contain 1 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.

[0257] Synthetic methods for incorporating isotopes into organic compounds are known in the art (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.

[0258] Substitution with heavier isotopes, such as deuterium, can confer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferable in some cases (see, e.g., 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 may confer one or more therapeutic advantages.

[0259] The radionuclide incorporated into the present radiolabeled compounds will depend on the particular application 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.

[0260] 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.

[0261] 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.

[0262] 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 tracking the label.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 the test compound to compete with the 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.

[0263] kit The present disclosure also includes pharmaceutical kits useful for treating or preventing diseases or disorders associated with KRAS activity, such as, for example, cancer or infectious diseases, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, II, or any of its embodiments. As would be readily apparent to one of skill in the art, such kits can further include one or more of a variety of conventional pharmaceutical kit components, such as a container containing one or more pharmaceutically acceptable carriers, additional containers, etc. 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, may also be included in the kit.

[0264] 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 according to at least one assay described herein. [Example]

[0265] 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-targeted fractionation system. The basic instrument setup, protocols, and control software for operating 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). Separated compounds were typically subjected to analytical liquid chromatography-mass spectrometry (LCMS) for purity analysis.

[0266] The separated compounds were typically analyzed under the following conditions: Instrument: Agilent 1100 series LC / MSD, Column: Waters Sunfire™ C 18The sample was subjected to analytical liquid chromatography-mass spectrometry (LCMS) for purity analysis using a 5 μm particle size column, 2.1 × 5.0 mm, buffer solution: mobile phase A: 0.025% TFA aqueous solution and mobile phase B: acetonitrile; a gradient of 2% to 80% B over 3 min (flow rate 2.0 mL / min).

[0267] 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) with MS detection as indicated in the examples. Typical preparative reversed-phase high-performance liquid chromatography (RP-HPLC) column conditions are as follows:

[0268] Purification at pH=2: Waters Sunfire™ C 18 The column was 5 μm in particle size, 19 × 100 mm, and eluted with mobile phase A: 0.1% aqueous TFA (trifluoroacetic acid) and mobile phase B: acetonitrile at a flow rate of 30 mL / min. The separation gradient was optimized for each compound using a published compound-specific method optimization protocol [see "Preparative LCMS Purification: Improved Compound-Specific Method Optimization," K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)]. The flow rate typically used with the 30 × 100 mm column was 60 mL / min.

[0269] Purification at pH=10: Waters XBridge C 18The column was 5 μm in particle size, 19 × 100 mm, and eluted with mobile phase A: 0.15% aqueous NH OH and mobile phase B: acetonitrile; the flow rate was 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)]. The flow rate typically used with the 30 × 100 mm column was 60 mL / min.

[0270] 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 value); 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.

[0271] Intermediate 1,7-bromo-2,4-dichloro-8-fluoro-6-iodo-3-nitroquinoline [ka]

[0272] Step 1. 2-Amino-4-bromo-3-fluoro-5-iodobenzoic acid [ka] To a solution of 2-amino-4-bromo-3-fluorobenzoic acid (10.0 g, 42.7 mmol) in DMF (100 mL) was added NIS (9.61 g, 42.7 mmol), and the reaction was stirred at 80° C. for 6 hours. The mixture was cooled with ice water, and then water (150 mL) was added and stirred for 20 minutes. The precipitate was filtered, washed with water, and dried to give the desired product as a solid. LCMS (M+H) + : m / z calculated for C7H5BrFINO2 359.9; found 359.8.

[0273] Step 2. 7-Bromo-8-fluoro-6-iodo-2H-benzo[d][1,3]oxazine-2,4(1H)-dione [ka] To a solution of 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (8.4 g, 23.34 mmol) in 1,4-dioxane (200 mL), triphosgene (6.34 g, 21.37 mmol) was added and stirred at 100 °C for 1 hour. After cooling to room temperature, ice was added until a solid precipitated. The mixture was then thoroughly diluted with water (final volume approximately 400 mL), and the solid was collected by filtration and then air-dried. The crude product was used in the next step without further purification.

[0274] Step 3. 7-Bromo-8-fluoro-6-iodo-3-nitroquinoline-2,4-diol [ka] To a solution of ethyl 2-nitroacetate (4.62 g, 17.36 mmol) in toluene (10.0 mL) was added DIPEA (6.06 ml, 34.7 mmol) at room temperature and stirred for 10 minutes. 7-Bromo-8-fluoro-6-iodo-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (6.7 g, 17.36 mmol) was then added to the reaction mixture, and the reaction was stirred at 95° C. for 3 hours. The reaction was cooled with ice water, and then 1N HCl (40 mL) was added. The solid precipitate was collected by filtration and washed with a small amount of ethyl acetate to give the desired product as a yellow solid (6 g, 81%). LCMS (M+H) + : m / z calculated for C9H4BrFIN2O4 428.8; found 428.8.

[0275] Step 4. 7-Bromo-2,4-dichloro-8-fluoro-6-iodo-3-nitroquinoline [ka] To 7-bromo-8-fluoro-6-iodo-3-nitroquinoline-2,4-diol (4.51 g, 10.51 mmol) in POCl (4.9 mL, 52.6 mmol) was added DIPEA (3.67 mL, 21.03 mmol) and the reaction was stirred for 3 h at 105° C. The solvent was removed in vacuo and then azeotroped three times with toluene to give the crude material, which was used in the next step without further purification.

[0276] Intermediate 2. (endo)-5-((3-amino-7-bromo-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-6-iodoquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl ester [ka]

[0277] Step 1. (endo)-5-((7-bromo-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-6-iodo-3-nitroquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] To a mixture of 7-bromo-2,4-dichloro-8-fluoro-6-iodo-3-nitroquinoline (1.53 g, 3.28 mmol) in CHCl (16.4 mL) was added tert-butyl (endo)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylate (651 mg, 3.28 mmol) and DIPEA (2.87 mL, 16.4 mmol), and the reaction was stirred at 55° C. for 4 hours. N,N-dimethylazetidin-3-amine dihydrochloride (739 mg, 4.27 mmol) was then added. After heating at 55° C. for an additional 4 hours, the mixture was concentrated to dryness and used without further purification. LCMS (M+H) + :m / zC 24 H 30 Calculated value for BrFIN6O4: 691.1; Found value: 691.2.

[0278] Step 2. (endo)-5-((3-amino-7-bromo-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-6-iodoquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl Sodium hydrosulfite (2.86 g, 16.4 mmol) in water (2.5 mL) was added to a solution of the above crude mixture and 30% aqueous ammonium hydroxide (4.26 mL, 32.8 mmol) in MeOH (30 mL) at 0 °C. After 10 min, water (30 mL) was added to the reaction mixture, followed by extraction with dichloromethane (30 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with 0-10% methanol / dichloromethane to give tert-butyl (endo)-5-((3-amino-7-bromo-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-6-iodoquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (1.9 g, 88% yield). LCMS (M+H) + :m / zC 24 H 32 Calculated for BrFIN6O2: 661.1; Found: 661.2

[0279] Intermediate 3. (endo)-5-((3-amino-7-bromo-6-(2-cyanoethyl)-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoroquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl ester [ka] In a 10-dram vial, to tert-butyl (endo)-5-((3-amino-7-bromo-2-(3-(dimethylamino)-azetidin-1-yl)-8-fluoro-6-iodoquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Intermediate 2, 1.17 g, 1.76 mmol), acrylonitrile (468 mg, 8.82 mmol), and aqueous tetramethylammonium formate (25%, 1.24 mL, 2.65 mmol) in DMF (3.5 mL) was added DIPEA (616 μL, 3.53 mmol) and Pd(PPh) (204 mg, 0.176 mmol). The reaction mixture was heated at 80 °C for 2 h, then concentrated to dryness and applied to a silica gel column, eluting with 0% to 5% methanol / dichloromethane to give tert-butyl (endo)-5-((3-amino-7-bromo-6-(2-cyanoethyl)-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoroquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (782 mg, 70% yield). LCMS (M+H) + :m / zC 27 H 36 Calculated for BrFN7O2 588.2 / 590.2; Found 588.2 / 590.2.

[0280] Intermediate 4. 2-(3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka]

[0281] Step 1. 1-Bromo-3-(methoxymethoxy)naphthalene [ka] A sample of 4-bromonaphthalen-2-ol (1.57 g, 7.04 mmol) was dissolved in DCM (14 mL) and stirred at room temperature. The solution was treated with N,N-diisopropylethylamine (1.4 mL, 7.8 mmol) and chloromethyl methyl ether (0.6 mL, 7.8 mmol). After 20 minutes, LCMS showed complete conversion to the desired product. The reaction was quenched with saturated aqueous NH4Cl and diluted with DCM. The layers were separated, and the aqueous layer was extracted with additional DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude material was dissolved in 50% DCM in hexanes and filtered through a silica plug. The filtrate was concentrated in vacuo to give 1-bromo-3-(methoxymethoxy)naphthalene (1.76 g, 6.59 mmol, 94% yield). LCMS (M-MeOH) + :m / zC 11 Calculated for H8BrO4 235.0, 237.0; Found: 235.0, 237.0.

[0282] Step 2. 2-(3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane A sample of 1-bromo-3-(methoxymethoxy)naphthalene (1.76 g, 6.59 mmol) was dissolved in dioxane (19 mL) and stirred at room temperature. The solution was treated with potassium acetate (1.9 g, 19.8 mmol) and bis(pinacolato)diboron (2.5 g, 9.9 mmol). Finally, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), DCM complex (0.270 g, 0.329 mmol) was added to the solution, which was then stirred at 100 °C. After 16 h, LCMS indicated complete conversion to the product. The reaction mixture was diluted with EtOAc, filtered to remove solids, and concentrated in vacuo. The crude material was purified by flash column chromatography (0-40% EtOAc / hexanes) to give 2-(3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.74 g, 5.53 mmol, 84% yield). LCMS (M-MeOH) + :m / zC 17 H 20Calculated value for BO3: 283.2; Measured value: 283.1.

[0283] Intermediate 5. (endo)-5-((3-amino-6-((E)-2-cyanovinyl)-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-Butyl [ka] In a 10-dram vial, to a solution of tert-butyl (endo)-5-((3-amino-7-bromo-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-6-iodoquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Intermediate 2, 1.59 g, 2.40 mmol), acrylonitrile (230 mg, 4.33 mmol), and triethylamine (670 μL, 4.81 mmol) in DMF (12 mL) was added PdOAc (54.0 mg, 0.240 mmol) and tri-o-tolylphosphine (146 mg, 0.481 mmol). The reaction mixture was heated at 80° C. for 2 hours. The reaction was then diluted with water (10 mL) and dioxane (10 mL). (3-(Methoxymethoxy)naphthalen-1-yl)boronic acid (Intermediate 4, 1.12 g, 4.81 mmol), Pd(PPh3)4 (278 mg, 0.240 mmol), and Na2CO3 (510 mg, 4.81 mmol) were added. The reaction mixture was heated at 105 °C for 15 h. HO (50 mL) was then added to the reaction mixture, followed by extraction with dichloromethane (50 mL × 3). The combined organic layers were washed with HO (50 mL), dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with 0-10% methanol / dichloromethane to give tert-butyl (endo)-5-((3-amino-6-((E)-2-cyanovinyl)-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (1.25 g, 75% yield) as a yellow solid. LCMS (M+H) + :m / zC 39 H 45 Calculated for FN7O4 694.4; Found 694.3.

[0284] Intermediate 6. (endo)-5-((3-amino-6-(2-cyanoethyl)-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-7-(3-hydroxynaphthalen-1-yl)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl ester [ka] To a solution of tert-butyl (endo)-5-((3-amino-7-bromo-6-(2-cyanoethyl)-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoroquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Intermediate 3, 1038 mg, 1.76 mmol) in water (2 mL) and dioxane (4 mL) was added (3-hydroxynaphthalen-1-yl)boronic acid (763 mg, 4.06 mmol), Pd(PPh) (204 mg, 0.176 mmol), and NaCO (374 mg, 3.53 mmol). The reaction mixture was heated to 100 °C for 4 h. HO (5 mL) was added to the reaction mixture, which was then extracted with dichloromethane (10 mL × 3). The combined organic layers were then washed with HO (20 mL), dried over NaSO, filtered, and concentrated. The crude product was added to a silica gel column and eluted with 0-5% methanol / dichloromethane to give tert-butyl (endo)-5-((3-amino-6-(2-cyanoethyl)-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-7-(3-hydroxynaphthalen-1-yl)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (0.93 g, 81% yield). LCMS (M+H) + :m / zC 37 H 43 Calculated value for FN7O3: 652.3; Measured value: 652.3.

[0285] Intermediate 7. 7-Bromo-2,4,6-trifluoro-8-fluoro-3-nitroquinoline [ka] This compound was prepared according to the procedure described for Intermediate 1, substituting NCS for NIS in step 1.

[0286] Intermediate 8. (endo)-5-((3-amino-7-bromo-6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoroquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl ester [ka] This compound was prepared according to the procedure described for Intermediate 2, replacing 7-bromo-2,4-dichloro-8-fluoro-6-iodo-3-nitroquinoline with 7-bromo-2,4,6-trichloro-8-fluoro-3-nitroquinoline (Intermediate 7) in Step 1. LCMS (M+H) + :m / zC 24 H 32 Calculated for BrClFN6O2 569.1; found 569.2.

[0287] Intermediate 9. tert-Butyl 5-(7-bromo-8-(2-cyanoethyl)-2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)-2-endo-azabicyclo[2.1.1]hexane-2-carboxylate [ka]

[0288] Step 1. tert-Butyl 5-(7-bromo-2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-8-iodo-1H-imidazo[4,5-c]quinolin-1-yl)-2-endo-azabicyclo[2.1.1]hexane-2-carboxylate [ka] A solution of tert-butyl 5-((3-amino-7-bromo-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-6-iodoquinolin-4-yl)amino)-2-endo-azabicyclo[2.1.1]hexane-2-carboxylate (Intermediate 2, 3.00 g, 4.54 mmol, 1.0 equiv.) and N,N-dimethyl-4-oxobutanamide (0.615 g, 4.76 mmol, 1.05 equiv.) in ethanol (9.1 mL) was heated at 85 °C in a sealed vial under air for 3 hours. The vial was cooled to 22 °C, n-butanol (9 mL) was added, the vial cap was removed, and the mixture was stirred vigorously (open to air) at 65 °C overnight. The next day, LCMS revealed complete conversion to the desired product. The volatiles were removed in vacuo, and the product was used without further purification (assuming quantitative yield). LCMS (M+H) + :m / zC 30 H 39 Calculated for BrFIN7O3: 770.1; Found: 770.1.

[0289] Step 2. tert-Butyl 5-(7-bromo-8-(2-cyanoethyl)-2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)-2-endo-azabicyclo[2.1.1]hexane-2-carboxylate Part A: In a 40 mL vial, tert-butyl 5-(7-bromo-2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-8-iodo-1H-imidazo[4,5-c]quinolin-1-yl)-2-endo-azabicyclo[2.1.1]hexane-2-carboxylate (3.50 g, 4.54 mmol) and bis(tri-o-tolylphosphine)palladium(0) (0.325 g, 0.454 mmol) were dissolved in DMF (15 mL). Triethylamine (1.266 mL, 9.09 mmol) and acrylonitrile (0.598 mL, 9.09 mmol) were added in one portion to the reaction mixture. The headspace was purged with nitrogen, and the vial was capped and stirred at 80 °C for 1 h. At this point, LCMS indicated the reaction was complete. The reaction mixture was cooled to room temperature and poured into rapidly stirring ice water, causing a yellow solid to precipitate. The solid was filtered and dried on the filter for 72 hours. The filter cake was used in the following reaction without further purification. LCMS (M+H) + :m / zC 33 H 41 Calculated for BrFN8O3: 695.2; Found: 695.3.

[0290] Part B: The filter cake from Part A was dissolved in THF (40 mL) and cooled to 0° C. Lithium triethylborohydride (8.2 mL, 1 M in THF, 1.81 equiv.) was added in four portions over 30 minutes, monitoring by LCMS after each addition. Water was added slowly to the reaction mixture (20 mL), and the mixture was extracted with DCM (3×20 mL), dried over MgSO4, and the volatiles were removed in vacuo. The residue was dried under high vacuum overnight to give a brittle brown / orange solid, which was used in the next step without further purification (3.24 g, quantitative). LCMS (M+H) + :m / zC 33 H 43 Calculated for BrFN8O3: 697.3; Found: 697.4.

[0291] Intermediate 10. 8-Bromo-2,4,7-trichloro-6-iodo-3-nitroquinoline [ka]

[0292] Step 1. 2-Amino-3-bromo-4-chloro-5-iodobenzoic acid [ka] To a solution of 2-amino-4-chlorobenzoic acid (10.0 g, 58.3 mmol) in DMF (194 mL) was added NIS (14.4 g, 64.1 mmol). The resulting mixture was stirred at 70° C. for 16 hours, cooled to room temperature, and then NBS (11.4 g, 64.1 mmol) was added. The resulting mixture was stirred at 70° C. overnight. The mixture was cooled with ice water, and then water (150 mL) was added and stirred for 20 minutes. The precipitate was filtered, washed with water, and dried to give the desired product as a solid. LCMS (M+H) + : m / z calculated for C7H5BrClINO2 375.8; found 375.8.

[0293] Step 2. 8-Bromo-2,4,7-trichloro-6-iodo-3-nitroquinoline This compound was prepared according to the procedure described for Intermediate 1, substituting 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid in step 2 with 2-amino-3-bromo-4-chloro-5-iodobenzoic acid.

[0294] Intermediate 11. (endo)-5-(6-bromo-7-chloro-8-(2-cyanoethyl)-2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-Butyl [ka]

[0295] Step 1. (endo)-5-((3-amino-8-bromo-7-chloro-2-(3-(dimethylamino)azetidin-1-yl)-6-iodoquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] This compound was prepared according to the procedure described for Intermediate 2, substituting 8-bromo-2,4,7-trichloro-6-iodo-3-nitroquinoline (Intermediate 10) for 7-bromo-2,4-dichloro-8-fluoro-6-iodo-3-nitroquinoline in Step 1. LCMS (M+H) + :m / zC 24 H 32 Calculated for BrClIN6O2 677.1; Found 677.1.

