Compounds as inhibitors of axl

Abstract

Compounds of Formula I that inhibit AXL, and compositions containing the compound(s) and methods for synthesizing the compounds, are described herein. Also described are the use of such compounds and compositions for the treatment of a diverse array of diseases, disorders, and conditions, including cancer, that are mediated, at least in part, by AXL.

1 . A compound represented by Formula (I) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 X is CR 5  or N; 
 G 1  is N or CR G1 ; 
 G 2  is CR G2  or N; 
 G 3  is CR G3  or N; 
 G 4  is CR G4  or N; 
 G 5  is CR G5  or N; 
 R G1  is selected from the group consisting of H, C 1-3  alkyl, halogen, C 1-3  haloalkyl, and CN; 
 each R G2 , R G3 , R G4  and R G5  is independently selected from the group consisting of H, halo, CN, C 1-7  alkyl, C 3-7  cycloalkyl, C 1-3  haloalkyl, —O—C 1-3  alkyl, —O—C 1-3  haloalkyl, —NR a R b , and 5- to 8-membered heterocycloalkyl having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, and wherein cycloalkyl and heterocycloalkyl are substituted with 0-3 groups independently selected from halo, CN, C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  hydroxyalkyl, —O—C 1-4  alkyl, and OH; 
 A is a fused ring selected from the group consisting of cycloheptane, cyclohexane, cyclopentane, azepane, 1,4-oxazepane, 1,4-diazepane, oxepane, tetrahydropyran, piperidine, bicyclo[4.2.1]nonane, bicyclo[4.1.1]octane, spiro[4.6]undecane, 1-azaspiro[4.6]undecane, and cyclooctane, each of which is substituted with from 1 to 4 R 2 , and further substituted with 0 or 1 oxo (═O) which is on a carbon atom adjacent to a nitrogen atom; 
 R 1  is selected from the group consisting of phenyl and a 5 to 6-membered heteroaryl having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, and wherein each phenyl and heteroaryl is substituted with one R 1a  and 0-3 R 3 ; 
 R 1a  is selected from the group consisting of phenyl and a 5 to 6-membered heteroaryl having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, wherein the N atom, when present, is optionally oxidized, and wherein each phenyl and heteroaryl is substituted with 0-4 R 4 ; 
 each R 2  is independently selected from the group consisting of C 1-7  alkyl, C 3-7  alkenyl, C 3-7  alkynyl, C 3-7  cycloalkyl, —Y 1 —O—C 1-7  alkyl, —Y 1 —O—C 3-7  cycloalkyl, —NR a R b , —C(O)—C 1-7  alkyl, —C(O)—C 3-7  cycloalkyl, —S(O) 2 —C 1-7  alkyl, —S(O) 2 —C 3-7  cycloalkyl, —C(O)NR a R b , 5- to 8-membered heterocycloalkyl, —NR a -(5- to 8-membered heterocycloalkyl), —C(O)-(5- to 8-membered heterocycloalkyl), —X 1 -5- to 8-membered heterocycloalkyl, and —O—X 1 -(5- to 8-membered heterocycloalkyl), wherein the heterocycloalkyl has 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, and wherein each cycloalkyl and heterocycloalkyl is substituted with from 0-3 groups independently selected from halo, CN, C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  hydroxyalkyl, —O—C 1-4  alkyl, and OH; 
 each R 3  is independently selected from the group consisting of halogen, CN, C 1-7  alkyl, C 2-7  alkenyl, C 3-7  alkynyl, C 1-4  haloalkyl, C 1-4  hydroxyalkyl, C 1-4  halohydroxyalkyl, —O—C 1-7  alkyl, —O—C 1-6  haloalkyl, —NR a R b , —C(O)—NR a R b , —S(O) 2 —NR a R b , —S(O)(NH)—C 1-7  alkyl, —S(O) 2 —C 1-7  alkyl, and —S(O) 2 —C 1-7  haloalkyl; 
 each R 4  is independently selected from the group consisting of C 1-7  alkyl, halo, C 1-7  haloalkyl, —O—C 1-7  alkyl, —O—C 1-7  haloalkyl, CN, —C 1-7  alkylene-CN, hydroxy, C 1-7  hydroxyalkyl, —C(O)NR a R b , C 3-7  cycloalkyl, —NR a —C(O)—C 1-7  alkyl, —NR a —C(O)—C 3-7  cycloalkyl, —NR a R b , —O—C 1-4  alkylene-O—C 1-4  alkyl, —O-(5- to 8-membered heterocycloalkyl) having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, -5- to 8-membered heterocycloalkyl having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, —S(O) 2 —C 1-7  alkyl, —S(O) 2 —C 3-7  cycloalkyl, —S(O) 2 —NR a R b , —NR a —S(O) 2 —C 1-7  alkyl, and —NR a —S(O) 2 —C 3-7  cycloalkyl, wherein each cycloalkyl and heterocycloalkyl is substituted with 0 to 2 groups independently selected from the group consisting of C 1-4  alkyl, halo, and hydroxy; 
 alternatively, two R 4  groups on the same ring vertex combine to form an oxo (═O); or 
 two R 4  groups on adjacent ring vertices combine to form a 5- to 6-membered heterocycloalkyl having from 1 to 2 heteroatom ring vertices selected from the group consisting of O, N, and S, wherein the 5- to 6-membered heterocycloalkyl is substituted with 0 to 2 groups independently selected from the group consisting of C 1-4  alkyl and halo; 
 R 5  is selected from the group consisting of H, C 1-4  alkyl, and —NH 2 ; 
 each X 1  is C 1-7  alkylene or C 3-7  cycloalkylene; 
 each Y 1  is C 2-7  alkylene or C 3-7  cycloalkylene; 
 each R a  and R b  are independently selected from group consisting of H, C 1-7  alkyl, C 1-7  haloalkyl, C 1-4  alkoxyC 1-4 alkyl, C 3-7  cycloalkyl, wherein said cycloalkyl is optionally substituted with —O—C 1-3  alkyl; or 
 R a  and R b  together with the nitrogen to which they are attached form a 4- to 8-membered heterocycloalkyl ring having 0-2 additional heteroatom ring vertices selected from the group consisting of O, N, and S, wherein the heterocycloalkyl ring is substituted with 0-3 groups, each group is independently selected from halo, CN, C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  hydroxyalkyl, —O—C 1-4  alkyl, and X 1 —O—C 1-3  alkyl, and OH; or two groups on the same ring vertex combine to form an oxo (═O). 
 
