Amino acid compounds and methods of use

Abstract

The invention relates to compounds of formula (A) and formula (I): or a salt thereof, wherein R 1 , R 2 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , q and p are as described herein. Compounds of formula (A), formula (I), and pharmaceutical compositions thereof are αvβ6 integrin inhibitors that are useful for treating fibrosis such as idiopathic pulmonary fibrosis (IPF) and nonspecific interstitial pneumonia (NSIP).

1 - 77 . (canceled) 
     
     
         78 : A method of inhibiting αvβ6 integrin in an individual comprising administering to the individual an effective amount of a compound of Formula II or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is C 6 -C 14  aryl or 5- to 10-membered heteroaryl wherein the C 6 -C 14  aryl and 5- to 10-membered heteroaryl are optionally substituted by R 1a ; 
         R 2  is hydrogen; deuterium; C 1 -C 6  alkyl optionally substituted by R 2a ; —OH; —O—C 1 -C 6  alkyl optionally substituted by R 2a ; C 3 -C 6  cycloalkyl optionally substituted by R 2b ; —O—C 3 -C 6  cycloalkyl optionally substituted by R 2b ; 3- to 12-membered heterocyclyl optionally substituted by R 2c ; or —S(O) 2 R 2d ; with the proviso that any carbon atom bonded directly to a nitrogen atom is optionally substituted with an R 2a  moiety other than halogen; 
         each R 1a  is independently C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 4 -C 8  cycloalkenyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C 6 -C 14  aryl, deuterium, halogen, —CN, —OR 3 , —SR 3 , —NR 4 R 5 , —NO 2 , —C═NH(OR 3 ), —C(O)R 3 , —OC(O)R 3 , —C(O)OR 3 , —C(O)NR 4 R 5 , —NR 3 C(O)R 4 , —NR 3 C(O)OR 4 , —NR 3 C(O)NR 4 R 5 , —S(O)R 3 , —S(O) 2 R 3 , —NR 3 S(O)R 4 , —NR 3 S(O) 2 R 4 , —S(O)NR 4 R 5 , —S(O) 2 NR 4 R 5 , or —P(O)(OR 4 )(OR 5 ), wherein each R 1a  is, where possible, independently optionally substituted by deuterium, halogen, oxo, —OR 6 , —NR 6 R 7 , —C(O)R 6 , —CN, —S(O)R 6 , —S(O) 2 R 6 , —P(O)(OR 6 )(OR 7 ), C 3 -C 8  cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C 6 -C 14  aryl, or C 1 -C 6  alkyl optionally substituted by deuterium, oxo, —OH or halogen; 
         each R 2a , R 2b , R 2 , R 2e , and R 2f  is independently oxo or R 1a ; 
         R 2d  is C 1 -C 6  alkyl optionally substituted by R 2e  or C 3 -C 5  cycloalkyl optionally substituted by R 2f ; 
         each R 3  is independently hydrogen, deuterium, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 6 -C 14  aryl, 5- to 10-membered heteroaryl or 3- to 12-membered heterocyclyl, wherein the C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 6 -C 14  aryl, 5- to 10-membered heteroaryl and 3- to 12-membered heterocyclyl of R 3  are independently optionally substituted by halogen, deuterium, oxo, —CN, —OR 8 , —NR 8 R 9 , —P(O)(OR 8 )(OR 9 ), or C 1 -C 6  alkyl optionally substituted by deuterium, halogen, —OH or oxo; 
         R 4  and R 5  are each independently hydrogen, deuterium, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 6 -C 14  aryl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclyl, wherein the C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 6 -C 14  aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl of R 4  and R 5  are independently optionally substituted by deuterium, halogen, oxo, —CN, —OR 8 , —NR 8 R 9  or C 1 -C 6  alkyl optionally substituted by deuterium, halogen, —OH or oxo; 
         or R 4  and R 5  are taken together with the atom to which they attached to form a 3- to 6-membered heterocyclyl optionally substituted by deuterium, halogen, oxo, —OR 8 , —NR 8 R 9  or C 1 -C 6  alkyl optionally substituted by deuterium, halogen, oxo or —OH: 
         R 6  and R 7  are each independently hydrogen, deuterium, C 1 -C 6  alkyl optionally substituted by deuterium, halogen, or oxo, C 2 -C 6  alkenyl optionally substituted by deuterium, halogen, or oxo, or C 2 -C 6  alkynyl optionally substituted by deuterium, halogen, or oxo; 
         or R 6  and R 7  are taken together with the atom to which they attached to form a 3- to 6-membered heterocyclyl optionally substituted by deuterium, halogen, oxo or C 1 -C 6  alkyl optionally substituted by deuterium, halogen, or oxo; and 
         R 8  and R 9  are each independently hydrogen, deuterium, C 1 -C 6  alkyl optionally substituted by deuterium, halogen, or oxo, C 2 -C 6  alkenyl optionally substituted by deuterium, halogen or oxo, or C 2 -C 6  alkynyl optionally substituted by deuterium, halogen, or oxo; 
         or R 8  and R 9  are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by deuterium, halogen, oxo or C 1 -C 6  alkyl optionally substituted by deuterium, oxo, or halogen. 
       
