Diaminotriazoles useful as inhibitors of protein kinases

1. A compound of formula II or II′:

or a pharmaceutically acceptable salt thereof, wherein

R 1 is hydrogen;

R 2 is Ar 1 , wherein Ar 1 is a phenyl group substituted with x independent occurrences of Q-R X , wherein x is 1-5; Q is a bond or is a C 1 -C 6 alkylidene chain wherein up to two methylene units of Q are optionally replaced by —NR—, —S—, —O—, —CS—, —CO 2 —, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO 2 —, —SO 2 NR—, —NRSO 2 —, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO 2 NR—, —SO—, —SO 2 —, —PO—, —PO 2 —, or —POR—; and each occurrence of R x is independently R′, halogen, NO 2 , CN, OR′, SR′, N(R′) 2 , NR′COR′, NR′CONR′ 2 , NR′CO 2 R′, COR′, CO 2 R′, OCOR′, CON(R′) 2 , OCON(R′) 2 , SOR′, SO 2 R′, SO 2 N(R′) 2 , NR′SO 2 R′, NR′SO 2 N(R′) 2 , COCOR′, or COCH 2 COR′, wherein at least one Q-R X is not hydrogen;

R 3 is Ar 2 , wherein Ar 2 is an optionally substituted aryl group selected from pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, imidazolyl, pyrazolyl, triazolyl, furanyl, thiophenyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, or an 8-12 membered bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein said aryl group is optionally substituted with y occurrences of Z-R Y ; wherein y is 0-5, Z is a bond or is a C 1 -C 6 alkylidene chain wherein up to two methylene units of Z are optionally replaced by —NR—, —S—, —O—, —CS—, —CO 2 —, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO 2 —, —SO 2 NR—, —NRSO 2 —, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO 2 NR—, —SO—, or —SO 2 —; and each occurrence of R Y is independently R′, halogen, NO 2 , CN, OR′, SR′, N(R′) 2 , NR′COR′, NR′CONR′ 2 , NR′CO 2 R′, COR′, CO 2 R′, OCOR′, CON(R′) 2 , OCON(R′) 2 , SOR′, SO 2 R′, SO 2 N(R′) 2 , NR′SO 2 R′, NR′SO 2 N(R′) 2 , COCOR′, or COCH 2 COR′; and

each occurrence of R is independently hydrogen or an optionally substituted C 1-6 aliphatic group; and each occurrence of R′ is independently hydrogen or an optionally substituted group selected from a C 1-6 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;

provided that:

a) when R 3 is pyridyl, pyrimidinedione, then R 2 is not phenyl simultaneously substituted with one occurrence of OMe in the meta position, and one occurrence of oxazole in the para position; or

b) when R 3 is unsubstituted pyrimidinyl, then R 2 is not p-OMe substituted phenyl, p-OEt substituted phenyl, or o-OMe substituted phenyl.

2. The compound of claim 1 , wherein said compound has the formula II-A-(i) or II-A-(i)′:

wherein each of m and n is 0.

3. The compound of claim 2 , wherein Ar 2 is selected from one of the following groups:

wherein any substitutable carbon or nitrogen atom is optionally substituted by ZR Y .

4. The compound of claim 2 , wherein Ar is selected from one of the following groups:

wherein any substitutable carbon or nitrogen atom is optionally substituted by ZR Y .

5. The compound of claim 1 , wherein Ar 2 is optionally substituted 2-pyridyl, 2-thiazolyl, 2-pyrimidinyl, 6-pyrimidinyl, 4-pyridyl, benzothiazolyl, or 2-quinolinyl, and said compound has one of the structures II-F-(i), II-G-(i), II-G′-(i), II-H-(i)′, II-I-(i), II-I′-(i), II-J-(i), II-F-(i)′, II-G-(i)′, II-G′-(i)′, II-H-(i)′, II-I-(i)′, II-I′-(i)′, or II-J-(i)′:

wherein n is 0.

6. The compound of claim 2 , wherein Ar 2 is pyridyl, pyrimidinyl, quinolinyl, or thiazolyl, each optionally substituted with 0-3 occurrences of ZR Y .

7. The compound of claim 6 , wherein x is 1-3; y is 0-3; and each occurrence of QR X or ZR Y is independently R′, halogen, CN, NO 2 , —N(R′) 2 , —CH 2 N(R′) 2 , —OR′, —CH 2 OR′, —SR′, —CH 2 SR′, —COOR′, —NRCOR′, —CON(R′) 2 , —SO 2 N(R′) 2 , —CONR(CH 2 ) 2 N(R′) 2 , —CONR(CH 2 ) 3 N(R′) 2 , —CONR(CH 2 ) 4 N(R′) 2 , —O(CH 2 ) 2 OR′, —O(CH 2 ) 3 )R′, —O(CH 2 ) 4 OR′, —O(CH 2 ) 2 N(R′) 2 , —O(CH 2 ) 3 N(R′) 2 , or —O(CH 2 ) 4 N(R′) 2 .