[0296] Step 2. (endo)-5-(6-bromo-7-chloro-2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-8-iodo-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] A mixture of (endo)-5-((3-amino-8-bromo-7-chloro-2-(3-(dimethylamino)azetidin-1-yl)-6-iodoquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl (780 mg, 1.151 mmol) and N,N-dimethyl-4-oxobutanamide (178 mg, 1.38 mmol) in EtOH (3.84 mL) / AcOH (0.767 mL) was stirred at 80° C. overnight. The resulting mixture was concentrated under reduced pressure and purified by column chromatography (0-20% MeOH:DCM) to give the desired product. LCMS (M+H) + :m / zC 30 H 39 Calculated for BrClIN7O3 786.1; found 786.2.

[0297] Step 3. (endo)-5-(6-bromo-7-chloro-8-(2-cyanovinyl)-2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] In a 40 mL vial, (endo)-5-(6-bromo-7-chloro-2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-8-iodo-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (1.58 g, 2.01 mmol), Pd(OAc) (0.045 g, 0.201 mmol), and tri-o-tolylphosphine (0.122 g, 0.402 mmol) were dissolved in DMF (5 mL). To the reaction mixture, TEA (560 μL, 4.02 mmol) and acrylonitrile (264 μL, 4.02 mmol) were added in one portion. The headspace was purged with nitrogen, the vial was capped, and stirred at 80 °C for 2 h, at which point LCMS indicated completion. The reaction mixture was cooled to room temperature, and water was added, followed by DCM. The mixture was extracted with DCM, and the combined organic extracts were washed with brine, dried, and concentrated under reduced pressure. Flash column chromatography (0-20% MeOH:DCM) afforded the desired product. LCMS (M+H) + :m / z=C 33 H 41 Calculated for BrClN8O3 711.2; found 711.3.

[0298] Step 4. (endo)-5-(6-bromo-7-chloro-8-(2-cyanoethyl)-2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl To a solution of tert-butyl (endo)-5-(6-bromo-7-chloro-8-(2-cyanovinyl)-2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (800 mg, 1.12 mmol) in THF (5.60 mL) was added dropwise at 0° C. Super-Hydride (1 M in THF) (1.70 mL, 1.70 mmol) was added dropwise at 0° C. The resulting mixture was stirred at 0° C. for 5 minutes. Additional Super-Hydride was added as needed, and the reaction was monitored by LCMS until completion (approximately 5 minutes after hydride addition). The resulting mixture was quenched with water and extracted with DCM. The combined organic extracts were dried and concentrated under reduced pressure. Flash column chromatography (0-20% MeOH:DCM) afforded the desired product. LCMS (M+H) + :m / zC 33 H 43 Calculated for BrClN8O3: 713.2; Found: 713.3.

[0299] Intermediate 12. (endo)-5-(2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-9-formyl-7-(3-(methoxymethoxy)naphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-Butyl [ka]

[0300] Step 1. 3-((5-bromo-3-chloro-2-fluorophenyl)amino)-3-oxopropanoic acid [ka] Ethyl malonyl chloride (9.41 g, 62.5 mmol) was added dropwise to a solution of 5-bromo-3-chloro-2-fluoroaniline (11.2 g, 50 mmol) in 100 mL of EtOAc and 100 mL of saturated aqueous NaHCO solution at 0 °C, and the resulting mixture was stirred for 30 min. The reaction mixture was diluted with EtOAc, and the organic layer was washed with brine, dried over NaSO, and concentrated in vacuo. The crude material was dissolved in 100 mL of THF, and a 2 N solution of LiOH (50 mL) was added, followed by MeOH (10 mL). The mixture was vigorously stirred at ambient temperature for 2 h. The reaction mixture was acidified with 1 N HCl, then extracted with EtOAc, washed with brine, dried over NaSO, and concentrated under reduced pressure to give the product (14.5 g, 93% yield), which was used in the next step without further purification.

[0301] Step 2. 5-Bromo-7-chloro-8-fluoroquinoline-2,4(1H,3H)-dione [ka] Methanesulfonic anhydride (16.3 g, 93 mmol) was added to a solution of 3-((5-bromo-3-chloro-2-fluorophenyl)amino)-3-oxopropanoic acid (14.5 g, 46.7 mmol) in Eaton's reagent (10 wt % phosphorus pentoxide solution in methanesulfonic acid, 100 mL), and the resulting mixture was stirred overnight at 60° C. Upon completion, the reaction solution was poured into cold water, and the precipitate was collected by filtration and air-dried to give the crude product (13.4 g, 98% yield), which was used in the next step without further purification.

[0302] Step 3. 5-Bromo-7-chloro-8-fluoro-3-nitroquinoline-2,4-diol [ka] To a solution of 5-bromo-7-chloro-8-fluoroquinoline-2,4(1H,3H)-dione (13.4 g, 45.8 mmol) in acetic acid (100 mL) was added nitric acid (92 wt%, 3.9 mL, 80 mmol) dropwise, and the mixture was stirred at ambient temperature while monitoring by LCMS. Upon completion, the reaction solution was poured into cold water with stirring, and the precipitate was collected by filtration, washed with ether, and air-dried to give the crude product (13.8 g, 89% yield), which was used in the next step without further purification.

[0303] Step 4. 5-Bromo-2,4,7-trichloro-8-fluoro-3-nitroquinoline [ka] To a solution of 5-bromo-7-chloro-8-fluoro-3-nitroquinoline-2,4-diol (1.0 g, 2.96 mmol) and POCl3 (2.2 mL, 23.7 mmol) in toluene (8 mL) was added DIPEA (2.070 mL, 11.85 mmol), and the mixture was stirred at 110 °C for 1 h. The solvent was removed in vacuo, then azeotroped three times with toluene to remove excess POCl3, and the residue was purified by flash chromatography (0–40% DCM in hexanes) to give the product (377 mg, 34% yield).

[0304] Step 5. (endo)-5-((5-bromo-7-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-3-nitroquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] To a mixture of 5-bromo-2,4,7-trichloro-8-fluoro-3-nitroquinoline (250 mg, 0.67 mmol) in DCM (5 mL) was added tert-butyl (endo)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylate (132 mg, 0.67 mmol) and DIPEA (0.58 mL, 3.34 mmol), and the reaction was stirred at 80 °C for 30 minutes. The reaction was cooled to room temperature, and N,N-dimethylazetidin-3-amine dihydrochloride (173 mg, 1.0 mmol) was added. After stirring at 80 °C for an additional hour, the reaction mixture was concentrated in vacuo to give the crude product, which was used in the next step without further purification. LCMS (M+H) + :m / zC 24 H 30 Calculated for BrClFN6O4 599.1; found 599.1.

[0305] Step 6. (endo)-5-((7-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-3-nitro-5-vinylquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] A solution of tert-butyl (endo)-5-((5-bromo-7-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-3-nitroquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (0.45 g, 0.75 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.46 g, 3.0 mmol), PdCl(dppf)-CHCl adduct (61 mg, 75 μmol), and KPO (0.32 g, 1.5 mmol) in dioxane (5 mL) and water (1 mL) was stirred at 100 °C for 5 h. The reaction was extracted with EtOAc, and the organic layer was washed with brine, dried over NaSO, and concentrated in vacuo. The residue was purified by flash chromatography to give the product (338 mg, 82% yield). LCMS (M+H) + :m / zC26 H 33 Calculated for ClFN6O4 547.2; found 547.2.

[0306] Step 7: (endo)-5-((3-amino-7-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-5-vinylquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] To a solution of tert-butyl (endo)-5-((7-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-3-nitro-5-vinylquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (338 mg, 0.62 mmol) and 30% aqueous ammonium hydroxide (0.8 mL, 6.18 mmol) in MeOH (5 mL) was added a solution of sodium hydrosulfite (382 mg, 1.85 mmol) in water (1 mL) at room temperature. After 10 min, the reaction was diluted with water and extracted three times with DCM. The combined organic layers were dried over NaSO, filtered, and concentrated to give the crude product, which was used in the next step without further purification.

[0307] Step 8: (endo)-5-(7-chloro-2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-9-vinyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] A solution of tert-butyl 5-((3-amino-7-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-5-vinylquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (0.26 g, 0.5 mmol) and N,N-dimethyl-4-oxobutanamide (0.193 g, 1.5 mmol) in i-PrOH (4 mL) was stirred at 80 °C for 4 h. The reaction mixture was concentrated, and the residue was purified by flash chromatography (0-10% MeOH in DCM) to give the product (156 mg, 50% yield). LCMS (M+H) + :m / zC 32 H 42 Calculated for ClFN7O3: 626.3; Found: 626.3.

[0308] Step 9: (endo)-5-(2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-9-vinyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] A mixture of tert-butyl 5-(7-chloro-2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-9-vinyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (100 mg, 0.16 mmol), 2-(3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (100 mg, 0.32 mmol), Xphos Pd G2 (12.57 mg, 0.016 mmol), and K3PO4 (102 mg, 0.48 mmol) in dioxane (1.6 mL) and water (0.4 mL) was stirred at 100 °C for 5 hours with LCMS monitoring. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (0-10% MeOH in DCM) to give the product (87 mg, 70% yield). LCMS (M+H) + :m / zC 44 H 53 Calculated for FN7O5 778.4; Found 778.4.

[0309] Step 10: (endo)-5-(2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-9-formyl-7-(3-(methoxymethoxy)naphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] To tert-butyl (endo)-5-(2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-9-vinyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (87 mg, 0.11 mmol) and sodium periodate (70.6 mg, 0.33 mmol) in THF (1.0 mL) and water (10.0 mL) in a 10-dram vial was added 0.4% aqueous osmium tetroxide solution (35 μL, 5.5 μmol). The reaction mixture was stirred for 3 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water and brine, dried over NaSO, and concentrated in vacuo. The residue was purified by flash chromatography (0-10% MeOH in DCM) to give Intermediate 12 (70 mg, 82% yield). LCMS (M+H) + :m / zC 43 H 51 Calculated for FN7O6 780.4; Found 780.4.

[0310] Examples 1a, 1b, and 1c. 1-(3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-8-methyl-1H-imidazo[4,5-c]quinolin-2-yl)piperidin-1-yl)ethan-1-one [ka]

[0311] Step 1. (endo)-5-((3-amino-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-7-(3-hydroxynaphthalen-1-yl)-6-methylquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] In a 10-dram vial, tert-butyl (endo)-5-((3-amino-7-bromo-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-6-iodoquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Intermediate 2: 1.070 g, 1.618 mmol), methylboronic acid (0.107 g, 1.780 mmol), Pd(PPh) (0.187 g, 0.162 mmol), and sodium carbonate (0.514 g, 4.85 mmol) were added in water (5 mL) and dioxane (10 mL). The reaction mixture was heated to 80° C. for 5 h. After the reaction was cooled to room temperature, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (0.437 g, 1.620 mmol) was added. The reaction mixture was heated to 100 °C for an additional 5 h. Water (10 mL) was added to the reaction mixture, followed by extraction with dichloromethane (10 mL × 4). The combined organic layers were dried over NaSO, filtered, and concentrated. The crude product was loaded onto a silica gel column and eluted with 0–10% methanol / dichloromethane to give tert-butyl (endo)-5-((3-amino-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-7-(3-hydroxynaphthalen-1-yl)-6-methylquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (0.9 g, 91% yield). LCMS(M+H) + :m / zC 35 H 42 Calculated for FN6O3 613.3; Found 613.2.

[0312] Step 2. 1-(3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-8-methyl-1H-imidazo[4,5-c]quinolin-2-yl)piperidin-1-yl)ethan-1-one In a 1-chloro-1,4-dichloro-2,4-di ... Example 1a Diastereomer 1: Peak 1: LCMS (M+H) + m / zC 38 H 43 Calculated value for FN7O2 648.3; Measured value 648.2. Example 1b Diastereomer 2: Peak 2: LCMS (M+H) + m / zC 38 H 43 Calculated value for FN7O2 648.3; Measured value 648.2. Example 1c Diastereomer 3: Peak 3: LCMS (M+H )+ m / zC 38 H 43 Calculated value for FN7O2 648.3; Measured value 648.2.

[0313] Example 2a and Example 2b: 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-8-methyl-1H-imidazo[4,5-c]quinolin-2-yl)-1-(4-(pyrimidin-2-yl)piperazin-1-yl)propan-1-one [ka]

[0314] Step 1. (endo)-5-((3-amino-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-7-(3-hydroxynaphthalen-1-yl)-6-methylquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] In a 10-dram vial, tert-butyl (endo)-5-((3-amino-7-bromo-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-6-iodoquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Intermediate 2: 1.070 g, 1.618 mmol), methylboronic acid (0.107 g, 1.780 mmol), Pd(PhP) (0.187 g, 0.162 mmol), and sodium carbonate (0.514 g, 4.85 mmol) were added in water (5 mL) and dioxane (10 mL). The reaction mixture was heated to 80° C. for 5 h. After cooling to room temperature, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (0.437 g, 1.620 mmol) was added. The reaction mixture was heated to 100 °C for an additional 5 h. Water (10 mL) was added to the reaction mixture, followed by extraction with dichloromethane (10 mL × 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was loaded onto a silica gel column and eluted with 0–10% methanol / dichloromethane to give tert-butyl (endo)-5-((3-amino-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-7-(3-hydroxynaphthalen-1-yl)-6-methylquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (0.9 g, 91% yield). LCMS(M+H) + :m / zC 35 H 42 Calculated for FN6O3 613.3; Found 613.2.

[0315] Step 2. 3-(1-((endo)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-8-methyl-1H-imidazo[4,5-c]quinolin-2-yl)propanoic acid [ka] In a 10-dram vial, tert-butyl (endo)-5-((3-amino-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-7-(3-hydroxynaphthalen-1-yl)-6-methylquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (650 mg, 1.061 mmol) and methyl 4-oxobutanoate (370 mg, 3.18 mmol) in ethanol (5.3 mL) were stirred at 60° C. for 18 hours. LiOH (203 mg, 8.49 mmol) in water (0.5 mL) was added. The reaction mixture was stirred at room temperature for an additional hour. The reaction mixture was diluted with acetonitrile / water and purified using preparative LCMS (XBridge C18 column eluting with a gradient of acetonitrile / water containing 0.1% TFA at a flow rate of 60 mL / min) to give the desired product 3-(1-((endo)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-8-methyl-1H-imidazo[4,5-c]quinolin-2-yl)propanoic acid (290 mg, 39.3% yield) as the TFA salt. LCMS (M+H) + :m / zC 34 H 36 Calculated for FN6O3 595.3; Found 595.2.

[0316] Step 3. 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-8-methyl-1H-imidazo[4,5-c]quinolin-2-yl)-1-(4-(pyrimidin-2-yl)piperazin-1-yl)propan-1-one To a 1-dram vial was added 3-(1-((endo)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-8-methyl-1H-imidazo[4,5-c]quinolin-2-yl)propanoic acid (7 mg, 10.07 μmol), 2-(piperazin-1-yl)pyrimidine (4 mg, 20.1 μmol), and DIPEA (5.28 μL, 0.030 mmol) in DCM (0.50 mL), BOP (5.79 mg, 0.013 mmol). The reaction mixture was stirred for 1 hour. Concentrated HCl (50 μL) was then added. After cooling to room temperature, the mixture was diluted with acetonitrile / water and purified using preparative LCMS (XBridge C18 column eluting with a gradient of acetonitrile / water containing 0.1% TFA at a flow rate of 60 mL / min) to give the desired product as the TFA salt. The product was isolated as a pair of diastereomers. Example 2a Diastereomer 1: Peak 1: LCMS (M+H) + m / zC 42 H 46 FN 10 Calculated value for O2 741.4; measured value 741.3. Example 2b Diastereomer 2: Peak 2: LCMS (M+H) + m / zC 42 H 46 FN 10 Calculated value for O2 741.4; measured value 741.3.

[0317] Example 3a and Example 3b. 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(3-oxo-3-(7-oxa-2-azaspiro[3.5]nonan-2-yl)propyl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile [ka]

[0318] Step 1. 3-(1-((endo)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-2-yl)propanoic acid [ka] Part A: In a 10-dram vial, to tert-butyl (endo)-5-((3-amino-6-((E)-2-cyanovinyl)-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Intermediate 5, 2.0 g, 2.88 mmol) in THF (14 mL) was added L-selectride (5.77 ml, 1 M in THF, 5.77 mmol) dropwise at 0 °C for 1 h. HO (30 mL) was then added to the reaction mixture, followed by extraction with dichloromethane (30 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated. The crude product was used as is without further purification.

