Compounds and methods for kinase modulation

1. A compound having Formula I:

or a pharmaceutically acceptable salt, a solvate, a tautomer, a stereoisomer, or a deuterated analog thereof, wherein:

A is N or —C(Z 3 )═;

W is —C(R 2 )═ or N;

Z 3 is hydrogen or halo;

Z 2 is:

L is —SO 2 —NR 6 R 7 , —NHC(O)R 4 , or —C(O)NR 3 R 4 ;

R 1 is C 1-6 alkyl, halo, or halo-C 1-6 alkyl;

R 2 is hydrogen, —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , or halo;

R 3 is hydrogen or C 1-6 alkyl;

R 4 is C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, cyano-C 3-6 cycloalkyl, cyano-C 3-6 cycloalkyl-C 1-3 alkylene, cyano-C 1-6 alkylene, heterocycloalkyl, heteroaryl, or —(CH 2 )—[(CR 10 )] 2 -OH, wherein the C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, cyano-C 3-6 cycloalkyl, cyano-C 3-6 cycloalkyl-C 1-3 alkyl, cyano-C 1-6 alkylene, heterocycloalkyl, and heteroaryl are optionally substituted with 1-2 G groups;

or R 3 and R 4 , together with the N atom to which they are attached, join to form a 4-6 membered heterocycloalkyl moiety substituted with 1-2 G groups;

R 6 is hydrogen, C 1-6 alkyl, cyano-C 1-6 alkylene optionally substituted with 1-2 G groups, or C 3-6 cycloalkyl optionally substituted with 1-2 G 2 groups;

R 7 is hydrogen or C 1-6 alkyl;

or R 6 and R 7 , together with the N atom to which they are attached, join to form a heterocycloalkyl moiety substituted with 1-2 G groups;

R 8 is C 1-3 alkyl, hydroxy-C 1-6 alkyl, halo-C 1-6 alkyl, cyano-C 1-6 alkylene, —[C(R 9 ) 2 ] 1-2 —C 3-6 cycloalkyl, —[C(R 9 ) 2 ] 1-2 -heterocycloalkyl, —[C(R 9 ) 2 ] 1-2 -heteroaryl, —[C(R 9 ) 2 ] 1-2 —SO 2 —C 1-3 alkyl, —[C(R 9 ) 2 ] 1-2 —C(O)—C 1-3 alkyl, —[C(R 9 ) 2 ] 1-2 —C(O)—N(C 1-3 alkyl) 2 , —[C(R 9 ) 2 ] 1-2 —C(O)—NH 2 , —[C(R 9 ) 2 ] 1-2 —C(O)—C 3-6 cycloalkyl, or —[C(R 9 ) 2 ] 1-2 —C(O)-heterocycloalkyl, or —CH 2 —C(O)-pyridyl;

each R 9 is independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, halo, and halo-C 1-6 alkyl;

each R 10 is C 1-3 alkyl or two R 10 , together with the C atom to which they are attached, join to form a C 3-6 cycloalkyl;

each G is independently hydroxyl, C 1-6 alkyl, C 3-6 cycloalkyl, or heterocycloalkyl;

each G 2 is independently C 1-6 alkyl, halogen, or cyano;

m is 0, 1, or 2; and

n is 0 or 2;

provided that the compound is not

N-(2-cyano-2-methyl-propyl)-6-[2-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl]pyridine-2-carboxamide,

N-(2-cyano-2-methyl-propyl)-6-[2-[1-(difluoromethyl)pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl]pyridine-2-carboxamide,

N-(1-cyano-1-methyl-ethyl)-6-[2-[1-(difluoromethyl)pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl]pyridine-2-carboxamide,

N-(1-cyano-1-methyl-ethyl)-6-[2-(2-isopropyl-4-methyl-thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]pyridine-2-carboxamide,

6-[2-[1-(2-cyanoethyl)pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide,

N-(1-cyano-1-methyl-ethyl)-6-[2-[1-(2-morpholinoethyl)pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl]pyridine-2-carboxamide,

N-(1-cyano-1-methyl-ethyl)-6-[2-(1-isopropyl-3-methyl-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]pyridine-2-carboxamide,

6-[3-chloro-2-[1-(difluoromethyl)pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide,

6-[3-chloro-2-(1-isopropyl-3-methyl-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide,

N-(1-cyano-1-methyl-ethyl)-6-[2-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl]pyridine-2-carboxamide,

N-(2-cyanopropan-2-yl)-6-(2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)picolinamide,

N-(2-cyanopropan-2-yl)-6-(2-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)picolinamide,

N-(2-cyanopropan-2-yl)-6-(2-(1-(oxetan-3-ylmethyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)picolinamide, and

N-(2-cyanopropan-2-yl)-6-(2-(1-((methylsulfonyl)methyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)picolinamide.

2. The compound according to claim 1 , wherein W is —C(R 2 )═, and R 2 is —CH 3 , F, Cl, or Br.

3. The compound according to claim 1 , wherein W is —C(R 2 )═, and R 2 is hydrogen.

4. The compound according to claim 1 , wherein W is N.

5. The compound according to claim 1 , wherein A is —C(Z 3 )═, and L is —C(O)NR 3 R 4 .

6. The compound according to claim 1 , wherein A is —C(Z 3 )═, and L is:

7. The compound according to claim 1 , wherein A is —C(Z 3 )═, and L is:

8. The compound according to claim 1 having one of the following Formulae:

wherein R 2 is —CH 3 , Cl, or F.

