Cycloalkylamino Acid Derivatives

Abstract

The invention relates to compounds of formula I and to pharmaceutically acceptable salts, prodrugs, solvates or hydrates thereof; wherein B, D, E, R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , m, n, p, q, r, s, t and u are as defined herein. This invention also relates to a method of using such compounds in the treatment of hyperproliferative diseases and autoimmune diseases in mammals, especially humans, and to pharmaceutical compositions containing such compounds.

1 . A compound of formula I 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein B is selected from the group consisting of phenyl and a (5 to 6-membered)-heteroaryl ring; 
       D is selected from the group consisting of phenyl and a (5 to 6-membered)-heteroaryl ring; 
       E is selected from the group consisting of phenyl and a (5 to 6-membered)-heteroaryl ring; 
       R 1  is a radical selected from the group consisting of hydrogen, —CN, (C 1 -C 6 )alkyl-, (C 2 -C 6 )alkenyl-, (C 2 -C 6 )alkynyl-, (C 3 -C 7 )cycloalkyl-, (C 2 -C 9 )heterocyclyl-, (C 6 -C 10 )aryl-, (C 1 -C 12 )heteroaryl-, R 7 —SO 2 —, R 7 —C(O)—, R 7 O—C(O)—, and (R 7 ) 2 N—C(O)—;
 wherein each of said (C 1 -C 6 )alkyl-, (C 2 -C 6 )alkenyl-, (C 2 -C 6 )alkynyl-, (C 3 -C 7 )cycloalkyl-, (C 2 -C 9 )heterocyclyl-, (C 6 -C 10 )aryl-, (C 1 -C 12 )heteroaryl-, R 7 —SO 2 —, R 7 —C(O)—, R 7 O—C(O)—, and (R 7 ) 2 N—C(O)—R 1  radicals may optionally be substituted by one to three moieties independently selected from the group consisting of hydroxy, halogen, —CN, (C 1 -C 6 )alkyl-, (C 1 -C 6 )alkoxy-, perhalo(C 1 -C 6 )alkyl-, (C 3 -C 7 )cycloalkyl-, (C 2 -C 9 )heterocyclyl-, (C 6 -C 10 )aryl-, and (C 1 -C 12 )heteroaryl-; 
 
       each R 2  is a radical independently selected from the group consisting of hydrogen, hydroxy, halogen, —CN, (C 1 -C 6 )alkyl-, (C 2 -C 6 )alkenyl-, (C 2 -C 6 )alkynyl-, (C 3 -C 7 )cycloalkyl-, (C 2 -C 9 )heterocyclyl-, (C 6 -C 10 )aryl-, and (C 1 -C 12 )heteroaryl-;
 wherein each of said (C 1 -C 6 )alkyl-, (C 2 -C 6 )alkenyl-, (C 2 -C 6 )alkynyl-, (C 3 -C 7 )cycloalkyl-, (C 2 -C 9 )heterocyclyl-, (C 6 -C 10 )aryl-, and (C 1 -C 12 )heteroaryl-R 2  radicals may optionally be substituted by one to three moieties independently selected from the group consisting of hydroxy, halogen, —CN, (C 1 -C 6 )alkyl-, perhalo(C 1 -C 4 )alkyl-, perhalo(C 1 -C 4 )alkoxy-, (C 3 -C 7 )cycloalkyl-, (C 2 -C 9 )heterocyclyl-, (C 6 -C 10 )aryl-, and (C 1 -C 12 )heteroaryl-; 
 
