Macrocyclic compounds as ALK, FAK and JAK2 inhibitors

The present invention provides compounds of Formula I or a pharmaceutically acceptable salt forms thereof, wherein R1, R2, R3, R4, R5, A and X are as defined herein, methods of treatment and uses thereof.

Pyrrolotriazines as ALK inhibitors

This application provides compounds of the general formula (I) and/or a salt thereof, where X, R 1 and R 2 are as defined herein. Compositions and therapeutic uses are also described.

Azaquinazoline inhibitors of atypical protein kinase C

The present application provides a compound of formula (I) or a salt thereof, wherein R 7 , R 8 , R 9 , G, and X are as defined herein. This application further describes compositions comprising the same. Compounds of formula (I) and their salts have aPKC inhibitory activity, and may be used to treat proliferative diseases.

Azaquinazoline inhibitors of Atypical protein Kinase C

The present application provides azaquinazoline compounds as defined herein. This application further describes compositions comprising the same. These azaquinazoline compounds and their salts have atypical protein kinase C (“aPKC”) inhibitory activity, and may be used to treat proliferative disorders.

FUSED BICYCLIC 2,4-DIAMINOPYRIMIDINE DERIVATIVE AS A DUAL ALK AND FAK INHIBITOR

The present invention provides a compound of formula (I) 2. The method of claim 1 , wherein the salt of the compound of Formula (I) comprises an acid addition salt.3. The method of claim 1 , wherein the salt of the compound of Formula (I) comprises an tribenzenesulfonate salt.4. The method of claim 3 , wherein the tribenzenesulfonate salt of Formula (I) has an XRPD pattern comprising one or more peaks selected from 7.62±0.2 degrees 2Θ claim 3 , 13.11±0.2 degrees 2Θ claim 3 , 13.76±0.2 degrees 2Θ claim 3 , and 14.05±0.2 degrees 2Θ.5. The method of claim 3 , wherein the tribenzenesulfonate salt of Formula (I) has an XRPD pattern comprising one or more peaks selected from 6.85±0.2 degrees 2Θ claim 3 , 7.62±0.2 degrees 2Θ claim 3 , 8.01±0.2 degrees 2Θ claim 3 , 13.11±0.2 degrees 2Θ claim 3 , 13.76±0.2 degrees 2Θ claim 3 , 14.05±0.2 degrees 2Θ claim 3 , and 14.60±0.2 degrees 2Θ.6. The method of claim 3 , wherein the tribenzenesulfonate salt of Formula (I) has an XRPD pattern comprising one or more peaks selected from 7.62±0.2 degrees 2Θ claim 3 , 13.11±0.2 degrees 2Θ claim 3 , 13.76±0.2 degrees 2Θ claim 3 , 14.05±0.2 degrees 2Θ claim 3 , 17.10±0.2 degrees 2Θ claim 3 , 17.86±0.2 degrees 2Θ claim 3 , and 18.10±0.2 degrees 2Θ.7. The method of claim 1 , wherein the salt of the compound of Formula (I) comprises a trihydrochloride dihydrate salt.8. The method of claim 7 , wherein the trihydrochloride dehydrate salt of Formula (I) has an XRPD pattern comprising one or more peaks selected from 5.42±0.2 degrees 2Θ claim 7 , 8.86±0.2 degrees 2Θ claim 7 , 14.06±0.2 degrees 2Θ claim 7 , 17.52±0.2 degrees 2Θ and 18.51±0.2 degrees 2Θ.9. The method of claim 7 , wherein the trihydrochloride dehydrate salt of Formula (I) has an XRPD pattern comprising one or more peaks selected from 5.42±0.2 degrees 2Θ claim 7 , 5.91±0.2 degrees 2Θ claim 7 , 8.86±0.2 degrees 2Θ claim 7 , 10.80±0.2 degrees 2Θ claim 7 , 11.79±0.2 degrees 2Θ claim 7 , 14.06±0.2 degrees 2Θ claim 7 , 14.72±0.2 degrees 2Θ ...

PYRROLOTRIAZINES AS ALK INHIBITORS

This application provides compounds of the general formula (I) 2. The single enantiomer according to that is (3R claim 1 ,4R)-1-(2-Hydroxy-ethyl)-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2 claim 1 ,1-f][1 claim 1 ,2 claim 1 ,4]triazin-2-ylamino]-phenyl}-piperidin-3-ol claim 1 , and/or a salt thereof.3. A compound selected from the group consisting of:(±)-3,4-cis-1-(2-Methoxy-ethyl)-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-3-ol;(±)-3,4-cis-1-(2-Hydroxy-ethyl)-4-{3-methoxy-4-[7-(2-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-3-ol;(±)-2-(3,4-trans-3-Fluoro-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2, 1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-ethanol;(±)-3,4-cis-4-{3-Methoxy-4-[7-(2-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-3-ol;(±)-[4-(3,4-trans-3-Fluoro-piperidin-4-yl)-2-methoxy-phenyl]-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine;(±)-2-(3,4-trans-3-fluoro-4-{3-methoxy-4-[7-(2-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-ethanol;(±)-2-(3,3-Difluoro-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-ethanol;(±)-1-(3,4-trans-3-Fluoro-4-{3-methoxy-4-[7-(2-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-2-methyl-propan-2-ol;(±)-2-(3,3-Difluoro-4-{3-methoxy-4-[7-(2-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-ethanol;(±)-[4-(3,3-Difluoro-piperidin-4-yl)-2-methoxy-phenyl]-[7-(2-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine;(±)-[4-(3,4-trans-3-Fluoro-piperidin-4-yl)-2-methoxy-phenyl]-[7-(2-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine;(3R,4S)-1-(2-Hydroxy-ethyl)-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-3-ol;(3S,4R)-1-(2-Hydroxy-ethyl)-4-{3-methoxy-4-[7-(2- ...

FUSED BICYCLIC 2,4-DIAMINOPYRIMIDINE DERIVATIVE AS A DUAL ALK AND FAK INHIBITOR

The present invention provides a compound of formula (I) 2. The method of claim 1 , wherein the salt of the compound of Formula (I) comprises an acid addition salt.3. The method of claim 1 , wherein the salt of the compound of Formula (I) comprises an tribenzenesulfonate salt.4. The method of claim 3 , wherein the tribenzenesulfonate salt of Formula (I) has an XRPD pattern comprising one or more peaks selected from 7.62±0.2 degrees 2θ claim 3 , 13.11±0.2 degrees 2θ claim 3 , 13.76±0.2 degrees 2θ claim 3 , and 14.05±0.2 degrees 2θ.5. The method of claim 3 , wherein the tribenzenesulfonate salt of Formula (I) has an XRPD pattern comprising one or more peaks selected from 6.85±0.2 degrees 2θ claim 3 , 7.62±0.2 degrees 2θ claim 3 , 8.01±0.2 degrees 2θ claim 3 , 13.11±0.2 degrees 2θ claim 3 , 13.76±0.2 degrees 2θ claim 3 , 14.05±0.2 degrees 2θ claim 3 , and 14.60±0.2 degrees 2θ.6. The method of claim 3 , wherein the tribenzenesulfonate salt of Formula (I) has an XRPD pattern comprising one or more peaks selected from 7.62±0.2 degrees 2θ claim 3 , 13.11±0.2 degrees 2θ claim 3 , 13.76±0.2 degrees 2θ claim 3 , 14.05±0.2 degrees 2θ claim 3 , 17.10±0.2 degrees 2θ claim 3 , 17.86±0.2 degrees 2θ claim 3 , and 18.10±0.2 degrees 2θ.7. The method of claim 1 , wherein the salt of the compound of Formula (I) comprises a trihydrochloride dihydrate salt.8. The method of claim 7 , wherein the trihydrochloride dehydrate salt of Formula (I) has an XRPD pattern comprising one or more peaks selected from 5.42±0.2 degrees 2θ claim 7 , 8.86±0.2 degrees 2θ claim 7 , 14.06±0.2 degrees 2θ claim 7 , 17.52±0.2 degrees 2θ and 18.51±0.2 degrees 2θ.9. The method of claim 7 , wherein the trihydrochloride dehydrate salt of Formula (I) has an XRPD pattern comprising one or more peaks selected from 5.42±0.2 degrees 2θ claim 7 , 5.91±0.2 degrees 2θ claim 7 , 8.86±0.2 degrees 2θ claim 7 , 10.80±0.2 degrees 2θ claim 7 , 11.79±0.2 degrees 2θ claim 7 , 14.06±0.2 degrees 2θ claim 7 , 14.72±0.2 degrees 2θ ...

