COMBINATION THERAPY FOR TREATMENT OF HEMATOLOGICAL DISEASESThe present application relates to treatment of a hematological disease selected from leukemia, lymphoma, and multiple myeloma in a patient in need thereof, comprising administering to the patient: (a) a therapeutically effective amount of a selective JAK1 inhibitor; (b) a therapeutically effective amount of an immunomodulatory agent, and (c) a therapeutically effective amount of a steroid.A method of treating a hematological disease selected from leukemia, lymphoma, and multiple myeloma in a patient in need thereof, comprisingadministering to the patient: (a) a therapeutically effective amount of a selective JAK1 inhibitor; (b) a therapeutically effective amount of an immunomodulatory agent, and (c) a therapeutically effective amount of a steroid; wherein:(a) the JAK1 inhibitor is selected from:{ 1 - { 1 - [3 -Fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl } -3 - [4-(7H- pyrrolo [2,3 -d]pyrimidin-4-yl)- 1 H-pyrazol- 1 -yl]azetidin-3 -yl } acetonitrile ;4- { 3 -(cyanomethyl)-3 - [4-(7H-pyrrolo [2,3 -d]pyrimidin-4-yl)- 1 H-pyrazol- 1 - yl]azetidin-l-yl}-N-[4-fluoro-2-(trifluoromethyl)phenyl]piperidine-l-carboxamide;[3 - [4-(7H-pyrrolo [2,3 -d]pyrimidin-4-yl)- 1 H-pyrazol- 1 -yl] - 1 -( 1 - { [2- (trifluoromethyl)pyrimidin-4-yl] carbonyl } piperidin-4-yl)azetidin-3 -yl] acetonitrile;4- [3 -(cyanomethyl)-3 -(3 ', 5 '-dimethyl- 1 H, 1 H-4,4'-bipyrazol- 1 -yl)azetidin- 1 - yl]-2,5-difluoro-N-[(lS)-2,2,2-trifluoro-l-methylethyl]benzamide;((2R,5S)-5-{2-[(lR)-l-hydroxyethyl]-lH-imidazo[4,5-d]thieno[3,2-b]pyridin- 1 -yl } tetrahydro-2H-pyran-2-yl)acetonitrile ;3 - [ 1 -(6-chloropyridin-2-yl)pyrrolidin-3 -yl] -3 - [4-(7H-pyrrolo [2,3 -d]pyrimidin- 4-yl)- 1 H-pyrazol- 1 -yl]propanenitrile;3 -( 1 - [ 1 , 3 ]oxazolo [5 ,4-b]pyridin-2-ylpyrrolidin-3 -yl)-3 - [4-(7H-pyrrolo [2,3- d]pyrimidin-4-yl)- lH-pyrazol- 1 -yl]propanenitrile;4- [(4- { 3 -cyano-2- [4-(7H-pyrrolo [2,3 -d]pyrimidin-4-yl)- 1 H-pyrazol- 1 - yl]propyl}piperazin-l-yl)carbonyl]-3-fluorobenzonitrile;4- [(4- { 3 -cyano-2- [3 -(7H-pyrrolo [2,3 -d]pyrimidin-4-yl)- 1 H-pyrrol- 1 - yl]propyl}piperazin-l-yl)carbonyl]-3-fluorobenzonitrile;[trans- 1 - [4-(7H-pyrrolo [2,3 -d]pyrimidin-4-yl)- 1 H-pyrazol- 1 -yl] -3 -(4- { [2- (trifluoromethyl)pyrimidin-4-yl] carbonyl } piperazin- 1 -yl)cyclobutyl] acetonitrile;(trans-3 -(4- { [4-[(3 -hydroxyazetidin- 1 -yl)methyl] -6-(trifluoromethyl)pyridin- 2-yl] oxy } piperidin- 1 -yl)- 1 - [4-(7H-pyrrolo [2,3 -d]pyrimidin-4-yl)- 1 H-pyrazol- 1 - yl] cyclobutyl } acetonitrile; { trans-3 -(4- { [4- { [(2 S)-2-(hydroxymethyl)pyrrolidin- 1 -yl] methyl } -6- (trifluoromethyl)pyridin-2-yl] oxy } piperidin- 1 -yl)- 1 - [4-(7H-pyrrolo [2,3 -djpyrimidin- 4-yl)- 1 H-pyrazol- 1 -yl] cyclobutyl } acetonitrile;(trans-3 -(4- { [4- { [(2R)-2-(hydroxymethyl)pyrrolidin- 1 -yl] methyl } -6- (trifluoromethyl)pyridin-2-yl] oxy (piperidin- 1 -yl)- 1 - [4-(7H-pyrrolo [2,3 -d]pyrimidin- 4-yl)- 1 H-pyrazol- 1 -yl] cyclobutyl } acetonitrile;4-(4- { 3 -[(dimethylamino)methyl] -5 -fluorophenoxy } piperidin- 1 -yl)-3 - [4-(7H- pyrrolo [2,3 -d]pyrimidin-4-yl)- 1 H-pyrazol- 1 -yl]butanenitrile;5 - { 3 -(cyanomethyl)-3 - [4-(7H-pyrrolo [2,3 -d]pyrimidin-4-yl)- 1 H-pyrazol- 1 - yl]azetidin- 1 -yl } -N-isopropylpyrazine-2-carboxamide;4- { 3 -(cyanomethyl)-3 - [4-(7H-pyrrolo [2,3 -d]pyrimidin-4-yl)- 1 H-pyrazol- 1 - yl]azetidin-l-yl}-2,5-difluoro-N-[(l S)-2,2,2-trifluoro-l-methylethyl]benzamide;5 - { 3 -(cyanomethyl)-3 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-4-yl)- 1 H-pyrazol- 1 - yl]azetidin- 1 -yl } -N-isopropylpyrazine-2-carboxamide;( 1 -(cis-4- {[6-(2-hydroxyethyl)-2-(trifluoromethyl)pyrimidin-4- yl] oxy } cyclohexyl)-3 - [4-(7H-pyrrolo [2,3 -d]pyrimidin-4-yl)- 1 H-pyrazol- 1 -yl] azetidin- 3 -yl} acetonitrile;{ l-(cis-4-{[4-[(ethylamino)methyl]-6-(trifluoromethyl)pyridin-2- yl] oxy } cyclohexyl)-3 - [4-(7H-pyrrolo [2,3 -d]pyrimidin-4-yl)- 1 H-pyrazol- 1 -yl] azetidin- 3 -yl} acetonitrile;{ 1 -(cis-4- { [4-( 1 -hydroxy- 1 -methyl ethyl)-6-(trifluoromethyl)pyridin-2- yl] oxy } cyclohexyl)-3 - [4-(7H-pyrrolo [2,3 -d]pyrimidin-4-yl)- 1 H-pyrazol- 1 -yl] azetidin-3 -yl} acetonitrile;{ 1 -(cis-4- { [4- { [(3R)-3 -hydroxypyrrolidin- 1 -yl] methyl } -6- (trifluoromethyl)pyridin-2-yl] oxy } cyclohexyl)-3 - [4-(7H-pyrrolo [2,3 -d]pyrimidin-4- yl)- 1 H-pyrazol- 1 -yl] azetidin-3 -yl } acetonitrile;{ 1 -(cis-4- { [4- { [(3 S)-3 -hydroxypyrrolidin- 1 -yl] methyl } -6- (trifluoromethyl)pyridin-2-yl] oxy } cyclohexyl)-3 - [4-(7H-pyrrolo [2,3 -d]pyrimidin-4- yl)- 1 H-pyrazol- 1 -yl] azetidin-3 -yl } acetonitrile;(trans-3 -(4-([4-(([(l S)-2-hydroxy- 1 -methyl ethyl] amino } methyl)-6- (trifluoromethyl)pyridin-2-yl] oxy (piperidin- 1 -yl)- 1 - [4-(7H-pyrrolo [2,3 -d]pyrimidin-4-yl)- 1 H-pyrazol- 1 -yl] cyclobutyl } acetonitrile; { trans-3 -(4- { [4-( { [(2R)-2-hydroxypropyl] amino } methyl)-6- (trifluoromethyl)pyridin-2-yl] oxy } piperidin- 1 -yl)- 1 - [4-(7H-pyrrolo [2,3 -djpyrimidin- 4-yl)- 1 H-pyrazol- 1 -yl] cyclobutyl } acetonitrile;{trans-3-(4-{[4-({[(2S)-2-hydroxypropyl]amino}methyl)-6- (trifluoromethyl)pyridin-2-yl] oxy } piperidin- 1 -yl)- 1 - [4-(7H-pyrrolo [2,3 -djpyrimidin- 4-yl)- 1 H-pyrazol- 1 -yl] cyclobutyl } acetonitrile; and(trans-3 -(4- {[4-(2-hydroxy ethyl)-6-(trifluoromethyl)pyridin-2- yl] oxy (piperidin- 1 -yl)- 1 - [4-(7H-pyrrolo [2,3 -d]pyrimidin-4-yl)- 1 H-pyrazol- 1 - yl] cyclobutyl } acetonitrile;or a pharmaceutically acceptable...
혈액 질환의 치료를 위한 병용 요법본 출원은 환자에게: (a) 치료적 유효량의 선택적 JAK1 억제제; (b) 치료적 유효량의 면역조절제, 및 (c) 치료적 유효량의 스테로이드를 투여하는 것을 포함하는, 이를 필요로 하는 환자의 백혈병, 림프종, 및 다발성 골수종으로부터 선택된 혈액 질환의 치료에 관한 것이다.환자에게: (a) 치료적 유효량의 선택적 JAK1 억제제; (b) 치료적 유효량의 면역조절제, 및 (c) 치료적 유효량의 스테로이드를 투여하는 것을 포함하는, 이를 필요로 하는 환자의 백혈병, 림프종, 및 다발성 골수종으로부터 선택된 혈액 질환의 치료 방법; 여기서: (a) JAK1 억제제는 다음으로부터 선택된다: {1-{1-[3-플루오로-2-(트리플루오로메틸)이소니코티노일]피페리딘-4-일}-3-[4-(7H-피롤로[2,3-d]피리미딘-4-일)-1H-피라졸-1-일]아제티딘-3-일}아세토니트릴;4-{3-(시아노메틸)-3-[4-(7H-피롤로[2,3-d]피리미딘-4-일)-1H-피라졸-1-일]아제티딘-1-일}-N-[4-플루오로-2-(트리플루오로메틸)페닐]피페리딘-1-카르복스아미드;[3-[4-(7H-피롤로[2,3-d]피리미딘-4-일)-1H-피라졸-1-일]-1-(1-{[2-(트리플루오로메틸)피리미딘-4-일]카르보닐}피페리딘-4-일)아제티딘-3-일]아세토니트릴;4-[3-(시아노메틸)-3-(3',5'-디메틸-1H,1'H-4,4'-비피라졸-1-일)아제티딘-1-일]-2,5-디플루오로-N-[(1S)-2,2,2-트리플루오로-1-메틸에틸]벤즈아미드; ((2R,5S)-5-{2-[(1R)-1-하이드록시에틸]-1H-이미다조[4,5-d]티에노[3,2-b]피리딘-1-일}테트라하이드로-2H-피란-2-일)아세토니트릴; 3-[1-(6-클로로피리딘-2-일)피롤리딘-3-일]-3-[4-(7H-피롤로[2,3-d]피리미딘-4-일)-1H-피라졸-1-일]프로판니트릴; 3-(1-[1,3]옥사졸로[5,4-b]피리딘-2-일피롤리딘-3-일)-3-[4-(7H-피롤로[2,3-d]피리미딘-4-일)-1H-피라졸-1-일]프로판니트릴;4-[(4-{3-시아노-2-[4-(7H-피롤로[2,3-d]피리미딘-4-일)-1H-피라졸-1-일]프로필}피페라진-1-일)카르보닐]-3-플루오로벤조니트릴;4-[(4-{3-시아노-2-[3-(7H-피롤로[2,3-d]피리미딘-4-일)-1H-피롤-1-일]프로필}피페라진-1-일)카르보닐]-3-플루오로벤조니트릴; [트랜스-1-[4-(7H-피롤로[2,3-d]피리미딘-4-일)-1H-피라졸-1-일]-3-(4-{[2-(트리플루오로메틸)피리미딘-4-일]카르보닐}피페라진-1-일)사이클로부틸]아세토니트릴;{트랜스-3-(4-{[4-[(3-하이드록시아제티딘-1-일)메틸]-6-(트리플루오로메틸)피리딘-2-일]옥시}피페리딘-1-일)-1-[4-(7H-피롤로[2,3-d]피리미딘-4-일)-1H-피라졸-1-일]사이클로부틸}아세토니트릴;{트랜스-3-(4-{[4-{[(2S)-2-(하이드록시메틸)피롤리딘-1-일]메틸}-6-(트리플루오로메틸)피리딘-2-일]옥시}피페리딘-1-일)-1-[4-(7H-피롤로[2,3-d]피리미딘-4-일)-1H-피라졸-1-일]사이클로부틸}아세토니트릴;{트랜스-3-(4-{[4-{[(2R)-2-(하이드록시메틸)피롤리딘-1-일]메틸}-6-(트리플루오로메틸)피리딘-2-일]옥시}피페리딘-1-일)-1-[4-(7H-피롤로[2,3-d]피리미딘-4-일)-1H-피라졸-1-일]사이클로부틸}아세토니트릴;4-(4-{3-[(디메틸아미노)메틸]-5-플루오로페녹시}피페리딘-1-일)-3-[4-(7H-피롤로[2,3-d]피리미딘-4-일)-1H-피라졸-1-일]부탄니트릴;5-{3-(시아노메틸)-3-[4-(7H-피롤로[2,3-d]피리미딘-4-일)-1H-피라졸-1-일]아제티딘-1-일}-N-이소프로필피라진-2-카르복스아미드;4-{3-(시아노메틸)-3-[4-(7H-피롤로[2,3-d]피리미딘-4-일)-1H-피라졸-1-일]아제티딘-1-일}-2,5-디플루오로-N-[(1S)-2,2,2-트리플루오로-1-메틸에틸]벤즈아미드;5-{3-(시아노메틸)-3-[4-(1H-피롤로[2,3-b]피리딘-4-일)-1H-피라졸-1-일]아제티딘-1-일}-N-이소프로필피라진-2-카르복스아미드;{1-(시스-4-{[6-(2-하이드록시에틸)-2-(트리플루오로메틸)피리미딘-4-일]옥시}사이클로헥실)-3-[4-(7H-피롤로[2,3-d]피리미딘-4-일)-1H-피라졸-1-일]아제티딘-3-일}아세토니트릴;{1-(시스-4-{[4-[(에틸아미노)메틸]-6-(트리플루오로메틸)피리딘-2-일]옥시}사이클로헥실)-3-[4-(7H-피롤로[2,3-d]피리미딘-4-일)-1H-피라졸-1-일]아제티딘-3-일}아세토니트릴;{1-(시스-4-{[4-(1-하이드록시-1-메틸에틸)-6-(트리플루오로메틸)피리딘-2-일]옥시}사이클로헥실)-3-[4-(7H-피롤로[2,3-d]피리미딘-4-일)-1H-피라졸-1-일]아제티딘-3-일}아세토니트릴;{1-(시스-4-{[4-{[(3R)-3-하이드록시피롤리딘-1-일]메틸}-6-(트리플루오로메틸)피리딘-2-일]옥시}사이클로헥실)-3-[4-(7H-피롤로[2,3-d]피리미딘-4-일)-1H-피라졸-1-일]아제티딘-3-일}아세토니트릴;{1-(시스-4-{[4-{[(3S)-3-하이드록시피롤리딘-1-일]메틸}-6-(트리플루오로메틸)피리딘-2-일]옥시}사이클로헥실)-3-[4-(7H-피롤로[2,3-d]피리미딘-4-일)-1H-피라졸-1-일]아제티딘-3-일}아세토니트릴;{트랜스-3-(4-{[4-({[(1S)-2-하이드록시-1-메틸에틸]아미노}메틸)-6-(트리플루오로메틸)피리딘-2-일]옥시}피페리딘-1-일)-1-[4-(7H-피롤로[2,3-d]피리미딘-4-일)-1H-피라졸-1-일]사이클로부틸}아세토니트릴;{트랜스-3-(4-{[4-({[(2R)-2-하이드록시프로필]아미노}메틸)-6-(트리플루오로메틸)피리딘-2-일]옥시}피페리딘-1-일)-1-[4-(7H-피롤로[2,3-d]피리미딘-4-일)-1H-피라졸-1-일]사이클로부틸}아세토니트릴;{트랜스-3-(4-{[4-({[(2S)-2-하이드록시프로필]아미노}메틸)-6-(트리플루오로메틸)피리딘-2-일]옥시}피페리딘-1-일)-1-[4-(7H-피롤로[2,3-d]피리미딘-4-일)-1H-피라졸-1-일]사이클로부틸}아세토니트릴; 및{트랜스-3-(4-{[4-(2-하이드록시에틸)-6-(트리플루오로메틸)피리딘-2-일]옥시}피페리딘-1-일)-1-[4-(7H-피롤로[2,3-d]피리미딘-4-일)-1H-피라졸-1-일]사이클로부틸}아세토니트릴;또는 전술한 임의의 것의 약제학적으로 허용 가능한 염;(b) 면역조절제는 탈리도마이드, 레날리도마이드, 아프레밀라스트, 리노마이드, 및 포말리도마이드, 또는 전술한 임의의 것의 약제학적으로 허용 가능한 염으로부터 선택된다;(c) 스테로이드는 프레드니손, 메틸프레드니솔론, 덱사메타손, 하이드록시코르티손, 코르티손, 데스옥시코르티코스테론, 플루드로코르티손, 베타메타손, 프레드니솔론, 메틸프레드니손, 파라메타손, 트리암시놀론, 플루메타손, 플루오시놀론, 플루오시노나이드, 플루프레드니솔론, 할시노나이드, 플루란드레놀라이드, 메프레드니손, 및 메드리손, 또는 전술한 임의의 것의 약제학적으로 허용 가능한 염으로부터 선택된다.