公开(公告)号：US10934286B2

公开(公告)日：2021-03-02

申请号：US16341474

申请日：2017-10-12

Applicant: BRISTOL-MYERS SQUIBB COMPANY

Inventor： Qingjie Liu ,  T. G. Murali Dhar ,  Lan-ying Qin ,  Lyndon A. M. Cornelius ,  Hai-Yun Xiao ,  Jianqing Li ,  Robert J. Cherney

IPC: C07D471/04 ,  C07D491/147

Abstract: There are described RORγ modulators of the formula (I), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein all substituents are defined herein. Also provided are pharmaceutical compositions comprising the same. Such compounds and compositions are useful in methods for modulating RORγ Gamma activity in a cell and methods for treating a subject suffering from a disease or disorder in which the subject would therapeutically benefit from modulation of RORγ Gamma activity, for example, autoimmune and/or inflammatory disorders.

公开(公告)号：US20190300523A1

公开(公告)日：2019-10-03

申请号：US16341474

申请日：2017-10-12

Applicant: BRISTOL-MYERS SQUIBB COMPANY

Inventor： Qingjie LIU ,  T.G. Murali Dhar ,  Lan-ying Qin ,  Lyndon A.M. Cornelius ,  Hai-Yun Xiao ,  Jianqing Li ,  Robert J. Cherney

IPC: C07D471/04 ,  C07D491/147

Abstract: There are described RORγ modulators of the formula (I), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein all substituents are defined herein. Also provided are pharmaceutical compositions comprising the same. Such compounds and compositions are useful in methods for modulating RORγ Gamma activity in a cell and methods for treating a subject suffering from a disease or disorder in which the subject would therapeutically benefit from modulation of RORγ Gamma activity, for example, autoimmune and/or inflammatory disorders.

公开(公告)号：US20170355698A1

公开(公告)日：2017-12-14

申请号：US15521199

申请日：2015-10-21

Applicant: BRISTOL-MYERS SQUIBB COMPANY

Inventor： Rajeev S. Bhide ,  Zheming Ruan ,  Robert J. Cherney ,  Lyndon A.M. Cornelius ,  T.G.Murali Dhar ,  Hua Gong ,  David Marcoux ,  Michael A. Poss ,  Lan-ying Qin ,  Qing Shi ,  Joseph A. Tino

IPC: C07D487/04

CPC classification number: C07D487/04

Abstract: Disclosed are compounds of Formula (I); or a salt thereof; wherein Qi is (i) Cl, Br, I, —CN, —CH3, or —CF3; or (ii) pyrazole, triazole, or pyridinyl, each substituted with R1; Q2 is pyridinyl, indazolyl, isoquinolinyl, or benzo[d]imidazolyl substituted with R2 and R3; and R1, R2, and R3 are defined herein. Also disclosed are methods of using such compounds as modulators of PI3K, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing inflammatory and autoimmune diseases.

公开(公告)号：US10711020B2

公开(公告)日：2020-07-14

申请号：US16295378

申请日：2019-03-07

Applicant: BRISTOL-MYERS SQUIBB COMPANY

Inventor： Jingwu Duan ,  T. G. Murali Dhar ,  David Marcoux ,  Robert J. Cherney

IPC: C07F9/6574 ,  C07D215/36 ,  C07D409/04 ,  C07D417/04 ,  C07D209/30 ,  C07D209/60 ,  C07D209/70 ,  C07D221/10 ,  C07D401/06 ,  C07D401/12 ,  C07D403/06 ,  C07D403/12 ,  C07D405/06 ,  C07D409/06 ,  C07D413/06 ,  C07D413/10 ,  C07D413/12 ,  C07D417/06 ,  C07D417/12 ,  C07D417/14 ,  C07D471/04 ,  C07D491/052 ,  C07D491/107 ,  C07D493/08 ,  C07D495/04 ,  C07D495/08

Abstract: There are described RORγ modulators of the formula (I), and formula (II) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein all substituents are defined herein. Also provided are pharmaceutical compositions comprising the same. Such compounds and compositions are useful in methods for modulating RORγ activity in a cell and methods for treating a subject suffering from a disease or disorder in which the subject would therapeutically benefit from modulation of RORγ activity, for example, autoimmune and/or inflammatory disorders.