MACROCYCLIC COMPOUNDS AS ALK, FAK AND JAK2 INHIBITORS

The present invention provides compounds of Formula I or a pharmaceutically acceptable salt forms thereof, wherein R1, R2, R3, R4, R5, A and X are as defined herein, methods of treatment and uses thereof.

Fused bicyclic 2,4-diaminopyrimidine derivative as a dual ALK and FAK inhibitor

The present invention provides a compound of formula (I) or a salt form thereof. The compound of formula (I) has ALK and FAK inhibitory activity, and may be used to treat proliferative disorders.

THIENOPYRIMIDINE INHIBITORS OF ATYPICAL PROTEIN KINASE C

The present application provides a compound of formula (I) 2. The compound claim 1 , or pharmaceutically acceptable salt thereof claim 1 , according to wherein Rand Rare H.3. The compound claim 1 , or pharmaceutically acceptable salt thereof claim 1 , according to wherein Ris H.4. The compound claim 1 , or pharmaceutically acceptable salt thereof claim 1 , according to wherein R claim 1 , Rand Rare H.5. The compound claim 1 , or pharmaceutically acceptable salt thereof claim 1 , according to wherein Ris selected from Calkyl optionally substituted by 1-13 Rand Carylalkyl optionally substituted by 1-9 R.6. The compound claim 1 , or pharmaceutically acceptable salt thereof claim 1 , according to wherein Ris H.7. The compound claim 1 , or pharmaceutically acceptable salt thereof claim 1 , according to wherein Ris selected from Calkyl claim 1 , phenyl claim 1 , Ccycloalkyl claim 1 , halogen and —OR.8. The compound claim 1 , or pharmaceutically acceptable salt thereof claim 1 , according to wherein R claim 1 , R claim 1 , R claim 1 , and Rare independently chosen from H and halogen.13. The method according to wherein the cancer is selected from squamous cell carcinoma claim 12 , leukemia claim 12 , prostate cancer claim 12 , non-Hodgkin's lymphoma claim 12 , endometrial cancer claim 12 , lung cancer and breast cancer.14. The method according to wherein the lung cancer is non-small cell lung cancer.15. The method according to wherein the squamous cell carcinoma is esophageal squamous cell carcinoma.16. The method according to wherein the non-Hodgkin's lymphoma is follicular lymphoma. This application is a continuation of U.S. application Ser. No. 14/285,007, filed May 22, 2014, which is a U.S. National Phase application under 35 U.S.C. §371 of International Patent Application No. PCT/US2012/065831, filed Nov. 19, 2012, which claims the benefit of U.S. Provisional Application No. 61/563,310, filed Nov. 23, 2011, the content of each of which is incorporated herein by ...

PYRROLOTRIAZINES AS ALK AND JAK2 INHIBITORS

The present invention provides a compound of formula I 2. A compound as defined in claim 1 , having an ALK kinase ICof <0.1 μM.3. A compound as defined in claim 1 , having a JAK2 kinase ICof <0.1 μM.4. A pharmaceutical composition comprising a compound as defined in and at least one pharmaceutically acceptable carrier claim 1 , diluent claim 1 , or excipient therefor.5. A method of treating a proliferative disorder in a subject claim 1 , comprising administering to the subject a therapeutically effective amount of a compound as defined in . This application is a continuation of International Application PCT/US2009/069006, filed Dec. 21, 2009, which claims the benefit of U.S. Provisional Application No. 61/139,545, filed Dec. 19, 2008, the disclosures of which are incorporated herein by reference in their entireties.Anaplastic Lymphoma Kinase (ALK) is a cell membrane-spanning receptor tyrosine kinase, which belongs to the insulin receptor subfamily. The most abundant expression of ALK occurs in the neonatal brain, suggesting a possible role for ALK in brain development (Duyster, J. et al., 2001, 20, 5623-5637).ALK is also implicated in the progression of certain tumors. For example, approximately sixty percent of anaplastic large cell lymphomas (ALCL) are associated with a chromosome mutation that generates a fusion protein consisting of nucleophosmin (NPM) and the intracellular domain of ALK. (Armitage, J. O. et al., 6edition, 2001, 2256-2316; Kutok J. L. & Aster J. C., 2002, 20, 3691-3702). This mutant protein, NPM-ALK, possesses a constitutively active tyrosine kinase domain that is responsible for its oncogenic property through activation of downstream effectors. (Falini, B. et al., 1999, 94, 3509-3515; Morris, S. W. et al., 2001, 113, 275-295; Duyster et al.; Kutok & Aster). In addition, the transforming EML4-ALK fusion gene has been identified in non-small-cell lung cancer (NSCLC) patients (Soda, M., et al., 2007, 448, 561-566) and represents another in a list ...

Macrocyclic Compounds as ALK, FAK and JAK2 Inhibitors

The present invention provides compounds of Formula I or a pharmaceutically acceptable salt forms thereof, wherein R1, R2, R3, R4, R5, A and X are as defined herein, methods of treatment and uses thereof.

Fused Bicyclic 2,4-diaminopyrimidine Derivative as a Dual ALK and FAK Inhibitor

The present invention provides a compound of formula (I) 2. The compound of formula I according to .3. A salt of the compound of formula (I) according to .4. A salt of the compound of formula (I) according to wherein the salt is an acid addition salt.5. A salt of the compound of formula (I) according to wherein the salt is an tribenzenesulfonate salt.6. A tribenzenesulfonate salt of the compound of formula (I) according to having a XRPD pattern comprising one or more peaks selected from 7.62±0.2 degrees 2Θ claim 5 , 13.11±0.2 degrees 2Θ claim 5 , 13.76±0.2 degrees 2Θ claim 5 , and 14.05±0.2 degrees 2Θ.7. A tribenzensulfonate salt of the compound of formula (I) according to having a XRPD pattern comprising one or more peaks selected from 6.85±0.2 degrees 2Θ claim 5 , 7.62±0.2 degrees 2Θ claim 5 , 8.01±0.2 degrees 2Θ claim 5 , 13.11±0.2 degrees 2Θ claim 5 , 13.76±0.2 degrees 2Θ claim 5 , 14.05±0.2 degrees 2Θ claim 5 , and 14.60±0.2 degrees 2Θ.8. A tribenzensulfonate salt of the compound of formula (I) according to having a XRPD pattern comprising one or more peaks selected from 7.62±0.2 degrees 2Θ claim 5 , 13.11±0.2 degrees 2Θ claim 5 , 13.76±0.2 degrees 2Θ claim 5 , 14.05±0.2 degrees 2Θ claim 5 , 17.10±0.2 degrees 2Θ claim 5 , 17.86±0.2 degrees 2Θ claim 5 , and 18.10±0.2 degrees 2Θ.9. A salt of the compound of formula (I) according to wherein the salt is a trihydrochloride dihydrate salt.10. A trihydrochloride dihydrate salt of the compound of formula (I) according to having a XRPD pattern comprising one or more peaks selected from 5.42±0.2 degrees 2Θ claim 9 , 8.86±0.2 degrees 2Θ claim 9 , 14.06±0.2 degrees 2Θ claim 9 , 17.52±0.2 degrees 20 and 18.51±0.2 degrees 2Θ.11. A trihydrochloride dihydrate salt of the compound of formula (I) according to having a XRPD pattern comprising one or more peaks selected from 5.42±0.2 degrees 2Θ claim 9 , 5.91±0.2 degrees 2Θ claim 9 , 8.86±0.2 degrees 2Θ claim 9 , 10.80±0.2 degrees 2Θ claim 9 , 11.79±0.2 degrees 2Θ claim 9 , 14.06± ...