[0319] Part B: To a solution of the above crude product in EtOH (20 mL) was added methyl 4-oxobutanoate (1.0 g, 8.65 mmol). The reaction mixture was stirred at 60° C. for 18 h. Then LiOH (0.414 g, 17.30 mmol) in water (2 mL) was added. After an additional hour, the reaction mixture was diluted with MeOH and then purified by preparative HPLC (pH=2, acetonitrile / water+TFA) to give the desired product 3-(1-((endo)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-2-yl)propanoic acid (270 mg, 12.0% yield) as the TFA salt. LCMS (M+H) + :m / zC 43 H 49 Calculated for FN7O6: 778.4; Found: 778.3

[0320] Step 2. 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(3-oxo-3-(7-oxa-2-azaspiro[3.5]nonan-2-yl)propyl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile To a 1-dram vial was added 3-(1-((endo)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-2-yl)propanoic acid (10 mg, 0.013 mmol), 7-oxa-2-azaspiro[3.5]nonane (3.2 mg, 0.026 mmol), and DIPEA (6.74 μL, 0.039 mmol) in DMF (0.5 mL), BOP (7.4 mg, 0.017 mmol). The reaction mixture was stirred for 1 hour. Concentrated HCl (50 μL) was then added. After 30 min, the mixture was diluted with acetonitrile / water and purified using preparative LCMS (XBridge C18 column eluting with a gradient of acetonitrile / water containing 0.1% TFA at a flow rate of 60 mL / min) to give the desired product as the TFA salt. The product was isolated as a pair of diastereomers. Example 3a Diastereomer 1: Peak 1: LCMS (M+H) + m / zC 43 H 48 Calculated for FN8O3: 743.4; Found: 743.3 Example 3b Diastereomer 2: Peak 2: LCMS (M+H) + m / zC 43 H 48 Calculated for FN8O3: 743.4; Found: 743.3

[0321] Example 4a and Example 4b. 3-(2-(3-(4-acetylpiperazin-1-yl)-3-oxopropyl)-1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile [ka] This compound was prepared by substituting 1-(piperazin-1-yl)ethan-1-one for 7-oxa-2-azaspiro[3.5]nonane according to the procedure described in Example 3, Step 2. The product, 3-(2-(3-(4-acetylpiperazin-1-yl)-3-oxopropyl)-1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile, was isolated as a pair of diastereomers. Example 4a Diastereomer 1: Peak 1: LCMS (M+H) + m / zC 42 H 47 Calculated for FN9O3: 744.4; Found: 744.3 Example 4b Diastereomer 2: Peak 2: LCMS (M+H) + m / zC 42 H 47 Calculated for FN9O3: 744.4; Found: 744.3

[0322] Example 5a and Example 5b. 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile [ka]

[0323] Step 1. (endo)-5-(2-(chloromethyl)-8-(2-cyanoethyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] In a 10-dram vial, (endo)-tert-butyl 5-((3-amino-6-(2-cyanoethyl)-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-7-(3-hydroxynaphthalen-1-yl)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Intermediate 6,774 mg, 0.891 mmol) and 2-chloro-1,1,1-triethoxyethane (525 mg, 2.67 mmol) in acetic acid (4.45 mL) were stirred at 100° C. for 0.5 h. The reaction mixture was concentrated and diluted with DCM. Saturated NaHCO (15 mL) was added to the reaction mixture, followed by extraction with dichloromethane (10 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated. The crude product was added to a silica gel column and eluted with 0-5% methanol / dichloromethane to give tert-butyl (endo)-5-(2-(chloromethyl)-8-(2-cyanoethyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (440 mg, 70% yield). LCMS (M+H) + :m / zC 39 H 42 Calculated for ClFN7O3 710.3; Found 710.3

[0324] Step 2. 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile In a 1-dram vial, 2.5 M nBuLi (56.3 μL, 0.141 mmol) in hexane was added to pyrrolidin-2-one (10.3 mg, 0.141 mmol) in THF (0.141 mL). After 15 minutes, tert-butyl (endo)-5-(2-(chloromethyl)-8-(2-cyanoethyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (20 mg, 0.028 mmol) in THF (0.5 mL) was added. The resulting mixture was stirred at 60° C. for 5 hours. Concentrated HCl (50 μL) was then added. After 30 min, the mixture was diluted with acetonitrile / water and purified using preparative LCMS (XBridge C18 column eluting with a gradient of acetonitrile / water containing 0.1% TFA at a flow rate of 60 mL / min) to give the desired product as the TFA salt. The product was isolated as a pair of diastereomers. Example 5a Diastereomer 1: Peak 1: LCMS (M+H) + m / zC 38 H 40 Calculated value for FN8O2: 659.3; Measured value: 659.3 Example 5b Diastereomer 2: Peak 2: LCMS (M+H) + m / zC 38 H 40 Calculated value for FN8O2: 659.3; Measured value: 659.3

[0325] Example 6a and Example 6b. 4-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-2-ethyl-6-fluoro-8-(oxazol-5-yl)-1H-imidazo[4,5-c]quinolin-7-yl)naphthalen-2-ol [ka]

[0326] Step 1. (endo)-5-(7-bromo-8-chloro-4-(3-(dimethylamino)azetidin-1-yl)-2-ethyl-6-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] In a 10-dram vial, tert-butyl (endo)-5-((3-amino-7-bromo-6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoroquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Intermediate 8, 2720 mg, 4.77 mmol) and 1,1,1-triethoxypropane (2881 μL, 14.32 mmol) in acetic acid (23 mL) were stirred at 80° C. for 0.5 h. The reaction mixture was concentrated and diluted with DCM. Saturated NaHCO (30 mL) was added to the reaction mixture, followed by extraction with dichloromethane (20 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated. The crude product was added to a silica gel column and eluted with 0-5% methanol / dichloromethane to give tert-butyl (endo)-5-(7-bromo-8-chloro-4-(3-(dimethylamino)azetidin-1-yl)-2-ethyl-6-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (3.9 g, 100% yield). LCMS (M+H) + :m / zC 27 H 34 Calculated for BrClFN6O2: 607.2; Found: 607.3

[0327] Step 2. (endo)-5-(8-chloro-4-(3-(dimethylamino)azetidin-1-yl)-2-ethyl-6-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] In a 10-dram vial, Pd(PhP) (0.214 g, 0.185 mmol) was added to tert-butyl (endo)-5-(7-bromo-8-chloro-4-(3-(dimethylamino)azetidin-1-yl)-2-ethyl-6-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (1.5 g, 1.850 mmol), 2-(3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate 4, 1.163 g, 3.70 mmol), and NaCO (0.981 g, 9.25 mmol) in 1,4-dioxane (10 mL) and water (2 mL). The reaction mixture was heated to 100 °C for 2 h. HO (5 mL) was added to the reaction mixture, which was then extracted with dichloromethane (10 mL × 3). The combined organic layers were then washed with HO (10 mL), dried over NaSO, filtered, and concentrated. The crude product was added to a silica gel column and eluted with 0-5% methanol / dichloromethane to give tert-butyl (endo)-5-(8-chloro-4-(3-(dimethylamino)azetidin-1-yl)-2-ethyl-6-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (1.36 g, 100% yield). LCMS (M+H) + :m / zC 39 H 45 Calculated for ClFN6O4 715.3; Found 715.3

[0328] Step 3. 4-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-2-ethyl-6-fluoro-8-(oxazol-5-yl)-1H-imidazo[4,5-c]quinolin-7-yl)naphthalen-2-ol In a 1-dram vial, (endo)-tert-butyl 5-(8-chloro-4-(3-(dimethylamino)azetidin-1-yl)-2-ethyl-6-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (20 mg, 0.028 mmol) and oxazol-5-ylboronic acid (5.66 mg, 0.034 mmol) were dissolved in 1,4-dioxane (0.5 mL) and water (0.1 mL). KPO (11.9 mg, 0.056 mmol) and XPhos Pd G (2.200 mg, 2.80 μmol) were added to the reaction mixture. The reaction mixture was heated to 105 °C for 2 hours. Concentrated HCl (50 μL) was then added. After 30 min, the mixture was diluted with acetonitrile / water and purified using preparative LCMS (XBridge C18 column eluting with a gradient of acetonitrile / water containing 0.1% TFA at a flow rate of 60 mL / min) to give the desired product as the TFA salt. The product was isolated as a pair of diastereomers. Example 6a Diastereomer 1: Peak 1: LCMS (M+H) + m / zC 35 H 35 Calculated for FN7O2 604.3; Measured 604.3 Example 6b Diastereomer 2: Peak 2: LCMS (M+H) + m / zC 35 H 35 Calculated for FN7O2 604.3; Measured 604.3

[0329] Examples 7a, 7b, and 7c. 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-8-yl)-3-(1H-pyrazol-1-yl)propanenitrile [ka]

[0330] Step 1. (endo)-5-(8-((E)-2-cyanovinyl)-4-(3-(dimethylamino)azetidin-1-yl)-2-ethyl-6-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] In a 10-dram vial, tert-butyl (endo)-5-((3-amino-6-((E)-2-cyanovinyl)-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Intermediate 5, 2720 mg, 4.77 mmol) and 1,1,1-triethoxypropane (2881 μL, 14.32 mmol) in acetic acid (23 mL) were stirred at 80° C. for 0.5 h. The reaction mixture was concentrated and diluted with DCM. Saturated NaHCO (30 mL) was added to the reaction mixture, followed by extraction with dichloromethane (20 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated. The crude product was added to a silica gel column and eluted with 0-5% methanol / dichloromethane to give tert-butyl (endo)-5-(8-((E)-2-cyanovinyl)-4-(3-(dimethylamino)azetidin-1-yl)-2-ethyl-6-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (1.36 g, 100% yield). LCMS (M+H) + :m / zC 42 H 47 Calculated for FN7O4: 732.4; Found: 732.3

[0331] Step 2. 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-8-yl)-3-(1H-pyrazol-1-yl)propanenitrile To tert-butyl (endo)-5-(8-((E)-2-cyanovinyl)-4-(3-(dimethylamino)azetidin-1-yl)-2-ethyl-6-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (10 mg, 0.014 mmol) in acetonitrile (0.137 mL) in a 1-dram vial was added pyrazole (10 mg, 0.14 mmol) and DBU (20.6 μL, 0.14 mmol). The reaction mixture was stirred at 95° C. for 5 hours. Concentrated HCl (50 μL) was then added. After 30 min, the mixture was diluted with acetonitrile / water and purified using preparative LCMS (XBridge C18 column eluting with a gradient of acetonitrile / water containing 0.1% TFA at a flow rate of 60 mL / min) to give the desired product as the TFA salt. The product was isolated as a pair of diastereomers. Example 7a Diastereomer 1: Peak 1: LCMS (M+H) + m / zC 38 H 39 Calculated value for FN9O: 656.3; Measured value: 656.3 Example 7b Diastereomer 2: Peak 2: LCMS (M+H) + m / zC 38 H 39 Calculated value for FN9O: 656.3; Measured value: 656.3 Example 7c Diastereomer 3: Peak 2: LCMS (M+H) + m / zC 38 H 39 Calculated value for FN9O: 656.3; Measured value: 656.3

[0332] Example 8a, Example 8b, and Example 8c. 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-8-yl)-3-(4-(hydroxymethyl)-1H-pyrazol-1-yl)propanenitrile [ka] This compound was prepared according to the procedure described in Example 7, substituting (1H-pyrazol-4-yl)methanol for pyrazole in step 2. The product, 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-8-yl)-3-(4-(hydroxymethyl)-1H-pyrazol-1-yl)propanenitrile, was isolated as a pair of diastereomers. Example 8a Diastereomer 1: Peak 1: LCMS (M+H) + m / zC 39 H 41 Calculated for FN9O2 686.3; Found 686.3 Example 8b Diastereomer 1: Peak 1: LCMS (M+H) + m / zC 39 H 41 Calculated for FN9O2 686.3; Found 686.3 Example 8c Diastereomer 1: Peak 1: LCMS (M+H) + m / zC 39 H 41 Calculated for FN9O2 686.3; Found 686.3

[0333] Example 9. 3-(8-((1H-pyrazol-1-yl)methyl)-1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-dimethylpropanamide [ka]

[0334] Step 1. (endo)-5-(7-bromo-8-chloro-2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] To tert-butyl (endo)-5-((3-amino-7-bromo-6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoroquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Intermediate 8, 1153 mg, 2.023 mmol) in ethanol (10 mL) in a 10-dram vial was added N,N-dimethyl-4-oxobutanamide (523 mg, 4.05 mmol). The reaction mixture was stirred at 70° C. for 18 hours. The reaction mixture was concentrated to dryness, loaded onto a silica gel column, and eluted with 0% to 5% methanol / dichloromethane to give tert-butyl (endo)-5-(7-bromo-8-chloro-2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (884 mg, 1.302 mmol, 64.3% yield). LCMS (M+H) + :m / zC 30 H 39Calculated for BrClFN7O3: 678.2; Found: 678.3

[0335] Step 2. (endo)-5-(8-chloro-2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] In a 10-dram vial, (endo)-5-(7-bromo-8-chloro-2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate in 1,4-dioxane (6.5 mL) and water (1.1 mL) To tert-butyl carboxylate (0.884 g, 1.302 mmol), 2-(3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate 4, 0.614 g, 1.953 mmol), and NaCO (0.690 g, 6.51 mmol) was added Pd(PhP) (0.301 g, 0.260 mmol). The reaction mixture was heated to 105 °C for 2 h. HO (10 mL) was added to the reaction mixture, which was then extracted with dichloromethane (10 mL × 3). The combined organic layers were then washed with HO (20 mL), dried over NaSO, filtered, and concentrated. The crude product was added to a silica gel column and eluted with 0-5% methanol / dichloromethane to give tert-butyl (endo)-5-(8-chloro-2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (0.895 g, 87% yield). LCMS (M+H) + :m / zC42 H 50 Calculated for ClFN7O5: 786.4; Found: 786.3

[0336] Step 3. (endo)-5-(2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-8-vinyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] In a 10-dram vial, XPhos Pd G2 (176 mg, 0.224 mmol) was added to tert-butyl (endo)-5-(8-chloro-2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (880 mg, 1.119 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (862 mg, 5.60 mmol), and KPO (712 mg, 3.36 mmol) in 1,4-dioxane (5.60 mL) and water (1.1 mL). The reaction mixture was heated to 110 °C for 2 h. HO (5 mL) was added to the reaction mixture, which was then extracted with dichloromethane (10 mL × 3). The combined organic layers were then washed with HO (20 mL), dried over NaSO, filtered, and concentrated. The crude product was added to a silica gel column and eluted with 0-5% methanol / dichloromethane to give tert-butyl (endo)-5-(2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-8-vinyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (480 mg, 55.1% yield). LCMS (M+H)+ :m / zC 44 H 53 Calculated for FN7O5: 778.4; Found: 778.3

[0337] Step 4. (endo)-5-(2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-8-formyl-7-(3-(methoxymethoxy)naphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] To a 10-dram vial was added tert-butyl (endo)-5-(2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-8-vinyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (462 mg, 0.594 mmol) and sodium periodate (191 mg, 0.891 mmol) in THF (3.0 mL) and water (3.0 mL), and 0.4% aqueous osmium tetroxide (466 μL, 5.94 μmol) was added. The reaction mixture was stirred for 3 hours. H2O (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (10 mL x 3), and then the combined organic layers were washed with H2O (20 mL), dried over Na2SO4, concentrated and used in the next step without further purification. LCMS (M+H) + :m / zC 43 H 51 Calculated for FN7O6: 780.4; Found: 780.3

[0338] Step 5. (endo)-5-(2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-8-(hydroxymethyl)-7-(3-(methoxymethoxy)naphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] To tert-butyl (endo)-5-(2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-8-formyl-7-(3-(methoxymethoxy)naphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (0.234 g, 0.3 mmol) in MeOH (3.0 mL) was added NaBH (0.011 g, 0.300 mmol) in a 10-dram vial. The reaction mixture was stirred for 30 minutes. HO (15 mL) was added to the reaction mixture, followed by extraction with dichloromethane (10 mL × 3), and the combined organic layers were then washed with HO (20 mL), dried over NaSO, filtered, and concentrated. The crude product was added to a silica gel column and eluted with 0-5% methanol / dichloromethane to give tert-butyl (endo)-5-(2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-8-(hydroxymethyl)-7-(3-(methoxymethoxy)naphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (80 mg, 34.1% yield). LCMS (M+H) + :m / zC 43 H 53 Calculated for FN7O6: 782.4; Found: 782.3

[0339] Step 6. 3-(8-((1H-pyrazol-1-yl)methyl)-1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-dimethylpropanamide To tert-butyl (endo)-5-(2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-8-(hydroxymethyl)-7-(3-(methoxymethoxy)naphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (0.02 g, 0.026 mmol) in DCM (0.5 mL) in a 1-dram vial was added TEA (0.021 mL, 0.153 mmol) and Ms-Cl (5.98 μL, 0.077 mmol) at −78° C. After 15 min, pyrazole (4.4 mg, 0.077 mmol) was added. The resulting mixture was slowly warmed and stirred at room temperature. After 16 hours, the reaction mixture was concentrated to dryness and dissolved in MeOH (0.5 mL). To the reaction mixture was added concentrated HCl (0.5 mL). After 30 minutes, the mixture was diluted with acetonitrile / water and purified using preparative LCMS (XBridge C18 column eluting with a gradient of acetonitrile / water containing 0.1% TFA at a flow rate of 60 mL / min) to give the desired product as a TFA salt and a mixture of diastereomers. LCMS (M+H) + m / zC 39 H 43 Calculated value for FN9O2: 688.4; Measured value: 688.3.

[0340] Example 10. 3-(1-(2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichloro-6-hydroxyphenyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-dimethylpropanamide [ka]

[0341] Step 1. tert-Butyl 5-(8-(2-cyanoethyl)-2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] To a 10-dram vial was added tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Intermediate 9, 1.2 g, 1.7 mmol), bis(pinacolato)diboron (2.6 g, 10.3 mmol), PCy3 Pd G4 (0.228 g, 0.344 mmol), and potassium acetate (1.013 g, 10.3 mmol) in DMF (17.2 mL). The reaction mixture was heated to 85° C. for 5 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was concentrated and purified by flash chromatography (DCM / MeOH = 0-20%) to give tert-butyl 5-(8-(2-cyanoethyl)-2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (0.5 g, 39% yield). LCMS (M+H) + :m / zC 39 H 55 Calculated for BFN8O5 745.4; Found 745.4

[0342] Step 2. 3-(1-(2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichloro-6-hydroxyphenyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-dimethylpropanamide In a 1-dram vial, 3-(1-(2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-dimethylpropanamide (30 mg, 0.04 mmol), 2-bromo-3,4-dichlorophenol (19.5 mg, 0.08 mmol), RuPhos Pd G3 (6.7 mg, 8.1 μmol), and RuPhos (3.8 mg, 8.1 μmol) in dioxane / water (4 / 1, 0.5 mL total) were stirred at 80° C. for 3 hours. The reaction mixture was filtered through a SiliaPrep SPE thiol cartridge. The filtrate was concentrated and then dissolved in DCM / TFA (1 / 1, 2.0 mL total). The mixture was then concentrated, diluted with acetonitrile / water, and purified using preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% TFA at a flow rate of 60 mL / min) to give the desired product as a TFA salt and a diastereomeric mixture. LCMS (M+H) + m / zC 34 H 38 Calculated for Cl2FN8O2 678.2; Found 678.2

[0343] Example 11. 3-(1-(2-azabicyclo[2.1.1]hexan-5-yl)-7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-dimethylpropanamide [ka]

[0344] Step 1. 7-Bromo-8-fluoro-2H-benzo[d][1,3]oxazine-2,4(1H)-dione [ka] To a solution of 2-amino-4-bromo-3-fluorobenzoic acid (10.0 g, 42.7 mmol) in 1,4-dioxane (300 mL), triphosgene (12.68 g, 42.7 mmol) was added and stirred at 100 °C for 1 hour. After cooling to room temperature, ice was added until a solid precipitated. The mixture was then thoroughly diluted with water (final volume approximately 600 mL), and the solid was collected by filtration and then air-dried. The crude product was used in the next step without further purification.

