5-HT2C RECEPTOR AGONISTS AND COMPOSITIONS AND METHODS OF USEThe present invention relates to compounds of Formula A and pharmaceutical compositions thereof that modulate the activity of the 5-HT2C receptor. Compounds of the present invention and pharmaceutical compositions thereof are directed to methods useful in the treatment of a 5-HT2C receptor-mediated disorder, such as, weight management, inducing satiety, and decreasing food intake, and for preventing and treating obesity, antipsychotic-induced weight gain, type 2 diabetes, Prader-Willi syndrome, tobacco/nicotine dependence, drug addiction, alcohol addiction and the like, obsessive-compulsive spectrum disorders and impulse control disorders (including nail-biting and onychophagia), sleep disorders, urinary incontinence, psychiatric disorders (including schizophrenia, anorexia nervosa, and bulimia nervosa), Alzheimer disease, sexual dysfunction, erectile dysfunction, epilepsy, movement disorders (including parkinsonism and antipsychotic-induced movement disorder), hypertension, dyslipidemia, nonalcoholic fatty liver disease, obesity-related renal disease, and sleep apnea. Also provided are compositions comprising a compound herein, optionally in combination with a supplemental agent.A compound selected from compounds of Formula A, and pharmaceutically acceptable salts, solvates, and hydrates thereof:Formula Awhereinn is 1 or 2;each of R6, R7, and R8 is independently selected from hydrogen and C1-C6 alkyl; R9 is hydrogen or C1-C6 alkyl;X2 is N or CR2;X3 is N or CR3;X4 is N or CR4;wherein each of R1, R2, R3, and R4 is independently selected from:a) hydrogen;b) C1-C6 alkyl optionally substituted with one or more groups each independently selected from:C6-C10 aryl optionally substituted with halogen;C1-C6 alkoxy optionally substituted with 3- to 8-membered heterocycloalkyl;C3-C8 cycloalkyl;OH;CN;3- to 8-membered heterocycloalkyl;5- to 10-membered heteroaryl; andhalogen;c) C2-C6 alkenyl;d) C3-C8 cycloalkyl;e) 5- to 10-membered heteroaryl optionally substituted with halogen;f) C6-C10 aryl optionally substituted with one or more groups each independently selected from halogen, C1-C6 alkoxy optionally substituted with halogen, and C1-C6 alkyl optionally substituted with halogen,wherein the C6-C10 aryl is optionally fused to a heterocyclic ring;g) CONHC1-C6 alkyl optionally substituted with halogen; h) NH(CO)R5, wherein R5 is selected from C1-C6 alkoxy, C1-C6 alkyl optionally substituted with C6-C10 aryl, C6-C10 aryl optionally substituted with halogen, 3- to 8-membered heterocycloalkyl, and C3-C8 cycloalkyl;i) halogen; andj) C1-C6 alkylthio;wherein at least one but not more than two of X2, X3 and X4 are N, and either(i) only one of X2, X3 and X4 is N and at least one of R1, R2, R3, and R4 is hydrogen; or (ii) only X2 and X4 are N. 2. The compound of claim 1, wherein n is 1. 3. The compound of claim 1, wherein n is 2. 4. The compound of any one of claims 1 to 3, wherein R1 is hydrogen. 5. The compound of any one of claims 1 to 3, wherein R1 is C1-C6 alkyl. 6. The compound of any one of claims 1 to 3, wherein R1 is C1-C6 alkyl substituted with C6-C10 aryl, C6-C10 aryl that is substituted with halogen, C1-C6 alkoxy, C1-C6 alkoxy that is substituted with 3- to 8-membered heterocycloalkyl, C3-C8 cycloalkyl¸ OH, CN, 3- to 8-membered heterocycloalkyl, 5- to 10-membered heteroaryl, or halogen. 7. The compound of any one of claims 1 to 3, wherein R1 is C6-C10 aryl optionally substituted with one or more groups each independently selected from halogen, C1-C6 alkoxy optionally substituted with halogen, and C1-C6 alkyl optionally substituted with halogen, wherein the C6- C10 aryl is optionally fused to a heterocyclic ring. 8. The compound of any one of claims 1 to 3, wherein R1 is CONHC1-C6 alkyl, CONHC1-C6 alkyl substituted with halogen, halogen, or C1-C6 alkylthio. 