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
 G 3  is CR G3 , and R G3  is H;   G 4  is CR G4  and R G4  is H;   G 5  are each CR G5  and R G5  is H;   G 1  is N or CR G1  wherein R G1  is H; and   G 2  is CR G2  and R G2  is H.   
     
     
         3 - 4 . (canceled) 
     
     
         5 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is CR 5  and R 5  is H. 
     
     
         6 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein A has a formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       each of which is substituted with from 1 to 4 R 2 . 
     
     
         7 . The compound of  claim 6 , or a pharmaceutically acceptable salt thereof, wherein A has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein one R 2  is —NR a R b . 
     
     
         9 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein one R 2  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 9 , or a pharmaceutically acceptable salt, wherein one R 2  is 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is selected from the group consisting of phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxadiazolyl, and pyrazolyl, wherein R 1  is substituted with one R 1a  and 0-2 R 3 . 
     
     
         12 . The compound of  claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 1  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein the subscript p is 0 or 1. 
     
     
         13 .- 14 . (canceled) 
     
     
         15 . The compound of claim  14 , or pharmaceutically acceptable salt thereof, wherein each R 3 , when present, is independently selected from the group consisting of halogen, C 1-4  alkyl, and —O—C 1-4  alkyl. 
     
     
         16 . (canceled) 
     
     
         17 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein R 1a  is selected from the group consisting of, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridyl N-oxide, and phenyl, wherein R 1a  is substituted with and 0-3 R 4 . 
     
     
         18 . The compound of  claim 17 , or pharmaceutically acceptable salt thereof, wherein R 1a  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein the subscript q is 0, 1, or 2. 
       
     
     
         19 . The compound of  claim 17 , or pharmaceutically acceptable salt thereof, wherein R 1a  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein the subscript q is 0, 1, or 2. 
       