[0345] Step 2. 7-Bromo-8-fluoro-3-nitroquinoline-2,4-diol [ka] To a solution of ethyl 2-nitroacetate (4.35 g, 32.7 mmol) in toluene (20.0 mL) was added DIPEA (11.4 ml, 65.4 mmol) at room temperature and stirred for 10 minutes. 7-Bromo-8-fluoro-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (8.5 g, 32.7 mmol) was then added to the reaction mixture, and the reaction was stirred at 95° C. for 3 hours. The reaction was cooled with ice water, and then 1N HCl (70 mL) was added. The solid precipitate was collected by filtration and washed with a small amount of ethyl acetate to give the desired product as a yellow solid (7.5 g, 76%). LCMS (M+H) + m / z Calculated for C9H5BrFN2O4 302.9; Found 302.9

[0346] Step 3. 7-Bromo-2,4-dichloro-8-fluoro-3-nitroquinoline [ka] To a mixture of 7-bromo-8-fluoro-3-nitroquinoline-2,4-diol (7.0 g, 23.1 mmol) in POCl (10.8 mL, 115 mmol) was added DIPEA (8.1 mL, 46.2 mmol), and the reaction was then stirred for 3 h at 105° C. The solvent was removed in vacuo and then azeotroped three times with toluene to give the crude material, which was used in the next step without further purification.

[0347] Step 4. tert-Butyl 5-((3-amino-7-bromo-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoroquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] To a mixture of 7-bromo-2,4-dichloro-8-fluoro-3-nitroquinoline (5.0 g, 14.7 mmol) in CHCl (100 mL), tert-butyl (endo)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylate (3.06 g, 15.44 mmol) and DIPEA (15.4 mL, 88 mmol) were added, and the reaction was stirred at 55 °C for 1 h. N,N-dimethylazetidin-3-amine dihydrochloride (3.01 g, 22.06 mmol) was then added. After heating at 55 °C for an additional 2 h, the mixture was concentrated to dryness. Sodium hydrosulfite (13.6 g, 66.2 mmol) in water (50 mL) was added to a solution of the above crude mixture and 30% aqueous ammonium hydroxide (50 mL) in MeOH (100 mL) at 0 °C. After 10 minutes, water (100 mL) was added to the reaction mixture, followed by extraction with dichloromethane (100 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with 0-10% methanol / dichloromethane to give tert-butyl 5-((3-amino-7-bromo-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoroquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (6.5 g, 83% yield). LCMS (M+H) + :m / zC 24H 33 Calculated for BrFN6O2: 535.2; Found: 535.2

[0348] Step 5. tert-Butyl 5-(7-bromo-2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] In a 1-dram vial, tert-butyl 5-((3-amino-7-bromo-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoroquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (0.5 g, 0.934 mmol) and N,N-dimethyl-4-oxobutanamide (0.18 g, 1.4 mmol) in ethanol (5 mL) were stirred at 80° C. for 2 hours while capped, then open to air for an additional 4 hours. The reaction mixture was concentrated and used directly in the next step without further purification. LCMS (M+H) + :m / zC 30 H 40 Calculated for BrFN7O3: 644.2; Found: 644.3

[0349] Step 6. 3-(1-(2-Azabicyclo[2.1.1]hexan-5-yl)-7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-dimethylpropanamide In a 1-dram vial, tert-butyl 5-(7-bromo-2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (30 mg, 0.047 mmol), 2-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (31.5 mg, 0.093 mmol), Pd(PPh) (10.8 mg, 9.31 μmol), and potassium carbonate (19.3 mg, 0.14 mmol) were added to dioxane / water (4 / 1, 0.5 mL total). The reaction mixture was refluxed for 3 h. After cooling to room temperature, the reaction mixture was filtered through a SiliaPrep SPE thiol cartridge. The filtrate was concentrated and then dissolved in DCM / TFA (1 / 1 ratio, 2.0 mL total). The mixture was then concentrated, diluted with acetonitrile / water, and purified using preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% TFA at a flow rate of 60 mL / min) to give the desired product as a TFA salt and a diastereomeric mixture. LCMS (M+H) + m / zC 34 H 40 Calculated for ClFN7O2 632.3; Found 632.3

[0350] Example 12. 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-6-(3-cyanophenyl)-4-(3-(dimethylamino)azetidin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-dimethylpropanamide [ka] A solution of tert-butyl (endo)-5-(6-bromo-7-chloro-8-(2-cyanoethyl)-2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Intermediate 11, 30 mg, 0.042 mmol), (3-cyanophenyl)boronic acid (9.3 mg, 0.063 mmol), palladium tetrakis (9.7 mg, 8.4 μmol), and KPO (26.8 mg, 0.126 mmol) in dioxane (1.0 mL) / water (0.2 mL) was flushed with N for 2 min and stirred at 100 °C for 1 h. The reaction mixture was cooled to room temperature, quenched with water and extracted with EtOAc. The combined organic extracts were dried, concentrated under reduced pressure and used without further purification. LCMS (M+H) + :m / zC 40 H 47 Calculated for ClN9O3 736.4; Found 736.4

[0351] A solution of the above residue, (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (17 mg, 0.063 mmol), XPhos Pd G2 (6.6 mg, 8.4 μmol), and K3PO4 (26.8 mg, 0.126 mmol) in dioxane (1.0 mL) / water (0.2 mL) was flushed with N2 for 2 min and stirred at 100 °C for 1 h. The resulting mixture was filtered through a thiol cartridge and concentrated. DCM (1 mL) was then added, followed by the slow addition of TFA (1 mL). The mixture was stirred at room temperature for 30 h, diluted with MeOH, and analyzed by preparative LCMS (XBridge eluting with a gradient of acetonitrile / water containing 0.1% TFA at a flow rate of 60 mL / min). Purification using a C18 column gave the desired product as a TFA salt. The product was isolated as a mixture of diastereomers. LCMS (M+H) + :m / zC 45 H 46 Calculated for ClN9O2 744.4; Found 744.4

[0352] Example 13. 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-4-(3-(dimethylamino)azetidin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-6-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-dimethylpropanamide [ka] This compound was prepared according to the procedure described in Example 12, substituting 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyridine for (3-cyanophenyl)boronic acid. The product was isolated as a TFA salt and a mixture of diastereomers. LCMS (M+H) + :m / zC 46 H 48 N 11 Calculated value for O2: 786.4; Measured value: 786.4

[0353] Example 14. 3-(6-(benzyloxy)-1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-4-(3-(dimethylamino)azetidin-1-yl)-7-(7-fluoronaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-dimethylpropanamide [ka]

[0354] Step 1. (endo)-5-(7-chloro-8-(2-cyanoethyl)-2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-hydroxy-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] To a solution of (endo)-5-(6-bromo-7-chloro-8-(2-cyanoethyl)-2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Intermediate 11, 220 mg, 0.308 mmol) and 40% aqueous tetrabutylammonium hydroxide (799 mg, 1.232 mmol) in 1,4-dioxane (3.0 mL) in a 1-dram vial was added tBuBrettPhos Gd G3 (40 mg, 0.046 mmol). The reaction mixture was flushed with N2 for 2 minutes and heated to 100 °C for 1 hour. The resulting mixture was quenched with water, extracted with EtOAc, dried, and concentrated under reduced pressure. The residue was redissolved in THF (3.0 mL), followed by the addition of TEA (429 μL, 3.08 mmol). The reaction mixture was cooled to 0° C., followed by the dropwise addition of TFAA (131 μL, 0.924 mmol). The resulting mixture was stirred at room temperature for 1 h, quenched with saturated aqueous NaHCO3, and extracted with EtOAc. The combined organic extracts were dried and concentrated under reduced pressure. The desired product was obtained by flash column chromatography (0-20% MeOH:DCM). LCMS (M+H) + :m / zC 33 H 44 Calculated for ClN8O4 651.3; Found 651.4

[0355] Step 2. (endo)-5-(8-(2-cyanoethyl)-2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-7-(7-fluoronaphthalen-1-yl)-6-hydroxy-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] A solution of tert-butyl (endo)-5-(7-chloro-8-(2-cyanoethyl)-2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-hydroxy-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (125 mg, 0.192 mmol), 2-(7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (78 mg, 0.29 mmol), XPhos Pd G (30 mg, 0.038 mmol), and KPO (122 mg, 0.576 mmol) in dioxane (1.0 mL) / water (0.2 mL). The reaction mixture was flushed with N2 for 2 minutes and stirred at 100 °C for 1 hour. The resulting mixture was cooled to room temperature, quenched with water, and extracted with EtOAc. The combined organic extracts were dried, concentrated under reduced pressure, and used without further purification. LCMS (M+H) + :m / zC 43 H 50 Calculated for FN8O4: 761.4; Found: 761.5

[0356] Step 3. 3-(6-(benzyloxy)-1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-4-(3-(dimethylamino)azetidin-1-yl)-7-(7-fluoronaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-dimethylpropanamide A solution of tert-butyl (endo)-5-(8-(2-cyanoethyl)-2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-7-(7-fluoronaphthalen-1-yl)-6-hydroxy-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (30 mg, 0.039 mmol), benzyl bromide (13 mg, 0.079 mmol), and CsCO (38.5 mg, 0.118 mmol) in MeCN (1.0 mL) was stirred at 70 °C for 1 h. The resulting mixture was cooled to room temperature, filtered through a PTFE syringe filter, and concentrated. The residue was diluted with DCM (1 mL), and then TFA (1 mL) was slowly added. The resulting mixture was stirred at room temperature for 15 minutes, diluted with MeOH, and purified using preparative LCMS (XBridge C18 column eluting with a gradient of acetonitrile / water containing 0.1% TFA at a flow rate of 60 mL / min) to give the desired product as a TFA salt. The product was isolated as a mixture of diastereomers. LCMS (M+H) + :m / zC 45 H 48 Calculated value for FN8O2: 751.4; Measured value: 751.5

[0357] Example 15. 3-(1-((endo)2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-9-(hydroxymethyl)-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-dimethylpropanamide [ka] To a solution of tert-butyl (endo)5-(2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-9-formyl-7-(3-(methoxymethoxy)naphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Intermediate 12, 25 mg, 0.03 mmol) in MeOH (1 mL) was added NaBH (3.64 mg, 0.1 mmol), and the mixture was stirred for 1 h. The reaction was concentrated in vacuo, then TFA (1 mL) was added, and the resulting mixture was stirred for 10 min to remove Boc and MOM. Upon completion, the reaction was diluted with MeOH and purified using preparative LCMS (XBridge C18 column eluting with a gradient of acetonitrile / water containing 0.1% TFA at a flow rate of 60 mL / min) to give Example 15 as the TFA salt. The product was isolated as a mixture of diastereomers. LCMS (M+H) + m / zC 36 H 41 Calculated for FN7O3 638.3; Found 638.3

[0358] Example 16. 3-(1-((endo)2-azabicyclo[2.1.1]hexan-5-yl)-9-((3-cyanopyrrolidin-1-yl)methyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-dimethylpropanamide [ka] To a solution of (endo)tert-butyl 5-(2-(3-(dimethylamino)-3-oxopropyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-9-formyl-7-(3-(methoxymethoxy)naphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Intermediate 12, 15 mg, 0.02 mmol) and pyrrolidine-3-carbonitrile (3.80 mg, 0.04 mmol) in DCE (1 mL) was added sodium triacetoxyborohydride (8.15 mg, 0.038 mmol), and the reaction mixture was stirred overnight at room temperature. The reaction was concentrated in vacuo, and then TFA (1 mL) was added. The resulting mixture was stirred for 10 minutes to remove the Boc and MOM. Upon completion, the reaction was diluted with MeOH and purified using preparative LCMS (XBridge C18 column eluting with a gradient of acetonitrile / water containing 0.1% TFA at a flow rate of 60 mL / min) to give Example 16 as the TFA salt. The product was isolated as a mixture of diastereomers. LCMS (M+H) + m / zC 41 H 47 Calculated for FN9O2 716.4; Found 716.4

[0359] Example 17a and Example 17b. 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-4-yl)-4-fluoro-N-methylbenzamide [ka]

[0360] Step 1. (endo)-5-((7-bromo-2-chloro-8-fluoro-6-iodo-3-nitroquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] A sample of tert-butyl (endo)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylate (10.6 g, 54 mmol) was dissolved in NMP (270 mL) and stirred at room temperature. The solution was treated with N,N-diisopropylethylamine (19 mL, 110 mmol) and 7-bromo-2,4-dichloro-8-fluoro-6-iodo-3-nitroquinoline (Intermediate 1, 25 g, 54 mmol). The reaction mixture was heated to 80 °C and stirred with a magnetic stir bar.

[0361] After 30 min, LCMS indicated complete conversion to the product, with approximately 5-10% double addition. The solution was cooled to room temperature and poured into a mixture of water (300 mL) and saturated NH4Cl (100 mL). The mixture was stirred at room temperature for 30 min, at which point the resulting suspension was vacuum filtered and the solid was dried with a continuous stream of air to give tert-butyl (endo)-5-((7-bromo-2-chloro-8-fluoro-6-iodo-3-nitroquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (36 g, 57 mmol, assumed quantitative yield) as a yellow powder. LCMS (M+H) + :m / zC 19 H 19 Calculated values ​​for BrClFIN4O4: 626.9, 628.9; Found values: 626.8, 628.8

[0362] Step 2. (endo)-5-((3-amino-7-bromo-2-chloro-8-fluoro-6-iodoquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] A sample of tert-butyl (endo)-5-((7-bromo-2-chloro-8-fluoro-6-iodo-3-nitroquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (36 g, 57 mmol) was dissolved in methanol (240 mL) and water (40 mL) and stirred at room temperature. The solution was treated with ammonium hydroxide (8.1 mL, 62 mmol). Sodium dithionate (53 g, 260 mmol) was then added as a powder in five portions to the solution every 5 minutes. After 1 hour, LCMS indicated complete reduction of the starting material with two product peaks (presumably reflecting different protonation states). The reaction was quenched with water and diluted with DCM. The layers were separated, and the aqueous layer was extracted repeatedly with additional DCM and finally with 25% isopropanol in chloroform. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The product (endo)-tert-butyl 5-((3-amino-7-bromo-2-chloro-8-fluoro-6-iodoquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (36 g, 61 mmol, assumed quantitative yield) was used crude in step 3 without further purification. LCMS (M+H)+: m / z C 19 H 21 Calculated for BrClFIN4O2: 597.0, 599.0; Found: 596.9, 598.9

[0363] Step 3. (endo)-5-(7-bromo-4-chloro-2-ethyl-6-fluoro-8-iodo-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] A crude sample of tert-butyl (endo)-5-((3-amino-7-bromo-2-chloro-8-fluoro-6-iodoquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (5.5 g, 9.2 mmol) was dissolved in DMF (46 mL) and acetic acid (23 mL) in a round-bottom flask and stirred at room temperature. The solution was treated with propionaldehyde (1.9 g, 32 mmol), warmed to 80 °C, stirred, and exposed to air.

[0364] After 16 h, LCMS indicated complete conversion to the desired product. The reaction was cooled to room temperature, quenched with water, and diluted with EtOAc. The layers were separated, and the aqueous layer was extracted with additional EtOAc. The combined organic layers were washed with saturated aqueous NaHCO3, dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography (0-100% EtOAc / hexanes) to give tert-butyl (endo)-5-(7-bromo-4-chloro-2-ethyl-6-fluoro-8-iodo-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (1.4 g, 2.1 mmol, 23% yield). LCMS (M+H)+: m / z C 25 H 23 Calculated for BrClFIN4O2: 635.0, 637.0; Found: 635.0, 637.0

[0365] Step 4. (endo)-5-(7-bromo-4-chloro-8-(2-cyanoethyl)-2-ethyl-6-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] A sample of tert-butyl (endo)-5-(7-bromo-4-chloro-2-ethyl-6-fluoro-8-iodo-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (1.35 g, 2.12 mmol) was dissolved in DMF (4.5 mL) and stirred at room temperature. The solution was treated with N,N-diisopropylethylamine (0.8 mL, 4.3 mmol) and acrylonitrile (340 μL, 8.6 mmol). Tetramethylammonium formate (1.5 mL, 3.2 mmol) was added as a 30% w / w aqueous solution. The solution was degassed by bubbling nitrogen gas through it while sonicating. Finally, the solution was treated with tetrakis(triphenylphosphine)palladium(0) (125 mg, 0.11 mmol) and stirred at 80 °C.

[0366] After 150 minutes, LCMS showed complete conversion to the product (desired coupling to proto-dehalogenation appears to be 70 / 30). The reaction was cooled to room temperature, quenched with saturated NH4Cl, and diluted with EtOAc. The layers were separated, and the aqueous layer was extracted with additional EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography (0-100% EtOAc / DCM) to give tert-butyl (endo)-5-(7-bromo-4-chloro-8-(2-cyanoethyl)-2-ethyl-6-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (700 mg, 1.25 mmol, 59% yield). LCMS (M+H)+: m / z C 25 H 27 Calculated for BrClFN5O2: 562.1, 564.1; Found: 562.2, 564.2

[0367] Step 5. (endo)-5-(7-bromo-8-(2-cyanoethyl)-2-ethyl-6-fluoro-4-(2-fluoro-5-(methylcarbamoyl)phenyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] A sample of tert-butyl (endo)-5-(7-bromo-4-chloro-8-(2-cyanoethyl)-2-ethyl-6-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (50 mg, 0.089 mmol) was dissolved in NMP (0.5 mL) and water (0.1 mL) and stirred at room temperature. This solution was treated with KCO (37 mg, 0.27 mmol) and (2-fluoro-5-(methylcarbamoyl)phenyl)boronic acid (35 mg, 0.18 mmol), and finally with tetrakis(triphenylphosphine)palladium(0) (10 mg, 9 μmol). The solution was then warmed to 80 °C.