9. The compound of any one of claims 1 to 3, wherein R1 is NH(CO)R5, wherein R5 is selected from the group consisting of: C1-C6 alkoxy, C1-C6 alkyl optionally substituted with C6-C10 aryl, C6-C10 aryl optionally substituted with halogen, 3- to 8-membered heterocycloalkyl, and C3-C8 cycloalkyl. 10. The compound of any one of claims 1 to 3, wherein R1 is selected from the group consisting of: benzo[d][1,3]dioxol-5-yl, methylcarbamoyl, hydrogen, 2-chlorobenzamido, 3- (trifluoromethoxy)phenyl, benzyl, 2-methoxyethyl, pentyl, pentan-2-yl, ethyl, isopropyl, butyl, propyl, isobutyl, 3-fluorobenzyl, 2-fluorobenzyl, methyl, isopentyl, methoxymethyl, cyclohexylmethyl, neopentyl, cyclobutyl(hydroxy)methyl, (ethoxycarbonyl)amino, 2- phenylacetamido, butyramido, thiophen-2-yl, cyclohexyl, 4-fluorobenzyl, pyrrolidine-1- carboxamido, (tetrahydro-2H-pyran-2-yl)methyl, ((tetrahydro-2H-pyran-4-yl)methoxy)methyl, 2-(trifluoromethyl)phenyl, 4-methoxyphenyl, bromo, cyclobutylmethyl, 2,3- difluorobenzamido, benzamido, (2,2-difluoroethyl)carbamoyl, cyclopropanecarboxamido, 2- cyanoethyl, pyridin-2-ylmethyl, but-2-en-1-yl, isopropoxymethyl, 5-chloropyridin-2-yl, cyclopentyl, cyclobutyl, chloro, cyclopropyl, 3,3,3-trifluoropropyl, phenethyl, and cyclopentylmethyl. 11. The compound of any one of claims 1 to 10, wherein X2 is CR2. 12. The compound of any one of claims 1 to 10, wherein X2 is CR2 and R2 is selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 alkyl substituted with C6-C10 aryl, C1-C6 alkyl substituted with C1-C6 alkoxy, C1-C6 alkyl substituted with C3-C8 cycloalkyl, C1-C6 alkyl substituted with 3- to 8-membered heterocycloalkyl, C3-C8 cycloalkyl, halogen, or C1-C6 alkylthio. 13. The compound of any one of claims 1 to 10, wherein X2 is CR2 and R2 is selected from the group consisting of: hydrogen, propyl, benzyl, 2-cyanoethyl, isopropoxymethyl,cyclohexylmethyl, (tetrahydro-2H-pyran-2-yl)methyl, cyclobutyl, chloro, andcyclopentylmethyl. 14. The compound of any one of claims 1 to 13, wherein X3 is CR3. 15. The compound of any one of claims 1 to 13, wherein X3 is CR3 and R3 is hydrogen or C1-C6 alkylthio. 16. The compound of any one of claims 1 to 13, wherein X3 is CR3 and R3 is selected from the group consisting of: hydrogen and methylthio. 17. The compound of any one of claims 1 to 16, wherein X4 is CR4. 18. The compound of any one of clai...
5-HT2C 수용체 효능제 및 조성물 및 사용 방법본 발명은 화학식 A의 화합물 및 5-HT2C수용체의 활성을 조절하는 이의 약학 조성물에 관한 것이다. 화학식 A 본 발명의 화합물 및 이의 약학 조성물은 5-HT2C 수용체-매개 장애의 치료, 예컨대, 체중 관리, 포만감 유도, 및 식품 섭취 감소, 비만, 항정신병제-유발 체중 증가, 제2형 당뇨병, 프레더-윌리 증후군, 담배/니코틴 의존, 약물 중독, 알콜 중독 등의 예방 및 치료, 강박 스펙트럼 장애 및 충동 조절 장애(손톱 물어뜯기 및 교조증 포함), 수면 장애, 요실금, 정신 장애(정신분열증, 신경성 식욕부진 및 신경성 폭식증 포함), 알츠하이머병, 성 기능 장애, 발기 부전, 간질, 운동 장애(파킨슨병 및 항정신병제-유발 운동 장애 포함), 고혈압, 이상지혈증, 비알콜성 지방간 질환, 비만-관련 신장 질환, 및 수면 무호흡의 치료에 유용한 방법에 관한 것이다. 또한 선택적으로 보충제와 조합되어 사용되는, 본원에서 제공된 화합물을 포함하는 조성물이 제공된다.화학식 A의 화합물, 및 이의 약학적으로 허용되는 염, 용매화물, 및 수화물로부터 선택되는 화합물:화학식 A여기서,n은 1 또는 2이고; 각각의 R6, R7, 및 R8은 수소 및 C1-C6 알킬로부터 독립적으로 선택되고;R9는 수소 또는 C1-C6 알킬이고; X2는 N 또는 CR2이고;X3은 N 또는 CR3이고;X4는 N 또는 CR4이고;여기서, 각각의 R1, R2, R3, 및 R4는 각각 독립적으로 다음으로부터 선택된다:a) 수소; b) 각각 독립적으로 다음으로부터 선택된 하나 이상의 기로 선택적으로 치환된 C1-C6 알킬: 할로겐으로 선택적으로 치환된 C6-C10 아릴;3- 내지 8-원 헤테로사이클로알킬로 선택적으로 치환된 C1-C6 알콕시;C3-C8 사이클로알킬;OH;CN;3- 내지 8-원 헤테로사이클로알킬;5- 내지 10-원 헤테로아릴; 및할로겐; c) C2-C6 알케닐;d) C3-C8 사이클로알킬;e) 할로겐으로 선택적으로 치환된 5- 내지 10-원 헤테로아릴; f) 할로겐, 할로겐으로 선택적으로 치환된 C1-C6 알콕시, 및 할로겐으로 선택적으로 치환된 C1-C6 알킬로부터 각각 독립적으로 선택된 하나 이상의 기로 선택적으로 치환된 C6-C10 아릴,여기서, C6-C10 아릴은 헤테로사이클릭 고리와 선택적으로 융합됨; g) 할로겐으로 선택적으로 치환된 CONHC1-C6 알킬;h) NH(CO)R5, 여기서, R5는 C1-C6 알콕시, C6-C10 아릴로 선택적으로 치환된 C1-C6 알킬, 할로겐으로 선택적으로 치환된 C6-C10 아릴, 3- 내지 8-원 헤테로사이클로알킬, 및 C3-C8 사이클로알킬로부터 선택됨;i) 할로겐; 및j) C1-C6 알킬티오;여기서, X2, X3 및 X4 중 2개를 초과하지 않는 적어도 하나는 N이고, (i) X2, X3 및 X4 중 오직 하나만이 N이고 R1, R2, R3, 및 R4 중 적어도 하나가 수소이거나; (ii) 오직 X2 및 X4만이 N이다.