Granted Patent B2

US 8,933,222 · App. 14/197,771 · Granted Jan 13, 2015

Abstract

Claims (123)

1. A method of synthesizing a compound of the following formula

comprising coupling a compound of formula XX

with an amine compound of the formula

or an acid salt thereof;

wherein

R is —(CH 2 ) p -G 1 -L 1 -G 2 , wherein

L 1 is selected from the group consisting of: a direct bond, —CH 2 —, —O—, —N(R 16 )—, —C(O)—, —CON(R 16 )—, —N(R 16 )C(O)—, —N(R 16 )SO 2 —, —SO 2 N(R 16 )—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O) 2 —, and —C≡C—, wherein

R 16 is selected from the group consisting of: -hydrogen, -alkyl, -aryl, -alkylene-aryl;

G 1 is selected from the group consisting of: alkynylene, arylene, heteroarylene, fused arylcycloalkylene, fused cycloalkylarylene, fused cycloalkylheteroarylene, fused heterocyclylarylene, and fused heterocyclylheteroarylene, wherein G 1 is optionally substituted 1-4 times with substituents independently selected from R 10 , wherein

R 10 is Rb,

G 2 is selected from the group consisting of: -aryl, -heteroaryl, -fused arylcycloalkyl, -fused cycloalkylaryl, -fused cycloalkylheteroaryl, -fused heterocyclylaryl, and -fused heterocyclylheteroaryl, wherein G 2 is optionally substituted 1-4 times with substituents independently selected from R 11 , wherein

R 11 is Rb,

R 1 is —CO 2 R 12 , wherein R 12 is selected from the group consisting of: —C 1-10 alkyl, -cycloalkyl, and -aryl, wherein R 12 is optionally substituted 1-4 times with a group independently selected from R c ;

R 2 is hydrogen;

R 3 is selected from R a ;

R 5 is -G 3 -L 2 -Q 2 -L 3 -G 4 , wherein

L 2 and L 3 are independently selected from the group consisting of: a direct bond, —CH 2 —, —O—, —N(R 26 )—, —C(O)—, —CON(R 26 )—, —N(R 26 )C(O)—, —N(R 26 )CON(R 27 )—, —N(R 26 )C(O)O—, —OC(O)N(R 26 )—, —N(R 26 )SO 2 —, —SO 2 N(R 26 )—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O) 2 —, and —N(R 26 )SO 2 N(R 27 )—, wherein

R 26 and R 27 are independently selected from the group consisting of: hydrogen, -alkyl, -aryl, and -alkylene-aryl, wherein R 26 and R 27 are optionally substituted 1-4 times with R c , or R 26 and R 27 are taken together with the atoms to which they are attached to form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur;

Q 2 is selected from the group consisting of: a direct bond, C 1-10 alkylene, C 2-10 alkenylene, and C 2-10 alkynylene,

G 3 is selected from the group consisting of: -arylene, -cycloalkylene, -heterocyclylene, -heteroarylene, -fused arylcycloalkylene, -fused cycloalkylarylene, -fused cycloalkylheteroarylene, -fused heterocyclylarylene, and -fused heterocyclylheteroarylene, wherein

G 3 is optionally substituted 1-4 times with substituents independently selected from R 8 , wherein R 8 is selected from R b ,

G 4 is selected from the group consisting of: -aryl, -cycloalkyl, -heterocyclyl, -heteroaryl, -fused arylcycloalkyl, -fused cycloalkylaryl, -fused cycloalkylheteroaryl, -fused heterocyclylaryl, and -fused heterocyclylheteroaryl, wherein

G 4 is optionally substituted 1-4 times with substituents independently selected from R 9 , wherein R 9 is selected from R b ,