[0368] After 1 h, LCMS showed complete conversion to the desired product. The solution was cooled to room temperature, diluted with 4:1 acetonitrile / water, filtered through a SiliaPrep thiol cartridge, and purified by HPLC (pH=6.5 Method) to give tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-2-ethyl-6-fluoro-4-(2-fluoro-5-(methylcarbamoyl)phenyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (12 mg, 0.018 mmol, 20% yield). LCMS (M+H)+: m / z C 33 H 34 Calculated for BrF2N6O3: 679.2, 681.2; Found: 679.3, 681.3

[0369] Step 6. 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-4-yl)-4-fluoro-N-methylbenzamide A sample of tert-butyl (endo)-5-(7-bromo-8-(2-cyanoethyl)-2-ethyl-6-fluoro-4-(2-fluoro-5-(methylcarbamoyl)phenyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (12 mg, 0.018 mmol) was dissolved in 1,4-dioxane (0.2 mL) and water (0.05 mL) and stirred at room temperature. This solution was treated with KCO (7 mg, 0.05 mmol) and (3-hydroxynaphthalen-1-yl)boronic acid (10 mg, 0.05 mmol). The solution was degassed by bubbling with nitrogen gas and sonicating for 5 minutes. Finally, the solution was treated with Pd XPhos G (2 mg, 3 μmol) and stirred at 80 °C.

[0370] After 90 minutes, LCMS showed complete conversion to the intermediate. The reaction was cooled to room temperature, quenched with saturated aqueous NH4Cl, and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with 25% IPA / CHCl3. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. LCMS (M+H)+: m / z C 43 H 41 Calculated for F2N6O4: 743.3; Found: 743.3

[0371] The crude material was dissolved in 1 mL of 50% TFA in DCM and stirred at room temperature. After 90 min, LCMS indicated complete deprotection. The solution was concentrated in vacuo, diluted with 4:1 acetonitrile / water, filtered through a SiliaPrep thiol cartridge, and purified by HPLC (pH = 2 method) to give two diastereomers: 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-2-ethyl-6-fluoro-7-(7-fluoronaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-4-yl)-N-methylbenzamide (Peak 1: 2.5 mg, 4 μmol, 18% yield; Peak 2: 3.3 mg, 5.3 μmol, 23% yield). Both isomers were isolated as their corresponding TFA salts. Example 17a Diastereomer 1: Peak 1: LCMS (M+H)+ m / zC 38 H 33 Calculated for F2N6O2 643.3; Found 643.3. *More intense peak Example 17b Diastereomer 2: Peak 2: LCMS (M+H) + m / zC 38 H 33 Calculated value for F2N6O2: 643.3; Measured value: 643.3

[0372] Example 18. 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-ethyl-4-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile [ka]

[0373] Step 1. (endo)-5-((7-bromo-8-fluoro-6-iodo-2-(methylthio)-3-nitroquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] A sample of tert-butyl (endo)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylate (22 g, 110 mmol) was dissolved in acetonitrile (540 mL) and stirred at room temperature. The solution was treated with N,N-diisopropylethylamine (23 mL, 130 mmol) and 7-bromo-2,4-dichloro-8-fluoro-6-iodo-3-nitroquinoline (Intermediate 1, 50.3 g, 110 mmol). The reaction mixture was heated to 60° C. and stirred. After 30 minutes, LCMS showed S N Complete conversion to the Ar adduct was observed. LCMS (M+H) + :m / zC 19 H 19 Calculated values ​​for BrClFIN4O4: 626.9, 628.9; Found values: 626.8, 628.8

[0374] The mixture was then cooled to 0°C, and sodium thiomethoxide (120 mL, 360 mmol) was added as a 21% w / w aqueous solution. DMF (20 mL) was added to aid solubility of the resulting suspension. The mixture was warmed to 22°C and stirred overnight. After 16 hours, LCMS showed complete conversion of the intermediate to the desired product. The mixture was poured into 1.8 L of ice water and stirred for 1 hour. The suspension was filtered, and the solid was washed with additional water. The solid was dried overnight under a continuous stream of air to give tert-butyl (endo)-5-((7-bromo-8-fluoro-6-iodo-2-(methylthio)-3-nitroquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (66 g, 104 mmol, 96% yield). LCMS (M+H) + :m / zC 20 H 22 Calculated values ​​for BrFIN4O4S: 639.0, 641.0; Found values: 638.9, 640.9

[0375] Step 2. (endo)-5-((3-amino-7-bromo-8-fluoro-6-iodo-2-(methylthio)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] A sample of tert-butyl (endo)-5-((7-bromo-8-fluoro-6-iodo-2-(methylthio)-3-nitroquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (16 g, 25 mmol) was dissolved in ethanol (125 mL) and stirred at room temperature. The solution was treated with sodium dithionate (75 mL, 75 mmol) as a 1.0 M aqueous solution and warmed to 70 °C.

[0376] After 90 minutes, LCMS indicated the reaction was complete. Two product peaks appeared, likely reflecting different protonation states. The mixture was cooled to room temperature and quenched with aqueous ammonium hydroxide (8.6 mL, 125 mmol). The mixture was concentrated in vacuo to a total volume of approximately 100 mL. The resulting solution was repeatedly extracted with 10% methanol in dichloromethane until LCMS aliquots of the aqueous phase showed no more product remaining. The combined organic fractions were dried over MgSO4, filtered, and concentrated in vacuo to give tert-butyl (endo)-5-((3-amino-7-bromo-8-fluoro-6-iodo-2-(methylthio)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (13.1 g, 22 mmol, 86% yield). LCMS (M+H)+: m / z C 20 H 24 Calculated values ​​for BrFIN4O2S: 609.0, 611.0; Found values: 608.9, 610.9

[0377] Step 3. (endo)-5-(7-bromo-2-ethyl-6-fluoro-8-iodo-4-(methylthio)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] This compound was prepared on a 9 g (14.8 mmol) scale according to the procedure described in Example 17, Step 3, with the following modifications to the work-up and purification.

[0378] The reaction was cooled to room temperature and then poured into 800 mL of ice water. The mixture was stirred for 1 hour, at which point the suspension was filtered. The solid was dried under continuous airflow to give tert-butyl (endo)-5-(7-bromo-2-ethyl-6-fluoro-8-iodo-4-(methylthio)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (8.6 g, 13 mmol, 90% yield). LCMS (M+H)+: m / z C 23 H 26Calculated values ​​for BrFIN4O2S: 647.0, 649.0; Found values: 646.9, 648.9

[0379] Step 4. (endo)-5-(7-bromo-8-(2-cyanoethyl)-2-ethyl-6-fluoro-4-(methylthio)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] This compound was prepared on an 8.6 g (13.3 mmol) scale according to the procedure described in Example 17, Step 4, with the following modifications to the purification.

[0380] After concentration to dryness, the crude material was dissolved in methanol, filtered through a SiliaPrep thiol cartridge, and purified by supercritical fluid chromatography (SFC) to give tert-butyl (endo)-5-(7-bromo-4-chloro-8-(2-cyanoethyl)-2-ethyl-6-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (500 mg, 0.90 mmol, 12% yield). LCMS (M+H)+: m / z C 26 H 30 Calculated for BrFN5O2S: 574.1, 576.1; Found: 574.2, 576.2

[0381] Step 5. (endo)-5-(8-(2-cyanoethyl)-2-ethyl-6-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-4-(methylthio)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] A sample of tert-butyl (endo)-5-(7-bromo-8-(2-cyanoethyl)-2-ethyl-6-fluoro-4-(methylthio)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (2 g, 3.5 mmol) was dissolved in 1,4-dioxane (28 mL) and water (7 mL) and stirred at room temperature. The solution was treated with KCO (1.4 g, 10 mmol) and 2-(3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate 4, 2.7 g, 8.7 mmol). The solution was degassed by bubbling with nitrogen and sonicating for 5 minutes. Finally, the solution was treated with Pd XPhos G2 (410 mg, 0.52 mmol) and stirred at 65 °C.

[0382] After 90 minutes, LCMS showed complete conversion to the product. The reaction was cooled to room temperature, quenched with saturated aqueous NH4Cl, and diluted with EtOAc. The layers were separated, and the aqueous layer was extracted several times with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo.

[0383] The crude material was purified by flash column chromatography (0-100% EtOAc / hexanes) to give tert-butyl (endo)-5-(8-(2-cyanoethyl)-2-ethyl-6-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-4-(methylthio)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (1.9 g, 2.7 mmol, 79% yield). LCMS (M+H)+: m / z C 38 H 41 Calculated for FN5O4S: 682.3; Found: 682.3

[0384] Step 6. 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-ethyl-4-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile A sample of tert-butyl (endo)-5-(8-(2-cyanoethyl)-2-ethyl-6-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-4-(methylthio)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (20 mg, 0.03 mmol) was dissolved in 1,4-dioxane (0.3 mL) in a vial containing a stir bar and stirred at room temperature. The solution was treated with tetrakis(triphenylphosphine)palladium(0) (7 mg, 6 μmol) and copper(I) 3-methylsalicylate (23 mg, 0.11 mmol). Finally, 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (18 mg, 0.073 mmol) was added, the vial was capped, and the solution was stirred at 120°C.

[0385] After 16 h, LCMS showed complete conversion to the desired intermediate. The reaction was cooled to room temperature, quenched with aqueous NH4OH, and diluted with DCM. The layers were separated, and the aqueous layer was extracted with additional DCM. The combined organic fractions were dried over MgSO4, filtered, and concentrated in vacuo. LCMS (M+H)+: m / z C 44 H 45 Calculated for FN6O5: 757.4; Found: 757.5

[0386] The crude material was dissolved in 1 mL of 50% TFA in DCM and stirred at room temperature. After 20 minutes, LCMS indicated complete deprotection. The solution was concentrated in vacuo, diluted with 4:1 acetonitrile / water, filtered through a SiliaPrep thiol cartridge, and purified by HPLC (pH = 2 method) to give two diastereomers: 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-ethyl-4-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile (Peak 1: 2.7 mg, 4.4 μmol, 15% yield; Peak 2: contaminated, yield not determined). Peak 1 was isolated as its corresponding TFA salt. Example 18. Diastereomer 1: Peak 1: LCMS (M+H) + m / zC 37 H 34 Calculated value for FN6O2: 613.3; Measured value: 613.4

[0387] Example 19a and Example 19b. 5-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-4-yl)-N-methylpicolinamide [ka] A sample of tert-butyl (endo)-5-(8-(2-cyanoethyl)-2-ethyl-6-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-4-(methylthio)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Example 18, Step 5, 40 mg, 0.06 mmol) was dissolved in 1,4-dioxane (0.6 mL) in a vial containing a stir bar and stirred at room temperature. The solution was treated with tetrakis(triphenylphosphine)palladium(0) (14 mg, 0.012 mmol) and copper(I) 3-methylsalicylate (45 mg, 0.21 mmol). Finally, N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide (77 mg, 0.29 mmol) was added, the vial was capped, and the solution was stirred at 120°C.

[0388] After 45 min, LCMS showed complete conversion to the desired intermediate. The reaction was cooled to room temperature, quenched with aqueous NH4OH, and diluted with DCM. The layers were separated, and the aqueous layer was extracted with additional DCM. The combined organic fractions were dried over MgSO4, filtered, and concentrated in vacuo. LCMS (M+H)+: m / z C 44 H 45 Calculated for FN7O5: 770.4; Found: 770.3

[0389] The crude material was dissolved in 1 mL of 50% TFA in DCM and stirred at room temperature. After 30 min, LCMS indicated complete deprotection. The solution was concentrated in vacuo, diluted with 4:1 acetonitrile / water, filtered through a SiliaPrep thiol cartridge, and purified by HPLC (pH = 2 method) to give two diastereomers: 5-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-4-yl)-N-methylpicolinamide (Peak 1: 3.9 mg, 6 μmol, 11% yield; Peak 2: 6.7 mg, 11 μmol, 18% yield). Both isomers were isolated as their corresponding TFA salts. Example 19a Diastereomer 1: Peak 1: LCMS (M+H) + m / zC 37 H 33 Calculated value for FN7O2: 626.3; Measured value: 626.2 Example 19b Diastereomer 2: Peak 2: LCMS (M+H) + m / zC 37 H 33 Calculated value for FN7O2: 626.3; Measured value: 626.2

[0390] Example 20a and Example 20b. 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-4-(oxazol-2-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile [ka] A sample of tert-butyl (endo)-5-(8-(2-cyanoethyl)-2-ethyl-6-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-4-(methylthio)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Example 18, Step 5, 20 mg, 0.03 mmol) was dissolved in 1,4-dioxane (0.3 mL) in a vial containing a stir bar and stirred at room temperature. The solution was treated with tetrakis(triphenylphosphine)palladium(0) (7 mg, 0.006 mmol) and copper(I) 3-methylsalicylate (23 mg, 0.11 mmol). Finally, 2-(tributylstannyl)oxazole (26 mg, 0.073 mmol) was added, the vial was capped, and the solution was stirred at 90 °C.

[0391] After 3 hours, LCMS showed complete conversion to the desired intermediate. The reaction was cooled to room temperature, quenched with aqueous NH4OH, and diluted with DCM. The layers were separated, and the aqueous layer was extracted with additional DCM. The combined organic fractions were dried over MgSO4, filtered, and concentrated in vacuo. LCMS (M+H)+: m / z C40 H 40 Calculated for FN6O5: 703.3; Found: 703.3

[0392] The crude material was dissolved in 1 mL of 50% TFA in DCM and stirred at room temperature. After 30 min, LCMS indicated complete deprotection. The solution was concentrated in vacuo, diluted with 4:1 acetonitrile / water, filtered through a SiliaPrep thiol cartridge, and purified by HPLC (pH = 2 Method) to give 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-4-(oxazol-2-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile as two diastereomers. Diastereomer 1 was contaminated and was further purified by HPLC (pH = 6.5 Method). (Peak 1: 0.4 mg, 0.7 μmol, 2% yield; Peak 2: 1.4 mg, 2.5 μmol, 9% yield). Peak 2 was isolated as its corresponding TFA salt. Example 20a Diastereomer 1: Peak 1: LCMS (M+H) + m / zC 33 H 28 Calculated value for FN6O2: 559.2; Measured value: 559.1 Example 20b Diastereomer 2: Peak 2: LCMS (M+H) + m / zC 33 H 28 Calculated value for FN6O2: 559.2; Measured value: 559.1

[0393] Example 21a and Example 21b. 3-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile [ka] This compound was prepared on a 20 mg (0.029 mmol) scale according to the procedure described in Example 20, substituting 7-(tributylstannyl)-[1,2,4]triazolo[1,5-a]pyridine (30 mg, 0.073 mmol) for 2-(tributylstannyl)oxazole and modifying the purification as described below. LCMS (M+H)+ of the intermediate: m / z=C 43 H 42 Calculated for FN8O4: 753.3; Found: 753.3

[0394] After deprotection as described above, the solution was concentrated in vacuo, diluted with 4:1 acetonitrile / water, filtered through a SiliaPrep thiol cartridge, and purified by HPLC (pH = 2 method) to give two diastereomers: 3-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile (Peak 1: 1.2 mg, 2.0 μmol, 7% yield; Peak 2: 2.8 mg, 4.6 μmol, 16% yield). Both diastereomers were isolated as their corresponding TFA salts. Example 21a Diastereomer 1: Peak 1: LCMS (M+H) + m / zC 36 H 30 Calculated value for FN8O: 609.3; Measured value: 609.2 Example 21b Diastereomer 2: Peak 2: LCMS (M+H) + m / zC 36 H 30 Calculated value for FN8O: 609.3; Measured value: 609.2

[0395] Example 22a and Example 22b. 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-4-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile [ka] This compound was prepared according to the procedure described in Example 19, substituting 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (22 mg, 0.073 mmol) for N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide and modifying the purification as described below. LCMS (M+H)+ of intermediate: m / z=C 47 H 52 Calculated for FN8O4: 811.4; Found: 811.3

[0396] After deprotection as described above, the solution was concentrated in vacuo, diluted with 4:1 acetonitrile / water, filtered through a SiliaPrep thiol cartridge, and purified by HPLC (pH = 2 method) to give two diastereomers: 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-4-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile (Peak 1: 0.9 mg, 1.4 μmol, 5% yield; Peak 2: 1.5 mg, 2.3 μmol, 8% yield). Both diastereomers were isolated as their corresponding TFA salts. Example 22a Diastereomer 1: Peak 1: LCMS (M+H) + m / zC 40 H 40 Calculated value for FN8O: 667.3; Measured value: 667.3 Example 22b Diastereomer 2: Peak 2: LCMS (M+H) + m / zC 40 H 40 Calculated value for FN8O: 667.3; Measured value: 667.3

[0397] Example 23a and Example 23b. 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-4-methyl-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile [ka] The title compound was prepared as an unexpected by-product of the following coupling reaction.

[0398] A sample of 4-bromooxazole (40 mg, 0.27 mmol) was dissolved in 1,4-dioxane (0.9 mL) and treated with hexamethylditin (84 μL, 0.41 mmol) and tetrakis(triphenylphosphine)palladium(0) (31 mg, 0.027 mmol). The solution was heated to 100° C. and stirred overnight. The mixture was cooled to room temperature, diluted with EtOAc, and filtered twice through a pad of Celite. The filtrate was concentrated and used directly. No mass corresponding to the desired product, 4-(trimethylstannyl)oxazole, was observed. A mass corresponding to the trimethyltin radical or anion was observed. LCMS (M+H) + m / z = Calculated for C3H9Sn: 165.0, 163.0, 161.0; Found: 164.9, 162.9, 160.9

[0399] The crude material was dissolved in 1,4-dioxane (0.44 mL) in a vial containing a stir bar and treated with a sample of tert-butyl (endo)-5-(8-(2-cyanoethyl)-2-ethyl-6-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-4-(methylthio)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Example 18, Step 5, 30 mg, 0.044 mmol) and stirred at room temperature. The solution was treated with tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.009 mmol) and copper(I) 3-methylsalicylate (34 mg, 0.16 mmol). The vial was capped and the solution was stirred at 90 °C.