Azaquinazoline Inhibitors of Atypical Protein Kinase C

The present application provides a compound of formula (I) 2. A compound according to claim 1 , wherein X is chosen from morpholinyl optionally substituted by 1-6 R claim 1 , piperidinyl optionally substituted by 1-6 R claim 1 , piperazinyl optionally substituted by 1-6 R claim 1 , and —NRR.4. A compound as defined in claim 1 , wherein Ris chosen from H claim 1 , Calkyl optionally substituted by 1-6 R claim 1 , Calkenyl optionally substituted by 1-6 R claim 1 , Caryl optionally substituted by 1-6 R claim 1 , Ccycloalkyl optionally substituted by 1-6 R claim 1 , 3-10 membered heterocycloalkyl optionally substituted by 1-6 R claim 1 , 5-10 membered heteroaryl optionally substituted by 1-6 R claim 1 , halogen claim 1 , —CN claim 1 , —C(═O)R claim 1 , —C(═O)OR claim 1 , —C(═O)NRR claim 1 , —NO claim 1 , —NRR claim 1 , —NRC(═O)R claim 1 , —NRS(═O)R claim 1 , —NRS(═O)NRR claim 1 , —OR claim 1 , —OC(═O)R claim 1 , —S(═O)R claim 1 , and —S(═O)NRR; Ris chosen from H claim 1 , Calkyl optionally substituted by 1-6 R claim 1 , halogen claim 1 , —NRR claim 1 , and —OR; and Ris chosen from H claim 1 , Calkyl optionally substituted by 1-6 R claim 1 , Calkenyl optionally substituted by 1-6 R claim 1 , Calkynyl optionally substituted by 1-6 R claim 1 , Caryl optionally substituted by 1-6 R claim 1 , Ccycloalkyl optionally substituted by 1-6 R claim 1 , 3-10 membered heterocycloalkyl optionally substituted by 1-6 R claim 1 , 5-10 membered heteroaryl optionally substituted by 1-6 R claim 1 , halogen claim 1 , —CN claim 1 , —C(═O)R claim 1 , —C(═O)OR claim 1 , —C(═O)NRR claim 1 , —NC claim 1 , —NO claim 1 , —NRR claim 1 , —NRC(═O)R claim 1 , —NRC(═O)OR claim 1 , —NRC(═O)NRR claim 1 , —NRS(═O)R claim 1 , —NRS(═O)NRR claim 1 , —OR claim 1 , —C(═O)R claim 1 , —OC(═O)NRR claim 1 , —S(═O)R claim 1 , and —S(═O)NRR.13. A compound as defined in claim 1 , wherein Rat each occurrence is independently chosen from Calkyl optionally substituted by 1-3 R claim 1 , Calkenyl optionally substituted by ...

Pyrimidinone derivatives as cdc7 inhibitors

The present invention relates to compounds of formula I as defined herein, and salts and solvates thereof, that function as inhibitors of cell division cycle 7 (Cdc7) kinase enzyme activity. The present invention also relates to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which Cdc7 kinase activity is implicated.

PYRROLOTRIAZINES AS ALK INHIBITORS

This application provides compounds of the general formula (I) 2. The compound according to wherein the other Ris halogen.3. The compound according to wherein the other Ris hydrogen.4. The compound according to wherein at least one Ris fluorine.5. The compound according to wherein the other Ris fluorine.6. The compound according to wherein X is CH.7. The compound according to wherein X is N.8. The compound according to wherein Ris H.9. The compound according to wherein Ris C-Calkyl optionally substituted with at least one R.10. The compound according to wherein the at least one Ris hydroxyl.11. The compound according to wherein the at least one Ris C-Calkoxy.12. The compound according to wherein the at least one Ris CON(R).13. The compound according to wherein the at least one Ris OCOR.14. The compound according to wherein Ris hydrogen.15. The compound according to wherein Ris C-Calkyl.16. The compound according to wherein Ris phenyl substituted with at least one halogen.17. The compound according to wherein Ris phenyl substituted with at least one bromine.19. The single enantiomer according to that is (3R claim 18 ,4R)-1-(2-Hydroxy-ethyl)-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2 claim 18 ,1-f][1 claim 18 ,2 claim 18 ,4]triazin-2-ylamino]-phenyl}-piperidin-3-ol claim 18 , and/or a salt thereof.20. A compound selected from the group consisting of:(±)-3,4-cis-1-(2-Methoxy-ethyl)-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-3-ol;(±)-3,4-cis-1-(2-Hydroxy-ethyl)-4-{3-methoxy-4-[7-(2-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-3-ol;(±)-2-(3,4-trans-3-Fluoro-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-ethanol;(±)-3,4-cis-4-{3-Methoxy-4-[7-(2-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-3-ol;(±)-[4-(3,4-trans-3-Fluoro-piperidin-4-yl)-2-methoxy-phenyl]-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4 ...

Azaquinazoline Inhibitors of Atypical Protein Kinase C

The present application provides a compound of formula (1) 1(5-Cyclobutyl-3-fluoro-pyridin-2-yl)-[4-(5-cy clopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;{5-Cyclopropyl-2-[2-(3,5,6-trifluoro-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-methyl-piperidin-4-yl-amine;(4-Chloro-1-ethyl-1H-pyrazol-3-y)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-[1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-amine;{4-[5-Cyclopropyl-4-(3,3-dimethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-[1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-amine; and{4-[5-Cyclopropyl-4-(3,3-dimethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(1-isopropyl-1H-pyrazol-3-yl)-amine;or a pharmaceutically acceptable salt thereof.. A compound selected from the group consisting of: This application claims the benefit of U.S. Provisional Application Nos. 61/707,340, filed Sep. 28, 2012 and 61/781,364, filed Mar. 14, 2013, the disclosures of which are incorporated herein by reference in their entireties.PKCι and PKCζ (accession numbers NM_002740 and NM_002744 respectively) together define the atypical sub-class of the protein kinase C (PKC) family. The aPKCs are structurally and functionally distinct from the other PKC sub-classes, classic/conventional and novel, as their catalytic activity is not dependent on diacylglycerol and calcium (Ono, Y., Fujii, T., Ogita, K., Kikkawa, U., Igarashi, K., and Nishizuka, Y. (1989). Protein kinase C zeta subspecies from rat brain: its structure, expression, and properties. Proc Natl Acad Sci USA 86, 3099-3103).Structurally, PKCι and PKCζ contain a C-terminal serine/threonine kinase domain (AGC class) and an N-terminal regulatory region containing a Phox Bem 1 (PB 1) domain involved in mediating protein:protein interactions critical for aPKC function. At the amino acid level the aPKCs share 72% ...

Thienopyrimidine inhibitors of atypical protein kinase c

or a salt thereof, wherein R1, R2, R3, R4, R5, R6, A, G, M, Q and X are as defined herein. A compound of formula (I) and its salts have a PKC inhibitory activity, and may be used to treat proliferative disorders.

PREPARATION AND USES OF PYRIMIDINONE DERIVATIVE

The present invention relates to compounds of formula (I), and salts and solvates thereof, that function as inhibitors of cell division cycle 7 (Cdc7) kinase enzyme activity: 2. A compound according to claim 1 , wherein X is chosen from halogen claim 1 , haloC-Calkyl claim 1 , NOand CN.3. A compound according to claim 1 , wherein Ris independently chosen from C-Calkyl claim 1 , C-Calkenyl claim 1 , C-Calkynyl claim 1 , C-Calkylaryl claim 1 , C-Calkylcycloalkyl claim 1 , C-Calkylheterocycloalkyl claim 1 , C-Calkylheteroaryl claim 1 , —CN claim 1 , —C(═O)C-CalkylR claim 1 , —C(═O)C-CalkylOR claim 1 , —C(═O)C-CalkylNRR claim 1 , —C(═O)C-CalkylC(═O)R claim 1 , haloC-Calkyl claim 1 , halogen claim 1 , —NO claim 1 , —NRR claim 1 , —NRC-CalkylOR claim 1 , —NRC-CalkylC(═O)R claim 1 , —NRC-Calkyl C(═O)OR—NRC-CalkylC(═O)NRR claim 1 , —C-CalkylOR.4. A compound according to claim 1 , wherein Ris independently chosen from C-Calkyl claim 1 , —CN claim 1 , haloC-Calkyl claim 1 , halogen claim 1 , —NO claim 1 , —NRR claim 1 , —C-CalkylOR.5. A compound according to claim 1 , wherein Ris selected from halogen claim 1 , CFor OH.6. A compound according to claim 1 , wherein Ris a group A-B-C wherein:{'sub': 1', '2, 'A is a bond or is C-Calkyl;'}{'sup': '3', 'B is absent or is chosen from S, NRor O; and'}{'sup': '5', 'C is a 3 to 12 membered heterocycloalkyl or a 4 to 8 membered cycloalkyl either of which is optionally substituted with one or more R.'}7. A compound according to wherein Ris a 3 to 8 membered heterocycloalkyl optionally substituted with one or more R claim 1 , wherein Ris selected from C-Calkyl claim 1 , haloC-Calkyl or halogen;8. A compound according to claim 1 , wherein Rand Rare each independently chosen from H claim 1 , C-Calkyl or haloC-Calkyl.9. A compound according to claim 1 , wherein each Ris independently chosen from C-Calkyl claim 1 , C-Calkenyl claim 1 , C-Calkynyl claim 1 , C-Calkylaryl claim 1 , C-Calkylcycloalkyl claim 1 , C-Calkylheterocycloalkyl claim 1 , ...

Cgrp antagonist compounds

The disclosures herein relate to novel compounds of Formula (1): and salts thereof, wherein A1, A2, Q, X, R1, R2 and R3 are defined herein, and their use in treating, preventing, ameliorating, controlling or reducing the risk of disorders associated with CGRP receptors.

Thienopyrimidine Inhibitors of Atypical Protein Kinase C

The present application provides a compound of formula (I) 2. A compound as defined in claim 1 , wherein A is NR.5. A compound as defined in claim 1 , wherein R claim 1 , R claim 1 , and Rare independently chosen from H and Calkyl optionally substituted by 1-3 R; R claim 1 , R claim 1 , R claim 1 , and Rare independently chosen from H claim 1 , Calkyl optionally substituted by 1-3 R claim 1 , halogen claim 1 , —CN claim 1 , —C(═O)R claim 1 , —C(═O)OR claim 1 , —C(═O)NRR claim 1 , —NO claim 1 , —NRR claim 1 , —NRC(O)R claim 1 , —NRS(═O)R claim 1 , OR claim 1 , OC(O)R claim 1 , S(O)R claim 1 , and S(═O)NRR; alternatively claim 1 , Rand Rcan claim 1 , together with the atoms linking them claim 1 , form a Caryl optionally substituted by 1-3 R claim 1 , Ccycloalkyl optionally substituted by 1-3 R claim 1 , 3-10 membered heterocycloalkyl optionally substituted by 1-3 Ror a 5-10 membered heteroaryl optionally substituted by 1-3 R; alternatively Rand Ror Rand Rcan together form a double bond; and alternatively any of Rand R claim 1 , Rand R claim 1 , Rand R claim 1 , Rand R claim 1 , Rand R claim 1 , and Rand Rcan claim 1 , together with the atoms linking them claim 1 , form a 5-15 membered heterocycloalkyl optionally substituted by 1-3 Ror a 5-15 membered heteroaryl optionally substituted by 1-3 R.6. A compound as defined in claim 1 , wherein R claim 1 , R claim 1 , R claim 1 , R claim 1 , and Rare independently chosen from H and Calkyl optionally substituted by 1-3 R; Ris chosen from H claim 1 , Calkyl optionally substituted by 1-3 R claim 1 , Carylalkyl optionally substituted by 1-3 R claim 1 , and 6-10 membered heteroarylalkyl optionally substituted by 1-3 R; Ris chosen from H claim 1 , Calkyl optionally substituted by 1-3 R claim 1 , Carylalkyl optionally substituted by 1-9 R claim 1 , Ccycloalkylalkyl optionally substituted by 1-6 R claim 1 , and 6-11 membered heteroarylalkyl optionally substituted by 1-7 R; and alternatively any of Rand R claim 1 , Rand R claim 1 , ...

Imidazo[4,5-b]pyridine Derivatives as ALK and JAK Modulators for the Treatment of Proliferative Disorders

This application relates to compounds of the Formula I 12. A compound according to claim 1 , or a salt thereof claim 1 , wherein Ris selected from hydrogen claim 1 , chlorine or bromine.13. A compound according to claim 9 , or a salt thereof claim 9 , wherein:{'sup': 1', '6, 'Ris selected from phenyl, piperidinyl, pyrazolyl, pyridinyl, pyrimidinyl, furanyl, pyrrolyl, thiophenyl, thiazolyl, isoxazolyl, tetrahydroimidazopyridinyl, or aminophenyl, wherein each of the foregoing may be optionally substituted with one or more Rgroups;'}{'sup': '2', 'Ris selected from hydrogen, chlorine or bromine; and'}{'sup': 4', '5, 'Rand Rare each independently selected from hydrogen, methyl, isopropyl, hydroxyethyl, or cyclopropyl.'}14. A compound according to that is selected from the following:(1S,2S,3R,4R)-3-[6-Chloro-2-(4-morpholin-4-ylmethyl-phenyl)-3H-imidazo[4,5-b]pyridine-7-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide;(1S,2S,3R,4R)-3-[6-Chloro-2-(4-morpholin-4-yl-phenyl)-3H-imidazo[4,5-b]pyridine-7-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide;(1S,2S,3R,4R)-3-[6-Chloro-2-(3-methoxy-phenyl)-3H-imidazo[4,5-b]pyridin-7-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide;(1S,2S,3R,4R)-3-[6-Chloro-2-(4-methoxy-phenyl)-3H-imidazo[4,5-b]pyridine-7-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide;(1S,2S,3R,4R)-3-[6-Chloro-2-(3-morpholin-4-yl-phenyl)-3H-imidazo[4,5-b]pyridine-7-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide;(1S,2S,3R,4R)-3-[6-Chloro-2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine-7-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide;(1S,2S,3R,4R)-3-[6-Chloro-2-(2-methoxy-phenyl)-3H-imidazo[4,5-b]pyridine-7-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide;(1S,2S,3R,4R)-3-{6-Chloro-2-[4-(4-methyl-piperazin-1-yl)-phenyl]-3H-imidazo[4,5-b]pyridine-7-ylamino}-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide;3-[7-((1R,2R,3S,4S)-3-Carbamoyl-bicyclo[2.2.1]hept-5-en-2-ylamino)-6-chloro-3H-imidazo[4,5-b] ...

Azaquinazoline Inhibitors Of Atypical Protein Kinase C

The present application provides a compound of formula (I) 2. The compound according to claim 1 , wherein Ris optionally substituted cyclopropyl.3. The compound according to claim 1 , wherein Ris optionally substituted cyclobutyl.4. The compound according to claim 1 , wherein Ris C-haloalkyl.5. The compound according to claim 1 , wherein Ris Calkyl.9. The compound according to claim 1 , wherein X is chosen from the group consisting of 3-10 membered heterocycloalkyl optionally substituted by 1-6 R claim 1 , 5-10 membered heteroaryl optionally substituted by 1-6 R claim 1 , —C(═O)R claim 1 , —C(═O)NRR claim 1 , —NRR claim 1 , —NRC(═O)R claim 1 , —NRS(═O)R claim 1 , —OC(═O)OR claim 1 , —OS(═O)R claim 1 , —OS(═O)R claim 1 , and —OR.10. The compound according to claim 9 , wherein X is chosen from the group consisting of 3-10 membered heterocycloalkyl optionally substituted by 1-6 R claim 9 , 5-10 membered heteroaryl optionally substituted by 1-6 R claim 9 , and —OR.11. The compound according to claim 1 , wherein Rand Rare each independently chosen from the group consisting of H claim 1 , halogen claim 1 , —CN claim 1 , —C(═O)R claim 1 , —C(═O)OR claim 1 , —C(═O)NRR claim 1 , —C(═O)C(═O)R claim 1 , —C(═NR)R claim 1 , —C(═NR)NRR claim 1 , —C(═NOH)NRR claim 1 , —C(═NOR)R claim 1 , —C(═NRRR)R claim 1 , —C(═NRRC(═O)R)R claim 1 , —C(═NNRC(═O)OR)R claim 1 , —C(═S)NRR claim 1 , —NC claim 1 , —NO claim 1 , —NRR claim 1 , —NRNRR claim 1 , —N═NR claim 1 , —NROR claim 1 , —NRC(═O)R claim 1 , —NRC(═O)C(═O)R claim 1 , —NRC(═O)OR claim 1 , —NRC(═O)C(═O)OR claim 1 , —NRC(═O)NRR claim 1 , —NRC(═O)NRC(═O)R claim 1 , —NRC(═O)NRC(═O)OR claim 1 , —NRC(═NR)NRR claim 1 , —NRC(═O)C(═O)NRR claim 1 , —NRC(═S)R claim 1 , —NRC(═S) OR claim 1 , —NRC(═S)NRR claim 1 , —NRS(═O)R claim 1 , —NRS(═O)NRR claim 1 , —NRP(═O)RR claim 1 , —NRP(═O)(NRR)(NRR) claim 1 , —OR claim 1 , —OCN claim 1 , —OC(═o)R claim 1 , —OC(═o)NRR claim 1 , —OC(═O)OR claim 1 , —OC(═NR)NRR claim 1 , —OS(═O)R claim 1 , —OS(═O)R claim ...

DEUTERATED CHLOROKYNURENINES FOR THE TREATMENT OF NEUROPSYCHIATRIC DISORDERS

Described are deuterated chlorokynurenines and compositions, and their application as pharmaceuticals for the treatment of disease. Methods of modulating N-methyl-D-aspartate (NMDA) receptor activity, methods of treating disorders, including neuropsychiatric disorders such as depression, epilepsy, schizophrenia, and Huntington's Disease, and use of said deuterated chlorokynurenines are also described. 3. The compound of claim 2 , wherein at least one of R-Rindependently has deuterium enrichment of no less than about 10%.4. The compound of claim 2 , wherein at least one of R-Rindependently has deuterium enrichment of no less than about 50%.5. The compound of claim 2 , wherein at least one of R-Rindependently has deuterium enrichment of no less than about 90%.6. The compound of claim 2 , wherein at least one of R-Rindependently has deuterium enrichment of no less than about 98%.9. The compound of claim 8 , wherein each position represented as D has deuterium enrichment of no less than about 10%.10. The compound of claim 8 , wherein each position represented as D has deuterium enrichment of no less than about 50%.11. The compound of claim 8 , wherein each position represented as D has deuterium enrichment of no less than about 90%.12. The compound of claim 8 , wherein each position represented as D has deuterium enrichment of no less than about 98%.1720-. (canceled)21. A pharmaceutical composition comprising the compound of and a pharmaceutically acceptable carrier.22. A method of treating a NMDA receptor-mediated disorder comprising administering to a patient in need thereof a therapeutically effective amount of the compound of .23. A method of treating a neuropsychiatric disorder claim 1 , a neurodegenerative disorder claim 1 , a seizure disorder claim 1 , an age-related cognitive disorder claim 1 , a perinatal brain disorder claim 1 , or a disorder of movement involving chorea claim 1 , dyskinesia claim 1 , or one or more tics in a patient claim 1 , comprising ...

Prodrugs of Chlorokynurenines

The present disclosure relates to prodrugs of 7-chlorokynurenic acid. In certain embodiments, the prodrugs include those having the structure of any one of formula (I)-(VIII), wherein R-R, monomer 1, monomer 2, and linker are defined herein. Also provided are methods of preparing and using these prodrugs. 4. The compound of claim 2 , wherein Ris optionally substituted Calkyl optionally substituted with optionally substituted aryl claim 2 , Calkyl substituted with optionally substituted heterocyclyl claim 2 , or optionally substituted aryl.5. The compound of claim 2 , wherein Ris alkylene glycol optionally substituted by C(O)aryl claim 2 , Calkyl claim 2 , phenyl claim 2 , —P(O)(OH) claim 2 , —P(O)(OH)(OCalkyl) claim 2 , or —S(O)OH.6. The compound of claim 2 , wherein Ris H.7. The compound of claim 2 , wherein Ris Calkyl or Calkoxy.10. The compound of claim 11 , wherein Ris Calkyl claim 11 , Calkoxy claim 11 , or optionally substituted arylCalkyleneoxyl.11. The compound of claim 11 , wherein Ris optionally substituted Ccycloalkyl claim 11 , optionally substituted aryl claim 11 , optionally substituted heteroaryl claim 11 , or optionally substituted heterocyclyl.12. The compound of claim 11 , wherein Ris —NH claim 11 , —NHCalkyl claim 11 , or —N(Calkyl).13. The compound of claim 11 , wherein Ris H or optionally substituted Calkyl.16. The compound of claim 18 , wherein said peptide moiety comprises 2 to about 4 amino acids.18. The compound of claim 1 , wherein one or more H is replaced with H claim 1 , one or more C is replaced with C claim 1 , or one or more N is replaced with N.19. A pharmaceutical composition comprising a compound of and a pharmaceutically acceptable excipient.20. A method of treating a neurodegenerative disorder claim 1 , enhancing learning claim 1 , memory claim 1 , or cognition claim 1 , treating a condition caused by neurological dysfunction claim 1 , treating depression claim 1 , treating hyperalgesia or reducing a L-DOPA associated dyskinesia ...

PRODRUGS OF CHLOROKYNURENINES

The present disclosure relates to prodrugs of 7-chlorokynurenic acid. In certain embodiments, the prodrugs include those having the structure of any one of formula (I)-(VIII), wherein R-R, monomer 1, monomer 2, and linker are defined herein. Also provided are methods of preparing and using these prodrugs. 6. The compound of claim 2 , wherein Ris optionally substituted Calkyl.7. The compound of claim 2 , wherein Ris Calkyl substituted with optionally substituted aryl.8. The compound of claim 2 , wherein Ris Calkyl substituted with optionally substituted phenyl.9. The compound of claim 2 , wherein Ris Calkyl substituted with optionally substituted heterocyclyl.10. The compound of claim 2 , wherein Ris optionally substituted aryl.11. The compound of claim 2 , wherein Ris optionally substituted alkylene glycol.12. The compound of claim 2 , wherein Ris alkylene glycol substituted by C(O)aryl.13. The compound of claim 2 , wherein Ris alkylene glycol substituted by C(O)phenyl.14. The compound of claim 2 , wherein said glycol is —O—CH(CH)—O—CH(CH).15. The compound of claim 2 , wherein Ris —P(O)(OH)or —P(O)(OH)(OCalkyl) claim 2 , or a pharmaceutically acceptable salt thereof.16. The compound of claim 2 , wherein Ris —S(O)OH claim 2 , or a pharmaceutically acceptable salt thereof.17. The compound of claim 2 , wherein Ris Calkyl claim 2 , phenyl claim 2 , —P(O)(OH) claim 2 , —P(O)(OH)(OCalkyl) claim 2 , or —S(O)OH.18. The compound of claim 2 , wherein Ris H.19. The compound of claim 2 , wherein Ris Calkyl.20. The compound of claim 2 , wherein Ris Calkoxy.23. The compound of claim 21 , wherein Rand Rare claim 21 , independently claim 21 , H.24. The compound of claim 21 , wherein Rand Rare claim 21 , independently claim 21 , optionally substituted Calkyl.25. The compound of claim 21 , wherein Rand Rare claim 21 , independently claim 21 , Calkyl substituted by amino.26. The compound of claim 21 , wherein Rand Rare claim 21 , independently claim 21 , SO(Calkyl).27. The compound of ...

Fused Bicyclic 2,4-Diaminopyrimidine Derivative as a Dual ALK and FAK Inhibitor

or a salt form thereof. The compound of formula (I) has ALK and FAK inhibitory activity, and may be used to treat proliferative disorders.

Pyrimidinone derivatives as cdc7 inhibitors

The present invention relates to compounds of formula I as defined herein, and salts and solvates thereof, that function as inhibitors of cell division cycle 7 (Cdc7) kinase enzyme activity. The present invention also relates to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which Cdc7 kinase activity is implicated.

Fused Bicyclic 2,4-diaminopyrimidine Derivative as a Dual ALK and FAK Inhibitor

The present invention provides a compound of formula (I) 2. The method of claim 1 , wherein the salt of the compound of Formula (I) comprises an acid addition salt.3. The method of claim 1 , wherein the salt of the compound of Formula (I) comprises an tribenzenesulfonate salt.4. The method of claim 3 , wherein the tribenzenesulfonate salt of Formula (I) has an XRPD pattern comprising one or more peaks selected from 7.62±0.2 degrees 2Θ claim 3 , 13.11±0.2 degrees 2Θ claim 3 , 13.76±0.2 degrees 2Θ claim 3 , and 14.05±0.2 degrees 2Θ.5. The method of claim 3 , wherein the tribenzenesulfonate salt of Formula (I) has an XRPD pattern comprising one or more peaks selected from 6.85±0.2 degrees 2Θ claim 3 , 7.62±0.2 degrees 2Θ claim 3 , 8.01±0.2 degrees 2Θ claim 3 , 13.11±0.2 degrees 2Θ claim 3 , 13.76±0.2 degrees 2Θ claim 3 , 14.05±0.2 degrees 2Θ claim 3 , and 14.60±0.2 degrees 2Θ.6. The method of claim 3 , wherein the tribenzenesulfonate salt of Formula (I) has an XRPD pattern comprising one or more peaks selected from 7.62±0.2 degrees 2Θ claim 3 , 13.11±0.2 degrees 2Θ claim 3 , 13.76±0.2 degrees 2Θ claim 3 , 14.05±0.2 degrees 2Θ claim 3 , 17.10±0.2 degrees 2Θ claim 3 , 17.86±0.2 degrees 2Θ claim 3 , and 18.10±0.2 degrees 2Θ.7. The method of claim 1 , wherein the salt of the compound of Formula (I) comprises a trihydrochloride dihydrate salt.8. The method of claim 7 , wherein the trihydrochloride dehydrate salt of Formula (I) has an XRPD pattern comprising one or more peaks selected from 5.42±0.2 degrees 2Θ claim 7 , 8.86±0.2 degrees 2Θ claim 7 , 14.06±0.2 degrees 2Θ claim 7 , 17.52±0.2 degrees 2Θ and 18.51±0.2 degrees 2Θ.9. The method of claim 7 , wherein the trihydrochloride dehydrate salt of Formula (I) has an XRPD pattern comprising one or more peaks selected from 5.42±0.2 degrees 2Θ claim 7 , 5.91±0.2 degrees 2Θ claim 7 , 8.86±0.2 degrees 2Θ claim 7 , 10.80±0.2 degrees 2Θ claim 7 , 11.79±0.2 degrees 2Θ claim 7 , 14.06±0.2 degrees 2Θ claim 7 , 14.72±0.2 degrees 2Θ ...

Spiro-cyclic β-amino acid derivatives as inhibitors of matrix metalloproteases and TNF-α converting enzyme (TACE)

The present application describes novel spiro-cyclic beta-amino acid derivatives of formula I:or pharmaceutically acceptable salt forms thereof, wherein ring B is a 3-13 membered carbocycle or heterocycle, ring C forms a 3-11 membered spiro-carbocycle or spiro-heterocycleon ring B, and the other variables are defined in the present specification, which are useful as as matrix metalloproteinases (MMP), TNF-alpha converting enzyme (TACE), and/or aggrecanase inhibitors.

Spiro-cyclic β-amino acid derivatives as inhibitors of matrix metalloproteases and TNF-α converting enzyme (TACE)

The present application describes novel spiro-cyclic β-amino acid derivatives of formula I: or pharmaceutically acceptable salt forms thereof, wherein ring B is a 3-13 membered carbocycle or heterocycle, ring C forms a 3-11 membered spiro-carbocycle or spiro-heterocycleon ring B, and the other variables are defined in the present specification, which are useful as as matrix metalloproteinases (MMP), TNF-α converting enzyme (TACE), and/or aggrecanase inhibitors.

Fusion of bicyclic 2,4-diaminopyrimidine derivatives as using ALK and c-Met inhibitors

Un compuesto de fórmula I o II **Fórmula** o una forma de sal farmacéuticamente aceptable de las mismas, en la que R1 es cloro; R2 es un grupo seleccionado entre alquilo C1-6, alquenilo C2-6, alquinilo C2-6, arilo C6-15, cicloalquilo C3-10, heterocicloalquilo de 3-15 miembros, y heteroarilo de 5-15 miembros, en la que el grupo R2 se sustituye opcionalmente por uno o más miembros seleccionados independientemente entre halógeno,-NO2, -OR20, >=O, - C(>=O)R20, -C(>=O)OR20, -C(>=O)NR22R23, -NR20R21, alquilo C1-6-(R25)x, arilo C6-15-(R25)x, heteroarilo de 5-15 miembros-(R25)x, cicloalquilo C3-10-(R25)x, heterocicloalquilo de 3-15 miembros-(R25)x, pseudohalógeno, - S(>=O)nR20, -S(>=O)2NR22R23, -OCH2F, -OCHF2, -OCF3, NHOH, -OC(>=O)R20, OC(>=O)NR22R23, - NR20C(>=O)R21, -NR20C(>=O)OR21, -NR20S(>=O)2R21, NR20C(>=O)NR22R23, -NR20S(>=O)2NR22R23, y -SCF3; R3, R4, y R5 se seleccionan independientemente entre H, halógeno, -NO2, -OR30,-C(>=O)R30, -C(>=O)OR30, - C(>=O)NR32R33, -NR30R31, alquilo C1-6-(R35)x, arilo C6-15-(R35)x, heteroarilo de 5-15 miembros-(R35)x, cicloalquilo C3-10-(R35)x, heterocicloalquilo de 3-15 miembros-(R35)x, pseudohalógeno, -S(>=O)nR30, - S(>=O)2NR32R33, -OCH2F, -OCHF2, -OCF3, NHOH, -OC(>=O)R30, -OC(>=O)NR32R33, NR30C(>=O)R31, - NR30C(>=O)OR31, -NR30S(>=O)2R31, - NR30C(>=O)NR12R33, -NR30S(>=O)2NR32R33, y -SCF3; A1, A2, A3, A4, y A5 son independientemente cada uno -CZ1Z2-, -(CZ1Z2)2- -C(>=O)-,-NZ3-, -S-, -S(>=O)-, -S(>=O)2-, o -O-, con la condición a lo sumo de A1, A2, A3, A4, y A5 es -(CZ1Z2)2-, en el que: (a) cuando cualquiera de Z1, Z2, y Z3 se encuentra en átomos adyacentes, pueden formar un enlace entre los átomos, (b) cualquiera de Z1, Z2, y Z3 se puede seleccionar independientemente entre H, halógeno,-NO2, -OR40, - C(>=O)R40, -C(>=O)OR40, -C(>=O)NR42R43, -NR40R41, alquilo C1-6-(R45)x, arilo C6-15-(R45)x, heteroarilo de 5-15 miembros-(R45)x, cicloalquilo C3-10-( ...

Fused bicyclic derivatives of 2,4-diaminopyrimidine as ALK and c-Met inhibitors

The present invention provides a compound of formula I or II or a pharmaceutically acceptable salt form thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , A 1 , A 2 , A 3 , A 4 , and A 5 , are as defined herein. The compounds of formula I or II have ALK and/or c-Met inhibitory activity, and may be used to treat proliferative disorders.

Fused bicyclic derivatives of 2,4-diaminopyrimidine as ALK and c-MET inhibitors

The present invention provides a compound of formula I or II or a pharmaceutically acceptable salt form thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , A 1 , A 2 , A 3 , A 4 , and A 5 , are as defined herein. The compounds of formula I or II have ALK and/or c-Met inhibitory activity, and may be used to treat proliferative disorders.

Preparation and uses of pyrimidinone derivatives

The present invention relates to compounds of formula (I), and salts and solvates thereof, that function as inhibitors of cell division cycle 7 (Cdc7) kinase enzyme activity: (Formula (I)) wherein X, R

Cyclic hydroxamic acids as inhibitors of matrix metalloproteinases and/or TNF- α converting enzyme (TACE)

The present application describes novel cyclic hydroxamic acids of formula I: or pharmaceutically acceptable salt forms thereof, wherein ring B is a 5-7 membered cyclic system containing from 0-2 heteroatoms selected from O, N, NR 1 , and S(O) p , and 0-1 carbonyl groups and the other variables are defined in the present specification, which are useful as inhibitors of matrix metalloproteinases (MMP), TNF-α converting enzyme (TACE), aggrecanase or a combination thereof, pharmaceutical compositions containing the same, and methods of using the same.

Condensed bicyclic 2,4-diaminopyrimidine derivative as dual inhibitor of ALK and FAK

Un compuesto de fórmula (I)**Fórmula** o una sal del mismo, para su uso en el tratamiento de una afección o trastorno mediado por ALK o FAK, en donde la afección o trastorno mediado por ALK o FAK es cáncer. A compound of formula (I) ** Formula ** or a salt thereof, for use in the treatment of a condition or disorder mediated by ALK or FAK, wherein the condition or disorder mediated by ALK or FAK is cancer.

compound, pharmaceutical composition and use of compound

“composto, composição farmacêutica e uso do composto” a presente invenção provê um composto de fórmula (i) ou um sal do mesmo, na qual r7, r8, r9, g, e x estão aqui definidos. um composto de fórmula (i) e seus sais têm uma atividade inibidora de apkc, e podem ser usados para tratar distúrbios proliferativos. "compound, pharmaceutical composition and use of the compound" the present invention provides a compound of formula (i) or a salt thereof, in which r7, r8, r9, g, and x are defined herein. a compound of formula (I) and its salts have an apkc inhibitory activity, and can be used to treat proliferative disorders.

Azaquinazoline inhibitors of atypical protein kinase c

The present invention provides a compound of formula (I) or a salt thereof, wherein R7, R8, R9, G, and X are as defined herein. A compound of formula (I) and its salts have a PKC inhibitory activity, and may be used to treat proliferative disorders.

Pyrrolotriazines as alk inhibitors

This application provides compounds of the general formula (I) and/or a salt thereof, where X, R1 and R2 are as defined herein. Compositions and therapeutic uses are also described.

Deuterated chlorokynurenines for the treatment of neuropsychiatric disorders

Described are deuterated chlorokynurenines and compositions, and their application as pharmaceuticals for the treatment of disease. Methods of modulating N-methyl-D-aspartate (NMDA) receptor activity, methods of treating disorders, including neuropsychiatric disorders such as depression, epilepsy, schizophrenia, and Huntington's Disease, and use of said deuterated chlorokynurenines are also described.

Pyrrolotriazines as alk inhibitors

This application provides compounds of the general formula (I) and/or a salt thereof, where X, R1 and R2 are as defined herein. Compositions and therapeutic uses are also described.

Thienopyrimidine inhibitors of atypical protein kinase c

The present invention provides a compound of formula (I) or a salt thereof, wherein R1, R2, R3, R4, R5, R6, A, G, M, Q and X are as defined herein. A compound of formula (I) and its salts have a PKC inhibitory activity, and may be used to treat proliferative disorders.

Thienopyrimidine inhibitors of atypical protein kinase c.

La presente invención proporciona un compuesto de la fórmula (I) (ver Fórmula) o una sal del mismo, en donde R1, R2, R3, R4, R5, R6, A, G, M, Q y X son como se define en la presente. Un compuesto de la fórmula (I) y sus sales tiene una actividad inhibidora de PKCa y pueden utilizarse para tratar trastornos proliferativos.

Prodrugs of chlorokynurenines

The present disclosure relates to prodrugs of 7-chlorokynurenic acid. In certain embodiments, the prodrugs include those having the structure of any one of formula (I)-(VIII), wherein R1-R13, monomer 1, monomer 2, and linker are defined herein. Also provided are methods of preparing and using these prodrugs.

Deuterated chlorokynurenines for the treatment of neuropsychiatric disorders

Described are deuterated chlorokynurenines and compositions, and their application as pharmaceuticals for the treatment of disease. Methods of modulating N-methyl-D-aspartate (NMDA) receptor activity, methods of treating disorders, including neuropsychiatric disorders such as depression, epilepsy, schizophrenia, and Huntington's Disease, and use of said deuterated chlorokynurenines are also described.

Azaquinazoline inhibitors of atypical protein kinase c

The present invention provides a compound of formula (I) or a salt thereof, wherein R7, R8, R9, G, and X are as defined herein. A compound of formula (I) and its salts have a PKC inhibitory activity, and may be used to treat proliferative disorders.

Azaquinazoline inhibitors of atypical protein kinase c

Fused bicyclic 2,4-diaminopyrimidine derivative as a dual alk and fak inhibitor

THE PRESENT INVENTION PROVIDES A COMPOUND OF FORMULA (I) OR A SALT FORM THEREOF. THE COMPOUND OF FORMULA (I) HAS ALK AND FAK INHIBITORY ACTIVITY, AND MAY BE USED TO TREAT PROLIFERATIVE DISORDERS.

Prodrugs of chlorokynurenines

Cyclic β-amino acid derivatives as inhibitors of matrix metalloproteases and TNF-α

Prodrugs of chlorokynurenines

The present disclosure relates to prodrugs of 7-chlorokynurenic acid. In certain embodiments, the prodrugs include those having the structure of any one of formula (I)-(VIII), wherein R 1 -R 13 , monomer 1, monomer 2, and linker are defined herein. Also provided are methods of preparing and using these prodrugs.

Compound 2 - [[5-chloro-2 - [[(6s) -6- [4- (2-hydroxyethyl) piperazin-1-yl] -1-methoxy-6,7,8,9-tetrahydro-5h- benzo anulen-2-yl] amino] pyrimidin-4-yl] amino] -n-methyl-benzamide, dual alk and fak inhibitor; compound salts; pharmaceutical composition; and method of treatment of gliobalstoma, prostate cancer and breast cancer, among others.