     
     
         20 . (canceled) 
     
     
         21 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein each R 4 , when present, is independently selected from the group consisting of C 1-4  alkyl, halo, C 1-4  haloalkyl, —O—C 1-4  alkyl, —O—C 1-4  haloalkyl, CN, —C 1-4  alkylene-CN, C 1-4  hydroxyalkyl, —C(O)NR a R b , C 3-7  cycloalkyl, —NR a —C(O)—C 3-7  cycloalkyl, —NR a R b , —O—C 1-4  alkylene-O—C 1-4  alkyl, —O-(5- to 6-membered heterocycloalkyl) having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, -5- to 8-membered heterocycloalkyl having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, —S(O) 2 —C 1-4  alkyl, and —S(O) 2 —NR a R b , wherein each cycloalkyl and heterocycloalkyl is substituted with 0 to 2 groups selected from the group consisting of C 1-4  alkyl, halo, and hydroxy. 
     
     
         22 . The compound of  claim 21 , or pharmaceutically acceptable salt thereof, wherein each R 4 , when present, is independently selected from the group consisting of methyl, ethyl, fluoro, chloro, difluoromethyl, trifluoromethyl, CN, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, 
       
         
           
           
               
               
           
         
       
     
     
         23 - 24 . (canceled) 
     
     
         25 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, having a structure selected from Formula (Ia), Formula (Ia1), Formula (Ib), and Formula (Ib1): 
       
         
           
           
               
               
           
         
       
       wherein for each of Formula (Ib) and Formula (Ib1), the subscript m is 0 or 1; and n is 0, 1 or 2, and each R 2  can be the same or different. 
     
     
         26 . (canceled) 
     
     
         27 . The compound of  claim 25 , or a pharmaceutically acceptable salt thereof, having a structure of Formula (If) or Formula (If1): 
       
         
           
           
               
               
           
         
       
     
     
         28 - 29 . (canceled) 
     
     
         30 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         31 . A compound represented by Formula (II) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 X is CH or N; 
 G 1  is N or CH; 
 A is a fused ring selected from the group consisting of cycloheptane, cyclohexane, and azepane, each of which is substituted with from 1 to 4 R 2 ; 
 R 1  is selected from the group consisting of phenyl and a 5 to 6-membered heteroaryl having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, and wherein each phenyl and heteroaryl is substituted with one R 1a  and 0-3 R 3 ; 
 R 1a  is selected from the group consisting of phenyl and a 5 to 6-membered heteroaryl having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, wherein the N atom, when present, is optionally oxidized, and wherein each phenyl and heteroaryl is substituted with 0-4 R 4 ; 
 each R 2  is independently selected from the group consisting of C 1-7  alkyl, C 3-7  cycloalkyl, —Y 1 —O—C 1-7  alkyl, —NR a R b , 5- to 8-membered heterocycloalkyl, and —NR a -(5- to 8-membered heterocycloalkyl), wherein the heterocycloalkyl has 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, and wherein each cycloalkyl and heterocycloalkyl is substituted with from 0-3 groups independently selected from C 1-4  alkyl, and —O—C 1-4  alkyl; 
 each R 3  is independently selected from the group consisting of halogen, C 1-7  alkyl, and —O—C 1-7  alkyl; 
 each R 4  is independently selected from the group consisting of C 1-7  alkyl, halo, C 1-7  haloalkyl, —O—C 1-7  alkyl, —O—C 1-7  haloalkyl, CN, —C 1-7  alkylene-CN, C 1-7  hydroxyalkyl, —C(O)NR a R b , C 3-7  cycloalkyl, —NR a —C(O)—C 3-7  cycloalkyl, —NR a R b , —O—C 1-4  alkylene-O—C 1-4  alkyl, —O-(5- to 8-membered heterocycloalkyl) having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, -5- to 8-membered heterocycloalkyl having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, —S(O) 2 —C 1-7  alkyl, and —S(O) 2 —NR a R b , wherein each cycloalkyl and heterocycloalkyl is substituted with 0 to 2 groups independently selected from the group consisting of C 1-4  alkyl, and hydroxy; 
 alternatively, two R 4  groups on adjacent ring vertices combine to form a 5- to 6-membered heterocycloalkyl having from 1 to 2 heteroatom ring vertices selected from the group consisting of O, N, and S, wherein the 5- to 6-membered heterocycloalkyl is substituted with 0 to 2 C 1-4  alkyl; 
 each X 1  is C 1-7  alkylene; 
 each Y 1  is C 2-7  alkylene; 
 each R a  and R b  are independently selected from group consisting of H, C 1-7  alkyl, C 3 -7 cycloalkyl, wherein said cycloalkyl is optionally substituted with —O—C 1-3  alkyl; or 
 R a  and R b  together with the nitrogen to which they are attached form a 4- to 8-membered heterocycloalkyl ring having 0-2 additional heteroatom ring vertices selected from the group consisting of O, N, and S, wherein the heterocycloalkyl ring is substituted with 0-3 groups, each group is independently selected from C 1-4  alkyl, —O—C 1-4  alkyl, and X 1 —O—C 1-3  alkyl; or two groups on the same ring vertex combine to form an oxo (═O). 
 