[0400] After 3 hours, LCMS showed complete conversion to tert-butyl (endo)-5-(8-(2-cyanoethyl)-2-ethyl-6-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-4-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate. The reaction was cooled to room temperature, quenched with aqueous NH4OH, and diluted with DCM. The layers were separated, and the aqueous layer was extracted with additional DCM. The combined organic fractions were dried over MgSO4, filtered, and concentrated in vacuo. LCMS (M+H)+: m / z C 38 H 41 Calculated for FN5O4: 650.3; Found: 650.4

[0401] The crude material was dissolved in 1 mL of 50% TFA in DCM and stirred at room temperature. After 30 min, LCMS indicated complete deprotection. The solution was concentrated in vacuo, diluted with 4:1 acetonitrile / water, filtered through a SiliaPrep thiol cartridge, and purified by HPLC (pH = 2 method) to give two diastereomers: 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-4-methyl-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile (Peak 1: 0.6 mg, 1.2 μmol, 3% yield; Peak 2: 1.4 mg, 2.8 μmol, 6% yield). Both diastereomers were isolated as their corresponding TFA salts. Example 23a Diastereomer 1: Peak 1: LCMS (M+H) + m / zC 31 H 29 Calculated value for FN5O: 506.2; Measured value: 506.2 Example 23b Diastereomer 2: Peak 2: LCMS (M+H) + m / zC 31 H 29 Calculated value for FN5O: 506.2; Measured value: 506.2

[0402] Example 24a and Example 24b. 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-4-phenoxy-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile [ka]

[0403] Step 1. (endo)-5-(8-(2-cyanoethyl)-2-ethyl-6-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-4-(methylsulfinyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] A sample of tert-butyl (endo)-5-(8-(2-cyanoethyl)-2-ethyl-6-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-4-(methylthio)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Example 18, Step 5; 460 mg, 0.675 mmol) was dissolved in dichloromethane (7 mL) and stirred at 0° C. The solution was treated with m-CPBA (160 mg, 75% w / w, 0.71 mmol).

[0404] After 45 minutes, LCMS showed complete conversion to the desired product, with approximately 10% of the corresponding sulfone. The reaction was quenched with saturated aqueous NaHCO3 and diluted with DCM. The layers were separated and the aqueous layer was extracted with additional DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give tert-butyl (endo)-5-(8-(2-cyanoethyl)-2-ethyl-6-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-4-(methylsulfinyl)-1H-imidazo-[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (220 mg, 0.31 mmol, 46% yield). LCMS (M+H)+: m / z C 38 H 41 Calculated for FN5O5S: 698.3; Found: 698.2

[0405] Step 2. 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-4-phenoxy-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile A sample of tert-butyl (endo)-5-(8-(2-cyanoethyl)-2-ethyl-6-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-4-(methylsulfinyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (20 mg, 0.03 mmol) was dissolved in anhydrous THF (0.3 mL) in a vial containing a stir bar and stirred at room temperature. The solution was treated with solid sodium phenolate (7 mg, 0.06 mmol) and stirred at 22 °C.

[0406] After 1 h, LCMS showed complete conversion to the desired product. The reaction was quenched with saturated aqueous NH4Cl and diluted with DCM. The layers were separated and the aqueous layer was extracted with additional DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. LCMS (M+H)+: m / z C 43 H 43 Calculated for FN5O5: 728.3; Found: 728.3

[0407] The crude material was dissolved in 1 mL of 50% TFA in DCM and stirred at room temperature. After 30 min, LCMS indicated complete deprotection. The solution was concentrated in vacuo, diluted with 4:1 acetonitrile / water, filtered through a SiliaPrep thiol cartridge, and purified by HPLC (pH = 2 method) to give two diastereomers: 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-4-phenoxy-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile (Peak 1: 1.7 mg, 2.9 μmol, 10% yield; Peak 2: 2.0 mg, 3.4 μmol, 12% yield). Both isomers were isolated as their corresponding TFA salts. Example 24a Diastereomer 1: Peak 1: LCMS (M+H) + m / zC 36 H 31 Calculated value for FN5O2: 584.3; Measured value: 584.2 Example 24b Diastereomer 2: Peak 2: LCMS (M+H)+ m / zC 36 H 31 Calculated value for FN5O2: 584.3; Measured value: 584.2

[0408] Example 25a and Example 25b. 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-cyclopropyl-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile [ka] To a solution of tert-butyl (endo)-5-((3-amino-6-(2-cyanoethyl)-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-7-(3-hydroxynaphthalen-1-yl)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Intermediate 6, 20 mg, 0.031 mmol) in EtOH (2 mL) was added cyclopropanecarbaldehyde (21.5 mg, 0.307 mmol). After stirring at room temperature for 3 days, the solution was concentrated under reduced pressure. The residue was dissolved in EtOH (2 mL) and HCl (4 M in 1,4-dioxane, 0.5 mL, 2 mmol). After stirring at 40°C for 1 hour, the mixture was diluted with acetonitrile / water and purified using preparative LCMS (XBridge column, eluting with a gradient of acetonitrile / water containing 0.1% NH4OH at a flow rate of 60 mL / min). The fractions containing the desired diastereomers were then concentrated, and the resulting material was dissolved in acetonitrile and purified by preparative LCMS (Sunfire C18 column, eluting with a gradient of acetonitrile / water containing 0.1% TFA at a flow rate of 60 mL / min). The products were isolated as a pair of diastereomers. Example 25a Diastereomer 1: Peak 1: LCMS (M+H) + m / zC 36 H 37 Calculated value for FN7O: 602.3; Measured value: 602.3 Example 25b Diastereomer 2: Peak 2: LCMS (M+H) + m / zC 36 H 37 Calculated value for FN7O: 602.3; Measured value: 602.2

[0409] Example 26a and Example 26b. 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile [ka] This compound was prepared according to the procedures described in Examples 25a and 25b, using tert-butyl 4-(4-formyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate instead of cyclopropanecarbaldehyde as the starting material, and the product was isolated as a pair of diastereomers. Example 26a Diastereomer 1: Peak 1: LCMS (M+H) + m / zC 40 H 43 FN 11 Calculated for O 712.4; Measured 712.4 Example 26b Diastereomer 2: Peak 2: LCMS (M+H) + m / zC 40 H 43 FN 11 Calculated for O 712.4; Measured 712.4

[0410] Examples 27a and 27b, 27c, and 27d. 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-(1-cyclobutyl-1H-1,2,3-triazol-4-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-4-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile [ka]

[0411] Step 1. (endo)-5-((7-bromo-8-fluoro-6-iodo-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-3-nitroquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] This compound was prepared according to the procedure described in Intermediate 2, Step 1, using (S)-(1-methylpyrrolidin-2-yl)methanol and sodium hydride instead of N,N-dimethylazetidin-3-amine dihydrochloride as starting materials. LCMS (M+H) + :m / zC 25 H 31 Calculated for BrFIN5O5: 706.1; Found: 706.3

[0412] Step 2. (endo)-5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-3-nitroquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] This compound was prepared according to the procedure described in Intermediate 3, using (endo)-5-((7-bromo-8-fluoro-6-iodo-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-3-nitroquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl instead of (endo)-5-((3-amino-7-bromo-2-(3-(dimethylamino)-azetidin-1-yl)-8-fluoro-6-iodoquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl as starting material. LCMS (M+H) + :m / zC 28 H 35 Calculated for BrFN6O5: 633.2; Found: 633.4

[0413] Step 3. (endo)-5-((3-amino-7-bromo-6-(2-cyanoethyl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] In a 100 mL round-bottom flask, tert-butyl (endo)-5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-3-nitroquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (1.44 g, 2.27 mmol), ammonium chloride (1.27 g, 23.8 mmol), and iron (1.27 g, 22.7 mmol) were mixed in a solution of THF (10 mL), methanol (10 mL), and water (10 mL). The mixture was stirred at 60 °C for 1 h. After cooling to room temperature, the resulting solution was filtered through Celite, and the residue was washed with water, methanol, and DCM. The filtrate was concentrated under reduced pressure to remove the organic solvent. The remaining mixture was extracted with DCM (100 mL × 3). The combined organic layers were washed with brine (100 mL x 1), dried over NaSO, and concentrated under reduced pressure. The residue was diluted with MeOH and purified by preparative LCMS (XBridge column eluted with a gradient of acetonitrile / water containing 0.1% NHOH at a flow rate of 60 mL / min) to give the desired product (360 mg, 0.596 mmol) in 26% yield from Step 2. LCMS (M+H) + m / zC 28 H 37 Calculated for BrFN6O3: 603.2; Found: 603.3

[0414] Step 4. (endo)-5-((3-amino-6-(2-cyanoethyl)-8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] This compound was prepared according to the procedure described for Intermediate 6, using (endo)-5-((3-amino-7-bromo-6-(2-cyanoethyl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl instead of (endo)-5-((3-amino-7-bromo-6-(2-cyanoethyl)-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoroquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate as the starting material. LCMS (M+H) + :m / zC 38 H 44 Calculated for FN6O4 667.3; Found 667.6.

[0415] Step 5. 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-(1-cyclobutyl-1H-1,2,3-triazol-4-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-4-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile This compound was prepared according to the procedures described in Examples 25a and 25b, using 1-cyclobutyl-1H-1,2,3-triazole-4-carbaldehyde instead of cyclopropanecarbaldehyde as the starting material, and the product was isolated as a single diastereomer. Example 27a Diastereomer 1: Peak 1: LCMS (M+H) + m / zC 40 H 41 Calculated value for FN9O2 698.3; found value 698.5. Example 27b Diastereomer 2: Peak 2: LCMS (M+H) + m / zC 40 H 41 Calculated value for FN9O2 698.3; found value 698.5. Example 27c Diastereomer 3: Peak 3: LCMS (M+H)+ m / zC 40 H 41 Calculated value for FN9O2 698.3; found value 698.5. Example 27d Diastereomer 4: Peak 4: LCMS (M+H) + m / zC 40 H 41 Calculated value for FN9O2 698.3; found value 698.5.

[0416] Example 28. 3-(1-(2-Azabicyclo[2.1.1]hexan-5-yl)-2-ethyl-6-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(5-methyl-1H-indol-3-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile [ka]

[0417] Step 1. (endo)-5-(7-bromo-8-(2-cyanoethyl)-2-ethyl-6-fluoro-4-(methylsulfonyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] To a 40 mL vial containing a magnetic stir bar was added tert-butyl (endo)-5-(7-bromo-8-(2-cyanoethyl)-2-ethyl-6-fluoro-4-(methylthio)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Example 18, Step 4; 736.7 mg, 1.282 mmol) and ethyl acetate (12.82 mL). The solution was cooled to 0 °C, and then m-CPBA (1.32 g, 3.85 mmol) was added in one portion. The mixture was stirred at 0 °C for 90 min. The reaction was diluted with water and ethyl acetate, the phases were separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organics were rinsed with saturated aqueous NaHCO (2x), brine, dried over sodium sulfate, filtered, and concentrated to the desired product (778 mg, 100%) as a white / pale yellow powder. This material was carried forward without further purification. LCMS (M+H) + :m / z=C 26 H 29 Calculated for BrFN5O4S 606.5; found 607.4.

[0418] Step 2. (endo)-5-(7-bromo-8-(2-cyanoethyl)-2-ethyl-6-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl [ka] To a 40 mL vial containing a magnetic stir bar was added tert-butyl (endo)-5-(7-bromo-8-(2-cyanoethyl)2-ethyl-6-fluoro-4-(methylsulfonyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (757 mg, 1.248 mmol), THF (24.96 mL), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (298 mg, 1.872 mmol), and finally potassium tert-butoxide (1 M in THF) (1872 μL, 1.872 mmol). The mixture was heated to 45 °C and stirred overnight (18 h). After the indicated time, the reaction was diluted with water and ethyl acetate, the phases were separated, and the aqueous phase was extracted with ethyl acetate (2x). The combined organics were rinsed with saturated aqueous NaHCO3, brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (0-100% ethyl acetate in hexanes, then 0-15% MeOH in dichloromethane) to give the desired product (157 mg, 19%) as a brown foam. LCMS (M+H) + :m / zC 33 H 39 Calculated for BrF2N6O3 685.6; found 686.2.

[0419] Step 3. 3-(1-(2-Azabicyclo[2.1.1]hexan-5-yl)-2-ethyl-6-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(5-methyl-1H-indol-3-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile In a 1-dram vial equipped with a stir bar, tert-butyl (endo)-5-(7-bromo-8-(2-cyanoethyl)-2-ethyl-6-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1]hexane-2-carboxylate (15 mg, 0.022 mmol), 5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (11.25 mg, 0.044 mmol), NaCO (6.96 mg, 0.066 mmol), and XPhos Pd G2 (0.861 mg, 1.094 μmol), dioxane (0.122 ml), and water (0.024 ml) were added. The mixture was capped and stirred at 100° C. for 1 hour. After this time, the reaction was cooled to room temperature, filtered to remove solids, and diluted with MeCN / water. To the mixture was added HCl (4 M in dioxane) (400 μl, 1.600 mmol). The whole was stirred at 60° C. After 30 minutes, the mixture was purified using preparative LCMS (XBridge C18 column eluting with a gradient of acetonitrile / water containing 0.1% TFA at a flow rate of 60 mL / min) to give the desired product as a TFA salt and a diastereomeric mixture. Example 28. LCMS (M+H) + m / zC 37 H 39 Calculated value for F2N7O 635.8; measured value 636.5.

[0420] Example 29. 4-((1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(2-(methylamino)ethyl)-1H-imidazo[4,5-c]quinolin-8-yl)methyl)benzonitrile [ka]

[0421] Step 1. tert-Butyl 5-(7-bromo-2-(2-((tert-butoxycarbonyl)(methyl)amino)ethyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-8-iodo-1H-imidazo[4,5-c]quinolin-1-yl)-(endo)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] To a 40 mL vial containing a magnetic stir bar was added tert-butyl (endo)-5-((3-amino-7-bromo-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-6-iodoquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Intermediate 2, 600 mg, 0.907 mmol), ethanol (4.54 mL), tert-butyl methyl(3-oxopropyl)carbamate (255 mg, 1.361 mmol), and acetic acid (51.9 μL, 0.907 mmol). The mixture was capped and stirred at 75° C. overnight (16 h). After the indicated time, the reaction was diluted with water and ethyl acetate. The phases were separated, and the aqueous layer was extracted twice more with ethyl acetate. The combined organics were rinsed with saturated aqueous NaHCO3, brine, dried over sodium sulfate, filtered, and concentrated to give the desired product as a pale yellow foam. This material was carried on to the next step without further purification. LCMS (M+H) + :m / zC 33 H 44 Calculated for BrFIN7O4 828.6; found 829.6.

[0422] Step 2. tert-Butyl 5-(7-bromo-2-(2-((tert-butoxycarbonyl)(methyl)amino)ethyl)-8-(4-cyanobenzyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)(endo)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka] To a 40 mL vial containing a magnetic stir bar was added tert-butyl 5-(7-bromo-2-(2-((tert-butoxycarbonyl)(methyl)amino)ethyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-8-iodo-1H-imidazo[4,5-c]quinolin-1-yl)(endo)-2-azabicyclo[2.1.1]hexane-2-carboxylate (50 mg, 0.060 mmol), THF (1.207 mL), Pd(Cl)(PPh) (8.47 mg, 0.012 mmol), and (2-cyanobenzyl)zinc(II) bromide (0.5 M in THF) (241 μL, 0.121 mmol). The mixture was degassed with N for 5 min, capped, and stirred at 60 °C. After 1 h, the reaction was filtered to remove solids and the filtrate was concentrated in vacuo to give the crude product as a yellow foam, which was carried on to the next step without further purification. LCMS (M+H) + :m / zC 41 H 50 Calculated for BrFN8O4 817.8; found 818.3.

[0423] Step 3. 4-((1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(2-(methylamino)ethyl)-1H-imidazo[4,5-c]quinolin-8-yl)methyl)benzonitrile In a 1-dram vial equipped with a stir bar, 4-((1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-7-bromo-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-2-(2-(methylamino)ethyl)-1H-imidazo[4,5-c]quinolin-8-yl)methyl)benzonitrile (15 mg, 0.024 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (13.12 mg, 0.049 mmol), NaCO (7.72 mg, 0.073 mmol), and XPhos Pd G2 (0.956 mg, 1.214 μmol), dioxane (0.135 ml), and water (0.027 ml) were added. The mixture was capped and stirred at 100° C. for 1 hour. After this time, the reaction was cooled to room temperature, filtered to remove solids, and diluted with acetonitrile / water. To this mixture was added HCl (4 M in dioxane) (267 μl, 1.069 mmol). The whole was stirred at 50° C. After 30 minutes, the mixture was purified using preparative LCMS (XBridge C18 column eluting with a gradient of acetonitrile / water containing 0.1% NH4OH at a flow rate of 60 mL / min) to give the desired product. The product was isolated as a mixture of diastereomers. Example 29. LCMS (M+H) + m / zC 41 H 41 Calculated value for FN8O 680.8; observed value 681.5.

[0424] Example 30. 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-ethyl-6-fluoro-7-(5-fluoro-1H-indol-3-yl)-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile [ka] This compound was prepared according to the procedure described in Example 28, replacing tert-butyl 5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate with tert-butyl 5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate in step 7.

