US 7,514,448 B2
Azaindoles useful as inhibitors of rock and other protein kinases
Jeremy Green, Burlington, Mass. (US); Andrew Miller, Abingdon (United Kingdom); Juan-Miguel Jimenez, Abingdon (United Kingdom); Craig Marhefka, Frederick, Md. (US); Jingrong Cao, Newton, Mass. (US); John Court, Littleton, Mass. (US); Upul Bandarage, Lexington, Mass. (US); Huai Gao, Lincoln, Mass. (US); and Suganthini Nanthakumar, Newton, Mass. (US)
Assigned to Vertex Pharmaceuticals Incorporated, Cambridge, Mass. (US)
Filed on Apr. 04, 2005, as Appl. No. 11/98,751.
Claims priority of provisional application 60/559041, filed on Apr. 02, 2004.
Prior Publication US 2006/0003968 A1, Jan. 05, 2006
Int. Cl. A01N 43/42 (2006.01); A61K 31/44 (2006.01); C07D 471/02 (2006.01); C07D 491/02 (2006.01); C07D 498/02 (2006.01); C07D 513/02 (2006.01); C07D 515/02 (2006.01)
U.S. Cl. 514—300  [546/113] 17 Claims
 
1. A compound of formula I:

OG Complex Work Unit Drawing
or a pharmaceutically acceptable salt thereof, wherein:
wherein

OG Complex Work Unit Drawing
x is 0, 1, 2, or 3;
R1 is halogen, —CN, —NO2, or —VmR′;
G is —NR2— or C═O;
R2 is —UnR′;
X1 and X2 are each independently CR4 or N;
each occurrence of R4 is independently halogen, CN, NO2, or VmR;
each occurrence of U or V is independently an optionally substituted C1-6 alkylidene chain, wherein up to two methylene units of the chain are optionally and independently replaced by —NR—, —S—, —O—, —CS—, —CO2—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO2—, —SO2NR—, —NRSO2—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO2NR—, —SO—, —SO2—, —PO—, —PO2—, or —POR—;
m and n are each independently 0 or 1;
each occurrence of R is independently hydrogen or an optionally substituted C1-6 aliphatic group; and each occurrence of R′ is independently hydrogen or an optionally substituted C1-6 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R and R′, two occurrences of R, or two occurrences of R′, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Q1 is —CO—, —SO2—, —NR2—, —NR2CO—, —CONR2—, or —SO2NR2—;
R3 is Q2-Ar1, or when G is —NR2—, R2 and Q1-R3, taken together with the nitrogen atom, form the cyclic group:

OG Complex Work Unit Drawing
where s is 1 or 2, Z is CH or N; each occurrence of Y is independently, as valency and stability permit, —CO—, —CS—, —SO2—, —O—, —S—, —NR5—, or —C(R5)2—, and R5 is UnR′;
Q2 and Q3 are each independently a bond or a C1-6 alkylidene chain, wherein up to two methylene units of the chain are each optionally and independently replaced by —NR′—, —S—, —O—, —CS—, —CO2—, —OCO—, —CO—, —COCO—, —CONR′—, —NR′CO—, —NR′CO2—, —SO2NR′—, —NR′SO2—, —CONR′NR′—, —NR′CONR′—, —OCONR′—, —NR′NR′—, —NR′SO2NR′—, —SO—, —SO2—, —PO—, —PO2—, or —POR′—; and wherein any carbon atom in the one or more methylene units is optionally substituted with one or two occurrences of R6, wherein each occurrence of R6 is independently halogen, —CN, —NO2, or —UnR′, or two occurrences of R6, or R′ and R6, taken together with the atoms to which they are bound, form an optionally substituted 3-6-membered cycloalkyl, heterocyclyl, aryl or heteroaryl ring; and
Ar1 and Ar2 are each independently a C1-6 aliphatic, a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein Ar1 and Ar2 are each optionally substituted with 0-5 independent occurrences of TR7; wherein T is a bond or is a C1-C6 alkylidene chain wherein up to two methylene units of T are optionally and independently replaced by —NR—, —S—, —O—, —CS—, —CO2—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO2—, —SO2NR—, —NRSO2—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO2NR—, —SO—, —SO2—, —PO—, —PO2—, or —POR—; and each occurrence of R7 is independently —R′, halogen, —NO2, —CN or ═O.