     
     
         32 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 
     
     
         33 . The pharmaceutical composition of  claim 32 , wherein the composition comprises 10 to 300 mg of the compound, or a pharmaceutically acceptable salt thereof. 
     
     
         34 . A method of treating cancer, fibrosis, a viral infection, or pain, said method comprising administering the compound of  claim 1 , or a pharmaceutically acceptable salt thereof, to a subject in need thereof. 
     
     
         35 . (canceled) 
     
     
         36 . The method of  claim 34 , wherein said disease, disorder, or condition is cancer. 
     
     
         37 . The method of  claim 36 , wherein said cancer is a cancer of the prostate, colon, rectum, pancreas, cervix, stomach, endometrium, uterus, brain, liver, bladder, ovary, fallopian tube, peritoneum, testis, head, neck, skin (including melanoma and basal carcinoma), mesothelial lining, white blood cell (including lymphoma and leukemia), esophagus, breast, muscle, connective tissue, intestine, lung (including small-cell lung carcinoma and non-small-cell lung carcinoma), adrenal gland, thyroid, kidney, or bone; or is glioblastoma, mesothelioma, renal cell carcinoma, gastric carcinoma, sarcoma (including Kaposi's sarcoma), choriocarcinoma, cutaneous basocellular carcinoma, or testicular seminoma, or any combinations thereof 
     
     
         38 . The method of  claim 36 , wherein said cancer is selected from the group consisting of skin cancer (e.g., melanoma), pancreatic cancer (e.g., pancreatic ductal adenocarcinoma), breast cancer (e.g., triple negative breast cancer), bladder cancer, liver cancer, lung cancer (e.g., non-small cell lung cancer), leukemia (e.g., acute myeloid leukemia or myelodysplastic syndrome), a brain tumor (e.g., glioblastoma), ovarian cancer (e.g., epithelial ovarian cancer (EOC), high grade serous ovarian cancer (HGSOC), or platinum resistant ovarian cancer (PROC)), kidney cancer (e.g., clear cell renal cell carcinoma), mesothelioma, and head and neck cancer (e.g., head and neck squamous cell carcinoma). 
     
     
         39 . The method of  claim 38 , wherein said cancer is acute myeloid leukemia, myelodysplastic syndrome, non-small cell lung cancer, ovarian cancer, or clear cell renal cell carcinoma. 
     
     
         40 . The method of  claim 34 , wherein the cancer is relapsed or resistant to radiation therapy, chemotherapy, or immunotherapy. 
     
     
         41 - 44 . (canceled) 
     
     
         45 . The method of  claim 34  further comprising administering at least one additional therapeutic agent to the subject. 
     
     
         46 . The method of  claim 45 , wherein said at least one additional therapeutic agent comprises one or more agents independently selected from the groups consisting of inhibitors of the CD47-SIRPα pathway (e.g., anti-CD47 antibodies), kinase inhibitors, inhibitors of HIF (e.g., a HIF-2α inhibitor), inhibitors of PARP, RAS signaling inhibitors, immune checkpoint inhibitors, agents that target the extracellular production of adenosine, radiation therapy, and chemotherapeutic agents. 
     
     
         47 - 87 . (canceled)