       each R 3  is a radical independently selected from the group consisting of hydrogen, halogen, hydroxy, —CN, (C 1 -C 6 )alkyl-, (C 2 -C 6 )alkenyl-, (C 2 -C 6 )alkynyl-, (C 3 -C 7 )cycloalkyl-, (C 1 -C 6 )alkoxy-, perhalo(C 1 -C 6 )alkyl-, and perhalo(C 1 -C 6 )alkoxy-; 
       each R 4  is a radical independently selected from the group consisting of hydrogen, halogen, hydroxy, —CN, —N(R 6 ) 2 , (C 1 -C 6 )alkyl-, (C 2 -C 6 )alkenyl-, (C 3 -C 6 )alkynyl-, (C 1 -C 6 )alkoxy-, perhalo(C 1 -C 6 )alkyl-, (C 1 -C 6 )alkyl-S(O) k —, R 10 C(O)N(R 10 )—, (R 10 ) 2 NC(O)—, R 10 C(O)—, R 10 OC(O)—, (R 10 ) 2 NC(O)N(R 10 )—, (R 10 ) 2 NS(O)—, (R 10 ) 2 NS(O) 2 —, (C 3 -C 7 )cycloalkyl-, (C 6 -C 10 )aryl-, (C 2 -C 9 )heterocyclyl-, and (C 1 -C 12 )heteroaryl-;
 wherein each of said (C 1 -C 6 )alkyl-, (C 2 -C 6 )alkenyl-, (C 3 -C 6 )alkynyl-, (C 1 -C 6 )alkoxy-, (C 1 -C 6 )-alkyl-S(O) k —, R 10 C(O)N(R 10 )—, (R 10 ) 2 NC(O)—, R 10 C(O)—, R 10 OC(O)—, (R 10 ) 2 NC(O)N(R 10 )—, (R 10 ) 2 NS(O)—, (R 10 ) 2 NS(O) 2 —, (C 3 -C 7 )cycloalkyl-, (C 6 -C 10 )aryl-, (C 2 -C 9 )heterocyclyl-, and (C 1 -C 12 )heteroaryl-R 4  radicals may optionally be substituted with from one to five moieties independently selected from the group consisting of halogen, hydroxy, —CN, (C 1 -C 6 )alkyl-, (C 3 -C 7 )cycloalkyl, —(C 1 -C 6 )alkoxy and -perhalo(C 1 -C 6 )alkoxy; 
 
       R 5  is a radical selected from the group consisting of hydrogen, halogen, —CN, (C 1 -C 10 )alkyl-, (C 1 -C 6 )alkoxy-, (C 2 -C 10 )alkenyl-, (C 2 -C 10 )alkynyl-, (C 3 -C 7 )cycloalkyl-, (C 6 -C 10 )aryl-, (C 2 -C 9 )heterocyclyl-, (C 1 -C 12 )heteroaryl-, (C 3 -C 7 )cycloalkyl-O—, (C 6 -C 10 )aryl-O—, (C 2 -C 9 )heterocyclyl-O—, (C 1 -C 12 )heteroaryl-O—, R 7 —S—, R 7 —SO—, R 7 —SO 2 —, R 7 —C(O)—, R 7 —C(O)—O—, R 7 O—C(O)—, and (R 7 ) 2 N—C(O)—;
 wherein each of said (C 1 -C 10 )alkyl-, (C 1 -C 6 )alkoxy-, (C 2 -C 10 )alkenyl-, and (C 2 -C 10 )alkynyl-R 5  radicals may optionally be substituted with from one to five moieties independently selected from the group consisting of halogen, hydroxy, —CN, (C 1 -C 6 )alkyl-, (C 3 -C 7 )cycloalkyl-, (C 6 -C 10 )aryl-, (C 1 -C 6 )alkoxy-, (C 2 -C 9 )heterocyclyl-, and (O 1 -C 12 )heteroaryl-; 
 wherein each of said (C 3 -C 7 )cycloalkyl- and (C 3 -C 7 )cycloalkyl-O—R 5  radicals may optionally be substituted with from one to five moieties independently selected from the group consisting of halogen, hydroxy, —CN, (C 1 -C 6 )alkyl-, (C 6 -C 10 )aryl-, (C 1 -C 6 )alkoxy-, (C 2 -C 9 )heterocyclyl-, and (C 1 -C 12 )heteroaryl-; 
 wherein each of said (C 6 -C 10 )aryl-, (C 2 -C 9 )heterocyclyl-, (C 1 -C 12 )heteroaryl-, (C 6 -C 10 )aryl-O—, (C 2 -C 9 )heterocyclyl-O—, and (C 1 -C 12 )heteroaryl-O—R 5  radicals may optionally be substituted with from one to five moieties independently selected from the group consisting of halogen, hydroxy, —CN, (C 1 -C 6 )alkyl-, and (C 1 -C 6 )alkoxy-; 
 