公开(公告)号：US20190241588A1

公开(公告)日：2019-08-08

申请号：US16295378

申请日：2019-03-07

Applicant: BRISTOL-MYERS SQUIBB COMPANY

Inventor： Jingwu DUAN ,  T.G. Murali Dhar ,  David Marcoux ,  Robert J. Cherney

IPC: C07F9/6574 ,  C07D209/30 ,  C07D209/60 ,  C07D409/04 ,  C07D215/36 ,  C07D495/08 ,  C07D209/70 ,  C07D221/10 ,  C07D401/06 ,  C07D401/12 ,  C07D403/06 ,  C07D403/12 ,  C07D405/06 ,  C07D409/06 ,  C07D413/06 ,  C07D413/10 ,  C07D413/12 ,  C07D417/06 ,  C07D417/12 ,  C07D417/14 ,  C07D471/04 ,  C07D491/052 ,  C07D491/107 ,  C07D493/08 ,  C07D495/04 ,  C07D417/04

Abstract: There are described RORγ modulators of the formula (I), and formula (II) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein all substituents are defined herein. Also provided are pharmaceutical compositions comprising the same. Such compounds and compositions are useful in methods for modulating RORγ activity in a cell and methods for treating a subject suffering from a disease or disorder in which the subject would therapeutically benefit from modulation of RORγ activity, for example, autoimmune and/or inflammatory disorders.

公开(公告)号：US10214537B2

公开(公告)日：2019-02-26

申请号：US15521202

申请日：2015-10-21

Applicant: BRISTOL-MYERS SQUIBB COMPANY

Inventor： Rajeev S. Bhide ,  Douglas G. Batt ,  Robert J. Cherney ,  Lyndon A. M. Cornelius ,  Qingjie Liu ,  David Marcoux ,  James Neels ,  Michael A. Poss ,  Zheming Ruan ,  Qing Shi ,  Anurag S. Srivastava ,  Lan-ying Qin ,  Joseph A. Tino ,  Scott Hunter Watterson

IPC: C07D487/04 ,  C07D491/08 ,  A61K31/53 ,  A61K31/541 ,  A61P29/00

Abstract: Disclosed are compounds of Formula (I) or a salt thereof; wherein: X is N or CH; Q1 is: (i) Cl, Br, I, —CN, —CH3, or —CF3; (ii) a 5-membered heteroaryl selected from pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl; (iii) a 6?membered heteroaryl selected from pyridinyl, pyridazinyl, and pyrimidinyl; or (iv) a bicyclic heteroaryl selected from indolyl, pyrrolopyridinyl, pyrazolopyridinyl and benzo[d]oxazolyl; wherein each of said 5-membered, 6-membered, and bicyclic heteroaryl is substituted with zero to 1 Ra and zero to 1 Rb; and R1, R2, R3, R4, R5, R6, Ra, and Rb are defined herein. Also disclosed are methods of using such compounds as modulators of PI3K, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing inflammatory and autoimmune diseases.

公开(公告)号：US20180002358A1

公开(公告)日：2018-01-04

申请号：US15701818

申请日：2017-09-12

Applicant: BRISTOL-MYERS SQUIBB COMPANY

Inventor： Jingwu Duan ,  T.G. Murali Dhar ,  David Marcoux ,  Qing Shi ,  Douglas G. Batt ,  Qingjie Liu ,  Robert J. Cherney ,  Lyndon A.M. Cornelius ,  Anurag S. Srivastava ,  Myra Beaudoin Bertrand ,  Carolyn A. Weigelt

IPC: C07F9/6574 ,  C07D209/30 ,  C07D493/08 ,  C07D491/107 ,  C07D491/052 ,  C07D471/04 ,  C07D417/14 ,  C07D417/12 ,  C07D417/06 ,  C07D417/04 ,  C07D413/12 ,  C07D413/10 ,  C07D413/06 ,  C07D409/06 ,  C07D409/04 ,  C07D405/06 ,  C07D403/12 ,  C07D403/06 ,  C07D401/12 ,  C07D401/06 ,  C07D221/10 ,  C07D215/36 ,  C07D209/70 ,  C07D209/60 ,  C07D495/04 ,  C07D495/08

CPC classification number: C07F9/65742 ,  C07D209/30 ,  C07D209/60 ,  C07D209/70 ,  C07D215/36 ,  C07D221/10 ,  C07D401/06 ,  C07D401/12 ,  C07D403/06 ,  C07D403/12 ,  C07D405/06 ,  C07D409/04 ,  C07D409/06 ,  C07D413/06 ,  C07D413/10 ,  C07D413/12 ,  C07D417/04 ,  C07D417/06 ,  C07D417/12 ,  C07D417/14 ,  C07D471/04 ,  C07D491/052 ,  C07D491/107 ,  C07D493/08 ,  C07D495/04 ,  C07D495/08

Abstract: There are described RORγ modulators of the formula (I), and formula (II) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein all substituents are defined herein. Also provided are pharmaceutical compositions comprising the same. Such compounds and compositions are useful in methods for modulating RORγ activity in a cell and methods for treating a subject suffering from a disease or disorder in which the subject would therapeutically benefit from modulation of RORγ activity, for example, autoimmune and/or inflammatory disorders.

公开(公告)号：US09815859B2

公开(公告)日：2017-11-14

申请号：US15148209

申请日：2016-05-06

Applicant: BRISTOL-MYERS SQUIBB COMPANY

Inventor： Jingwu Duan ,  T. G. Murali Dhar ,  David Marcoux ,  Qing Shi ,  Douglas G. Batt ,  Qingjie Liu ,  Robert J. Cherney ,  Lyndon A. M. Cornelius ,  Anurag S. Srivastava ,  Myra Beaudoin Bertrand ,  Carolyn A. Weigelt

IPC: A61K31/437 ,  C07F9/6574 ,  C07D215/36 ,  C07D409/04 ,  C07D417/04 ,  C07D209/30 ,  C07D209/60 ,  C07D209/70 ,  C07D221/10 ,  C07D401/06 ,  C07D401/12 ,  C07D403/06 ,  C07D403/12 ,  C07D405/06 ,  C07D409/06 ,  C07D413/06 ,  C07D413/10 ,  C07D413/12 ,  C07D417/06 ,  C07D417/12 ,  C07D417/14 ,  C07D471/04 ,  C07D491/052 ,  C07D491/107 ,  C07D493/08 ,  C07D495/04 ,  C07D495/08

CPC classification number: C07F9/65742 ,  C07D209/30 ,  C07D209/60 ,  C07D209/70 ,  C07D215/36 ,  C07D221/10 ,  C07D401/06 ,  C07D401/12 ,  C07D403/06 ,  C07D403/12 ,  C07D405/06 ,  C07D409/04 ,  C07D409/06 ,  C07D413/06 ,  C07D413/10 ,  C07D413/12 ,  C07D417/04 ,  C07D417/06 ,  C07D417/12 ,  C07D417/14 ,  C07D471/04 ,  C07D491/052 ,  C07D491/107 ,  C07D493/08 ,  C07D495/04 ,  C07D495/08

Abstract: There are described RORγ modulators of the formula (I), and formula (II) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein all substituents are defined herein. Also provided are pharmaceutical compositions comprising the same. Such compounds and compositions are useful in methods for modulating RORγ activity in a cell and methods for treating a subject suffering from a disease or disorder in which the subject would therapeutically benefit from modulation of RORγ activity, for example, autoimmune and/or inflammatory disorders.

公开(公告)号：US20160326195A1

公开(公告)日：2016-11-10

申请号：US15148209

申请日：2016-05-06

Applicant: BRISTOL-MYERS SQUIBB COMPANY

Inventor： Jingwu Duan ,  T.G. Murali Dhar ,  David Marcoux ,  Qing Shi ,  Douglas G. Batt ,  Qingjie Liu ,  Robert J. Cherney ,  Lyndon A.M. Cornelius ,  Anurag S. Srivastava ,  Myra Beaudoin Bertrand ,  Carolyn A. Weigelt

IPC: C07F9/6574 ,  C07D221/10 ,  C07D401/06 ,  C07D209/70 ,  C07D409/06 ,  C07D491/052 ,  C07D401/12 ,  C07D403/06 ,  C07D417/06 ,  C07D493/08 ,  C07D405/06 ,  C07D413/10 ,  C07D413/06 ,  C07D471/04 ,  C07D417/14 ,  C07D495/04 ,  C07D495/08 ,  C07D417/12 ,  C07D413/12 ,  C07D403/12 ,  C07D491/107 ,  C07D209/60

CPC classification number: C07F9/65742 ,  C07D209/30 ,  C07D209/60 ,  C07D209/70 ,  C07D215/36 ,  C07D221/10 ,  C07D401/06 ,  C07D401/12 ,  C07D403/06 ,  C07D403/12 ,  C07D405/06 ,  C07D409/04 ,  C07D409/06 ,  C07D413/06 ,  C07D413/10 ,  C07D413/12 ,  C07D417/04 ,  C07D417/06 ,  C07D417/12 ,  C07D417/14 ,  C07D471/04 ,  C07D491/052 ,  C07D491/107 ,  C07D493/08 ,  C07D495/04 ,  C07D495/08

Abstract: There are described RORγ modulators of the formula (I), and formula (II) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein all substituents are defined herein. Also provided are pharmaceutical compositions comprising the same. Such compounds and compositions are useful in methods for modulating RORγ activity in a cell and methods for treating a subject suffering from a disease or disorder in which the subject would therapeutically benefit from modulation of RORγ activity, for example, autoimmune and/or inflammatory disorders.

Abstract translation: 或其立体异构体，互变异构体，其药学上可接受的盐，溶剂合物或前药，其中所有取代基均在本文中定义。 还提供了包含其的药物组合物。 这样的化合物和组合物可用于调节细胞中RORγ活性的方法和用于治疗受试者治疗受益于RORγ活性（例如自身免疫和/或炎症性疾病）的疾病或病症的受试者的方法。

公开(公告)号：US20130158039A1

公开(公告)日：2013-06-20

申请号：US13746389

申请日：2013-01-22

Applicant: Bristol-Myers Squibb Company

Inventor： Percy H. Carter ,  Robert J. Cherney

IPC: A61K31/53

CPC classification number: A61K31/53 ,  C07D487/04

Abstract: The present invention provides a novel antagonist: N-((1R,2S,5R)-5-(tert-butylamino)-2-((S)-3-(7-tert-butylpyrazolo[1,5-a][1,3,5]triazin-4-ylamino)-2-oxopyrrolidin-1-yl)cyclohexyl)acetamide: or a pharmaceutically acceptable salt, solvate or prodrug, thereof, having unexpected dual CCR-2 and CCR-5 receptor activity. Crystalline forms, metabolites, pharmaceutical compositions containing the same and methods of using the same as agents for the treatment of inflammatory diseases, allergic, autoimmune, metabolic, cancer and/or cardiovascular diseases are also disclosed. The present disclosure also provides processes for preparing compounds of Formula (I) as provided herein, including N-((1R,2S,5R)-5-(tert-butylamino)-2-((S)-3-(7-tert-butylpyrazolo[1,5-a][1,3,5]triazin-4-ylamino)-2-oxopyrrolidin-1-yl)cyclohexyl)acetamide. Compounds that are useful intermediates of the process are also provided herein.

Abstract translation: 本发明提供新的拮抗剂：N - （（1R，2S，5R）-5-（叔丁基氨基）-2 - （（S）-3-（7-叔丁基吡唑并[1,5-a] 1,3,5]三嗪-4-基氨基）-2-氧代吡咯烷-1-基）环己基）乙酰胺：或其药学上可接受的盐，溶剂合物或前药，具有意想不到的双重CCR-2和CCR-5受体活性。 还公开了结晶形式，代谢物，含有其的药物组合物和使用其作为治疗炎性疾病，过敏性，自身免疫性，代谢性，癌症和/或心血管疾病的药剂的方法。 本公开还提供了制备本文提供的式（I）化合物的方法，包括N - （（1R，2S，5R）-5-（叔丁基氨基）-2 - （（S） 叔丁基吡唑并[1,5-a] [1,3,5]三嗪-4-基氨基）-2-氧代吡咯烷-1-基）环己基）乙酰胺。 本文还提供了该方法有用中间体的化合物。