[0425] In a 1-dram vial equipped with a stir bar, tert-butyl (endo)-5-(7-bromo-8-(2-cyanoethyl)-2-ethyl-6-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (117 μL, 0.029 mmol), tert-butyl 5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (21.07 mg, 0.058 mmol), NaCO (9.28 mg, 0.088 mmol), and XPhos Pd G2 (1.148 mg, 1.459 μmol), dioxane (0.162 ml), and water (0.032 ml) were added. The mixture was capped and stirred at 100° C. for 1 hour. After this time, the reaction was cooled to room temperature, filtered to remove solids, and diluted with MeCN / water. To the mixture was added TFA (200 μl, 2.60 mmol). The whole was stirred at 70° C. After 30 minutes, the mixture was purified using preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% TFA at a flow rate of 60 mL / min) to give the desired product. The product was isolated as a TFA salt and a diastereomeric mixture. Example 30. LCMS (M+H) + m / zC 36 H 36 Calculated value for F3N7O 639.7...

Claims

1. Compound of formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein 【Chemical 2】 is -NR ５ -C(=O)-, -N=N-, and -N=CR ６ - selected from; R １ is selected from H, D, C １－２ alkyl, and C １－２ haloalkyl; said C １－２ alkyl is optionally substituted by one or two substituents independently selected from R １１ ; Cy １ is selected from C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 6- to 10-membered heteroaryl; said 4- to 10-membered heterocycloalkyl and 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; the ring-forming carbon atoms of the 6- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl are optionally substituted by oxo to form a carbonyl group; said C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 6- to 10-membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from R １０ ; R ４ is selected from H, C １－３ alkyl, C １－３ haloalkyl, 5- to 10-membered heteroaryl, OR ａ３ , and NR ｃ３ R ｊ３ ; said C １－３ alkyl and 5- to 10-membered heteroaryl are each optionally substituted by one or two substituents independently selected from R ３０ ; or R ４ is [Chemical Formula 3] is selected from; R ５ is selected from H, C １－２ alkyl and C １－２ haloalkyl; R ７ is selected from H, C １－３ alkyl, C １－３ haloalkyl, phenyl, 5- to 6-membered heteroaryl, F, Cl, D, CN, OR ａ７ , and NR ｃ７ R ｄ７ ; said phenyl and 5- to 6-membered heteroaryl are each optionally substituted by one or two substituents independently selected from R ７０ ; Cy ２ is 【Chemical Formula 4】 is selected from; Cy ２ is Cy ２ -a and 【Chemical Formula 5】 is -N=CR ６ when it is -, R ６ is H, D, C １－３ alkyl, C １－３ haloalkyl, C ３－６ cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-10 membered heteroaryl; said C １－３ alkyl, C ３－６ cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-10 membered heteroaryl are each optional and R ６０ is substituted by 1 or 2 substituents independently selected from; Cy ２ is Cy ２ -a, R ２ is H, C １－２ alkyl, C １－２ haloalkyl, F, Cl, and -CH ２ CH ２ CN; selected from Cy ２ is Cy ２ -b, and moreover 【Chemical Formula 6】 is -N=CR ６ - when, R ６ is C １－３ alkyl, C １－３ haloalkyl, C ３－６ cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-10 membered heteroaryl; said C １－３ alkyl, C ３－６ cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-10 membered heteroaryl are each optional and R ６０ is substituted by 1 or 2 substituents independently selected from; Cy ２ is Cy ２ -b, R ２ is H, C １－２ alkyl, C １－２ haloalkyl, F, -CH ２ CH ２ CN, 【Chemical Formula 7】 is selected from; Each R １０ is independently C １－３ alkyl, C １－３ haloalkyl, C ３－６ cycloalkyl, halo, D, CN, OR ａ１０ , C(O)NR ｃ１０ R ｄ１０ , NR ｃ１０ C(O)OR ａ１０ , NR ｃ１０ C(O)NR ｃ１０ R ｄ１０ , and NR ｃ１０ R ｄ１０ is selected from; said C １－３ alkyl and C ３－６ cycloalkyl are each optionally substituted by 1 or 2 substituents independently selected from R ｇ ; Each R １１ is independently selected from C １－２ alkyl, C １－２ haloalkyl, C ３－６ cycloalkyl, 4-6 membered heterocycloalkyl, halo, D, CN, OR ａ１１ and NR ｃ１１ R ｄ１１ and is optionally substituted by one or two substituents independently selected from １－２ C ３－６ alkyl, C ｇ cycloalkyl, and 4-6 membered heterocycloalkyl; Each R ２１ is independently selected from C １－３ alkyl, C １－３ haloalkyl, halo, D, CN, OR ａ２１ , and NR ｃ２１ R ｄ２１ ; and is selected from Each R ３０ is independently C １－３ alkyl, C １－３ haloalkyl, 4- to 10-membered heterocycloalkyl, halo, D, CN, OR ａ３０ , C(O)NR ｃ３０ R ｄ３０ , NR ｃ３０ C(O)OR ａ３０ , NR ｃ３０ C(O)NR ｃ３０ R ｄ３０ , and NR ｃ３０ R ｄ３０ is selected from; said C １－３ alkyl and 4- to 6-membered heterocycloalkyl are each optionally substituted with one or two substituents independently selected from R ３１ ; Each R ３１ is independently selected from C １－３ alkyl, C １－３ haloalkyl, halo, D, and CN; Each R ６０ is 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 ａ６０ , C(O)R ｂ６０ , C(O)NR ｃ６０ R ｄ６０ , and NR ｃ６０ R ｄ６０ is selected from; said C １－３ alkyl, C ３－６ cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R ６１ ; Each R ６１ is independently C １－３ alkyl, C １－３ haloalkyl, C ３－６ cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, halo, D, CN, OR ａ６１ , C(O)R ｂ６１ , and NR ｃ６１ R ｄ６１ is selected from; Each R ７０ is independently selected from C １－３ alkyl, C １－３ haloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, CN, OR ａ７０ , and NR ｃ７０ R ｄ７０ ; and is selected from Each R ａ３ and R ｃ３ is independently selected from H, C １－３ alkyl, C １－３ haloalkyl, 5-6 membered heteroaryl, and phenyl; said C １－３ alkyl, 5-6 membered heteroaryl, and phenyl are each optionally substituted by 1 or 2 substituents independently selected from R ３０ ; Each R ｊ３ is independently selected from C １－３ alkyl and C １－３ haloalkyl; Each R ａ７ , R ｃ７ , and R ｄ７ is independently selected from H, C １－３ alkyl, and C １－３ haloalkyl; said C １－３ alkyl is optionally substituted by one or two substituents independently selected from R ７０ ; Each R ａ１０ , R ｃ１０ and R ｄ１０ are independently selected from H, C １－３ alkyl and C １－３ haloalkyl; Each R ａ１１ , R ｃ１１ and R ｄ１１ are independently selected from H, C １－３ alkyl and C １－３ haloalkyl; R ｂ２０ is selected from NH ２ , C １－３ alkyl, C １－３ haloalkyl, C ３－６ cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl; said C １－３ alkyl, C ３－６ cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R ２１ ; Each R ａ２１ , R ｃ２１ , and R ｄ２１ is independently selected from H, C １－３ alkyl, and C １－３ haloalkyl; Each R ａ３０ , R ｃ３０ and R ｄ３０ is independently selected from H, C １－３ alkyl, and C １－３ haloalkyl; Each R ａ６０ , R ｂ６０ , R ｃ６０ and R ｄ６０ are independently selected from H, C １－３ alkyl, C １－３ haloalkyl, C ３－６ cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl; said C １－３ alkyl, C ３－６ cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R ６１ ; 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-, 5-, 6-, 7-, 8- or 9-membered heterocycloalkyl group optionally substituted by one or two substituents independently selected from R ６１ ; Each R ａ６１ , R ｂ６１ , R ｃ６１ and R ｄ６１ is independently selected from H, C １－３ alkyl and C １－３ haloalkyl; Each R ａ７０ , R ｃ７０ , and R ｄ７０ are independently selected from H, C １－３ alkyl and C １－３ haloalkyl; Each R ｇ is independently selected from D, OH, CN, halo, C １－２ alkyl, amino and C １－２ haloalkyl; provided that the compound of formula I is 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-dimethylpropanamide, 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-2-ethyl-6-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile, 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-((3-oxomorpholino)methyl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile, 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-2-yl)-N-methyl-N-(pyridin-2-ylmethyl)propanamide, and 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(2-(piperazin-1-yl)thiazol-4-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile except for the condition that it is a compound, or a pharmaceutically acceptable salt thereof.

2. 【Chemical Drawing 8】 is -NR ５ -C(=O)-, -N=N-, and -N=CR ６ selected from; R １ is selected from H, D, C １－２ alkyl, and C １－２ haloalkyl; said C １－２ alkyl is optionally substituted by one or two substituents independently selected from R １１ ;; Cy １ is selected from C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 6- to 10-membered heteroaryl; said 4- to 10-membered heterocycloalkyl and 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; the ring-forming carbon atoms of the 6- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl are optionally substituted by oxo to form a carbonyl group; said C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 6- to 10-membered heteroaryl are each optionally and independently substituted with 1, 2, or 3 substituents selected from R １０ ; and R ４ is OR ａ３ selected from; R ５ is selected from H, C １－２ alkyl and C １－２ haloalkyl; R ７ is selected from H, C １－３ alkyl, C １－３ haloalkyl, phenyl, 5- to 6-membered heteroaryl, F, Cl, D, CN, OR ａ７ , and NR ｃ７ R ｄ７ ; said phenyl and 5- to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R ７０ ; Cy ２ is 【Chemical Formula 9】 is selected from; Cy ２ is Cy ２ -a, and 【Chemical Formula 10】 is -N=CR ６ wherein, when R ６ is H, D, C １－３ alkyl, C １－３ haloalkyl, C ３－６ cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-10 membered heteroaryl; said C １－３ alkyl, C ３－６ cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-10 membered heteroaryl are each optionally and independently substituted by 1 or 2 substituents selected from ６０ R; Cy ２ is Cy ２ -a, R ２ is H, C １－２ alkyl, C １－２ haloalkyl, F, Cl, and -CH ２ CH ２ CN; selected from Cy ２ is Cy ２ -b, and 【Chemical 11】 is -N=CR ６ wherein, when R ６ is C １－３ alkyl, C １－３ haloalkyl, C ３－６ cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-10 membered heteroaryl; said C １－３ alkyl, C ３－６ cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-10 membered heteroaryl are each optionally and independently substituted by 1 or 2 substituents selected from ６０ R; Cy ２ is Cy ２ -b, R ２ is H, C １－２ alkyl, C １－２ haloalkyl, F, -CH ２ CH ２ CN, 【Chemical Formula 12】 is selected from; Each R １０ is independently C １－３ alkyl, C １－３ haloalkyl, C ３－６ cycloalkyl, halo, D, CN, OR ａ１０ , C(O)NR ｃ１０ R ｄ１０ , NR ｃ１０ C(O)OR ａ１０ , NR ｃ１０ C(O)NR ｃ１０ R ｄ１０ , and NR ｃ１０ R ｄ１０ is selected from; said C １－３ alkyl and C ３－６ cycloalkyl are each optionally substituted by 1 or 2 substituents independently selected from R ｇ ; Each R １１ is independently selected from C １－２ alkyl, C １－２ haloalkyl, C ３－６ cycloalkyl, 4-6 membered heterocycloalkyl, halo, D, CN, OR ａ１１ and NR ｃ１１ R ｄ１１ ; said C １－２ alkyl, C ３－６ cycloalkyl, and 4-6 membered heterocycloalkyl are each optionally substituted by one or two substituents independently selected from R ｇ ; Each R ２１ is independently selected from C １－３ alkyl, C １－３ haloalkyl, halo, D, CN, OR ａ２１ , and NR ｃ２１ R ｄ２１ ; and is selected from Each R ３０ is independently C １－３ alkyl, C １－３ haloalkyl, 4- to 10-membered heterocycloalkyl, halo, D, CN, OR ａ３０ , C(O)NR ｃ３０ R ｄ３０ , NR ｃ３０ C(O)OR ａ３０ , NR ｃ３０ C(O)NR ｃ３０ R ｄ３０ , and NR ｃ３０ R ｄ３０ is selected from; said C １－３ alkyl and 4- to 6-membered heterocycloalkyl are each optionally substituted by one or two substituents independently selected from R ３１ ; Each R ３１ is independently selected from C １－３ alkyl, C １－３ haloalkyl, halo, D, and CN; Each R ６０ is independently C １－３ alkyl, C １－３ haloalkyl, C ３－６ cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, halo, D, CN, OR ａ６０ , C(O)R ｂ６０ , C(O)NR ｃ６０ R ｄ６０ , and NR ｃ６０ R ｄ６０ is selected from; said C １－３ alkyl, C ３－６ cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl and 5- to 6-membered heteroaryl are each optionally substituted by one or two substituents independently selected from R ６１ ; Each R ６１ is independently C １－３ alkyl, C １－３ haloalkyl, C ３－６ cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, halo, D, CN, OR ａ６１ , C(O)R ｂ６１ , and NR ｃ６１ R ｄ６１ is selected from; Each R ７０ is independently C １－３ alkyl, C １－３ haloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, CN, OR ａ７０ , and NR ｃ７０ R ｄ７０ is selected from; Each R ａ３ is independently selected from H, C １－３ alkyl, C １－３ haloalkyl, 5- to 6-membered heteroaryl, and phenyl; said C １－３ alkyl, 5- to 6-membered heteroaryl, and phenyl are each optionally substituted by 1 or 2 substituents independently selected from R ３０ ; Each R ａ７ , R ｃ７ , and R ｄ７ are independently selected from H, C １－３ alkyl, and C １－３ haloalkyl; said C １－３ alkyl is optionally substituted by 1 or 2 substituents independently selected from R ７０ ; Each R ａ１０ , R ｃ１０ and R ｄ１０ are independently selected from H, C １－３ alkyl and C １－３ haloalkyl; Each R ａ１１ , R ｃ１１ and R ｄ１１ are independently selected from H, C １－３ alkyl and C １－３ haloalkyl; R ｂ２０ is selected from NH ２ , C １－３ alkyl, C １－３ haloalkyl, C ３－６ cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl; said C １－３ alkyl, C ３－６ cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R ２１ ; Each R ａ２１ , R ｃ２１ and R ｄ２１ are independently selected from H, C １－３ alkyl, and C １－３ haloalkyl; Each R ａ３０ , R ｃ３０ and R ｄ３０ are independently selected from H, C １－３ alkyl, and C １－３ haloalkyl; Each R ａ６０ 、R ｂ６０ 、R ｃ６０ and R ｄ６０ are independently selected from H, C １－３ alkyl, C １－３ haloalkyl, C ３－６ cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl; said C １－３ alkyl, C ３－６ cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are each optionally substituted by one or two substituents independently selected from R ６１ ; 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-, 5-, 6-, 7-, 8- or 9-membered heterocycloalkyl group optionally substituted with one or two substituents independently selected from R ６１ ; Each R ａ６１ 、R ｂ６１ 、R ｃ６１ and R ｄ６１ are independently selected from H, C １－３ alkyl and C １－３ haloalkyl; Each R ａ７０ , R ｃ７０ , and R ｄ７０ are independently selected from H, C １－３ alkyl and C １－３ haloalkyl; Each R ｇ is independently selected from D, OH, CN, halo, C １－２ alkyl, amino and C １－２ haloalkyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. wherein 【Chemical Formula 13】 is -NR ５ -C(=O)-, -N=N-, and -N=CR ６ selected from; R １ is selected from H, D, C １－２ alkyl, and C １－２ haloalkyl; said C １－２ alkyl is optionally substituted by 1 or 2 substituents independently selected from R １１ ; Cy １ is selected from C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 6- to 10-membered heteroaryl; said 4- to 10-membered heterocycloalkyl and 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; the ring-forming carbon atoms of the 6- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl are optionally substituted by oxo to form a carbonyl group; said C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 6- to 10-membered heteroaryl are each optionally and independently substituted by 1, 2, or 3 substituents selected from R １０ and R ４ is OR ａ３ selected from; R ５ is H, C １－２ alkyl and C １－２ selected from haloalkyl; R ７ is H, C １－３ alkyl, C １－３ haloalkyl, phenyl, 5- to 6-membered heteroaryl, F, Cl, D, CN, OR ａ７ , and NR ｃ７ R ｄ７ selected from; said phenyl and 5- to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R ７０ ; Cy ２ is 【Chemical Formula 14】 is selected from; Cy ２ is Cy ２ -a, and 【Chemical Formula 15】 is -N=CR ６ when it is -, R ６ is H, D, C １－３ alkyl and C １－３ is selected from haloalkyl; said C １－３ alkyl is optionally substituted by 1 or 2 substituents independently selected from R ６０ ; Cy ２ is Cy ２ -a, R ２ is H, C １－２ alkyl, C １－２ haloalkyl, F, Cl, and -CH ２ CH ２ CN; selected from Cy ２ is Cy ２ -b, and 【Chemical Formula 16】 is -N=CR ６ when it is -, R ６ is C １－３ alkyl, C １－３ haloalkyl, C ３－６ cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-10 membered heteroaryl; said C １－３ alkyl, C ３－６ cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-10 membered heteroaryl are each optional and R ６０ is substituted by 1 or 2 substituents independently selected from; Cy ２ is Cy ２ -b, R ２ is H, C １－２ alkyl, C １－２ haloalkyl, F, -CH ２ CH ２ CN, 【Chemical 17】 is selected from; Each R １０ is independently C １－３ alkyl, C １－３ haloalkyl, C ３－６ cycloalkyl, halo, D, CN, OR ａ１０ , C(O)NR ｃ１０ R ｄ１０ , and NR ｃ１０ R ｄ１０ selected from; said C １－３ alkyl and C ３－６ cycloalkyl are each optionally substituted by 1 or 2 substituents independently selected from R ｇ ; Each R １１ is independently selected from C １－２ alkyl, C １－２ haloalkyl, C ３－６ cycloalkyl, 4-6 membered heterocycloalkyl, halo, D, CN, OR ａ１１ and NR ｃ１１ R ｄ１１ ; said C １－２ alkyl, C ３－６ cycloalkyl, and 4-6 membered heterocycloalkyl are each optionally substituted by one or two substituents independently selected from R ｇ ; Each R ２１ is independently selected from C １－３ alkyl, C １－３ haloalkyl, halo, D, and CN; Each R ３０ is independently C １－３ alkyl, C １－３ haloalkyl, 4-10 membered heterocycloalkyl, halo, D, CN, OR ａ３０ , C(O)NR ｃ３０ R ｄ３０ , and NR ｃ３０ R ｄ３０ selected from; said C １－３ alkyl and 4-6 membered heterocycloalkyl are each optionally substituted by 1 or 2 substituents independently selected from R ３１ ; Each R ３１ is independently selected from C １－３ alkyl, C １－３ haloalkyl, halo, D, and CN; Each R ６０ is 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 ａ６０ , C(O)R ｂ６０ , C(O)NR ｃ６０ R ｄ６０ , and NR ｃ６０ R ｄ６０ is selected from; said C １－３ alkyl, C ３－６ cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R ６１ ; Each R ６１ is independently C １－３ alkyl, C １－３ haloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, CN, OR ａ６１ , C(O)R ｂ６１ , and NR ｃ６１ R ｄ６１ is selected from; Each R ７０ is independently selected from C １－３ alkyl, C １－３ haloalkyl, phenyl, 5- to 6-membered heteroaryl, halo, D, and CN; Each R ａ３ is independently selected from H, C １－３ alkyl, C １－３ haloalkyl, 5- to 6-membered heteroaryl, and phenyl; said C １－３ alkyl, 5- to 6-membered heteroaryl, and phenyl are each optionally substituted by 1 or 2 substituents independently selected from R ３０ ; Each R ａ７ , R ｃ７ , and R ｄ７ are independently selected from H, C １－３ alkyl, and C １－３ haloalkyl; said C １－３ alkyl is optionally substituted by one or two substituents independently selected from R ７０ ; Each R ａ１０ , R ｃ１０ and R ｄ１０ are independently selected from H, C １－３ alkyl and C １－３ haloalkyl; Each R ａ１１ , R ｃ１１ and R ｄ１１ are independently selected from H, C １－３ alkyl and C １－３ haloalkyl; R ｂ２０ is selected from NH ２ , C １－３ alkyl, C １－３ haloalkyl, C ３－６ cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl; said C １－３ alkyl, C ３－６ cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are each optionally substituted by one or two substituents independently selected from R ２１ ; Each R ａ２１ , R ｃ２１ , and R ｄ２１ are independently selected from H, C １－３ alkyl, and C １－３ haloalkyl; Each R ａ３０ , R ｃ３０ and R ｄ３０ are independently selected from H, C １－３ alkyl, and C １－３ haloalkyl; Each R ａ６０ , R ｂ６０ , R ｃ６０ and R ｄ６０ is independently selected from H, C １－３ alkyl, and C １－３ haloalkyl; said C １－３ alkyl is optionally substituted by one or two substituents independently selected from R ６１ ; 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-, 5-, 6- or 9-membered heterocycloalkyl group optionally substituted with one or two substituents independently selected from R ６１ ; Each R ａ６１ , R ｂ６１ , R ｃ６１ and R ｄ６１ is independently selected from H, C １－３ alkyl and C １－３ haloalkyl; and Each R ｇ independently is selected from D, OH, CN, halo, C １－２ alkyl, amino and C １－２ haloalkyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