       wherein each of said R 7 —S—, R 7 —SO—, R 7 —SO 2 —, R 7 —C(O)—, R 7 —C(O)—O—, R 7 O—C(O)—, and (R 7 ) 2 N—C(O)—R 5  radicals may optionally be substituted with from one to five moieties independently selected from the group consisting of halogen, hydroxy, —CN, (C 1 -C 6 )alkyl-, (C 3 -C 7 )cycloalkyl, and (C 1 -C 6 )alkoxy-; 
       wherein each of aforesaid (C 1 -C 6 )alkyl-, (C 1 -C 6 )alkoxy-, (C 6 -C 10 )aryl-, (C 1 -C 6 )alkoxy-, (C 2 -C 9 )heterocyclyl-, and (C 1 -C 12 )heteroaryl-moieties for each of aforesaid R 5  radicals may optionally be substituted with one to five halogen groups; 
       optionally said R 5  radical and one R 4  radical or two R 4  radicals may be taken together with E to form an (8 to 10-membered)-fused bicyclic ring optionally containing 1 to 4 heteroatoms selected from the group consisting of O, S, and N(R 6 ); 
       wherein said (8 to 10-membered)-fused bicyclic ring is additionally optionally substituted with one to two oxo (═O) groups; 
       each R 6  is a bond or a radical independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl-, —CN, and perhalo(C 1 -C 6 )alkyl-; 
       each R 7  is a radical independently selected from the group consisting of hydrogen, —CN, (C 1 -C 6 )alkyl-, perhalo(C 1 -C 6 )alkyl-, (C 2 -C 6 )alkenyl-, (C 2 -C 6 )alkynyl-, (C 3 -C 7 )cycloalkyl-, (C 2 -C 9 )heterocyclyl-, (C 6 -C 10 )aryl-, and (C 1 -C 12 )heteroaryl-; 
       each R 8  is a radical independently selected from the group consisting of hydrogen, hydroxy, halogen, —CN, —NH(R 9 ), (C 1 -C 6 )alkyl-, perhalo(C 1 -C 6 )alkyl- and (C 1 -C 6 )alkoxy-;
 wherein each of said (C 1 -C 6 )alkyl- and (C 1 -C 6 )alkoxy-R 8  radicals is optionally substituted with from one to five moieties selected from the group consisting of perhalo(C 1 -C 6 )alkyl-, —O(R 9 ) and —N(R 9 ) 2 ; 
 
       each R 9  is a radical independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl-, (C 2 -C 6 )alkenyl-, (C 2 -C 6 )alkynyl-, (C 3 -C 7 )cycloalkyl-, (C 2 -C 9 )heterocyclyl-, (C 6 -C 10 )aryl-, (C 1 -C 12 )heteroaryl-, R 7 —S—, R 7 —SO—, R 7 —SO 2 —, R 7 —C(O)—, R 7 —C(O)—O—, R 7 O—C(O)—, and (R 7 ) 2 N—C(O)—;
 wherein each of said (C 1 -C 6 )alkyl-, (C 2 -C 6 )alkenyl-, (C 2 -C 6 )alkynyl-, (C 3 -C 7 )cycloalkyl-, (C 2 -C 9 )heterocyclyl-, (C 6 -C 10 )aryl-, and (C 1 -C 12 )heteroaryl-R 9  radicals is optionally substituted by one to three moieties independently selected from the group consisting of hydroxy, halogen, —CN, (C 1 -C 6 )alkyl-, (C 1 -C 6 )alkoxy-, perhalo(C 1 -C 6 )alkyl-, (C 3 -C 7 )cycloalkyl-, (C 2 -C 9 )heterocyclyl-, (C 6 -C 10 )aryl-, and (C 1 -C 12 )heteroaryl-; 
 
       each R 10  is a radical selected from the group consisting of hydrogen and (C 1 -C 6 )alkyl-; 
       k is an integer from 0 to 2; 
       m and n are each independently an integer from 0 to 3; 
       p is an integer from 1 to 2; 
       q is an integer from 0 to 2; and 
       r, s, t and u are each independently an integer from 0 to 4. 
     
   
   
       2 . A compound according to  claim 1 , wherein B is phenyl. 
   
   
       3 . A compound according to  claim 1 , wherein D is a 5-membered-heteroaryl. 
   
   
       4 . A compound according to  claim 1 , wherein E is phenyl. 
   
   
       5 . A compound according to  claim 1 , wherein R 1  is a radical selected from the group consisting of hydrogen, —CN, (C 1 -C 6 )alkyl-, (C 2 -C 6 )alkenyl-, and (C 2 -C 6 )alkynyl-, wherein each of said (C 1 -C 6 )alkyl-, (C 2 -C 6 )alkenyl-, and (C 2 -C 6 )alkynyl-R 1  radicals is optionally substituted by one to three moieties independently selected from the group consisting of hydroxy, halogen, (C 1 -C 6 )alkyl-, (C 1 -C 6 )alkoxy-, perhalo(C 1 -C 6 )alkyl-, (C 3 -C 7 )cycloalkyl-, (C 2 -C 9 )heterocyclyl-, (C 6 -C 10 )aryl-, and (C 1 -C 12 )heteroaryl-. 
   