     
     
         79 : A method of inhibiting TGFβ activation in a cell comprising administering to the cell an effective amount of a compound of Formula II or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is C 6 -C 14  aryl or 5- to 10-membered heteroaryl wherein the C 6 -C 14  aryl and 5- to 10-membered heteroaryl are optionally substituted by R 1a ; 
         R 2  is hydrogen; deuterium; C 1 -C 6  alkyl optionally substituted by R 2a ; —OH; —O—C 1 -C 6  alkyl optionally substituted by R 2a ; C 3 -C 6  cycloalkyl optionally substituted by R 2b ; —O—C 3 -C 6  cycloalkyl optionally substituted by R 2b ; 3- to 12-membered heterocyclyl optionally substituted by R 2c ; or —S(O) 2 R 2d ; with the proviso that any carbon atom bonded directly to a nitrogen atom is optionally substituted with an R 2a  moiety other than halogen; 
         each R 1a  is independently C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 4 -C 8  cycloalkenyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C 6 -C 14  aryl, deuterium, halogen, —CN, —OR 3 , —SR 3 , —NR 4 R 5 , —NO 2 , —C═NH(OR 3 ), —C(O)R 3 , —OC(O)R 3 , —C(O)OR 3 , —C(O)NR 4 R 5 , —NR 3 C(O)R 4 , —NR 3 C(O)OR 4 , —NR 3 C(O)NR 4 R 5 , —S(O)R 3 , —S(O) 2 R 3 , —NR 3 S(O)R 4 , —NR 3 S(O) 2 R 4 , —S(O)NR 4 R 5 , —S(O) 2 NR 4 R 5 , or —P(O)(OR 4 )(OR 5 ), wherein each R 1a  is, where possible, independently optionally substituted by deuterium, halogen, oxo, —OR 6 , —NR 6 R 7 , —C(O)R 6 , —CN, —S(O)R 6 , —S(O) 2 R 6 , —P(O)(OR 6 )(OR 7 ), C 3 -C 8  cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C 6 -C 14  aryl, or C 1 -C 6  alkyl optionally substituted by deuterium, oxo, —OH or halogen; 
         each R 2a , R 2b , R 2c , R 2e , and R 2f  is independently oxo or R 1a ; 
         R 2d  is C 1 -C 6  alkyl optionally substituted by R 2e  or C 3 -C 5  cycloalkyl optionally substituted by R 2f ; 
         each R 3  is independently hydrogen, deuterium, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 6 -C 14  aryl, 5- to 10-membered heteroaryl or 3- to 12-membered heterocyclyl, wherein the C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 6 -C 14  aryl, 5- to 10-membered heteroaryl and 3- to 12-membered heterocyclyl of R 3  are independently optionally substituted by halogen, deuterium, oxo, —CN, —OR 8 , —NR 8 R 9 , —P(O)(OR 8 )(OR 9 ), or C 1 -C 6  alkyl optionally substituted by deuterium, halogen, —OH or oxo; 
         R 4  and R 5  are each independently hydrogen, deuterium, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 6 -C 14  aryl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclyl, wherein the C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 6 -C 14  aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl of R 4  and R 5  are independently optionally substituted by deuterium, halogen, oxo, —CN, —OR 8 , —NR 8 R 9  or C 1 -C 6  alkyl optionally substituted by deuterium, halogen, —OH or oxo; 
         or R 4  and R 5  are taken together with the atom to which they attached to form a 3- to 6-membered heterocyclyl optionally substituted by deuterium, halogen, oxo, —OR 8 , —NR 8 R 9  or C 1 -C 6  alkyl optionally substituted by deuterium, halogen, oxo or —OH; 
         R 6  and R 7  are each independently hydrogen, deuterium, C 1 -C 6  alkyl optionally substituted by deuterium, halogen, or oxo, C 2 -C 6  alkenyl optionally substituted by deuterium, halogen, or oxo, or C 2 -C 6  alkynyl optionally substituted by deuterium, halogen, or oxo; 
         or R 6  and R 7  are taken together with the atom to which they attached to form a 3- to 6-membered heterocyclyl optionally substituted by deuterium, halogen, oxo or C 1 -C 6  alkyl optionally substituted by deuterium, halogen, or oxo; and 
         R 8  and R 9  are each independently hydrogen, deuterium, C 1 -C 6  alkyl optionally substituted by deuterium, halogen, or oxo, C 2 -C 6  alkenyl optionally substituted by deuterium, halogen or oxo, or C 2 -C 6  alkynyl optionally substituted by deuterium, halogen, or oxo; 
         or R 8  and R 9  are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by deuterium, halogen, oxo or C 1 -C 6  alkyl optionally substituted by deuterium, oxo, or halogen. 
       
