Synta Pharmaceuticals Corporation

Shionogi Bioresearch Corporation

Other

Madrigal Pharmaceuticals, Inc.

Fuji Immunopharmaceuticals Corp.

Shiongi Bioresearch Corp.

Yumiko Wada

Mitsunori Ono

Lijun Sun

Teresa Przewloka

Elena Kostik

Zachary Demko

Hao Li

Howard P Ng

Keizo Koya

Shijie Zhang

Weiwen Ying

Wojciech Wrona

Stephen D Gillies

Dinesh U Chimmanamada

David James

Natalie Alysia Dales

Sylvia Holden

Wenli Ding

Xueliang Tao

Kin-Ming Lo

Hiroshi Kitaguchi

James G Barsoum

Noriaki Tatsuta

Rongzhen Lu

Yaming Wu

Dan Zhou

Naoto Yamaguchi

Ryoichi Nemori

Patricia Rao

Masazumi Nagai

Ronald K Blackman

Beatrice Brunkhorst

Nha Huu Vo

Tadeusz Warchol

Yumiko Jimbo

Albert Y Hsia

M Ono

Elena Kostic

Jifeng Duan

The present invention is directed to compositions and methods for modulating c-Rel-dependent cytokine production without materially altering the level of expression of NF&#x3ba;B and/or the amount of I&#x3ba;B. The present invention is also directed to screening for modulators of c-Rel activity as determined by assaying for altered subcellular localization of c-Rel but where the level of expression of NF&#x3ba;B and/or the amount of I&#x3ba;B is materially unaltered.

Compositions and methods for modulating c-Rel-dependent cytokine production

Improved cancer treatments with bis[thiohydrazide amide] compounds such as elesclomol, in particular for identifying patient populations that would benefit from such treatments.

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This invention provides fused heterocyclic compounds, pharmaceutical compositions of the compounds, and methods of using the compounds for the treatment of, inter alia, IL-12 related disease and disorders.

Fused hetrocyclic compounds

This invention features compounds of formula (I): pharmaceutical compositions of the compounds, and methods of using the compounds for the treatment of, inter alia, IL-12-related diseases and disorders.

Pyridine compounds

This invention relates to compounds having a formula (I): or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, prodrug or polymorph thereof wherein X is &#x2014;C(R)&#x2550;N-A. The invention also relates to methods of treating IL-12 overproduction-related disorders, methods of treating or preventing disorders related with excessive bone loss, methods for inhibiting osteoclast formation, and methods for treating or preventing a disorder associated with excessive bone resorption.

Heteroaryl-hydrazone compounds

This invention relates to compounds of formula (I): or pharmaceutically acceptable salts, solvate, clathrates hydrates or polymorphs thereof, their compositions and methods of use and methods of making thereof. The compounds (and compositions) are useful in modulating IL-12 production and processes mediated by IL-12.

2-substituted heteroaryl compounds

This invention features pyrimidine compounds of formula (I):  aryl, or heteroaryl; each of Rand R, independently, is R, halogen, nitro, cyano, isothionitro, SR, or OR; or Rand R, taken together, is carbonyl; Ris R, alkenyl, alkynyl, OR, OC(O)R, SOR, S(O)R, S(O)NRR, SR, NRR, NRCOR, NRC(O)OR, NRC(O)NRR, NRSOR, COR, C(O)OR, or C(O)NRR; Ris H or alkyl; n is 0, 1, 2, 3, 4, 5, or 6; X is O, S, S(O), S(O), or NR; Y is a covalent bond, CH, C(O), C&#x2550;N&#x2014;R, C&#x2550;N&#x2014;OR, C&#x2550;N&#x2014;SR, O, S, S(O), S(O), or NR; Z is N or CH; one of U and V is N, and the other is CR; and W is O, S, S(O), S(O), NR, or NC(O)R; in which each of Rand R, independently, is H, alkyl, aryl, heteroaryl; and each of Rand R, independently, is H, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, or alkylcarbonyl. The featured compounds inhibit the production of IL-12, IL-23 and IL-27 and are useful for treating disorders associated with IL-12, IL-23 and IL-27 overproduction or misregulation, such as inflammatory and immune disorders.

Pyrimidine compounds and uses thereof

Fused heterocyclic compounds

This invention features pyrimidine compounds of formula (I):  each of Rand Ris H; Ris H, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, or alkylcarbonyl; Ris H or alkyl; n is 0, 1, 2, 3, 4, 5, or 6; X is NR; Y is covalent bond, CH, C(O), C&#x2550;N&#x2014;R, C&#x2550;N&#x2014;OR, C&#x2550;N&#x2014;SR, O, S, S(O), S(O), or NR; Z is N or CH; one of U and V is N, and the other is CR; and W is O, S, S(O), S(O), NR, or NC(O)R; in which each of Rand R, independently, is H, alkyl, aryl, heteroaryl; and Ris H, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, or alkylcarbonyl.

Pyrimidine compounds

This invention features pyrimidine compounds of formula (I): Ris in which one of Rand Ris H or alkyl, and the other is aryl or heteroaryl optionally substituted with Rand R; each of Rand Ris H; Ris H, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, or alkylcarbonyl; Ris H or alkyl; n is 0, 1, 2, 3, 4, 5, or 6; X is NR; Y is covalent bond, CH, C(O), C&#x2550;N&#x2014;R, C&#x2550;N&#x2014;OR, C&#x2550;N&#x2014;SR, O, S, S(O), S(O), or NR; Z is N or CH; one of U and V is N, and the other is CR; and W is O, S, S(O), S(O), NR, or NC(O)R; in which Ris H, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, or alkylcarbonyl; Ris halogen, CN, alkyl, alkyloxy, alkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, hydroxyalkyl, alkylamino, or alkylaminocarbonyl; Ris halogen, CN, hydroxyl, alkyl, aryl, heteroaryl, alkoxyl, aryloxyl, or heteroaryloxyl; and m is 0, 1, 2, 3, or 4. The pyrimidine compounds can be used to treat an IL-12 overproduction-related disorder (e.g., rheumatoid arthritis, sepsis, Crohn's disease, multiple sclerosis, psoriasis, or insulin-dependent diabetes mellitus).

This invention features pyrimidine compounds of formula (I):  Ris aryl, or heteroaryl; each of Rand R, independently, is R, halogen, nitro, cyano, isothionitro, SR, or OR; or Rand R, taken together, is carbonyl; Ris R, alkenyl, alkynyl, OR, OC(O)R, SOR, S(O)R, S(O)NRR, SR, NRR, NRCOR, NRC(O)OR, NRC(O)NRR, NRSOR, COR, C(O)OR, or C(O)NRR; Ris H or alkyl; n is 0, 1, 2, 3, 4, 5, or 6; X is O, S, S(O), S(O), or NR; Y is a covalent bond, CH, C(O), C&#x2550;N&#x2014;R, C&#x2550;N&#x2014;OR, C&#x2550;N&#x2014;SR, O, S, S(O), S(O), or NR; Z is N or CH; one of U and V is N, and the other is CR; and W is O, S, S(O), S(O), NR, or NC(O)R; in which each of Rand R, independently, is H, alkyl, aryl, heteroaryl; and each of Rand R, independently, is H, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, or alkylcarbonyl.

This invention features a compound of formula (I): Ris aryl or heteroaryl; each of Rand R, independently, is H, halogen, CN, alkyl, OR, or NRR; Ris H, halogen, CN, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, OR, OC(O)R, OC(O)NRR, NRR, NRC(O)R, NRS(O)RNRS(O)R, NRC(O)NRR, NRC(S)NRR, NRC(NR)NRR, NRC(O)OR, S(O)NRR, S(O)NRR, S(O)R, S(O)R, C(O)R, C(O)OR, or C(O)NRR; Ris H or alkyl; n is 0, 1, 2, 3, 4, 5, or 6; A is O, S, S(O), S(O), or NR; B is N or CR; X is O, S, S(O), S(O), NR, or C(O); Y is a covalent bond, C(O), C&#x2550;NR, O, S, S(O), S(O), or NR; Z is N or CH; each of U and V, independently, is N or CR; and W is O, S, or NR; in which each of R, R, R, and R, independently, is H, alkyl, aryl, heteroaryl, cyclyl, or heterocyclyl; Ris H, alkyl, aryl, acyl, or sufonyl; and Ris H, alkyl, aryl, acyl, sulfonyl, alkoxyl, amino, ester, amide, CN, or halogen. The compound is useful for treating an interleukin-12 overproduction-related disorder.

Heterocyclic compounds

This invention features a compound of formula (I): Ris aryl or heteroaryl; each of Rand R, independently, is H, halogen, CN, alkyl, OR, or NRR; Ris H, halogen, CN, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, OR, OC(O)R, OC(O)NRR, NRR, NRC(O)R, NRS(O)R, NRS(O)R, NRC(O)NRR, NRC(S)NRR, NRC(NR)NRR, NRC(O)OR, S(O)NRR, S(O)NRR, S(O)R, S(O)R, C(O)R, C(O)OR, or C(O)NRR; Ris H or alkyl; n is 0, 1, 2, 3, 4, 5, or 6; A is O, S, S(O), S(O), or NR; B is N or CR; X is O, S, S(O), S(O), NR, or C(O); Y is a covalent bond, C(O), C&#x2550;NR, O, S, S(O), S(O), or NR; Z is N or CH; each of U and V, independently, is N or CR; and W is O, S, or NR; in which each of R, R, R, and R, independently, is H, alkyl, aryl, heteroaryl, cyclyl, or heterocyclyl; Ris H, alkyl, aryl, acyl, or sufonyl; and Ris H, alkyl, aryl, acyl, sulfonyl, alkoxyl, amino, ester, amide, CN, or halogen. The compound is useful for treating an interleukin-12 overproduction-related disorder.

Growing community of inventors

Billerica, MA, United States of America

Yumiko Wada