R a is selected from the group consisting of:

a) -hydrogen,

b) —S(O) m R d ,

c) —S(O) 2 OR d ,

d) —S(O) m NR d R e ,

e) —C(O)R d ,

f) —CO 2 R d ,

g) —C(O)NR d R e ,

h) -haloalkyl,

i) -cycloalkyl,

j) -heterocyclyl,

k) —C 1-10 alkyl,

l) —C 2-10 alkenyl,

m) —C 2-10 alkynyl,

n) -aryl,

o) -heteroaryl,

p) —C 1-10 alkylene-aryl,

q) —C 2-10 alkynylene-aryl,

r) —C 1-10 alkylene-heteroaryl,

s) —C 2-10 alkynylene-heteroaryl, and

t) —C(R f R g ) n -aryl,

wherein alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, and cycloalkyl groups are optionally substituted 1-4 times with a group independently selected from R c ;

R b is selected from the group consisting of:

a) -cycloalkyl,

b) -cyano,

c) —OR d ,

d) —NO 2 ,

e) -halogen,

f) —S(O) m R d ,

g) —SR d ,

h) —S(O) 2 OR d ,

i) —S(O) m NR d R e ,

j) —NR d R e ,

k) —O(CR f R g ) n NR d R e ,

l) —C(O)R d ,

m) —CO 2 R d ,

n) —CO 2 (CR f R g ) n CONR d R e ,

o) —OC(O)R d ,

p) —C(O)NR d R e ,

q) —NR d C(O)R e ,

r) —OC(O)NR d R e ,

s) —NR d C(O)OR e ,

t) —NR d C(O)NR d R e ,

u) —CF 3 ,

v) —OCF 3 ,

w) -haloalkyl,

x) -haloalkoxy,

y) —C 1-10 alkyl,

z) —C 2-10 alkenyl,

aa) —C 2-10 alkynyl,

ab) —C 1-10 alkylene-aryl,

ac) —C 1-10 alkylene-heteroaryl, and

ad) -heteroaryl,

wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl, and cycloalkyl groups are optionally substituted 1-4 times with a group independently selected from R c ;

R c is selected from the group consisting of:

a) -halogen,

c) -amino,

c) -carboxy,

d) -cyano,

e) —C 1-4 alkyl,

f) —O—C 1-4 alkyl,

g) —O—CF 3 ,

h) -cycloalkyl,

i) —O-cycloalkyl,

j) -aryl,

k) —C 1-4 alkylene-aryl,

l) -hydroxy,

m) —CF 3 ,

n) -haloalkyl,

o) -haloalkoxy,

p) —O-aryl,

q) -heteroaryl,

r) -heteroarylene-C 1-10 alkyl,

s) -heterocyclyl,

t) —CO 2 —C 1-10 alkyl,

u) —CO 2 —C 1-10 alkyl-aryl,

v) -fused arylcycloalkyl,

w) -alkynylene-heteroaryl,

x) -alkylene-aryl,

y) -alkynylene-aryl,

z) -nitro,

aa) —N(H)—C(O)—C 1-6 -alkyl, and

bb) —S—C 1-6 -alkyl,

R d and R e are independently selected from the group consisting of: hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloalkyl, —C 1-10 alkylene-cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl groups are optionally substituted with one to four substituents independently selected from R c ; or R d and R e together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen and optionally substituted with 1-3 times with R c ,

R f and R g are independently selected from the group consisting of: hydrogen, C 1-10 alkyl, cycloalkyl, —C 1-10 alkylene-cycloalkyl, -carboxy, and aryl, wherein alkyl, cycloalkyl, and aryl groups are optionally substituted with one to four substituents independently selected from R c ; or R f and R g together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen optionally substituted with 1-3 times with R c ;

m is an integer from 1 to 2;

n is an integer from 1 to 10; and

p is an integer from 0 to 2.

2. The method of claim 1 , wherein the compound of formula XX and the amine compound are coupled in the presence of o-benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (HBTU).

3. A method of synthesizing a compound of the following formula

comprising coupling a compound of formula XX

with an amine compound of the formula

or an acid salt thereof;

wherein

R is

R 1 is —CO 2 R 12 , wherein R 12 is methyl;

R 2 is hydrogen;

R 3 is —(R)-1-phenyl-propyl or —(S)-1-phenyl-propyl; and

R 5 is

4. The method of claim 3 , wherein the compound of formula XX and the amine compound are coupled in the presence of o-benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (HBTU).

Assignments (10)