     
     
         80 - 81 . (canceled) 
     
     
         82 : A method of modulating the activity of at least one integrin in a subject in need thereof, comprising administering to the subject an amount of a compound of Formula II or a pharmaceutically acceptable salt thereof effective to modulate the activity of the at least one integrin in the subject: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is C 6 -C 14  aryl or 5- to 10-membered heteroaryl wherein the C 6 -C 14  aryl and 5- to 10-membered heteroaryl are optionally substituted by R 1a ; 
         R 2  is hydrogen; deuterium; C 1 -C 6  alkyl optionally substituted by R 2a ; —OH; —O—C 1 -C 6  alkyl optionally substituted by R 2a ; C 3 -C 6  cycloalkyl optionally substituted by R 2b ; —O—C 3 -C 6  cycloalkyl optionally substituted by R 2b ; 3- to 12-membered heterocyclyl optionally substituted by R 2c : or —S(O) 2 R 2d ; with the proviso that any carbon atom bonded directly to a nitrogen atom is optionally substituted with an R 2a  moiety other than halogen; 
         each R 1a  is independently C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 4 -C 8  cycloalkenyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C 6 -C 14  aryl, deuterium, halogen, —CN, —OR 3 , —SR 3 , —NR 4 R 5 , —NO 2 , —C═NH(OR 3 ), —C(O)R 3 , —OC(O)R 3 , —C(O)OR 3 , —C(O)NR 4 R 5 , —NR 3 C(O)R 4 , —NR 3 C(O)OR 4 , —NR 3 C(O)NR 4 R 5 , —S(O)R 3 , —S(O) 2 R 3 , —NR 3 S(O)R 4 , —NR 3 S(O) 2 R 4 , —S(O)NR 4 R 5 , —S(O) 2 NR 4 R 5 , or —P(O)(OR 4 )(OR 5 ), wherein each R 1a  is, where possible, independently optionally substituted by deuterium, halogen, oxo, —OR 6 , —NR 6 R 7 , —C(O)R 6 , —CN, —S(O)R 6 , —S(O) 2 R 6 , —P(O)(OR 6 )(OR 7 ), C 3 -C 8  cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C 6 -C 14  aryl, or C 1 -C 6  alkyl optionally substituted by deuterium, oxo, —OH or halogen; 
         each R 2a , R 2b , R 2c , R 2e , and R 2f  is independently oxo or R 1a ; 
         R 2d  is C 1 -C 6  alkyl optionally substituted by R 2e  or C 3 -C 5  cycloalkyl optionally substituted by R 2f ; 
         each R 3  is independently hydrogen, deuterium, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 6 -C 14  aryl, 5- to 10-membered heteroaryl or 3- to 12-membered heterocyclyl, wherein the C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 6 -C 14  aryl, 5- to 10-membered heteroaryl and 3- to 12-membered heterocyclyl of R 3  are independently optionally substituted by halogen, deuterium, oxo, —CN, —OR 8 , —NR 8 R 9 , —P(O)(OR 8 )(OR 9 ), or C 1 -C 6  alkyl optionally substituted by deuterium, halogen, —OH or oxo; 
         R 4  and R 5  are each independently hydrogen, deuterium, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 6 -C 14  aryl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclyl, wherein the C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 6 -C 14  aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl of R 4  and R 5  are independently optionally substituted by deuterium, halogen, oxo, —CN, —OR 8 , —NR 8 R 9  or C 1 -C 6  alkyl optionally substituted by deuterium, halogen, —OH or oxo; 
         or R 4  and R 5  are taken together with the atom to which they attached to form a 3- to 6-membered heterocyclyl optionally substituted by deuterium, halogen, oxo, —OR 8 , —NR 8 R 9  or C 1 -C 6  alkyl optionally substituted by deuterium, halogen, oxo or —OH; 
         R 6  and R 7  are each independently hydrogen, deuterium, C 1 -C 6  alkyl optionally substituted by deuterium, halogen, or oxo, C 2 -C 6  alkenyl optionally substituted by deuterium, halogen, or oxo, or C 2 -C 6  alkynyl optionally substituted by deuterium, halogen, or oxo; 
         or R 6  and R 7  are taken together with the atom to which they attached to form a 3- to 6-membered heterocyclyl optionally substituted by deuterium, halogen, oxo or C 1 -C 6  alkyl optionally substituted by deuterium, halogen, or oxo; and 
         R 8  and R 9  are each independently hydrogen, deuterium, C 1 -C 6  alkyl optionally substituted by deuterium, halogen, or oxo, C 2 -C 6  alkenyl optionally substituted by deuterium, halogen or oxo, or C 2 -C 6  alkynyl optionally substituted by deuterium, halogen, or oxo; 
         or R 8  and R 9  are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by deuterium, halogen, oxo or C 1 -C 6  alkyl optionally substituted by deuterium, oxo, or halogen 
       