8. The compound of claim 5 , wherein x is 1-3; y is 0-3; and each occurrence of QR X or ZR Y is independently Cl, Br, F, CF 3 , Me, Et, CN, —COGH, —N(CH 3 ) 2 , —N(Et) 2 , —N(iPr) 2 , —O(CH 2 ) 2 OCH 3 , —CONH 2 , —COOCH 3 , —OH, —CH 2 OH, —NHCOCH 3 , —SO 2 NH 2 , methylenedioxy, ethylenedioxy, —O(CH 2 ) 2 N-morpholino, —O(CH 2 ) 3 N-morpholino, —O(CH 2 ) 4 N-morpholino, —O(CH 2 ) 2 N-piperazinyl, —O(CH 2 ) 3 N-piperizinyl, —O(CH 2 ) 4 N-piperizinyl, —NHCH(CH 2 OH)phenyl, —CONH(CH 2 ) 2 N-morpholino, —CONH(CH 2 ) 2 N-piperazinyl, —CONH(CH 2 ) 3 N-morpholino, —CONH(CH 2 ) 3 N-piperazinyl, —CONH(CH 2 ) 4 N-morpholino, —CONH(CH 2 ) 4 N-piperazinyl, —SO 2 NH(CH 2 ) 2 N-morpholino, —SO 2 NH(CH 2 ) 2 N-piperazinyl, —SO 2 NH(CH 2 ) 3 N-morpholino, —SO 2 NH(CH 2 ) 3 N-piperazinyl, —SO 2 NH(CH 2 ) 4 N-morpholino, —SO 2 NH(CH 2 ) 4 N-piperazinyl, where each of the foregoing phenyl, morpholino, piperazinyl, or piperidinyl groups is optionally substituted, or an optionally substituted group selected from C 1-4 alkoxy, phenyl, phenyloxy, benzyl, piperidinyl, piperazinyl, morpholino, or benzyloxy.

9. The compound of claim 1 , having one of the formulae:

10. The compound of claim 9 , wherein x is 1-3; y is 0-3; and each occurrence of QR X or ZR Y is independently R′, halogen, CN, NO 2 -N(R′) 2 , —CH 2 N(R′) 2 , —OR′, —CH 2 OR′, —SR′, —CH 2 SR′, —COOR′, —NRCOR′, —CON(R′) 2 , —SO 2 N(R′) 2 , —CONR(CH 2 ) 2 N(R′) 2 , —CONR(CH 2 ) 3 N(R′) 2 , —CONR(CH 2 ) 4 N(R′,) 2 , —O(CH 2 ) 2 OR′, —O(CH 2 ) 3 OR′, —O(CH 2 ) 40 R′, —O(CH 2 ) 2 N(R′) 2 , —O(CH 2 ) 3 N(R′) 2 , or —O(CH 2 ) 4 N(R′) 2 .

11. The compound of claim 10 , wherein QR X or ZR Y groups are each independently Cl, Br, F, CF 3 , Me, Et, CN, —COOH, —N(CH 3 ) 2 , —N(Et) 2 , —N(iPr) 2 , —O(CH 2 ) 20 CH 3 , —CONH 2 , —COOCH 3 , —OH, —CH 2 OH, —NHCOCH 3 , —SO 2 NH 2 , methylenedioxy, ethylenedioxy, —O(CH 2 ) 2 N-morpholino, —O(CH 2 ) 3 N-morpholino, —O(CH 2 ) 4 N-morpholino, —O(CH 2 ) 2 N-piperazinyl, —O(CH 2 ) 3 N-piperizinyl, —O(CH 2 ) 4 N-piperizinyl, —NHCH(CH 2 OH)phenyl, —CONH(CH 2 ) 2 N-morpholino, —CONH(CH 2 ) 2 N-piperazinyl, —CONH(CH 2 ) 3 N-morpholino, —CONH(CH 2 ) 3 N-piperazinyl, —CONH(CH 2 ) 4 N-morpholino, —CONH(CH 2 ) 4 N-piperazinyl, —SO 2 NH(CH 2 ) 2 N-morpholino, —SO 2 NH(CH 2 ) 2 N-piperazinyl, —SO 2 NH(CH 2 ) 3 N-morpholino, —SO 2 NH(CH 2 ) 3 N-piperazinyl, —SO 2 NH(CH 2 ) 4 N-morpholino, —SO 2 NH(CH 2 ) 4 N-piperazinyl, where each of the foregoing phenyl, morpholino, piperazinyl, or piperidinyl groups is optionally substituted, or an optionally substituted group selected from C 1-4 alkoxy, phenyl, phenyloxy, benzyl, piperidinyl, piperazinyl, morpholino, or benzyloxy.

12. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

13. The composition of claim 12 , further comprising an additional therapeutic agent selected mechlorethamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide, methotrexate, 6-mercaptopurine, 5-fluorouracil, cytarabile, gemcitabine, vinblastine, vincristine, vinorelbine, paclitaxel, etoposide, irinotecan, topotecan, doxorubicin, bleomycin, mitomycin, carmustine, lomustine, cisplatin, carboplatin, asparaginase, tamoxifen, leuprolide, flutamide, megestrol, imatinib mesylate, adriamycin, dexamethasone, cyclophosphamide, donepezil (Aricept®), rivastigmine (Excelon®)), L-DOPAlcarbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, amantadine, glatiramer (Copaxone®), mitoxantrone, albuterol, montelukast (Singulair®), zyprexa, risperdal, seroquel, haloperidol, a corticosteroid, a TNF blocker, IL-1 RA, azathioprine, cyclophosphamide, sulfasalazine, cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, an interferon, cyclophosphamide, azathioprine, sulfasalazine, an acetylcholinesterase inhibitor, a monoamine oxidase inhibitor, an interferon, an anti-convulsant, an ion channel blocker, riluzole, a beta-blocker, an acetyl cholinesterase inhibitor, a diuretic, a nitrate, a calcium channel blocker, a statin, cholestyramine, or gamma globulin.

14. A method of inhibiting FLT-3 or c-KIT kinase activity in a biological sample in vitro selected from a cell culture, saliva, urine, feces, semen, tears, or extracts thereof, comprising the step of contacting said biological sample with:

a) a composition according to claim 12 ; or

b) a compound according to claim 1 .

15. The compound of claim 1 , wherein said compound is selected from the following: