TW201818964A

TW201818964A - Methods of using tryptophan hydroxylase inhibitors

Info

Publication number: TW201818964A
Application number: TW106133695A
Authority: TW
Inventors: 維敘瓦斯帕拉卡爾; 羅伯特 J 愛羅
Original assignee: 瑞士商諾伊曼特醫療公司
Priority date: 2016-09-30
Filing date: 2017-09-29
Publication date: 2018-06-01
Also published as: WO2018060949A1

Abstract

The present disclosure is directed to the treatment or prevention of liver diseases such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma using compounds which are inhibitors of tryptophan hydroxylase 1 (TPH1).

Description

Method of using tryptophan hydroxylase inhibitor

本發明係針對使用為色胺酸羥化酶1 (TPH1)抑制劑之化合物或其前藥治療或預防肝病，諸如非酒精性脂肪肝病(NAFLD)、非酒精性脂肪變性肝炎(NASH)及肝細胞癌。The present invention is directed to the use of a compound which is a tryptophan hydroxylase 1 (TPH1) inhibitor or a prodrug thereof for the treatment or prevention of liver diseases such as nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatosis hepatitis (NASH) and liver Cellular cancer.

諸如非酒精性脂肪肝病(NAFLD)之肝病表徵為無酒精史存在下有或無發炎及纖維化情況下肝脂肪變性存在。NAFLD包括非酒精性脂肪肝(non-alcoholic fatty liver，NAFL)及非酒精性脂肪變性肝炎(NASH)。根據the National Heath Instistute，NASH影響約2至5%的美國人。NASH可存在於幾乎不飲用或不飲用酒精的人中，且通常為幾乎沒有症狀或沒有症狀的無症狀病。NASH可藉由為非正常的肝中有脂肪以及發炎及損傷表徵。儘管患有NASH的一些人可感覺正常，但NASH可能變得嚴重且導致纖維化及肝硬化，其中肝永久受損且有疤痕。舉例而言，由NASH相關之肝硬化引起的患病或受損肝組織可能最終導致肝細胞癌。血清素(5-羥色胺，5-HT)為藉由對神經元、平滑肌及其他細胞類型起作用來調節中樞及周邊功能的神經傳遞素。5-HT與控制及調節多個生理及心理過程有關。周邊5-HT傳訊系統之調節異常已報導為與數種病況之病源學有關，諸如發炎(例如Margolis, K. G.等人Pharmacological Reduction of Mucosal but Not Neuronal Serotonin Opposes Inflammation In Mouse Intestine.Gut doi:10.1136/gutjnl-2013-304901 (2013)；Duerschmied, D.等人Platelet Serotonin Promotes The Recruitment Of Neutrophils To Sites Of Acute Inflammation In Mice.Blood 121 , 1008-15 (2013)；Li, N.等人Serotonin Activates Dendritic Cell Function In The Context Of Gut Inflammation.The American Journal of Pathology 178 , 662-71 (2011))，及肝病或失調(例如Ebrahimkhani, M. R.等人Stimulating Healthy Tissue Regeneration By Targeting The 5-HT2B Receptor In Chronic Liver Disease.Nature Medicine 17 , 1668-73 (2011))。亦參見Nocito, A.等人Gastroenterology 2007, 133,第608-618頁；Watanabe, H.等人Endocrinology , 2010年十月, 151(10): 4776-4786；及Crane, J.D.等人Nature Medicine 21(2), 166-172 (2015)。已識別色胺酸羥化酶(TPH)之兩種脊椎動物同功異型物，即TPH1及TPH2。TPH1主要表現於松果體腺及非神經元組織，諸如位於腸胃(gastrointestinal，GI)道中之腸親鉻(enterochromaffin，EC)細胞中。TPH2 (大腦中之主要形式)獨佔地表現於神經元細胞，諸如中縫背(dorsal raphe)或腸肌叢(myenteric plexus)細胞中。分離與5-HT生物合成有關之周邊及中樞系統，其中5-HT不能穿過血腦障壁。因此，5-HT之藥理效應可藉由影響周邊中之TPH，主要影響腸中之TPH1的藥劑來調節。已提出增加之5-HT藉由多種機理影響肝之病理生理學。舉例而言，脂質之積聚可能使肝對與NASH相關之病理生理學敏感；5-HT之肝氧化可能產生引起粒線體功能障礙之脂質過氧化物及ROS；且由5-HT受體結合及TGFβ信號傳遞介導之促纖維變性及細胞分裂活性導致纖維化。需要治療諸如NAFLD、NASH及肝細胞癌的肝病之新穎療法。採用TPH1抑制劑之本文所描述之方法意欲解決此需要。Liver disease such as nonalcoholic fatty liver disease (NAFLD) is characterized by the presence of hepatic steatosis in the presence or absence of inflammation and fibrosis in the absence of alcohol. NAFLD includes non-alcoholic fatty liver (NAFL) and nonalcoholic steatosis hepatitis (NASH). According to the National Heath Instistute, NASH affects approximately 2 to 5% of Americans. NASH can be present in people who drink little or no alcohol and are usually asymptomatic with few or no symptoms. NASH can be characterized by fat, inflammation, and damage to the abnormal liver. Although some people with NASH may feel normal, NASH may become severe and cause fibrosis and cirrhosis, where the liver is permanently damaged and scarred. For example, diseased or damaged liver tissue caused by NASH-associated cirrhosis may eventually lead to hepatocellular carcinoma. Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that regulates central and peripheral functions by acting on neurons, smooth muscle, and other cell types. 5-HT is involved in the control and regulation of multiple physiological and psychological processes. Abnormalities in the regulation of peripheral 5-HT signaling systems have been reported to be associated with the etiology of several conditions, such as inflammation (eg Margolis, KG et al. Pharmacological Reduction of Mucosal but Not Neuronal Serotonin Opposes Inflammation In Mouse Intestine. Gut doi: 10.1136/gutjnl -2013-304901 (2013); Duerschmied, D. et al. Platelet Serotonin Promotes The Recruitment Of Neutrophils To Sites Of Acute Inflammation In Mice. Blood 121 , 1008-15 (2013); Li, N. et al. Serotonin Activated Dendritic Cell Function In The Context Of Gut Inflammation. The American Journal of Pathology 178 , 662-71 (2011)), and liver disease or disorders (eg Ebrahimkhani, MR et al. Stimulating Healthy Tissue Regeneration By Targeting The 5-HT2B Receptor In Chronic Liver Disease. Nature Medicine 17 , 1668-73 (2011)). See also Nocito, A. et al. Gastroenterology 2007, 133, pp. 608-618; Watanabe, H. et al., Endocrinology, 2010 In October 151 (10): 4776-4786; and Crane, JD et al., Nature Medicine 21 (2), 166-172 (2015). Two vertebrate isoforms of tryptophan hydroxylase (TPH) have been identified, namely TPH1 and TPH2. TPH1 is mainly expressed in the pineal gland and non-neuronal tissues, such as enterochromaffin (EC) cells located in the gastrointestinal (GI) tract. TPH2 (the predominant form in the brain) is exclusively present in neuronal cells, such as dorsal raphe or myenteric plexus cells. Peripheral and central systems associated with 5-HT biosynthesis are isolated in which 5-HT does not cross the blood-brain barrier. Therefore, the pharmacological effect of 5-HT can be regulated by an agent that affects TPH in the periphery and mainly affects TPH1 in the intestine. It has been suggested that the increased 5-HT affects the pathophysiology of the liver by a variety of mechanisms. For example, accumulation of lipids may make the liver sensitive to the pathophysiology associated with NASH; hepatic oxidation of 5-HT may produce lipid peroxides and ROS that cause mitochondrial dysfunction; and is bound by 5-HT receptors. And the promotion of fibrosis and cell division activity mediated by TGFβ signaling leads to fibrosis. There is a need for novel therapies for the treatment of liver diseases such as NAFLD, NASH and hepatocellular carcinoma. The methods described herein using TPHl inhibitors are intended to address this need.

本發明係關於治療或預防患者中之諸如非酒精性脂肪肝病(NAFLD)、非酒精性脂肪變性肝炎(NASH)及肝細胞癌之肝病的方法，該等方法包含向患者投與治療有效量之TPH1抑制劑或其前藥。本發明亦關於減少患者中之丙胺酸轉胺酶(ALT)、天冬胺酸轉胺酶(AST)、膽固醇、三酸甘油酯或葡萄糖之方法，該等方法包含向患者投與治療有效量之TPH1抑制劑或其前藥。本發明亦關於減少患者之肝中之脂質沈積物的方法，該等方法包含向患者投與治療有效量之TPH1抑制劑或其前藥。本發明進一步關於TPH1抑制劑或其前藥，其用於治療或預防患者中之肝病，諸如非酒精性脂肪肝病(NAFLD)、非酒精性脂肪變性肝炎(NASH)及肝細胞癌。本發明進一步關於TPH1抑制劑或其前藥在治療或預防患者中之諸如非酒精性脂肪肝病(NAFLD)、非酒精性脂肪變性肝炎(NASH)及肝細胞癌之肝病中的用途。本發明進一步關於TPH1抑制劑或其前藥用於製備藥劑之用途，該藥劑用於治療或預防患者中之諸如非酒精性脂肪肝病(NAFLD)、非酒精性脂肪變性肝炎(NASH)及肝細胞癌之肝病。The present invention relates to a method for treating or preventing liver diseases such as nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatosis hepatitis (NASH) and hepatocellular carcinoma in a patient, the method comprising administering to the patient a therapeutically effective amount TPH1 inhibitor or a prodrug thereof. The invention also relates to a method of reducing alanine transaminase (ALT), aspartate transaminase (AST), cholesterol, triglyceride or glucose in a patient, the method comprising administering to the patient a therapeutically effective amount A TPH1 inhibitor or a prodrug thereof. The invention also relates to methods of reducing lipid deposits in the liver of a patient, the methods comprising administering to the patient a therapeutically effective amount of a TPHl inhibitor or a prodrug thereof. The present invention further relates to a TPHl inhibitor or a prodrug thereof for use in the treatment or prevention of liver diseases in a patient, such as nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatosis hepatitis (NASH), and hepatocellular carcinoma. The invention further relates to the use of a TPHl inhibitor or a prodrug thereof for the treatment or prevention of liver diseases such as nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatosis hepatitis (NASH) and hepatocellular carcinoma in a patient. The invention further relates to the use of a TPHl inhibitor or a prodrug thereof for the preparation of a medicament for the treatment or prevention of non-alcoholic fatty liver disease (NAFLD), nonalcoholic steatosis hepatitis (NASH) and hepatocytes in a patient Liver disease of cancer.

本發明係關於治療或預防患者中之諸如非酒精性脂肪肝病(NAFLD)、非酒精性脂肪變性肝炎(NASH)及肝細胞癌之肝病的方法，該等方法包含向該患者投與治療有效量之TPH抑制劑，諸如TPH1抑制劑或其前藥。在一些實施例中，疾病為NAFLD。在一些實施例中，疾病為NASH。在一些實施例中，疾病為肝細胞癌。本發明亦包括治療或預防患者中之一或多種可與NAFLD、NASH或肝細胞癌相關之疾病或症狀的方法，該等方法包含向患者投與治療有效量之TPH抑制劑，諸如TPH1抑制劑或其前藥。此等疾病或症狀包括例如：發炎、纖維化、肝硬化、疲乏、體重減輕、無力、流體滯留、肌肉萎縮、腸出血、肝臟衰竭、體重增加、肥胖、糖尿病(例如，2型糖尿病或1型糖尿病)、前期糖尿病、脂質失調、升高之血清脂質、升高之血清中之肝酶、升高之膽固醇及升高之三酸甘油酯。本文亦提供減少患者中(例如，患者血清濃度及/或肝中)之丙胺酸轉胺酶(ALT)、天冬胺酸轉胺酶(AST)、膽固醇、三酸甘油酯或葡萄糖之方法，該等方法包含向患者投與治療有效量之TPH抑制劑，諸如TPH1抑制劑或其前藥。在一些實施例中，本文所提供之方法亦包括減少患者肝中之脂質沈積物，該等方法包含投與治療有效量之TPH抑制劑，諸如TPH1抑制劑或其前藥。在一些實施例中，該方法為降低患者血清或肝中之ALT濃度之方法。在一些實施例中，該方法為降低患者血清或肝中之AST濃度之方法。可根據本發明之方法使用的TPH1抑制劑及其對應前藥之實例描述於例如以下中：美國專利公開案第2016/0272655號、第2016/0096836號、第2015/0366865號、第2015/00080393號、第2014/0378489號、第2014/0303197號、第2014/0017677號、第2013/0137635號、第2013/0274261號、第2013/0303763號、第2013/0338176號、第2013/0316924號、第2013/0053343號、第2012/0316171號、第2011/0112094號、第2011/0281899號、第2011/0152220號、第2010/0317664號、第2009/0054308號、第2009/0029993號、第2009/0005382號、第2009/0005381號及第2008/0108077號，以及描述於PCT公開案第WO 2016/109501號及第WO 2016/109501號中，其各者以全文引用之方式併入本文中。可根據本發明之方法使用的實例前藥為酯化合物(S)-8-(2-胺基-6-((R)-1-(5-氯-[1,1'-聯苯]-2-基)-2,2,2-三氟乙氧基)嘧啶-4-基)-2,8-二氮螺[4.5]癸烷-3-羧酸乙酯，其可由患者內部代謝以形成對應酸化合物(S)-8-(2-胺基-6-((R)-1-(5-氯-[1,1'-聯苯]-2-基)-2,2,2-三氟乙氧基)嘧啶-4-基)-2,8-二氮螺[4.5]癸烷-3-羧酸，其為TPH1抑制劑。在一些實施例中，可根據本發明之方法使用之化合物為式I化合物：I 或其醫藥學上可接受之鹽，其中：環A為C₃ _- ₁₀ 環烷基、C₆ _- ₁₀ 芳基、4至10員雜環烷基或5至10員雜芳基； L為O或NR⁴ ； W為N或CR⁵ ； X為N或CR⁶ ； Y為N或CR⁷ ；其中X及Y中之僅一者為N； R¹ 為H、C₁ _- ₁₀ 烷基、C₃ _- ₁₀ 環烷基、4-10員雜環烷基、5-10員雜芳基、苯基、-(CR⁸ R⁹ )_p OC(O)R¹⁰ 、-(CR⁸ R⁹ )_p NR¹¹ R¹² 或-(CR⁸ R⁹ )_p C(O)NR¹¹ R¹² ，其中該C₁ _- ₁₀ 烷基、C₃ _- ₁₀ 環烷基、4-10員雜環烷基、5-10員雜芳基及苯基各自視情況經1、2、3、4或5個獨立地選自F、Cl、Br、CN、C₁ _- ₄ 烷基及C₁ _- ₄ 鹵烷基之取代基取代； R² 及R³ 各自獨立地選自H、C₁ _- ₄ 烷基及C₁ _- ₄ 鹵烷基； R⁴ 為H或C₁ _- ₄ 烷基； R⁵ 及R⁶ 各自獨立地選自H、鹵基及C₁ _- ₄ 烷基； R⁷ 為H、C₁ _- ₄ 烷基、C₂ _- ₆ 烯基、C₃ _- ₁₀ 環烷基、C₃ _- ₁₀ 環烷基-C₁ _- ₄ 烷基、C₆ _- ₁₀ 芳基、C₆ _- ₁₀ 芳基-C₁ _- ₄ 烷基、4-10員雜環烷基、(4-10員雜環烷基)-C₁ _- ₄ 烷基、5-10員雜芳基、(5-10員雜芳基)-C₁ _- ₄ 烷基、NR¹³ R¹⁴ 、OR¹⁵ 、C(O)R¹⁶ 、S(O)_q R¹⁷ ，其中該C₁ _- ₄ 烷基、C₂ _- ₆ 烯基、C₃ _- ₁₀ 環烷基、C₃ _- ₁₀ 環烷基-C₁ _- ₄ 烷基、C₆ _- ₁₀ 芳基、C₆ _- ₁₀ 芳基-C₁ _- ₄ 烷基、4-10員雜環烷基、(4-10員雜環烷基)-C₁ _- ₄ 烷基、5-10員雜芳基及(5-10員雜芳基)-C₁ _- ₄ 烷基各自視情況經1、2或3個選自以下之取代基取代：鹵基、C₁ _- ₄ 烷基、C₂ _- ₆ 烯基、胺基、C₁ _- ₄ 烷胺基、C₂ _- ₈ 二烷胺基、羥基及C₁ _- ₄ 烷氧基； R⁸ 及R⁹ 各自獨立地選自H及C₁ _- ₄ 烷基； R¹⁰ 為C₁ _- ₆ 烷基，視情況經1、2或3個獨立地選自以下之取代基取代：C₁ _- ₆ 鹵烷基、C₃ _- ₁₀ 環烷基、OR^a 及NR^c R^d ； R¹¹ 及R¹² 各自獨立地選自H及C₁ _- ₆ 烷基； R¹³ 為H或C₁ _- ₄ 烷基； R¹⁴ 為H、C₁ _- ₄ 烷基、C₃ _- ₇ 環烷基、C₃ _- ₇ 環烷基-C₁ _- ₄ 烷基、C₆ _- ₁₀ 芳基、C₆ _- ₁₀ 芳基-C₁ _- ₄ 烷基、4-10員雜環烷基、(4-10員雜環烷基)-C₁ _- ₄ 烷基、5-10員雜芳基或(5-10員雜芳基)-C₁ _- ₄ 烷基、C(O)R^b1 、C(O)OR^a1 、C(O)NR^c1 R^d1 、S(O)R^b1 、S(O)₂ R^b1 或S(O)₂ NR^c1 R^d1 ，其中該C₁ _- ₄ 烷基、C₃ _- ₇ 環烷基、C₃ _- ₇ 環烷基-C₁ _- ₄ 烷基、C₆ _- ₁₀ 芳基、C₆ _- ₁₀ 芳基-C₁ _- ₄ 烷基、4-10員雜環烷基、(4-10員雜環烷基)-C₁ _- ₄ 烷基、5-10員雜芳基及(5-10員雜芳基)-C₁ _- ₄ 烷基各自視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、C₁ _- ₄ 烷基、C₁ _- ₄ 鹵烷基、CN、NO₂ 、OR^a1 、SR^a1 、C(O)R^b1 、C(O)NR^c1 R^d1 、C(O)OR^a1 、OC(O)R^b1 、OC(O)NR^c1 R^d1 、NR^c1 R^d1 、NR^c1 C(O)R^b1 、NR^c1 C(O)OR^a1 、NR^c1 C(O)NR^c1 R^d1 、NR^c1 S(O)R^b1 、NR^c1 S(O)₂ R^b1 、NR^c1 S(O)₂ NR^c1 R^d1 、S(O)R^b1 、S(O)NR^c1 R^d1 、S(O)₂ R^b1 及S(O)₂ NR^c1 R^d1 ；或R¹³ 及R¹⁴ 連同其所連接之N原子形成視情況經1、2或3個獨立地選自以下之取代基取代的4員、5員、6員或7員雜環烷基：C₁ _- ₆ 烷基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基、5-6員雜芳基、鹵基、CN、OR^a1 、SR^a1 、C(O)R^b1 、C(O)NR^c1 R^d1 、C(O)OR^a1 、OC(O)R^b1 、OC(O)NR^c1 R^d1 、NR^c1 R^d1 、NR^c1 C(O)R^b1 、NR^c1 C(O)NR^c1 R^d1 、NR^c1 C(O)OR^a1 、S(O)R^b1 、S(O)NR^c1 R^d1 、S(O)₂ R^b1 、NR^c1 S(O)₂ R^b1 、NR^c1 S(O)₂ NR^c1 R^d1 及S(O)₂ NR^c1 R^d1 ，其中該C₁ _- ₆ 烷基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基及5-6員雜芳基各自視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、CN、OR^a1 、SR^a1 、C(O)R^b1 、C(O)NR^c1 R^d1 、C(O)OR^a1 、OC(O)R^b1 、OC(O)NR^c1 R^d1 、NR^c1 R^d1 、NR^c1 C(O)R^b1 、NR^c1 C(O)NR^c1 R^d1 、NR^c1 C(O)OR^a1 、S(O)R^b1 、S(O)NR^c1 R^d1 、S(O)₂ R^b1 、NR^c1 S(O)₂ R^b1 、NR^c1 S(O)₂ NR^c1 R^d1 及S(O)₂ NR^c1 R^d1 ； R¹⁵ 為H、C₁ _- ₄ 烷基、C₃ _- ₇ 環烷基、C₃ _- ₇ 環烷基-C₁ _- ₄ 烷基、C₆ _- ₁₀ 芳基、C₆ _- ₁₀ 芳基-C₁ _- ₄ 烷基、4-10員雜環烷基、(4-10員雜環烷基)-C₁ _- ₄ 烷基、5-10員雜芳基或(5-10員雜芳基)-C₁ _- ₄ 烷基，其中該C₁ _- ₄ 烷基、C₃ _- ₇ 環烷基、C₃ _- ₇ 環烷基-C₁ _- ₄ 烷基、C₆ _- ₁₀ 芳基、C₆ _- ₁₀ 芳基-C₁ _- ₄ 烷基、4-10員雜環烷基、(4-10員雜環烷基)-C₁ _- ₄ 烷基、5-10員雜芳基及(5-10員雜芳基)-C₁ _- ₄ 烷基各自視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基、5-6員雜芳基、CN、OR^a1 、SR^a1 、C(O)R^b1 、C(O)NR^c1 R^d1 、C(O)OR^a1 、OC(O)R^b1 、OC(O)NR^c1 R^d1 、NR^c1 R^d1 、NR^c1 C(O)R^b1 、NR^c1 C(O)NR^c1 R^d1 、NR^c1 C(O)OR^a1 、S(O)R^b1 、S(O)NR^c1 R^d1 、S(O)₂ R^b1 、NR^c1 S(O)₂ R^b1 、NR^c1 S(O)₂ NR^c1 R^d1 及S(O)₂ NR^c1 R^d1 ； R¹⁶ 為C₁ _- ₄ 烷基或NR^18a R^18b ，其中該C₁ _- ₄ 烷基視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基、5-6員雜芳基、CN、OR^a1 、SR^a1 、C(O)R^b1 、C(O)NR^c1 R^d1 、C(O)OR^a1 、OC(O)R^b1 、OC(O)NR^c1 R^d1 、NR^c1 R^d1 、NR^c1 C(O)R^b1 、NR^c1 C(O)NR^c1 R^d1 、NR^c1 C(O)OR^a1 、S(O)R^b1 、S(O)NR^c1 R^d1 、S(O)₂ R^b1 、NR^c1 S(O)₂ R^b1 、NR^c1 S(O)₂ NR^c1 R^d1 及S(O)₂ NR^c1 R^d1 ； R¹⁷ 為C₁ _- ₄ 烷基、NR^18a R^18b 或OR^18c ，其中該C₁ _- ₄ 烷基視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基、5-6員雜芳基、CN、OR^a1 、SR^a1 、C(O)R^b1 、C(O)NR^c1 R^d1 、C(O)OR^a1 、OC(O)R^b1 、OC(O)NR^c1 R^d1 、NR^c1 R^d1 、NR^c1 C(O)R^b1 、NR^c1 C(O)NR^c1 R^d1 、NR^c1 C(O)OR^a1 、S(O)R^b1 、S(O)NR^c1 R^d1 、S(O)₂ R^b1 、NR^c1 S(O)₂ R^b1 、NR^c1 S(O)₂ NR^c1 R^d1 及S(O)₂ NR^c1 R^d1 ； R^18a 及R^18b 各自獨立地選自H及C₁ _- ₄ 烷基，其中該C₁ _- ₄ 烷基視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基、5-6員雜芳基、CN、OR^a1 、SR^a1 、C(O)R^b1 、C(O)NR^c1 R^d1 、C(O)OR^a1 、OC(O)R^b1 、OC(O)NR^c1 R^d1 、NR^c1 R^d1 、NR^c1 C(O)R^b1 、NR^c1 C(O)NR^c1 R^d1 、NR^c4 C(O)OR^a1 、S(O)R^b1 、S(O)NR^c1 R^d1 、S(O)₂ R^b1 、NR^c1 S(O)₂ R^b1 、NR^c1 S(O)₂ NR^c1 R^d1 及S(O)₂ NR^c1 R^d1 ；或R^18a 及R^18b 連同其所連接之N原子形成視情況經1、2或3個獨立地選自以下之取代基取代的4員、5員、6員或7員雜環烷基：C₁ _- ₆ 烷基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基、5-6員雜芳基、鹵基、CN、OR^a1 、SR^a1 、C(O)R^b1 、C(O)NR^c1 R^d1 、C(O)OR^a1 、OC(O)R^b1 、OC(O)NR^c1 R^d1 、NR^c1 R^d1 、NR^c1 C(O)R^b1 、NR^c1 C(O)NR^c1 R^d1 、NR^c1 C(O)OR^a1 、S(O)R^b1 、S(O)NR^c1 R^d1 、S(O)₂ R^b1 、NR^c1 S(O)₂ R^b1 、NR^c1 S(O)₂ NR^c1 R^d1 及S(O)₂ NR^c1 R^d1 ，其中該C₁ _- ₆ 烷基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基及5-6員雜芳基各自視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、CN、OR^a1 、SR^a1 、C(O)R^b1 、C(O)NR^c1 R^d1 、C(O)OR^a1 、OC(O)R^b1 、OC(O)NR^c1 R^d1 、NR^c1 R^d1 、NR^c1 C(O)R^b1 、NR^c1 C(O)NR^c1 R^d1 、NR^c1 C(O)OR^a1 、S(O)R^b1 、S(O)NR^c1 R^d1 、S(O)₂ R^b1 、NR^c1 S(O)₂ R^b1 、NR^c1 S(O)₂ NR^c1 R^d1 及S(O)₂ NR^c1 R^d1 ； R^18c 為H、C₁ _- ₆ 烷基、C₃ _- ₁₀ 環烷基、C₃ _- ₇ 環烷基-C₁ _- ₄ 烷基、C₆ _- ₁₀ 芳基、C₆ _- ₁₀ 芳基-C₁ _- ₄ 烷基、4-10員雜環烷基、(4-10員雜環烷基)-C₁ _- ₄ 烷基、5-10員雜芳基或(5-10員雜芳基)-C₁ _- ₄ 烷基，其中該C₁ _- ₆ 烷基、C₃ _- ₇ 環烷基、C₃ _- ₁₀ 環烷基-C₁ _- ₄ 烷基、C₆ _- ₁₀ 芳基、C₆ _- ₁₀ 芳基-C₁ _- ₄ 烷基、4-10員雜環烷基、(4-10員雜環烷基)-C₁ _- ₄ 烷基、5-10員雜芳基及(5-10員雜芳基)-C₁ _- ₄ 烷基各自視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、C₁ _- ₄ 烷基、C₁ _- ₄ 鹵烷基、CN、NO₂ 、OR^a1 、SR^a1 、C(O)R^b1 、C(O)NR^c1 R^d1 、C(O)OR^a1 、OC(O)R^b1 、OC(O)NR^c1 R^d1 、NR^c1 R^d1 、NR^c1 C(O)R^b1 、NR^c1 C(O)OR^a1 、NR^c1 C(O)NR^c1 R^d1 、NR^c1 S(O)R^b1 、NR^c1 S(O)₂ R^b1 、NR^c1 S(O)₂ NR^c1 R^d1 、S(O)R^b1 、S(O)NR^c1 R^d1 、S(O)₂ R^b1 及S(O)₂ NR^c1 R^d1 ； R^A 為H、Cy¹ 、鹵基、C₁ _- ₆ 烷基、C₂ _- ₆ 烯基、CN、NO₂ 、OR^a2 、SR^a2 、C(O)R^b2 、C(O)NR^c2 R^d2 、C(O)OR^a2 、OC(O)R^b2 、OC(O)NR^c2 R^d2 、NR^c2 R^d2 、NR^c2 C(O)R^b2 、NR^c2 C(O)OR^a2 、NR^c2 C(O)NR^c2 R^d2 、NR^c2 S(O)R^b2 、NR^c2 S(O)₂ R^b2 、NR^c2 S(O)₂ NR^c2 R^d2 、S(O)R^b2 、S(O)NR^c2 R^d2 、S(O)₂ R^b2 或S(O)₂ NR^c2 R^d2 ，其中該C₁ _- ₆ 烷基及C₂ _- ₆ 烯基各自視情況經1、2、3、4或5個獨立地選自以下之取代基取代：Cy¹ 、鹵基、C₁ _- ₆ 烷基、C₂ _- ₆ 烯基、C₁ _- ₆ 鹵烷基、CN、NO₂ 、OR^a2 、SR^a2 、C(O)R^b2 、C(O)NR^c2 R^d2 、C(O)OR^a2 、OC(O)R^b2 、OC(O)NR^c2 R^d2 、NR^c2 R^d2 、NR^c2 C(O)R^b2 、NR^c2 C(O)OR^a2 、NR^c2 C(O)NR^c2 R^d2 、NR^c2 S(O)R^b2 、NR^c2 S(O)₂ R^b2 、NR^c2 S(O)₂ NR^c2 R^d2 、S(O)R^b2 、S(O)NR^c2 R^d2 、S(O)₂ R^b2 及S(O)₂ NR^c2 R^d2 ； R^B 為H、Cy² 、鹵基、C₁ _- ₆ 烷基、C₂ _- ₆ 烯基、C₁ _- ₆ 鹵烷基、CN、NO₂ 、OR^a3 、SR^a3 、C(O)R^b3 、C(O)NR^c3 R^d3 、C(O)OR^a3 、OC(O)R^b3 、OC(O)NR^c3 R^d3 、NR^c3 R^d3 、NR^c3 C(O)R^b3 、NR^c3 C(O)OR^a3 、NR^c3 C(O)NR^c3 R^d3 、NR^c3 S(O)R^b3 、NR^c3 S(O)₂ R^b3 、NR^c3 S(O)₂ NR^c3 R^d3 、S(O)R^b3 、S(O)NR^c3 R^d3 、S(O)₂ R^b3 或S(O)₂ NR^c3 R^d3 ，其中該C₁ _- ₆ 烷基及C₂ _- ₆ 烯基各自視情況經1、2、3、4或5個獨立地選自以下之取代基取代：Cy² 、鹵基、C₁ _- ₆ 烷基、C₂ _- ₆ 烯基、C₁ _- ₆ 鹵烷基、CN、NO₂ 、OR^a3 、SR^a3 、C(O)R^b3 、C(O)NR^c3 R^d3 、C(O)OR^a3 、OC(O)R^b3 、OC(O)NR^c3 R^d3 、NR^c3 R^d3 、NR^c3 C(O)R^b3 、NR^c3 C(O)OR^a3 、NR^c3 C(O)NR^c3 R^d3 、NR^c3 S(O)R^b3 、NR^c1 S(O)₂ R^b3 、NR^c3 S(O)₂ NR^c3 R^d3 、S(O)R^b3 、S(O)NR^c3 R^d3 、S(O)₂ R^b3 及S(O)₂ NR^c3 R^d3 ； R^C 及R^D 各自獨立地選自：H、鹵基、C₁ _- ₆ 烷基、C₂ _- ₆ 烯基、C₁ _- ₆ 鹵烷基、CN、NO₂ 、OR^a4 、SR^a4 、C(O)R^b4 、C(O)NR^c4 R^d4 、C(O)OR^a4 、OC(O)R^b4 、OC(O)NR^c4 R^d4 、NR^c4 R^d4 、NR^c4 C(O)R^b4 、NR^c4 C(O)OR^a4 、NR^c4 C(O)NR^c4 R^d4 、NR^c4 S(O)R^b4 、NR^c4 S(O)₂ R^b4 、NR^c4 S(O)₂ NR^c4 R^d4 、S(O)R^b4 、S(O)NR^c4 R^d4 、S(O)₂ R^b4 及S(O)₂ NR^c4 R^d4 ；其中該C₁ _- ₆ 烷基及C₂ _- ₆ 烯基各自視情況經1、2、3、4或5個獨立地選自以下之取代基取代：C₆ _- ₁₀ 芳基、C₃ _- ₁₀ 環烷基、5-10員雜芳基、4-10員雜環烷基、鹵基、C₁ _- ₆ 烷基、C₂ _- ₆ 烯基、C₁ _- ₆ 鹵烷基、CN、NO₂ 、OR^a4 、SR^a4 、C(O)R^b4 、C(O)NR^c4 R^d4 、C(O)OR^a4 、OC(O)R^b4 、OC(O)NR^c4 R^d4 、NR^c4 R^d4 、NR^c4 C(O)R^b4 、NR^c4 C(O)OR^a4 、NR^c4 C(O)NR^c4 R^d4 、NR^c4 S(O)R^b4 、NR^c4 S(O)₂ R^b4 、NR^c4 S(O)₂ NR^c4 R^d4 、S(O)R^b4 、S(O)NR^c4 R^d4 、S(O)₂ R^b4 及S(O)₂ NR^c4 R^d4 ； Cy¹ 及Cy² 各自獨立地選自：C₆ _- ₁₀ 芳基、C₃ _- ₁₀ 環烷基、5-10員雜芳基及4-10員雜環烷基，其各者視情況經1、2、3、4或5個獨立地選自R^Cy 之取代基取代；各R^Cy 獨立地選自：鹵基、C₁ _- ₆ 烷基、C₁ _- ₆ 鹵烷基、C₂ _- ₆ 烯基、C₆ _- ₁₀ 芳基、C₃ _- ₁₀ 環烷基、5-10員雜芳基、4-10員雜環烷基、CN、NO₂ 、OR^a5 、SR^a5 、C(O)R^b5 、C(O)NR^c5 R^d5 、C(O)OR^a5 、OC(O)R^b5 、OC(O)NR^c5 R^d5 、NR^c5 R^d5 、NR^c5 C(O)R^b5 、NR^c5 C(O)OR^a5 、NR^c5 C(O)NR^c5 R^d5 、NR^c5 S(O)R^b5 、NR^c5 S(O)₂ R^b5 、NR^c5 S(O)₂ NR^c5 R^d5 、S(O)R^b5 、S(O)NR^c5 R^d5 、S(O)₂ R^b5 及S(O)₂ NR^c5 R^d5 ，其中該C₁ _- ₆ 烷基、C₂ _- ₆ 烯基C₆ _- ₁₀ 芳基、C₃ _- ₁₀ 環烷基、5-10員雜芳基及4-10員雜環烷基各自視情況經1、2、3、4或5個獨立地選自以下之取代基取代：鹵基、C₁ _- ₆ 烷基、CN、NO₂ 、OR^a5 、SR^a5 、C(O)R^b5 、C(O)NR^c5 R^d5 、C(O)OR^a5 、OC(O)R^b5 、OC(O)NR^c5 R^d5 、NR^c5 R^d5 、NR^c5 C(O)R^b5 、NR^c5 C(O)OR^a5 、NR^c5 C(O)NR^c5 R^d5 、NR^c5 S(O)R^b5 、NR^c5 S(O)₂ R^b5 、NR^c5 S(O)₂ NR^c5 R^d5 、S(O)R^b5 、S(O)NR^c5 R^d5 、S(O)₂ R^b5 及S(O)₂ NR^c5 R^d5 ；各R^a 、R^a1 、R^a2 、R^a3 、R^a4 及R^a5 獨立地選自：H、C₁ _- ₆ 烷基、C₁ _- ₄ 鹵烷基、C₂ _- ₆ 烯基、C₆ _- ₁₀ 芳基、C₃ _- ₁₀ 環烷基、5-10員雜芳基、4-10員雜環烷基、C₆ _- ₁₀ 芳基-C₁ _- ₄ 烷基、C₃ _- ₁₀ 環烷基-C₁ _- ₄ 烷基、(5-10員雜芳基)-C₁ _- ₄ 烷基或(4-10員雜環烷基)-C₁ _- ₄ 烷基，其中該C₁ _- ₆ 烷基、C₂ _- ₆ 烯基、C₆ _- ₁₀ 芳基、C₃ _- ₁₀ 環烷基、5-10員雜芳基、4-10員雜環烷基、C₆ _- ₁₀ 芳基-C₁ _- ₄ 烷基、C₃ _- ₁₀ 環烷基-C₁ _- ₄ 烷基、(5-10員雜芳基)-C₁ _- ₄ 烷基及(4-10員雜環烷基)-C₁ _- ₄ 烷基各自視情況經1、2、3、4或5個獨立地選自以下之取代基取代：C₁ _- ₄ 烷基、鹵基、CN、OR^a6 、C(O)R^b6 、C(O)NR^c6 R^d6 、C(O)OR^a6 、OC(O)R^b6 、OC(O)NR^c6 R^d6 、NR^c6 R^d6 、NR^c6 C(O)R^b6 、NR^c6 C(O)NR^c6 R^d6 、NR^c6 C(O)OR^a6 、S(O)R^b6 、S(O)NR^c6 R^d6 、S(O)₂ R^b6 、NR^c6 S(O)₂ R^b6 、NR^c6 S(O)₂ NR^c6 R^d6 及S(O)₂ NR^c6 R^d6 ；各R^b1 、R^b2 、R^b3 、R^b4 及R^b5 獨立地選自：H、C₁ _- ₆ 烷基、C₁ _- ₄ 鹵烷基、C₂ _- ₆ 烯基、C₆ _- ₁₀ 芳基、C₃ _- ₁₀ 環烷基、5-10員雜芳基、4-10員雜環烷基、C₆ _- ₁₀ 芳基-C₁ _- ₄ 烷基、C₃ _- ₁₀ 環烷基-C₁ _- ₄ 烷基、(5-10員雜芳基)-C₁ _- ₄ 烷基或(4-10員雜環烷基)-C₁ _- ₄ 烷基，其中該C₁ _- ₆ 烷基、C₂ _- ₆ 烯基、C₆ _- ₁₀ 芳基、C₃ _- ₁₀ 環烷基、5-10員雜芳基、4-10員雜環烷基、C₆ _- ₁₀ 芳基-C₁ _- ₄ 烷基、C₃ _- ₁₀ 環烷基-C₁ _- ₄ 烷基、(5-10員雜芳基)-C₁ _- ₄ 烷基及(4-10員雜環烷基)-C₁ _- ₄ 烷基各自視情況經1、2、3、4或5個獨立地選自以下之取代基取代：C₁ _- ₄ 烷基、鹵基、CN、OR^a6 、C(O)R^b6 、C(O)NR^c6 R^d6 、C(O)OR^a6 、OC(O)R^b6 、OC(O)NR^c6 R^d6 、NR^c6 R^d6 、NR^c6 C(O)R^b6 、NR^c6 C(O)NR^c6 R^d6 、NR^c6 C(O)OR^a6 、S(O)R^b6 、S(O)NR^c6 R^d6 、S(O)₂ R^b6 、NR^c6 S(O)₂ R^b6 、NR^c6 S(O)₂ NR^c6 R^d6 及S(O)₂ NR^c6 R^d6 ；各R^c 、R^d 、R^c1 、R^d1 、R^c2 、R^d2 、R^c3 、R^d3 、R^c4 、R^d4 、R^c5 及R^d5 獨立地選自：H、C₁ _- ₆ 烷基、C₁ _- ₄ 鹵烷基、C₂ _- ₆ 烯基、C₆ _- ₁₀ 芳基、C₃ _- ₁₀ 環烷基、5-10員雜芳基、4-10員雜環烷基、C₆ _- ₁₀ 芳基-C₁ _- ₄ 烷基、C₃ _- ₁₀ 環烷基-C₁ _- ₄ 烷基、(5-10員雜芳基)-C₁ _- ₄ 烷基或(4-10員雜環烷基)-C₁ _- ₄ 烷基，其中該C₁ _- ₆ 烷基、C₂ _- ₆ 烯基、C₆ _- ₁₀ 芳基、C₃ _- ₁₀ 環烷基、5-10員雜芳基、4-10員雜環烷基、C₆ _- ₁₀ 芳基-C₁ _- ₄ 烷基、C₃ _- ₁₀ 環烷基-C₁ _- ₄ 烷基、(5-10員雜芳基)-C₁ _- ₄ 烷基及(4-10員雜環烷基)-C₁ _- ₄ 烷基各自視情況經1、2、3、4或5個獨立地選自以下之取代基取代：C₁ _- ₄ 烷基、鹵基、CN、OR^a6 、SR^a6 、C(O)R^b6 、C(O)NR^c6 R^d6 、C(O)OR^a6 、OC(O)R^b6 、OC(O)NR^c6 R^d6 、NR^c6 R^d6 、NR^c6 C(O)R^b6 、NR^c6 C(O)NR^c6 R^d6 、NR^c6 C(O)OR^a6 、S(O)R^b6 、S(O)NR^c6 R^d6 、S(O)₂ R^b6 、NR^c6 S(O)₂ R^b6 、NR^c6 S(O)₂ NR^c6 R^d6 及S(O)₂ NR^c6 R^d6 ；或任何R^c 及R^d 連同其所連接之N原子形成視情況經1、2或3個獨立地選自以下之取代基取代的4員、5員、6員或7員雜環烷基：C₁ _- ₆ 烷基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基、5-6員雜芳基、鹵基、CN、OR^a6 、SR^a6 、C(O)R^b6 、C(O)NR^c6 R^d6 、C(O)OR^a6 、OC(O)R^b6 、OC(O)NR^c6 R^d6 、NR^c6 R^d6 、NR^c6 C(O)R^b6 、NR^c6 C(O)NR^c6 R^d6 、NR^c6 C(O)OR^a6 、S(O)R^b6 、S(O)NR^c6 R^d6 、S(O)₂ R^b6 、NR^c6 S(O)₂ R^b6 、NR^c6 S(O)₂ NR^c6 R^d6 及S(O)₂ NR^c6 R^d6 ，其中該C₁ _- ₆ 烷基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基及5-6員雜芳基視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、CN、OR^a6 、SR^a6 、C(O)R^b6 、C(O)NR^c6 R^d6 、C(O)OR^a6 、OC(O)R^b6 、OC(O)NR^c6 R^d6 、NR^c6 R^d6 、NR^c6 C(O)R^b6 、NR^c6 C(O)NR^c6 R^d6 、NR^c6 C(O)OR^a6 、S(O)R^b6 、S(O)NR^c6 R^d6 、S(O)₂ R^b6 、NR^c6 S(O)₂ R^b6 、NR^c6 S(O)₂ NR^c6 R^d6 及S(O)₂ NR^c6 R^d6 ；或任何R^c1 及R^d1 連同其所連接之N原子形成視情況經1、2或3個獨立地選自以下之取代基取代的4員、5員、6員或7員雜環烷基：C₁ _- ₆ 烷基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基、5-6員雜芳基、鹵基、CN、OR^a6 、SR^a6 、C(O)R^b6 、C(O)NR^c6 R^d6 、C(O)OR^a6 、OC(O)R^b6 、OC(O)NR^c6 R^d6 、NR^c6 R^d6 、NR^c6 C(O)R^b6 、NR^c6 C(O)NR^c6 R^d6 、NR^c6 C(O)OR^a6 、S(O)R^b6 、S(O)NR^c6 R^d6 、S(O)₂ R^b6 、NR^c6 S(O)₂ R^b6 、NR^c6 S(O)₂ NR^c6 R^d6 及S(O)₂ NR^c6 R^d6 ，其中該C₁ _- ₆ 烷基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基及5-6員雜芳基各自視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、CN、OR^a6 、SR^a6 、C(O)R^b6 、C(O)NR^c6 R^d6 、C(O)OR^a6 、OC(O)R^b6 、OC(O)NR^c6 R^d6 、NR^c6 R^d6 、NR^c6 C(O)R^b6 、NR^c6 C(O)NR^c6 R^d6 、NR^c6 C(O)OR^a6 、S(O)R^b6 、S(O)NR^c6 R^d6 、S(O)₂ R^b6 、NR^c6 S(O)₂ R^b6 、NR^c6 S(O)₂ NR^c6 R^d6 及S(O)₂ NR^c6 R^d6 ；或任何R^c2 及R^d2 連同其所連接之N原子形成視情況經1、2或3個獨立地選自以下之取代基取代的4員、5員、6員或7員雜環烷基：C₁ _- ₆ 烷基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基及5-6員雜芳基、C₁ _- ₆ 鹵烷基、鹵基、CN、OR^a6 、SR^a6 、C(O)R^b6 、C(O)NR^c6 R^d6 、C(O)OR^a6 、OC(O)R^b6 、OC(O)NR^c6 R^d6 、NR^c6 R^d6 、NR^c6 C(O)R^b6 、NR^c6 C(O)NR^c6 R^d6 、NR^c6 C(O)OR^a6 、S(O)R^b6 、S(O)NR^c6 R^d6 、S(O)₂ R^b6 、NR^c6 S(O)₂ R^b6 、NR^c6 S(O)₂ NR^c6 R^d6 及S(O)₂ NR^c6 R^d6 ，其中該C₁ _- ₆ 烷基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基及5-6員雜芳基各自視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、CN、OR^a6 、SR^a6 、C(O)R^b6 、C(O)NR^c6 R^d6 、C(O)OR^a6 、OC(O)R^b6 、OC(O)NR^c6 R^d6 、NR^c6 R^d6 、NR^c6 C(O)R^b6 、NR^c6 C(O)NR^c6 R^d6 、NR^c6 C(O)OR^a6 、S(O)R^b6 、S(O)NR^c6 R^d6 、S(O)₂ R^b6 、NR^c6 S(O)₂ R^b6 、NR^c6 S(O)₂ NR^c6 R^d6 及S(O)₂ NR^c6 R^d6 ；或任何R^c3 及R^d3 連同其所連接之N原子形成視情況經1、2或3個獨立地選自以下之取代基取代的4員、5員、6員或7員雜環烷基：C₁ _- ₆ 烷基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基、5-6員雜芳基、C₁ _- ₆ 鹵烷基、鹵基、CN、OR^a6 、SR^a6 、C(O)R^b6 、C(O)NR^c6 R^d6 、C(O)OR^a6 、OC(O)R^b ⁶ 、OC(O)NR^c6 R^d6 、NR^c6 R^d6 、NR^c6 C(O)R^b6 、NR^c6 C(O)NR^c6 R^d6 、NR^c6 C(O)OR^a6 、S(O)R^b6 、S(O)NR^c6 R^d6 、S(O)₂ R^b6 、NR^c6 S(O)₂ R^b6 、NR^c6 S(O)₂ NR^c6 R^d6 及S(O)₂ NR^c6 R^d6 ，其中該C₁ _- ₆ 烷基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基及5-6員雜芳基各自視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、CN、OR^a6 、SR^a6 、C(O)R^b6 、C(O)NR^c6 R^d6 、C(O)OR^a6 、OC(O)R^b6 、OC(O)NR^c6 R^d6 、NR^c6 R^d6 、NR^c6 C(O)R^b6 、NR^c6 C(O)NR^c6 R^d6 、NR^c6 C(O)OR^a6 、S(O)R^b6 、S(O)NR^c6 R^d6 、S(O)₂ R^b6 、NR^c6 S(O)₂ R^b6 、NR^c6 S(O)₂ NR^c6 R^d6 及S(O)₂ NR^c6 R^d6 ；或任何R^c4 及R^d4 連同其所連接之N原子形成視情況經1、2或3個獨立地選自以下之取代基取代的4員、5員、6員或7員雜環烷基：C₁ _- ₆ 烷基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基、5-6員雜芳基、C₁ _- ₆ 鹵烷基、鹵基、CN、OR^a6 、SR^a6 、C(O)R^b6 、C(O)NR^c6 R^d6 、C(O)OR^a6 、OC(O)R^b6 、OC(O)NR^c6 R^d6 、NR^c6 R^d6 、NR^c6 C(O)R^b6 、NR^c6 C(O)NR^c6 R^d6 、NR^c6 C(O)OR^a6 、S(O)R^b6 、S(O)NR^c6 R^d6 、S(O)₂ R^b6 、NR^c6 S(O)₂ R^b6 、NR^c6 S(O)₂ NR^c6 R^d6 及S(O)₂ NR^c6 R^d6 ，其中該C₁ _- ₆ 烷基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基及5-6員雜芳基各自視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、CN、OR^a6 、SR^a6 、C(O)R^b6 、C(O)NR^c6 R^d6 、C(O)OR^a6 、OC(O)R^b6 、OC(O)NR^c6 R^d6 、NR^c6 R^d6 、NR^c6 C(O)R^b6 、NR^c6 C(O)NR^c6 R^d6 、NR^c6 C(O)OR^a6 、S(O)R^b6 、S(O)NR^c6 R^d6 、S(O)₂ R^b6 、NR^c6 S(O)₂ R^b6 、NR^c6 S(O)₂ NR^c6 R^d6 及S(O)₂ NR^c6 R^d6 ；或任何R^c5 及R^d5 連同其所連接之N原子形成視情況經1、2或3個獨立地選自以下之取代基取代的4員、5員、6員或7員雜環烷基：C₁ _- ₆ 烷基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基、5-6員雜芳基、C₁ _- ₆ 鹵烷基、鹵基、CN、OR^a6 、SR^a6 、C(O)R^b6 、C(O)NR^c6 R^d6 、C(O)OR^a6 、OC(O)R^b ⁶ 、OC(O)NR^c6 R^d6 、NR^c6 R^d6 、NR^c6 C(O)R^b6 、NR^c6 C(O)NR^c6 R^d6 、NR^c6 C(O)OR^a6 、S(O)R^b6 、S(O)NR^c6 R^d6 、S(O)₂ R^b6 、NR^c6 S(O)₂ R^b6 、NR^c6 S(O)₂ NR^c6 R^d6 及S(O)₂ NR^c6 R^d6 ，其中該C₁ _- ₆ 烷基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基及5-6員雜芳基各自視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、CN、OR^a6 、SR^a6 、C(O)R^b6 、C(O)NR^c6 R^d6 、C(O)OR^a6 、OC(O)R^b6 、OC(O)NR^c6 