4. wherein: 【Chemical 18】 is -NR ５ -C(=O)-, -N=N-, and -N=CR ６ selected from; R １ is selected from H and C １－２ alkyl; said C １－２ alkyl is optionally substituted by one or two substituents independently selected from R １１ ; Cy １ is selected from C ３－１０ cycloalkyl, C ６－１０ aryl, and 6-10-membered heteroaryl; each of said 6-10-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; the ring-forming carbon atoms of the 6-10-membered heteroaryl are optionally substituted by oxo to form a carbonyl group; said C ３－１０ cycloalkyl, C ６－１０ aryl, and 6-10-membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from R １０ ; R ４ is OR ａ３ selected from; R ５ is H; R ７ is phenyl, 5- or 6-membered heteroaryl, F, and OR ａ７ is selected from; said phenyl and 5- or 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R ７０ ; Cy ２ is 【Chemical Formula 19】 is selected from; Cy ２ is Cy ２ -a and 【Chemical 20】 is -N=CR ６ when it is -, R ６ is H; Cy ２ is Cy ２ -a, R ２ is Cl; Cy ２ is Cy ２ -b, and moreover 【Chemical 21】 is N=CR ６ - when it is, R ６ is C １－３ alkyl, C ３－６ cycloalkyl, 4-6 membered heterocycloalkyl, and 5-10 membered heteroaryl; said C １－３ alkyl, C ３－６ cycloalkyl, 4-6 membered heterocycloalkyl, and 5-10 membered heteroaryl are each optional and R ６０ is substituted by one or two substituents independently selected from; Cy ２ is Cy ２ -b, R ２ is H, C １－２ alkyl, -CH ２ CH ２ CN, 【Chemical 22】 is selected from; Each R １０ is independently C １－３ alkyl, C １－３ haloalkyl, C ３－６ cycloalkyl, halo, CN, OR ａ１０ , and NR ｃ１０ R ｄ１０ selected from; said C １－３ alkyl and C ３－６ cycloalkyl are each optionally substituted by 1 or 2 substituents independently selected from R ｇ ; Each R １１ is independently selected from 4- to 6-membered heterocycloalkyl and OR ａ１１ ; said 4- to 6-membered heterocycloalkyl is optionally substituted by one or two substituents independently selected from ｇ R; Each R ２１ is CN; Each R ３０ is independently a 4- to 10-membered heterocycloalkyl, and C(O)NR ｃ３０ R ｄ３０ is selected from; said 4- to 6-membered heterocycloalkyl is optionally substituted by 1 or 2 substituents independently selected from R ３１ ; Each R ３１ is independently selected from C １－３ alkyl; Each R ６０ is independently C １－３ alkyl, C ３－６ cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C(O)R ｂ６０ , C(O)NR ｃ６０ R ｄ６０ , and NR ｃ６０ R ｄ６０ selected from; said C １－３ alkyl, C ３－６ cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R ６１ ; Each R ６１ is independently selected from phenyl, 5- to 6-membered heteroaryl, and C(O)R ｂ６１ ; Each R ７０ is independently selected from phenyl, 5- to 6-membered heteroaryl, and CN; Each R ａ３ is independently selected from C １－３ alkyl, and phenyl; said C １－３ alkyl and phenyl are each optionally substituted by one or two substituents independently selected from R ３０ ; Each R ａ７ is C １－３ alkyl; said C １－３ alkyl is optionally substituted by one or two substituents independently selected from R ７０ ; R ａ１０ 、R ｃ１０ 、and R ｄ１０ are each H; Each R ａ１１ is H; R ｂ２０ is NH ２ , C １－３ alkyl, C ３－６ cycloalkyl, and 5- to 6-membered heteroaryl; said C １－３ alkyl, C ３－６ cycloalkyl, and 5- to 6-membered heteroaryl are each optionally substituted by one or two substituents independently selected from R ２１ ; Each R ｃ３０ and R ｄ３０ are independently selected from H, and C １－３ alkyl; Each R ｂ６０ , R ｃ６０ and R ｄ６０ are independently selected from H and C １－３ alkyl; said C １－３ alkyl is optionally substituted by one or two substituents independently selected from R ６１ ; or any R attached to the same N atom ｃ６０ and R ｄ６０ together with the N atom to which they are attached, independently form a 6- or 9-membered heterocycloalkyl group optionally substituted with one or two substituents selected from R ６１ ; Each R ｂ６１ is C １－３ alkyl; and Each R ｇ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein each R is CN.

5. 【Fig. 23】 is -NR ５ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein it is -C(=O)-.

6. 【Fig. 24】 is -N=N-, the compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

7. 【Fig. 25】 is -N=CR ６ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein it is

8. R １ is selected from H and C １－２ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R is selected from H and C alkyl.

9. R １ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R is H.

10. Cy １ is selected from C ６－１０ aryl and 6- to 10-membered heteroaryl; said 6- to 10-membered heteroaryl having at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; the ring-forming carbon atoms of the 6- to 10-membered heteroaryl optionally being substituted by oxo to form a carbonyl group; said C ６－１０ aryl and 6- to 10-membered heteroaryl each optionally being substituted with 1, 2, or 3 substituents independently selected from R １０ ; a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

11. Cy １ is selected from phenyl and 6-10 membered heteroaryl; said 6-10 membered heteroaryl has at least one ring-forming carbon atom and one or two ring-forming heteroatoms independently selected from N, O, and S; said phenyl and 6-10 membered heteroaryl are each optionally, R １０ substituted with 1, 2 or 3 substituents independently selected from, a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

12. Cy １ is 【Chemical 26】 The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, selected from

13. R ４ is C １－３ alkyl, C １－３ haloalkyl, 5-10 membered heteroaryl, and OR ａ３ selected from; said C １－３ alkyl and 5-10 membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R ３０ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is substituted with

14. R ４ is 【Chemical 27】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from

15. R ４ is H, C １－３ alkyl, C １－３ heteroalkyl, 5- to 10-membered heteroaryl, OR ａ３ , and NR ｃ３ R ｊ３ selected from; said C １－３ alkyl and 5- to 10-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R ３０ ; the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

16. R ４ is OR ａ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

17. R ７ is phenyl, 5- or 6-membered heteroaryl, F and OR ａ７ is selected from, and the phenyl and 5- or 6-membered heteroaryl are each optionally substituted with one or two substituents independently selected from R ７０ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

18. R ７ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R is F.

19. Cy ２ is Cy ２ -a, and 【Chemical 28】 is -N=CR ６ when it is -, R ６ is selected from H and C １－３ alkyl; said C １－３ alkyl is optionally substituted with 1 or 2 substituents independently selected from R ６０ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is substituted with a substituent.

20. Cy ２ is Cy ２ -a, and 【Chemical 29】 is —N═CR ６ when it is —, R ６ is H, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

21. Cy ２ is Cy ２ -a, R ２ is Cl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

22. Cy ２ is Cy ２ -b, and moreover 【Chemical Formula 30】 is -N=CR ６ wherein, when it is - ６ R is C １－３ alkyl or C １－３ haloalkyl; said C １－３ alkyl is optionally substituted with one or two substituents independently selected from R ６０ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

23. Cy ２ is Cy ２ -b, and 【Chemical 31】 is -N=CR ６ wherein, when it is - ６ R is C １－３ alkyl; said C １－３ alkyl is optionally substituted with one or two substituents independently selected from R ６０ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

24. Cy ２ is Cy ２ -b, R ２ is H, C １－２ alkyl, -CH ２ CH ２ CN, 【Chemical 32】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from

25. Each R １０ is independently C １－３ alkyl, C １－３ haloalkyl, C ３－６ cycloalkyl, halo, CN, OR ａ１０ , and NR ｃ１０ R ｄ１０ selected from; said C １－３ alkyl and C ３－６ cycloalkyl are each optionally substituted with one or two substituents independently selected from R ｇ , a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.

26. R １１ is independently 4- to 6-membered heterocycloalkyl and OR ａ１１ is selected from; said 4- to 6-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from R ｇ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which is substituted with

27. Each R ２１ independently is halo, CN, and OR ａ２１ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from

28. Each R ２１ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R is CN.

29. Each R ３０ is independently a 4- to 10-membered heterocycloalkyl, and C(O)NR ｃ３０ R ｄ３０ is selected from, the 4- to 6-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from R ３１ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

30. Each R ３１ is independently C １－３ alkyl and C １－３ haloalkyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

31. Each R ６０ is independently C １－３ alkyl, C(O)NR ｃ６０ R ｄ６０ , and NR ｃ６０ R ｄ６０ selected from; said C １－３ alkyl is optionally substituted with 1 or 2 substituents independently selected from R ６１ , the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

32. Each R ６１ independently is phenyl, 5- or 6-membered heteroaryl, and C(O)R ｂ６１ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein each R is independently selected from phenyl, 5- or 6-membered heteroaryl, and C(O)R

33. Each R ７０ independently, is selected from phenyl, 5- to 6-membered heteroaryl, and CN, the compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.

34. R ｇ wherein R is independently selected from OH, CN, and halo, the compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.

35. Each R ｇ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R is CN.

36. Each R ａ３ is independently selected from C １－３ alkyl, and said C １－３ alkyl is optionally substituted with one or two substituents independently selected from R ３０ ; a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.

37. R ｂ２０ is NH ２ and C １－３ alkyl selected from; said C １－３ alkyl is optionally substituted with one or two substituents independently selected from R ２１ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which is substituted with

38. Each R ｂ６０ , R ｃ６０ , and R ｄ６０ are independently selected from H and C １－３ alkyl; said C １－３ alkyl is optionally substituted by one or two substituents independently selected from R ６１ ; or any R ｃ６０ and R ｄ６０ bonded to the same N atom, together with said N atom to which they are bonded, form a 6-membered or 9-membered heterocycloalkyl group optionally substituted by one or two substituents independently selected from R ６１ , a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.

39. The compound of formula I is 1-(3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-8-methyl-1H-imidazo[4,5-c]quinolin-2-yl)piperidin-1-yl)ethan-1-one; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-8-methyl-1H-imidazo[4,5-c]quinolin-2-yl)-1-(4-(pyrimidin-2-yl)piperazin-1-yl)propan-1-one; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(3-oxo-3-(7-oxa-2-azaspiro[3.5]nonan-2-yl)propyl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 3-(2-(3-(4-acetylpiperazin-1-yl)-3-oxopropyl)-1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 4-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-2-ethyl-6-fluoro-8-(oxazol-5-yl)-1H-imidazo[4,5-c]quinolin-7-yl)naphthalen-2-ol; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-8-yl)-3-(1H-pyrazol-1-yl)propanenitrile; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-8-yl)-3-(4-(hydroxymethyl)-1H-pyrazol-1-yl)propanenitrile; 3-(8-((1H-pyrazol-1-yl)methyl)-1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-dimethylpropanamide; 3-(1-(2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichloro-6-hydroxyphenyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-dimethylpropanamide; 3-(1-(2-Azabicyclo[2.1.1]hexan-5-yl)-7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-dimethylpropanamide; 3-(1-((endo)-2-Azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-6-(3-cyanophenyl)-4-(3-(dimethylamino)azetidin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-dimethylpropanamide; 3-(1-((endo)-2-Azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-4-(3-(dimethylamino)azetidin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-6-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-dimethylpropanamide; 3-(6-(Benzyloxy)-1-((endo)-2-Azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-4-(3-(dimethylamino)azetidin-1-yl)-7-(7-fluoronaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-dimethylpropanamide; 3-(1-((endo)2-Azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-9-(hydroxymethyl)-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-dimethylpropanamide; 3-(1-((endo)2-Azabicyclo[2.1.1]hexan-5-yl)-9-(((3-cyanopyrrolidin-1-yl)methyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-dimethylpropanamide; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-4-yl)-4-fluorobenzamide; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-ethyl-4-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 5-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-4-yl)-N-methylpicolinamide; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-4-(oxazol-2-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 3-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-4-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-4-methyl-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-ethyl-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-4-phenoxy-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-cyclopropyl-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-(1-cyclobutyl-1H-1,2,3-triazol-4-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-4-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 3-(1-(2-azabicyclo[2.1.1]hexan-5-yl)-2-ethyl-6-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(5-methyl-1H-indol-3-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 4-(((1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(2-(methylamino)ethyl)-1H-imidazo[4,5-c]quinolin-8-yl)methyl)benzonitrile; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-2-ethyl-6-fluoro-7-(5-fluoro-1H-indol-3-yl)-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 3-(7-(3-aminoisquinolin-1-yl)-1-endo-(2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-dimethylpropanamide; 3-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-1-endo-(2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-dimethylpropanamide; 3-(1-endo-(2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(7,7-difluoro-5,6,7,8-tetrahydronaphthalen-1-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-dimethylpropanamide; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(1-phenyl-1H-pyrazol-3-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-2-(1-ethyl-1H-pyrazol-3-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 3-(2-(1-Benzyl-1H-pyrazol-3-yl)-1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(2-(pyrimidin-2-yl)ethyl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; (3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(1H-indazol-5-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile; 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-imidazo[4,5-c]quinolin-7-yl)-1-naphthonitrile; 8-(8-chloro-1-((2S,4S)-1-(2-cyanoacetyl)-2-(cyanomethyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-imidazo[4,5-c]quinolin-7-yl)-1-naphthonitrile; 8-(8-chloro-1-((2S,4S)-2-(cyanomethyl)-1-(1H-1,2,4-triazole-3-carbonyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-imidazo[4,5-c]quinolin-7-yl)-1-naphthonitrile; (2S,4S)-4-(8-chloro-7-(8-cyanonaphthalen-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-imidazo[4,5-c]quinolin-1-yl)-2-(cyanomethyl)piperidine-1-carboxamide; 8-(8-chloro-1-((2S,4S)-2-(cyanomethyl)-1-(cyclopropanecarbonyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-imidazo[4,5-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-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-1-naphthonitrile; and 8-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-7-yl)-1-naphthonitrile; A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

40. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or additive.

41. A medicament for use in a method of inhibiting KRAS activity, comprising a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, the method comprising contacting the compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, with KRAS.

42. The medicament according to claim 41, wherein contacting comprises administering the compound to a patient.

43. A medicament for treating a disease or disorder associated with inhibition of KRAS interaction, comprising a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

44. A medicament for treating a disease or disorder associated with inhibition of a KRAS protein having a G12D mutation, comprising a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

45. A medicament for treating cancer, comprising a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

46. The medicament according to claim 45, wherein the cancer is selected from carcinoma, hematological cancer, sarcoma, and glioblastoma.

47. The medicament according to claim 46, wherein the hematological cancer is selected from myeloproliferative neoplasm, myelodysplastic syndrome, chronic and juvenile myelomonocytic leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, and multiple myeloma.

48. The medicament according to claim 46, wherein the carcinoma is selected from carcinomas of the pancreas, colon, lung, bladder, stomach, esophagus, breast, head and neck, cervix, skin, and thyroid.

49. The medicament according to claim 44, wherein the disease or disorder is an immunological disorder or an inflammatory disorder.

50. The medicament according to claim 49, wherein the immunological disorder or inflammatory disorder is a Ras-related lymphoproliferative disorder and juvenile myelomonocytic leukemia caused by somatic mutations of KRAS.

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