       the at least one integrin including at least one of α V β 1  integrin and α V β 6  integrin. 
     
     
         83 : The method of  claim 82 , comprising inhibiting the activity of one or both of α V β 1  integrin and α V β 6  integrin in the subject. 
     
     
         84 : The method of  claim 82 , wherein the subject has or is at risk of a fibrotic disease selected from the group consisting of: idiopathic pulmonary fibrosis (IPF), interstitial lung disease, radiation-induced pulmonary fibrosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), alcoholic liver disease induced fibrosis, Alport syndrome, primary sclerosing cholangitis (PSC), primary biliary cholangitis, biliary atresia, systemic sclerosis associated interstitial lung disease, scleroderma, diabetic nephropathy, diabetic kidney disease, focal segmental glomerulosclerosis, chronic kidney disease, and Crohn's Disease; and
 wherein the method comprises inhibiting the activity of one or both of α V β 1  integrin and α V β 6  integrin in the subject, thereby treating the fibrotic disease in the subject.   
     
     
         85 : The method of  claim 82 , wherein the subject is in need of treatment for NASH, the amount of the compound or a pharmaceutically acceptable salt thereof administered to the subject being effective to inhibit the activity of at least α V β 1  integrin, thereby treating the subject for NASH. 
     
     
         86 : The method of  claim 82 , the subject being in need of treatment for IPF, the amount of the compound or a pharmaceutically acceptable salt thereof administered to the subject being effective to inhibit the activity of at least α V β 6  integrin, thereby treating the subject for IPF. 
     
     
         87 : The method of  claim 82 , the subject being in need of treatment for PSC, the amount of the compound or a pharmaceutically acceptable salt thereof administered to the subject being effective to inhibit the activity of at least one of α V β 6  integrin and α V β 1  integrin, thereby treating the subject for PSC. 
     
     
         88 : The method of  claim 78 , wherein the compound of Formula II is (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. 
     
     
         89 : The method of  claim 78 , wherein the compound of Formula II is a pharmaceutically acceptable salt of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. 
     
     
         90 : The method of  claim 82 , wherein the compound of Formula II is (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. 
     
     
         91 : The method of  claim 82 , wherein the compound of Formula II is a pharmaceutically acceptable salt of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid.