公开(公告)号：WO2013104591A1

公开(公告)日：2013-07-18

申请号：PCT/EP2013/050170

申请日：2013-01-08

Applicant: F. HOFFMANN-LA ROCHE AG ,  GALLEY, Guido ,  GOERGLER, Annick ,  NORCROSS, Roger ,  PFLIEGER, Philippe

Inventor： GALLEY, Guido ,  GOERGLER, Annick ,  NORCROSS, Roger ,  PFLIEGER, Philippe

IPC: C07D413/10 ,  C07D413/14 ,  C07D471/04 ,  A61K31/5377 ,  A61P25/00

CPC classification number: C07D413/10 ,  C07D413/14 ,  C07D471/04 ,  C07D487/04

Abstract: The present invention relates to compounds of formula (I) wherein R 1 is a one or two membered heteroaryl group, selected from the group consisting of formula (a), (b), (c), (d), (e), (f), (g), (h), (i), (j); R 2 is hydrogen or halogen; or R 1 and R 2 may form together with the carbon atoms to with they are attached the following rings formula (k), (l), (m), (n), (o). R 3 is hydrogen, halogen or lower alkyl; n is 1 or 2; R 4 is phenyl, optionally substituted by one or two substituents, selected from halogen or cyano, or is pyridinyl, optionally substituted by halogen, or is tetrahydropyran, or is -NH-C(O)-phenyl, optionally substituted by halogen; R 5 is hydrogen or halogen; R 6 – R 13 are phenyl, optionally substituted by halogen: R 14 is –NH-C(O)-phenyl, substituted by halogen; R 15 is hydrogen, lower alkyl substituted by halogen or is halogen; R 16 is hydrogen or lower alkoxy; R 17 is pyridinyl, optionally substituted by lower alkoxy or lower alkyl substituted by halogen; or to a pharmaceutically suitable acid addition salt thereof, to all racemic mixtures, to all their corresponding enantiomers and/or optical isomers and to all tautomeric forms of compounds of formula I. The compounds of formula I have a good affinity to the trace amine associated receptors (TAARs), especially for TAAR1. The compounds may be used for the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.

Abstract translation: 本发明涉及式（I）化合物，其中R 1是选自式（a），（b），（c），（d），（e），（d） f），（g），（h），（i），（j）; R2是氢或卤素; 或者R 1和R 2可以与碳原子一起形成，它们连接下列环（k），（l），（m），（n），（o）。 R3是氢，卤素或低级烷基; n为1或2; R4是任选被一个或两个选自卤素或氰基的取代基取代的苯基，或是任选被卤素取代的吡啶基，或是四氢吡喃，或者是任选被卤素取代的-NH-C（O） - 苯基; R5是氢或卤素; R6-R13是任选被卤素取代的苯基; R 14是被卤素取代的-NH-C（O） - 苯基; R 15是氢，被卤素取代的低级烷基或是卤素; R 16是氢或低级烷氧基; R 17为吡啶基，任选被低级烷氧基或被卤素取代的低级烷基取代; 或其药学上合适的酸加成盐，与所有相应的对映异构体和/或光学异构体以及式I化合物的所有互变异构体形式。式I化合物与微量胺相关联具有良好的亲和力 受体（TAAR），特别是TAAR1。 这些化合物可用于治疗抑郁症，焦虑障碍，双相情感障碍，注意力缺陷多动障碍（ADHD），应激相关疾病，精神病性精神障碍如精神分裂症，神经系统疾病如帕金森病，神经变性疾病如阿尔茨海默病， 癫痫，偏头痛，高血压，药物滥用和代谢障碍如进食障碍，糖尿病，糖尿病并发症，肥胖症，血脂异常，能量消耗和同化障碍，体温平衡紊乱和失调，睡眠和昼夜节律紊乱以及心血管疾病 。

公开(公告)号：WO2012168260A1

公开(公告)日：2012-12-13

申请号：PCT/EP2012/060627

申请日：2012-06-06

Applicant: F. HOFFMANN-LA ROCHE AG ,  GALLEY, Guido ,  GHELLAMALLAH, Cédric ,  NORCROSS, Roger ,  PFLIEGER, Philippe

Inventor： GALLEY, Guido ,  GHELLAMALLAH, Cédric ,  NORCROSS, Roger ,  PFLIEGER, Philippe

IPC: A61K31/4245 ,  C07D413/12 ,  C07D413/14 ,  A61P25/00

CPC classification number: C07D413/14 ,  C07D413/12

Abstract: The invention relates to compounds of formula wherein R 1 is hydrogen or phenyl, optionally substitutes by halogen, CN or lower alkoxy or lower alkoxy substituted by halogen; R 2 is hydrogen or lower alkyl; R 3 is hydrogen or lower alkyl or is phenyl optionally substituted by one or more substituents, selected from halogen, cyano or lower alkoxy substituted by halogen, or is pyridinyl, optionally substituted by halogen or lower alkyl substituted by halogen, or is pyrimidinyl, optionally substituted by lower alkyl substituted by halogen, or is pyrazinyl, optionally substituted by halogen, cyano or lower alkyl substituted by halogen; R 4 is hydrogen, lower alkyl or phenyl; Z is a bond, -CH 2 - or -O-; or to a pharmaceutically suitable acid addition salt thereof. It has now been found that the compounds of formulas IA and IB have a good affinity to the trace amine associated receptors (TAARs), especially for TAAR1. The compounds may be used for the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.

Abstract translation: 本发明涉及下式的化合物，其中R 1是氢或苯基，任选地被卤素，CN或被卤素取代的低级烷氧基或低级烷氧基取代; R2是氢或低级烷基; R 3是氢或低级烷基或被任选被一个或多个选自卤素，氰基或被卤素取代的低级烷氧基的取代基取代的苯基，或是任选被卤素取代的吡啶基或被卤素取代的低级烷基，或者是嘧啶基， 被卤素取代的低级烷基，或任选被卤素，氰基或被卤素取代的低级烷基取代的吡嗪基; R4是氢，低级烷基或苯基; Z是键，-CH 2 - 或-O-; 或其药学上合适的酸加成盐。 现已发现式IA和IB的化合物对微量胺相关受体（TAAR）具有良好的亲和力，特别是对于TAAR1。 这些化合物可用于治疗抑郁症，焦虑障碍，双相情感障碍，注意力缺陷多动障碍（ADHD），应激相关疾病，精神病性精神障碍如精神分裂症，神经系统疾病如帕金森病，神经变性疾病如阿尔茨海默病， 癫痫，偏头痛，高血压，药物滥用和代谢障碍如进食障碍，糖尿病，糖尿病并发症，肥胖症，血脂异常，能量消耗和同化障碍，体温平衡紊乱和失调，睡眠和昼夜节律紊乱以及心血管疾病 。

公开(公告)号：WO2011057973A9

公开(公告)日：2012-02-02

申请号：PCT/EP2010066960

申请日：2010-11-08

Applicant: HOFFMANN LA ROCHE ,  GALLEY GUIDO ,  NORCROSS ROGER ,  POLARA ALESSANDRA

Inventor： GALLEY GUIDO ,  NORCROSS ROGER ,  POLARA ALESSANDRA

IPC: C07D263/28 ,  A61K31/421 ,  A61K31/422 ,  A61K31/4439 ,  A61K31/506 ,  A61P25/00 ,  C07D401/12 ,  C07D401/14 ,  C07D403/10 ,  C07D403/12 ,  C07D409/12 ,  C07D413/12 ,  C07D413/14 ,  C07D417/12 ,  C07D471/04

CPC classification number: C07D263/28 ,  C07D401/12 ,  C07D401/14 ,  C07D403/10 ,  C07D403/12 ,  C07D409/12 ,  C07D413/12 ,  C07D413/14 ,  C07D417/12 ,  C07D471/04

Abstract: The invention relates to compounds of formula (I) wherein the definitions of X, R and R1 are provided in claim 1. It has now been found that the compounds of formula (I) have a good affinity to the trace amine associated receptors (TAARs), especially for TAARl. The compounds may be used for the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.

Abstract translation: 本发明涉及式（I）化合物，其中X，R和R 1的定义在权利要求1中提供。现已发现式（I）化合物对微量胺相关受体（TAARs）具有良好的亲和力 ），特别是对于TAARl。 该化合物可用于治疗抑郁症，焦虑障碍，双相情感障碍，注意力缺陷多动障碍（ADHD），应激相关疾病，精神病性精神障碍如精神分裂症，神经系统疾病如帕金森病，神经变性疾病如阿尔茨海默病， 癫痫，偏头痛，高血压，物质滥用和代谢紊乱，如进食障碍，糖尿病，糖尿病并发症，肥胖症，血脂异常，能量消耗和同化障碍，体温平衡紊乱和失调，睡眠和昼夜节律紊乱以及心血管疾病 。

公开(公告)号：WO2011057973A1

公开(公告)日：2011-05-19

申请号：PCT/EP2010/066960

申请日：2010-11-08

Applicant: F. HOFFMANN-LA ROCHE AG ,  GALLEY, Guido ,  NORCROSS, Roger ,  POLARA, Alessandra

Inventor： GALLEY, Guido ,  NORCROSS, Roger ,  POLARA, Alessandra

IPC: C07D263/28 ,  C07D401/12 ,  C07D401/14 ,  C07D403/10 ,  C07D403/12 ,  C07D409/12 ,  C07D413/12 ,  C07D413/14 ,  C07D417/12 ,  C07D471/04 ,  A61K31/421 ,  A61K31/4439 ,  A61K31/506 ,  A61K31/422 ,  A61P25/00

CPC classification number: C07D263/28 ,  C07D401/12 ,  C07D401/14 ,  C07D403/10 ,  C07D403/12 ,  C07D409/12 ,  C07D413/12 ,  C07D413/14 ,  C07D417/12 ,  C07D471/04

Abstract: The invention relates to compounds of formula (I) wherein the definitions of X, R and R 1 are provided in claim 1. It has now been found that the compounds of formula (I) have a good affinity to the trace amine associated receptors (TAARs), especially for TAARl. The compounds may be used for the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.

Abstract translation: 本发明涉及式（I）化合物，其中X，R和R 1的定义在权利要求1中提供。现已发现式（I）化合物与微量胺相关受体（TAARs）具有良好的亲和力 ），特别是TAARl。 这些化合物可用于治疗抑郁症，焦虑障碍，双相情感障碍，注意力缺陷多动障碍（ADHD），应激相关疾病，精神病性精神障碍如精神分裂症，神经系统疾病如帕金森病，神经变性疾病如阿尔茨海默病， 癫痫，偏头痛，高血压，药物滥用和代谢障碍如进食障碍，糖尿病，糖尿病并发症，肥胖症，血脂异常，能量消耗和同化障碍，体温平衡紊乱和失调，睡眠和昼夜节律紊乱以及心血管疾病 。

公开(公告)号：WO2009003868A2

公开(公告)日：2009-01-08

申请号：PCT/EP2008057989

申请日：2008-06-24

Applicant: HOFFMANN LA ROCHE ,  GALLEY GUIDO ,  GROEBKE ZBINDEN KATRIN ,  NORCROSS ROGER ,  STALDER HENRI

Inventor： GALLEY GUIDO ,  GROEBKE ZBINDEN KATRIN ,  NORCROSS ROGER ,  STALDER HENRI

IPC: C07D233/10 ,  A61K31/415 ,  A61K31/4155 ,  A61P25/00 ,  C07D233/20 ,  C07D233/22 ,  C07D233/24 ,  C07D233/42 ,  C07D233/50 ,  C07D233/52 ,  C07D405/12

CPC classification number: C07D233/24 ,  C07D233/20 ,  C07D233/22 ,  C07D233/42 ,  C07D233/52 ,  C07D405/12

Abstract: The present invention relates to compounds of formula (I) wherein X-Y is -N(R2) -CH(R3)-, CH(R3)-N(R2)-, -NH-NH-, -O-CHR3-, -CHR3-O-, -S-CHR3, -CHR3-S- or -CHR3-CHR3 -; R1 is hydrogen, halogen, lower alkyl, lower alkoxy, -(CH2)o-phenyl optionally substituted by lower alkoxy, -(CH2)o-C(O)-phenyl optionally substituted by lower alkoxy, -(CH2)o-O-phenyl optionally substituted by lower alkoxy, -(CH2)o-O-phenyl, CF3, cycloalkyl, NO2, amino or hydroxy; R2 is hydrogen, lower alkyl, phenyl optionally substituted by hydroxy or benzyl; R3/R3' are independently from each other hydrogen, lower alkyl or benzyl; Ar is phenyl, naphthyl, benzofuranyl or benzo [1,3] dioxolyl; n is 1, 2, 3 or 4; o is 0, 1, 2, 3 and to their pharmaceutically active salts, It has been found that the compounds of formula (I) have a good affinity to the trace amine associated receptors (TAARs), especially for TAAR1. The compounds may be used for the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.

Abstract translation: 本发明涉及式（I）化合物，其中XY是-N（R2）-CH（R3） - ，CH（R3）-N（R2） - ， - NH-NH-，-O-CHR3-， - CHR 3 -O-，-S-CHR 3，-CHR 3 -S-或-CHR 3 -CHR 3 - ; 任选被低级烷氧基取代的 - （CH 2）o C（O） - 苯基，任选被低级烷氧基取代的 - （CH 2）o O-苯基， - （CH 2） （CH 2）o O-苯基，CF 3，环烷基，NO 2，氨基或羟基; R2是氢，低级烷基，任意被羟基或苄基取代的苯基; R3 / R3'彼此独立地为氢，低级烷基或苄基; Ar是苯基，萘基，苯并呋喃基或苯并[1,3]二氧杂环戊烯基; n为1,2,3或4; o是0,1,2,3及其药学活性盐。已经发现式（I）化合物对微量胺相关受体（TAAR）具有良好的亲和力，特别是对于TAAR1。 这些化合物可用于治疗抑郁症，焦虑障碍，双相情感障碍，注意力缺陷多动障碍（ADHD），应激相关疾病，精神病性精神障碍如精神分裂症，神经系统疾病如帕金森病，神经变性疾病如阿尔茨海默病， 癫痫，偏头痛，高血压，药物滥用和代谢障碍如进食障碍，糖尿病，糖尿病并发症，肥胖症，血脂异常，能量消耗和同化障碍，体温平衡紊乱和失调，睡眠和昼夜节律紊乱以及心血管疾病 。

公开(公告)号：WO2008058867A2

公开(公告)日：2008-05-22

申请号：PCT/EP2007/061921

申请日：2007-11-06

Applicant: F. HOFFMANN-LA ROCHE AG ,  GALLEY, Guido ,  GROEBKE ZBINDEN, Katrin ,  NORCROSS, Roger ,  STALDER, Henri

Inventor： GALLEY, Guido ,  GROEBKE ZBINDEN, Katrin ,  NORCROSS, Roger ,  STALDER, Henri

IPC: C07D403/06 ,  C07D401/06 ,  C07D413/06 ,  A61K31/4178

CPC classification number: C07D401/06 ,  C07D403/06 ,  C07D413/06

Abstract: The present invention relates to compounds of formula (I) wherein R 1 is hydrogen or lower alkyl; R 2 is hydrogen or lower alkyl; R 3 is hydrogen, lower alkyl, lower alkoxy, phenyloxy, benzyloxy, halogen or lower alkyl substituted by halogen; R 4 is hydrogen or lower alkyl; X is -CH 2 -, -CH- or -O-; Y is -CH 2 -, -CH 2 CH 2 -, -CH- or a bond; when X is -O-, then Y is -CH 2 -; Z is -CH 2 - or -CH-; m is 1 or 2; when m is 2, R 2 may be the same or not; n is 1 or 2; when n is 2, R 3 may be the same or not; and to pharmaceutically acceptable acid addition salts. It has been found that the compounds of formula I have a good affinity to the trace amine associated receptors (TAARs), especially for TAAR1. The compounds may be used for the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.

Abstract translation: 本发明涉及式（I）的化合物，其中R 1为氢或低级烷基; R 2是氢或低级烷基; R 3是氢，低级烷基，低级烷氧基，苯氧基，苄氧基，卤素或被卤素取代的低级烷基; R 4是氢或低级烷基; X是-CH 2 - ， - CH-或-O-; Y是-CH 2 - ， - CH 2 CH 2 - ， - CH-或键; 当X是-O-时，则Y是-CH 2 - ; - Z为-CH 2 - 或-CH-; m是1或2; 当m是2时，R 2可以相同或不相同; n是1或2; 当n是2时，R 3可以相同或不同; 并涉及药学上可接受的酸加成盐。 已经发现式I化合物对痕量胺相关受体（TAAR）具有良好的亲和力，特别是对于TAAR1。 该化合物可用于治疗抑郁症，焦虑症，双相性精神障碍，注意力缺陷多动障碍（ADHD），压力相关障碍，精神障碍如精神分裂症，神经疾病如帕金森病，神经变性障碍如阿尔茨海默病， 癫痫症，偏头痛，高血压，药物滥用和代谢障碍例如进食障碍，糖尿病，糖尿病并发症，肥胖症，血脂异常，能量消耗和同化障碍，体温平衡紊乱和障碍，睡眠和昼夜节律紊乱以及心血管疾病

公开(公告)号：WO2007085557A3

公开(公告)日：2007-09-20

申请号：PCT/EP2007050443

申请日：2007-01-17

Applicant: HOFFMANN LA ROCHE ,  GALLEY GUIDO ,  GROEBKE ZBINDEN KATRIN ,  HOENER MARIUS ,  KOLCZEWSKI SABINE ,  NORCROSS ROGER ,  STALDER HENRI

Inventor： GALLEY GUIDO ,  GROEBKE ZBINDEN KATRIN ,  HOENER MARIUS ,  KOLCZEWSKI SABINE ,  NORCROSS ROGER ,  STALDER HENRI

IPC: A61K31/4164 ,  A61K31/4174 ,  A61P25/00 ,  C07D233/06 ,  C07D233/54 ,  C07D401/04 ,  C07D405/06 ,  C07D409/06

CPC classification number: C07D233/06 ,  A61K31/4164 ,  A61K31/4178 ,  C07D233/20 ,  C07D233/22 ,  C07D233/56 ,  C07D233/64 ,  C07D401/10 ,  C07D403/06 ,  C07D405/06 ,  C07D409/06

Abstract: The present invention relates to the use of compounds of Formula (I), wherein R is hydrogen, tritium, hydroxy, amino, lower alkyl, cycloalkyl, lower alkoxy, halogen, cyano, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, phenyl, O-phenyl, -S-phenyl, optionally substituted by halogen, or is benzyl, benzyloxy, NHC(O)-lower alkyl or pyridin-2,3 or 4-yl; R 1 is hydrogen, hydroxy or lower alkyl; R 2 is hydrogen or lower alkyl; aryl is an aromatic group, selected from phenyl, naphthalen-1-yl or naphthalen-2-yl; hetaryl is an aromatic group, containing at least one O, N or S ring atom, selected from the group consisting of pyridine-3-yl, pyrazolyl, benzofuran-3-yl, benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl, benzofuran-7-yl, thiophen-2-yl, thiophen-3-yl, benzo[b]thiophen-3-yl or indol-3-yl; n is 1, 2, 3, 4 or 5; when n is 2, 3, 4 or 5, R may be the same or not; the dotted line may be a bond or not; and to their pharmaceutically active salts for the preparation of medicaments for the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder, stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.

Abstract translation: 本发明涉及式（I）化合物的用途，其中R是氢，氚，羟基，氨基，低级烷基，环烷基，低级烷氧基，卤素，氰基，被卤素取代的低级烷基， 苯基，O-苯基，-S-苯基，任选被卤素取代，或者是苄基，苄氧基，NHC（O） - 低级烷基或吡啶-2,3或4-基; R 1是氢，羟基或低级烷基; R 2是氢或低级烷基; 芳基是选自苯基，萘-1-基或萘-2-基的芳族基团; 杂芳基是含有至少一个O，N或S环原子的芳族基团，其选自吡啶-3-基，吡唑基，苯并呋喃-3-基，苯并呋喃-4-基，苯并呋喃-5-基， 苯并呋喃-6-基，苯并呋喃-7-基，噻吩-2-基，噻吩-3-基，苯并[b]噻吩-3-基或吲哚-3-基; n是1,2,3,4或5; 当n为2,3,4或5时，R可以相同或不同; 虚线可能是债券或不是; 及其药物活性盐在制备用于治疗抑郁症，焦虑症，双相性精神障碍，注意力缺陷多动障碍，压力相关障碍，精神障碍如精神分裂症，神经疾病如帕金森病，神经变性病症例如 阿尔茨海默病，癫痫，偏头痛，高血压，物质滥用和代谢障碍，例如进食障碍，糖尿病，糖尿病并发症，肥胖症，血脂异常，能量消耗和同化障碍，体温平衡紊乱和功能障碍，睡眠和昼夜节律紊乱， 和心血管疾病。

公开(公告)号：WO2007020190A1

公开(公告)日：2007-02-22

申请号：PCT/EP2006/064935

申请日：2006-08-02

Applicant: F. HOFFMANN-LA ROCHE AG ,  FLOHR, Alexander ,  GALLEY, Guido ,  JAKOB-ROETNE, Roland ,  KITAS, Eric Argirios ,  WOSTL, Wolfgang

Inventor： FLOHR, Alexander ,  GALLEY, Guido ,  JAKOB-ROETNE, Roland ,  KITAS, Eric Argirios ,  WOSTL, Wolfgang

IPC: C07D223/12 ,  C07D413/12 ,  C07D401/12 ,  C07D403/12 ,  C07D409/14 ,  A61K31/55 ,  A61P25/28 ,  A61P35/00

CPC classification number: C07D409/14 ,  C07D223/12 ,  C07D401/12 ,  C07D403/12 ,  C07D413/12

Abstract: The invention relates to compounds of general formula (I), wherein R 1 is lower alkyl substituted by halogen, or is aryl or heteroaryl, unsubstituted or substituted by halogen; R 2 is heterocycloalkyl, aryl or heteroaryl, which are unsubstituted or substituted by one or more substituents, selected from the group consisting of halogen, lower alkyloxy, lower alkyl substituted by halogen, O-lower alkyl substituted by halogen or are substituted by C(O)-NR" 2 , (CR 2 )m-C(O)-R’ heteroaryl or S(O) 2 -lower alkyl; R 3 /R 3’ , R 4 /R 4’ and R 5 /R5’ are independently from each other hydrogen or fluoro, wherein at least one of R4/R4’ or R 5 /R 5’ is always fluoro; R' is aryl or hydroxy; R" is hydrogen, cycloalkyl or is heterocycloalkyl; R is hydrogen or lower alkyl; m is 0, 1, 2 or 3; and to pharmaceutically suitable acid addition salts, optically pure enantiomers, racemates or diastereomeric mixtures thereof. It has been found that the compounds of general formula (I) are γ-secretase inhibitors and the related compounds may be useful in the treatment of Alzheimer's disease or common cancers including but not limited to cervical carcinomas and breast carcinomas and malignancies of the hematopoietic system.

Abstract translation: 本发明涉及通式（I）的化合物，其中R 1为被卤素取代的低级烷基，或未取代或被卤素取代的芳基或杂芳基; R 2是未取代的或被一个或多个选自以下的取代基取代的杂环烷基，芳基或杂芳基：卤素，低级烷氧基，被卤素取代的低级烷基，被 卤素或被C（O）-NR“2取代，（CR 2）m C（O）-R'杂芳基或S（O） /低级烷基; R 3，R 3，R 3，R 4，R 4，R 4， R 5 / R 5'或R 5'或R 5'中的至少一个独立地为氢或氟，其中R 4 / R 4'或R 5' 总是氟; R'是芳基或羟基; R“是氢，环烷基或杂环烷基; R是氢或低级烷基; m为0,1,2或3; 以及药学上合适的酸加成盐，旋光纯对映异构体，外消旋体或非对映体混合物。 已经发现通式（I）的化合物是γ-分泌酶抑制剂，相关化合物可用于治疗阿尔茨海默病或常见癌症，包括但不限于宫颈癌和乳腺癌以及造血系统的恶性肿瘤 。

公开(公告)号：WO2015165085A1

公开(公告)日：2015-11-05

申请号：PCT/CN2014/076623

申请日：2014-04-30

Applicant: F.HOFFMANN-LA ROCHE AG ,  NORCROSS, Roger ,  GALLEY, Guido ,  CECERE, Giuseppe ,  PFLIEGER, Philippe ,  SHEN, Hong ,  HU, Yimin

Inventor： NORCROSS, Roger ,  GALLEY, Guido ,  CECERE, Giuseppe ,  PFLIEGER, Philippe ,  SHEN, Hong ,  HU, Yimin

IPC: C07D413/04 ,  C07D413/14 ,  A61K31/5377 ,  A61P25/22 ,  A61P25/24 ,  A61P25/18 ,  A61P25/16 ,  A61P25/28 ,  A61P3/00 ,  A61P3/04 ,  A61P3/10 ,  A61P9/00 ,  A61P9/12

CPC classification number: C07D413/04 ,  C07D413/12 ,  C07D413/14

Abstract: The present invention relates to compounds of formula (I), wherein X is CH or N; L is a bond, -C(O)- or -C(O)NH-; Ar is phenyl or a five or six membered heteroaryl group, containing one or two N atoms; R 1 is halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen or cycloalkyl; n is 0, 1, 2 or 3; or to a pharmaceutically suitable acid addition salt thereof, to all racemic mixtures,all their corresponding enantiomers and/or optical isomers, which may be used for the treatment of depression, anxiety disorders, bipolar disorder,attention deficit hyperactivity disorder (ADHD), stress-related disorders, psychotic disorders, schizophrenia, neurological diseases, Parkinson's disease, neurodegenerative disorders, Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse, metabolic disorders, eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.

Abstract translation: 本发明涉及式（I）化合物，其中X为CH或N; L是键，-C（O） - 或-C（O）NH-; Ar是苯基或含有一个或两个N原子的五或六元杂芳基; 卤素，低级烷基，被卤素取代的低级烷基，低级烷氧基，被卤素或环烷基取代的低级烷氧基; n为0,1,2或3; 或其药学上合适的酸加成盐，可用于所有外消旋混合物，其所有相应的对映体和/或光学异构体，其可用于治疗抑郁症，焦虑障碍，双相情感障碍，注意力缺陷多动障碍（ADHD），应激 相关疾病，精神病，精神分裂症，神经系统疾病，帕金森病，神经变性疾病，阿尔茨海默氏病，癫痫，偏头痛，高血压，物质滥用，代谢紊乱，进食障碍，糖尿病，糖尿病并发症，肥胖，血脂异常，能量障碍， 同化，紊乱和体温平衡失调，睡眠障碍和昼夜节律，以及心血管疾病。

公开(公告)号：WO2012168265A1

公开(公告)日：2012-12-13

申请号：PCT/EP2012/060637

申请日：2012-06-06

Applicant: F. HOFFMANN-LA ROCHE AG ,  GALLEY, Guido ,  NORCROSS, Roger ,  PFLIEGER, Philippe

Inventor： GALLEY, Guido ,  NORCROSS, Roger ,  PFLIEGER, Philippe

IPC: C07D265/30 ,  C07D401/12 ,  C07D413/12 ,  C07D413/14 ,  A61K31/4245 ,  A61P25/00

CPC classification number: C07D413/14 ,  C07D265/30 ,  C07D401/12 ,  C07D413/12

Abstract: The present invention relates to compounds of formula (I) wherein R 1 is hydrogen, halogen, cyano, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen or C(O)NH 2 , or is phenyl optionally substituted by halogen, cyano or lower alkoxy substituted by halogen, or is 2,2-difluorobenzo[d][1,3]dioxol-5-yl, or is 6-(trifluoromethyl)pyrazin-2-yl or 5-(trifluoromethyl)pyrazin-2-yl or is 6-(trifluoromethyl)pyrimidin-4-yl, or is 6- (trifluoromethyl)pyridin-3-yl, or is 5-cyanopyrazin-2-yl or is 2- (trifluoromethyl)pyrimidin-4-yl; n is 1 or 2 R 2 is halogen, lower alkyl or cyano and R 3 is hydrogen, or R 2 is hydrogen and R3 is halogen, lower alkyl or cyano; X is a bond, -NR'-, -CH 2 NH- or -CHR'-; R' is hydrogen or lower alkyl; Z is a bond, -CH 2 - or -O-; Ar is phenyl or is heteroaryl, selected from the group consisting of 1H-indazole-3yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, pyrimidine-5-yl, lH-pyrazole-3-yl, 1H- pyrazole-4-yl or lH-pyrazole-5-yl; or to a pharmaceutically suitable acid addition salt thereof, which may be used for the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, psychotic disorders, schizophrenia, neurological diseases, Parkinson's disease, neurodegenerative disorders, Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse, metabolic disorders, eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.

Abstract translation: 本发明涉及式（I）化合物，其中R 1是氢，卤素，氰基，低级烷基，被卤素取代的低级烷基，低级烷氧基，被卤素或C（O）NH 2取代的低级烷氧基） 卤素，氰基或被卤素取代的低级烷氧基，或是2,2-二氟苯并[d] [1,3]间二氧杂环戊烯-5-基，或是6-（三氟甲基）吡嗪-2-基或5-（三氟甲基）吡嗪 或是6-（三氟甲基）嘧啶-4-基，或是6-（三氟甲基）吡啶-3-基，或是5-氰基吡嗪-2-基或是2-（三氟甲基）嘧啶-4-基 - 基; n为1或2，R2为卤素，低级烷基或氰基，R3为氢，R2为氢，R3为卤素，低级烷基或氰基; X是键，-NR' - ， - CH 2 NH-或-CHR' - ; R'是氢或低级烷基; Z是键，-CH 2 - 或-O-; Ar是苯基或是杂芳基，其选自1H-吲唑-3-基，吡啶-2-基，吡啶-3-基，吡啶-4-基，嘧啶-5-基，1H-吡唑-3-基 ，1H-吡唑-4-基或1H-吡唑-5-基; 或其药学上合适的酸加成盐，其可用于治疗抑郁症，焦虑障碍，双相情感障碍，注意缺陷多动障碍（ADHD），应激相关障碍，精神病性障碍，精神分裂症，神经系统疾病，帕金森病， 神经变性疾病，阿尔茨海默病，癫痫，偏头痛，高血压，药物滥用，代谢紊乱，进食障碍，糖尿病，糖尿病并发症，肥胖症，血脂异常，能量消耗和同化障碍，体温平衡失调和失调，睡眠和昼夜节律 节律和心血管疾病。