   
       6 . A compound according to  claim 1 , wherein R 5  is a radical independently selected from the group consisting of hydrogen, halogen, and —CN. 
   
   
       7 . A compound according to  claim 1 , wherein R 5  is a radical selected from the group consisting of (C 1 -C 10 )alkyl-, (C 1 -C 6 )alkoxy-, (C 2 -C 10 )alkenyl-, and (C 2 -C 10 )alkynyl-, wherein each of said (C 1 -C 10 )alkyl-, (C 1 -C 6 )alkoxy-, (C 2 -C 10 )alkenyl-, and (C 2 -C 10 )alkynyl-R 5  radicals is optionally substituted with from one to five moieties independently selected from the group consisting of halogen, hydroxy, —CN, (C 1 -C 6 )alkyl-, (C 3 -C 7 )cycloalkyl-, (C 6 -C 10 )aryl-, (C 1 -C 6 )alkoxy-, (C 2 -C 9 )heterocyclyl-, and (C 1 -C 12 )heteroaryl-. 
   
   
       8 . A compound according to  claim 1 , wherein R 5  is selected from the group consisting of (C 3 -C 7 )cycloalkyl- and (C 3 -C 7 )cycloalkyl-O—, wherein each of said (C 3 -C 7 )cycloalkyl- and (C 3 -C 7 )cycloalkyl-O—R 5  radicals is optionally substituted with from one to five moieties independently selected from the group consisting of halogen, hydroxy, —CN, (C 1 -C 6 )alkyl-, (C 6 -C 10 )aryl-, (C 1 -C 6 )alkoxy-, (C 2 -C 9 )heterocyclyl-, and (C 1 -C 12 )heteroaryl-. 
   
   
       9 . A compound according to  claim 1 , wherein R 5  is selected from the group consisting of (C 6 -C 10 )aryl-, (C 2 -C 9 )heterocyclyl-, (C 1 -C 12 )heteroaryl-, (C 6 -C 10 )aryl-O—, (C 2 -C 9 )heterocyclyl-O—, and (C 1 -C 12 )heteroaryl-O—, wherein each of said (C 6 -C 10 )aryl-, (C 2 -C 9 )heterocyclyl-, (C 1 -C 12 )heteroaryl-, (C 6 -C 10 )aryl-O—, (C 2 -C 9 )heterocyclyl-O—, and (C 1 -C 12 )heteroaryl-O—R 5  radicals is optionally substituted with from one to five moieties independently selected from the group consisting of halogen, hydroxy, —CN, (C 1 -C 6 )alkyl-, and (C 1 -C 6 )alkoxy-. 
   
   
       10 . A compound according to  claim 1 , wherein p island q is 1. 
   
   
       11 . (canceled) 
   
   
       12 . (canceled) 
   
   
       13 . A pharmaceutical composition comprising an amount of a compound according to  claim 1  and a pharmaceutically acceptable carrier. 
   
   
       14 . A method for the treatment of cancer in a mammal in need of such treatment comprising administering to said mammal an amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, that is effective in treating said cancer. 
   
   
       15 . A method for the treatment of a disease or condition selected from the group consisting of: autoimmune diseases, rheumatoid arthritis, juvenile arthritis, type I diabetes, lupus, systemic lupus erythematosus, inflammatory bowel disease, optic neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis, vasculitis, acute and chronic inflammatory conditions, osteoarthritis, adult Respiratory Distress Syndrome, Respiratory Distress Syndrome of infancy, ischemia reperfusion injury, glomerulonephritis, allergic conditions, asthma, atopic dermatitis, chronic obstructive pulmonary disease, infection associated with inflammation, viral inflammation, influenza, hepatitis, Guillian-Barre syndrome, chronic bronchitis, xeno-transplantation, transplantation tissue rejection (chronic and acute), organ transplant rejection (chronic and acute), atherosclerosis, restenosis, granulomatous diseases, sarcoidosis, leprosy, scleroderma, ulcerative cholitis, Crohn's disease, and Alzheimer's disease; in a mammal comprising administering to said mammal an amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, that is effective in treating said disease or condition.