9. The compound according to claim 8 having one of Formulae I(a), I(e), I(g), I(k), I(m), I(t), I(u), I(x), I(aa), I(dd), I(gg), I(jj), or I(oo).

10. The compound according to claim 8 having one of Formulae I(c), I(f), I(i), I(l), I(o), I(q), I(w), I(z), I(cc), I(ff), I(ii), I(ll), or I(pp).

11. The compound according to claim 8 having one of Formulae I(b), I(d), I(h), I(j), I(n), I(r), I(v), I(y), I(bb), I(ee), I(hh), I(kk), or I(mm).

12. The compound according to claim 8 having one of Formulae I(a), I(b), I(c), I(d), I(e), or I(f).

13. The compound according to claim 1 , wherein R 8 is —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CH 3 , —CH 2 CH 2 F, —CH 2 CHF 2 , —CH 2 CF 3 , —C(CH 3 ) 2 —OH, —CH 2 C(CH 3 ) 2 —OH, —CH 2 —S(O) 2 —CH 3 , —CH 2 —CN, —CH 2 -oxetanyl, —CH 2 —C(O)—NH 2 , —CH 2 —C(O)—N(C 1 -C 3 alkyl) 2 , or —CH 2 —C(O)-heterocycloalkyl.

14. The compound according to claim 1 , wherein R 8 is —CHF 2 , —C(CH 3 ) 2 —OH, —CH 2 C(CH 3 ) 2 —OH, —CH 2 —S(O) 2 —CH 3 , —CH 2 —C(O)—NH 2 , —CH 2 —C(O)—N(CH 3 ) 2 , or —CH 2 —C(O)-pyridyl.

15. The compound according to claim 1 , wherein Z 3 is F or Cl.

16. A compound having the structure:

or a pharmaceutically acceptable salt, a solvate, a tautomer, a stereoisomer, or a deuterated analog of any one of the above compounds.

17. A pharmaceutical composition comprising a compound according to claim 1 , and a pharmaceutically acceptable carrier.

18. The pharmaceutical composition according to claim 17 , further comprising a second pharmaceutical agent selected from: an alkylating agent selected from adozelesin, altretamine, bizelesin, busulfan, carboplatin, carboquone, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven, lomustine, mechlorethamine, melphalan, oxaliplatin, piposulfan, semustine, streptozocin, temozolomide, thiotepa, and treosulfan; ii) an antibiotic selected from bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, mitomycin, mitoxantrone, neocarzinostatin, pentostatin, and plicamycin; iii) an antimetabolite selected from the group consisting of azacitidine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil, ftorafur, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, pemetrexed, raltitrexed, thioguanine, and trimetrexate; iv) an antibody therapy agent selected from alemtuzumab, bevacizumab, cetuximab, galiximab, gemtuzumab, nivolumab, ipilimumab, panitumumab, pembrolizumab, pertuzumab, rituximab, tositumomab, trastuzumab, and 90 Y ibritumomab tiuxetan; v) a hormone or hormone antagonist selected from the group consisting of anastrozole, androgens, buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprolide, magestrol, raloxifene, tamoxifen, and toremifene; vi) a taxane selected from DJ-927, docetaxel, TPI 287, paclitaxel and DHA-paclitaxel; vii) a retinoid selected from alitretinoin, bexarotene, fenretinide, isotretinoin, and tretinoin; viii) an alkaloid selected from etoposide, homoharringtonine, teniposide, vinblastine, vincristine, vindesine, and vinorelbine; ix) an antiangiogenic agent selected from AE-941 (GW786034, Neovastat), ABT-510, 2-methoxyestradiol, lenalidomide, and thalidomide; x) a topoisomerase inhibitor selected from amsacrine, edotecarin, exatecan, irinotecan, SN-38 (7-ethyl-10-hydroxy-camptothecin), rubitecan, topotecan, and 9-aminocamptothecin; xi) a kinase inhibitor selected from erlotinib, gefitinib, flavopiridol, imatinib mesylate, lapatinib, sorafenib, sunitinib malate, AEE-788, AG-013736, AMG 706, AMN107, BMS-354825, BMS-599626, UCN-01 (7-hydroxystaurosporine), vemurafenib, dabrafenib, trametinib, cobimetinib selumetinib and vatalanib; xii) a targeted signal transduction inhibitor selected from bortezomib, geldanamycin, and rapamycin; xiii) a biological response modifier selected from imiquimod, interferon-α and interleukin-2; xiv) a chemotherapeutic agent selected from 3-AP (3-amino-2-carboxyaldehyde thiosemicarbazone), altrasentan, aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide, elesclomol, eribulin mesylate (E7389), ixabepilone, lonidamine, masoprocol, mitoguanazone, oblimersen, sulindac, testolactone, tiazofurin, a mTOR inhibitor, a PI3K inhibitor, a Cdk4 inhibitor, an Akt inhibitor, a Hsp90 inhibitor, a farnesyltransferase inhibitor, and an aromatase inhibitor; xv) a Mek inhibitor; xvi) a tyrosine kinase inhibitor; xvii) an EGFR inhibitor; and xviii) an anti-retroviral agent selected from entry inhibitors, fusion inhibitors, reverse transcriptase inhibitors, nucleoside/nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase inhibitors, protease inhibitors, and multi-class combination products.