Compositions useful as inhibitors of rock and other protein kinases

1. A compound of formula V-A′:

or a pharmaceutically acceptable salt thereof, wherein:

Ring B is a 5-membered heteroaryl ring selected from pyrazole, triazole, or oxadiazole, wherein Ring B is optionally substituted with 0-3 R 4 groups;

R Z is halogen, CN, NO 2 , or U (n) R′;

each R 1 is independently halogen, CN, NO 2 , or V (m) R;

V is an optionally substituted C 1-6 alkylidene chain, wherein up to two methylene units of the chain are optionally and independently replaced by —S—, —O—, —CS—, —CO 2 —, —OC(O)—, —C(O)—, —C(O)C(O)—, —C(O)NR—, —SO 2 NR—, —C(O)NRNR—, —OC(O)NR—, —S(O)—, or —SO 2 —;

R 2 is U (n) R′;

each occurrence of R 4 is independently halogen, CN, NO 2 , or U (n) R;

each occurrence of U is independently an optionally substituted C 1-6 alkylidene chain, wherein up to two methylene units of the chain are optionally and independently replaced by —NR—, —S—, —O—, —CS—, —CO 2 —, —OC(O)—, —C(O)—, —C(O)C(O)—, —C(O)NR—, —NRC(O)—, —NRCO 2 —, —SO 2 NR—, —NRSO 2 —, —C(O)NRNR—, —NRC(O)NR—, —OC(O)NR—, —NRNR—, —NRSO 2 NR—, —S(O)—, or —SO 2 —;

m and n are each independently 0 or 1;

each occurrence of R is independently hydrogen or an optionally substituted C 1-6 aliphatic group;

each occurrence of R′ is independently hydrogen or an optionally substituted C 1-6 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 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;

q is 0, 1, 2, or 3;

each occurrence of R 6 is independently halogen, CN, NO 2 , or U (n) R′, or: two occurrences of R 6 , or R′ and R 6 , taken together with the atoms to which they are bound, form an optionally substituted 3-6-membered cycloalkyl, heterocyclyl, aryl or heteroaryl ring;

Ar 1 is a 5-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 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 Ar 1 is optionally substituted with 0-5 occurrences of TR 7 ;

T is a valence bond or is a C 1 -C 6 alkylidene chain wherein up to two methylene units of T are optionally and independently replaced by —NR—, —S—, —O—, —CS—, —CO 2 —, —OC(O)—, —C(O)—, —C(O)C(O)—, —C(O)NR—, —NRC(O)—, —NRCO 2 —, —SO 2 NR—, —NRSO 2 —, —C(O)NRNR—, —NRC(O)NR—, —OC(O)NR—, —NRNR—, —NRSO 2 NR—, —S(O)—, or —SO 2 —; and

each occurrence of R 7 is independently R′, halogen, NO 2 , or CN, wherein

optional substituents on an unsaturated carbon of an aryl or heteroaryl group are selected from halogen; R o ; OR o ; SR o ; 1,2-methylene-dioxy; 1,2-ethylenedioxy; phenyl, optionally substituted with R o ; —O(phenyl) optionally substituted with R o ; (CH 2 ) 1-2 (phenyl), optionally substituted with R o ; CH═CH(phenyl), optionally substituted with R o ; NO 2 ; CN; N(R o ) 2 ; NR o C(O)R o ; NR o C(O)N(R o ) 2 ; NR o CO 2 R o ; —NR o NR o C(O)R o ; NR o NR o C(O)N(R o ) 2 ; NR o NR o CO 2 R o ; C(O)C(O)R o ; C(O)CH 2 C(O)R o ; CO 2 R o ; C(O)R o ; C(O)N(R o ) 2 ; OC(O)N(R o ) 2 ; S(O) 2 R o ; SO 2 N(R o ) 2 ; S(O)R o ; NR o SO 2 N(R o ) 2 ; NR o SO 2 R o ; C(═S)N(R o ) 2 ; C(═NH)—N(R o ) 2 ; or (CH 2 ) 0-2 NHC(O)R o , wherein each independent occurrence of R o is selected from hydrogen, optionally substituted C 1-6 aliphatic, an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl, O(phenyl), or CH 2 (phenyl), or, notwithstanding the definition above, two independent occurrences of R o , on the same substituent or different substituents, taken together with the atom(s) to which each R o group is bound, form a 3-8 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein optional substituents on the aliphatic group of R o are selected from NH 2 , NH(C 1-4 aliphatic), N(C 1-4 aliphatic) 2 , halogen, C 1-4 aliphatic, OH, O(C 1-4 aliphatic), NO 2 , CN, CO 2 H, CO 2 (C 1-4 aliphatic), O(haloC 1-4 aliphatic), or haloC 1-4 aliphatic,

optional substituents on an aliphatic group or on a non-aromatic heterocyclic ring are selected from those defined above for the unsaturated carbon of an aryl or heteroaryl group and the following: ═O, ═S, ═NNHR* ═NN(R*) 2 , ═NNHC(O)R* ═NNHCO 2 (alkyl), ═NNHSO 2 (alkyl), or ═NR* where each R* is independently selected from hydrogen or an optionally substituted C 1-6 aliphatic, wherein substituents on the aliphatic group of R* are selected from NH 2 , NH(C 1-4 aliphatic), N(C 1-4 aliphatic) 2 , halogen, C 1-4 aliphatic, OH, O(C 1-4 aliphatic), NO 2 , CN, CO 2 H, CO 2 (C 1-4 aliphatic), O(halo C 1-4 aliphatic), or halo(C 1-4 aliphatic), and

optional substituents on the nitrogen of a non-aromatic heterocyclic ring are selected from R + , N(R + ) 2 , C(O)R + , CO 2 R + , C(O)C(O)R + , C(O)CH 2 C(O)R + , SO 2 R + , SO 2 N(R + ) 2 , C(═S)N(R + ) 2 , C(═NH)—N(R + ) 2 , or NR + SO 2 R + , wherein R + is hydrogen, an optionally substituted C 1-6 aliphatic, optionally substituted phenyl, optionally substituted O(phenyl), optionally substituted CH 2 (phenyl), optionally substituted (CH 2 ) 1-2 (phenyl), optionally substituted CH═CH(phenyl), or an unsubstituted 5-6 membered heteroaryl or heterocyclic ring having one to four heteroatoms independently selected from oxygen, nitrogen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R + , on the same substituent or different substituents, taken together with the atom(s) to which each R + group is bound, form a 3-8-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein optional substituents on the aliphatic group or the phenyl ring of R + are selected from NH 2 , NH(C 1-4 aliphatic), N(C 1-4 aliphatic) 2 , halogen, C 1-4 aliphatic, OH, O(C 1-4 aliphatic), NO 2 , CN, CO 2 H, CO 2 (C 1-4 aliphatic), O(halo C 1-4 aliphatic), or halo(C 1-4 aliphatic).

2. The compound according to claim 1 , wherein:

each occurrence of R 1 is optionally substituted C 1 -C 4 aliphatic, OH, OR, SR, or N(R) 2 ;

each R 2 is independently hydrogen, or is U (n) R′, where n is 1, and U is —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —CH 2 O—, —CH 2 S—, —CH 2 NR—, —CH 2 CH 2 O—, —CH 2 CH 2 S—, —CH 2 CH 2 NR—, —CH 2 CH 2 CH 2 O—, —CH 2 CH 2 CH 2 S—, —CH 2 CH 2 CH 2 NR—, —CH 2 CH 2 CH 2 CH 2 O—, —CH 2 CH 2 CH 2 CH 2 S—, —CH 2 CH 2 CH 2 CH 2 NR—, —CH 2 CH 2 OCH 2 CH 2 —, —(CH 2 ) 4 NHCH 2 —, —(CH 2 ) 3 NHCH 2 CH 2 —, or —CH 2 CH 2 NHCH 2 CH 2 —,

each R′ is independently hydrogen, C 1 -C 4 alkyl, an optionally substituted group selected from tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyridinyl, imidazolyl, phenyl, or cyclohexyl, or: R and R′, taken together with the nitrogen atom to which they are bound, form an optionally substituted 5- or 6-membered saturated, partially unsaturated, or unsaturated heterocyclyl ring;

each occurrence of R 4 is independently hydrogen, C 1-6 aliphatic, CN, C(O)R, C(O)OR, C(O)N(R) 2 , or halogen;

each q is independently 1, 2, or 3; and

each R 6 is independently R′, —N(R)(R′), —(CH 2 ) 1-4 N(R)(R′), —(CH 2 ) 1-4 C(CH 3 ) 2 N(R)(R′), —OR′, —(CH 2 ) 1-4 OR′, —NR(CH 2 ) 1-4 N(R)(R′), —NR(CH 2 ) 1-4 SO 2 R′, —NR(CH 2 ) 1-4 C(O)OR′, or —NR(CH 2 ) 1-4 COR′, or: two occurrences of R 6 , taken together with the atoms to which they are bound, form an optionally substituted 3-6-membered saturated, partially unsaturated, or fully unsaturated ring.

3. The compound according to claim 1 , wherein

is selected from any of the following:

4. A compound selected from the group consisting of:

5. A composition comprising an effective amount of compound of claim 1 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

6. A method of treating or lessening the severity of a disease condition or disorder selected from allergy, asthma, diabetes, or glaucoma comprising the step of administering to said patient a compound of claim 1 or a composition of claim 5 .

7. The method of claim 6 , wherein disease, condition, or disorder is allergy, asthma, or diabetes.

8. The method of claim 6 , wherein disease, condition, or disorder is glaucoma.