Fused bicyclic derivatives of 2,4-diaminopyrimidine as ALK and c-Met inhibitors

The present invention provides a compound of formula I or II or a pharmaceutically acceptable salt form thereof, wherein R

cgrp antagonist compounds

compostos antagonistas de cgrp. as divulgações aqui referem-se a novos compostos da fórmula (1a): e sais dos mesmos, em que w, z, l, r1 e r2 são definidos aqui, e seu uso no tratamento, prevenção, melhoria, controle ou redução do risco de distúrbios associados aos receptores de cgrp. cgrp antagonist compounds. the disclosures herein pertain to novel compounds of formula (1a): and salts thereof, wherein w, z, l, r1 and r2 are defined herein, and their use in treating, preventing, ameliorating, controlling or reducing risk of disorders associated with cgrp receptors.

Macrocyclic compounds as alk, fak and jak2 inhibitors

The present invention provides compounds of Formula I or a pharmaceutically acceptable salt forms thereof, wherein R1, R2, R3, R4, R5, A and X are as defined herein, methods of treatment and uses thereof.

Fused bicyclic derivatives of 2,4-diaminopyrimidine as alk and c-met inhibitors

Pyrimidinone derivatives as Cdc7 inhibitors

The present invention relates to compounds of formula I as defined herein, and salts and solvates thereof, that function as inhibitors of cell division cycle 7 (Cdc7) kinase enzyme activity. The present invention also relates to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which Cdc7 kinase activity is implicated.

FUSED BICYCLIC DERIVATIVES OF 2,4-DIAMINOPYRIMIDINE AS ALK AND c-MET INHIBITORS

The present invention provides a compound of formula I or II or a pharmaceutically acceptable salt form thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , A 1 , A 2 , A 3 , A 4 , and A 5 , are as defined herein. The compounds of formula I or II have ALK and/or c-Met inhibitory activity, and may be used to treat proliferative disorders.

CGRP antagonist compounds

The disclosures herein relate to novel compounds of Formula (1a): and salts thereof, wherein W, Z, L, R

Fused bicyclic derivatives of 2,4-diaminopyrimidine as alk and c-met inhibitors

The present invention provides a compound of formula I or II or a pharmaceutically acceptable salt form thereof, wherein R1, R2, R3, R4, R5, A1, A2, A3, A4, and A5, are as defined herein. The compounds of formula I or II have ALK and/or c-Met inhibitory activity, and may be used to treat proliferative disorders.

Pyrimidinone derivatives as cdc7 inhibitors

The present invention relates to compounds of formula I as defined herein, and salts and solvates thereof, that function as inhibitors of cell division cycle 7 (Cdc7) kinase enzyme activity Formula (I). The present invention also relates to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which Cdc7 kinase activity is implicated.

Azaquinazoline inhibitors of atypical protein kinase c

The present invention provides a compound of formula (I) or a salt thereof. A compound of formula (I) and its salts have aPKC inhibitory activity, and may be used to treat proliferative disorders.

Imidazo[4,5-b]pyridine derivatives as ALK and JAK modulators for the treatment of proliferative disorders

This application relates to compounds of the Formula I as defined herein, and/or salts thereof. This application further relates to compositions and methods of using these compounds and/or salts thereof. The compounds of Formula I are useful as ALK and JAK modulators for the treatment of proliferative disorders.

Cgrp antagonist compounds

The disclosures herein relate to novel compounds of Formula (1): and salts thereof, wherein A 1 , A 2 , Q, X, R 1 , R 2 and R 3 are defined herein, and their use in treating, preventing, ameliorating, controlling or reducing the risk of disorders associated with CGRP receptors.

Cgrp antagonist compounds

The disclosures herein relate to novel compounds of Formula (1): and salts thereof, wherein A 1 , A 2 , Q, X, R 1 , R 2 and R 3 are defined herein, and their use in treating, preventing, ameliorating, controlling or reducing the risk of disorders associated with CGRP receptors.

Cgrp antagonist compounds

The disclosures herein relate to novel compounds of Formula (1): and salts thereof, wherein A1, A2, Q, X, R1, R2 and R3 are defined herein, and their use in treating, preventing, ameliorating, controlling or reducing the risk of disorders associated with CGRP receptors.

CGRP antagonist compounds

The disclosures herein relate to novel compounds of Formula (1): and salts thereof, wherein A

Compostos antagonistas do cgrp

compostos antagonistas do cgrp. a presente invenção refere-se a novos compostos de fórmula (1): e sais dos mesmos, em que a1, a2, q, x, r1, r2 e r3 são aqui definidos, e seu uso no tratamento, prevenção, melhora, controle ou redução do risco de distúrbios associados com receptores de cgrp.

Imidazo [4, 5 - b]pyridine derivatives as alk and jak modulators for the treatment of proliferative disorders

This application relates to compounds of the Formula I as defined herein, and/or salts thereof. This application further relates to compositions and methods of using these compounds and/or salts thereof. The compounds of Formula I are useful as ALK and JAK modulators for the treatment of proliferative disorders.

作為治療增殖性病症的 調節劑的咪唑並 吡啶衍生物

Bicyclic-heterocycle derivatives and related uses

The present disclosure relates to compounds of Formula (T): and to their prodrugs, pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods for their preparation. The compounds disclosed herein are useful for modulating orexin receptor activity and may be used in the treatment of disorders in which orexin receptor activity is implicated, such as narcolepsy, a hypersomnia disorder, a neurodegenerative disorder, a symptom of a rare genetic disorder, a mental health disorder, a metabolic syndrome, osteoporosis, cardiac failure, coma, or a complication in emergence from anaesthesia.

Pyrimidinone derivatives as cdc7 inhibitors

The present invention relates to compounds of formula I as defined herein, and salts and solvates thereof, that function as inhibitors of cell division cycle 7 (Cdc7) kinase enzyme activity Formula (I). The present invention also relates to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which Cdc7 kinase activity is implicated.

Pyrimidinone derivatives as CDC7 inhibitors

The present invention relates to compounds of formula I as defined herein, and salts and solvates thereof, that function as inhibitors of cell division cycle 7 (Cdc7) kinase enzyme activity. The present invention also relates to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which Cdc7 kinase activity is implicated.

Medium- or macro-cyclic benzyl-substituted heterocycle derivatives and related uses

The present disclosure relates to compounds of Formula (I') and to their prodrugs, pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods for their preparation The compounds disclosed herein are useful for modulating orexin-2 receptor activity and may be used in the treatment of disorders in which orexin-2 receptor activity is implicated, such as narcolepsy, a hypersomnia disorder, a neurodegenerative disorder, a symptom of a rare genetic disorder, a mental health disorder, a metabolic syndrome, osteoporosis, cardiac failure, coma, or facilitating emergence from anaesthesia.

Pyrrolotriazines as alk and jak2 inhibitors alk jak2

Medium- or macro-cyclic benzyl-substituted heterocycle derivatives and related uses

The present disclosure relates to compounds of Formula (I') and to their prodrugs, pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods for their preparation The compounds disclosed herein are useful for modulating orexin-2 receptor activity and may be used in the treatment of disorders in which orexin-2 receptor activity is implicated, such as narcolepsy, a hypersomnia disorder, a neurodegenerative disorder, a symptom of a rare genetic disorder, a mental health disorder, a metabolic syndrome, osteoporosis, cardiac failure, coma, or facilitating emergence from anaesthesia.

Pyrrolotriazines as alk and jak2 inhibitors

The present invention provides a compound of formula (I) or a salt form thereof, wherein Q 1 , Q 2 , Q 3 , and Q 4 are as defined herein. The compound of formula (I) has ALK and/or JAK2 inhibitory activity, and may be used to treat proliferative disorders.

Thienopyrimidine inhibitors of atypical protein kinase C

The present application provides a compound of formula (I) or a salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A, G, M, Q and X are as defined herein. A compound of formula (I) and its salts have aPKC inhibitory activity, and may be used to treat proliferative disorders.