R^d6 、NR^c6 R^d6 、NR^c6 C(O)R^b6 、NR^c6 C(O)NR^c6 R^d6 、NR^c6 C(O)OR^a6 、S(O)R^b6 、S(O)NR^c6 R^d6 、S(O)₂ R^b6 、NR^c6 S(O)₂ R^b6 、NR^c6 S(O)₂ NR^c6 R^d6 及S(O)₂ NR^c6 R^d6 ；各R^a6 、R^b6 、R^c6 及R^d6 獨立地選自：H、C₁ _- ₄ 烷基、C₂ _- ₄ 烯基、C₃ _- ₇ 環烷基、苯基、5-6員雜芳基及4-7員雜環烷基，其中該C₁ _- ₄ 烷基、C₂ _- ₄ 烯基、C₃ _- ₇ 環烷基、苯基、5-6員雜芳基及4-7員雜環烷基各自視情況經1、2或3個獨立地選自以下之取代基取代：OH、CN、胺基、鹵基、C₁ _- ₄ 烷基、C₁ _- ₄ 烷氧基、C₁ _- ₄ 烷硫基、C₁ _- ₄ 烷胺基及二(C₁ _- ₄ 烷基)胺基； n為1或2； p為1、2或3；且 q為1或2；其中任何前述4-10員或4-7員雜環烷基視情況包含1、2或3個側氧取代基，其中存在之各側氧取代基在形成4-10員或4-7員雜環烷基之碳、氮或硫原子之環上經取代。在一些實施例中，本文所描述之TPH抑制化合物為式I化合物：I 或其醫藥學上可接受之鹽，其中：環A為C₃ _- ₁₀ 環烷基、C₆ _- ₁₀ 芳基、4至10員雜環烷基或5至10員雜芳基； L為O或NR⁴ ； W為N或CR⁵ ； X為N或CR⁶ ； Y為N或CR⁷ ；其中X及Y中之僅一者為N； R¹ 為H、C₁ _- ₁₀ 烷基、C₃ _- ₁₀ 環烷基、苯基、-(CR⁸ R⁹ )_p OC(O)R¹⁰ 、-(CR⁸ R⁹ )_p NR¹¹ R¹² 或-(CR⁸ R⁹ )_p C(O)NR¹¹ R¹² ，其中該C₁ _- ₁₀ 烷基、C₃ _- ₁₀ 環烷基及苯基各自視情況經1、2、3、4或5個獨立地選自以下之取代基取代：F、Cl、Br、CN、C₁ _- ₄ 烷基及C₁ _- ₄ 鹵烷基； R² 及R³ 各自獨立地選自H、C₁ _- ₄ 烷基及C₁ _- ₄ 鹵烷基； R⁴ 為H或C₁ _- ₄ 烷基； R⁵ 及R⁶ 各自獨立地選自H、鹵基及C₁ _- ₄ 烷基； R⁷ 為H、C₁ _- ₄ 烷基、C₂ _- ₆ 烯基、C₃ _- ₁₀ 環烷基、C₃ _- ₁₀ 環烷基-C₁ _- ₄ 烷基、C₆ _- ₁₀ 芳基、C₆ _- ₁₀ 芳基-C₁ _- ₄ 烷基、4-10員雜環烷基、(4-10員雜環烷基)-C₁ _- ₄ 烷基、5-10員雜芳基、(5-10員雜芳基)-C₁ _- ₄ 烷基、NR¹³ R¹⁴ 、OR¹⁵ 、C(O)R¹⁶ 、S(O)_q R¹⁷ ，其中該C₁ _- ₄ 烷基、C₂ _- ₆ 烯基、C₃ _- ₁₀ 環烷基、C₃ _- ₁₀ 環烷基-C₁ _- ₄ 烷基、C₆ _- ₁₀ 芳基、C₆ _- ₁₀ 芳基-C₁ _- ₄ 烷基、4-10員雜環烷基、(4-10員雜環烷基)-C₁ _- ₄ 烷基、5-10員雜芳基及(5-10員雜芳基)-C₁ _- ₄ 烷基各自視情況經1、2或3個選自以下之取代基取代：鹵基、C₁ _- ₄ 烷基、C₂ _- ₆ 烯基、胺基、C₁ _- ₄ 烷胺基、C₂ _- ₈ 二烷胺基、羥基及C₁ _- ₄ 烷氧基； R⁸ 及R⁹ 各自獨立地選自H及C₁ _- ₄ 烷基； R¹⁰ 為C₁ _- ₆ 烷基，視情況經1、2或3個獨立地選自以下之取代基取代：C₁ _- ₆ 鹵烷基、C₃ _- ₁₀ 環烷基、OR^a 及NR^c R^d ； R¹¹ 及R¹² 各自獨立地選自H及C₁ _- ₆ 烷基； R¹³ 為H或C₁ _- ₄ 烷基； R¹⁴ 為H、C₁ _- ₄ 烷基、C₃ _- ₇ 環烷基、C₃ _- ₇ 環烷基-C₁ _- ₄ 烷基、C₆ _- ₁₀ 芳基、C₆ _- ₁₀ 芳基-C₁ _- ₄ 烷基、4-10員雜環烷基、(4-10員雜環烷基)-C₁ _- ₄ 烷基、5-10員雜芳基或(5-10員雜芳基)-C₁ _- ₄ 烷基、C(O)R^b1 、C(O)OR^a1 、C(O)NR^c1 R^d1 、S(O)R^b1 、S(O)₂ R^b1 或S(O)₂ NR^c1 R^d1 ，其中該C₁ _- ₄ 烷基、C₃ _- ₇ 環烷基、C₃ _- ₇ 環烷基-C₁ _- ₄ 烷基、C₆ _- ₁₀ 芳基、C₆ _- ₁₀ 芳基-C₁ _- ₄ 烷基、4-10員雜環烷基、(4-10員雜環烷基)-C₁ _- ₄ 烷基、5-10員雜芳基及(5-10員雜芳基)-C₁ _- ₄ 烷基各自視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、C₁ _- ₄ 烷基、C₁ _- ₄ 鹵烷基、CN、NO₂ 、OR^a1 、SR^a1 、C(O)R^b1 、C(O)NR^c1 R^d1 、C(O)OR^a1 、OC(O)R^b1 、OC(O)NR^c1 R^d1 、NR^c1 R^d1 、NR^c1 C(O)R^b1 、NR^c1 C(O)OR^a1 、NR^c1 C(O)NR^c1 R^d1 、NR^c1 S(O)R^b1 、NR^c1 S(O)₂ R^b1 、NR^c1 S(O)₂ NR^c1 R^d1 、S(O)R^b1 、S(O)NR^c1 R^d1 、S(O)₂ R^b1 及S(O)₂ NR^c1 R^d1 ；或R¹³ 及R¹⁴ 連同其所連接之N原子形成視情況經1、2或3個獨立地選自以下之取代基取代的4員、5員、6員或7員雜環烷基：C₁ _- ₆ 烷基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基、5-6員雜芳基、鹵基、CN、OR^a1 、SR^a1 、C(O)R^b1 、C(O)NR^c1 R^d1 、C(O)OR^a1 、OC(O)R^b1 、OC(O)NR^c1 R^d ¹ 、NR^c1 R^d1 、NR^c1 C(O)R^b1 、NR^c1 C(O)NR^c1 R^d1 、NR^c1 C(O)OR^a1 、S(O)R^b1 、S(O)NR^c1 R^d1 、S(O)₂ R^b1 、NR^c1 S(O)₂ R^b1 、NR^c1 S(O)₂ NR^c1 R^d1 及S(O)₂ NR^c1 R^d1 ，其中該C₁ _- ₆ 烷基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基及5-6員雜芳基各自視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、CN、OR^a1 、SR^a1 、C(O)R^b1 、C(O)NR^c1 R^d1 、C(O)OR^a1 、OC(O)R^b1 、OC(O)NR^c1 R^d1 、NR^c1 R^d1 、NR^c1 C(O)R^b1 、NR^c1 C(O)NR^c1 R^d1 、NR^c1 C(O)OR^a1 、S(O)R^b1 、S(O)NR^c1 R^d1 、S(O)₂ R^b1 、NR^c1 S(O)₂ R^b1 、NR^c1 S(O)₂ NR^c1 R^d1 及S(O)₂ NR^c1 R^d1 ； R¹⁵ 為H、C₁ _- ₄ 烷基、C₃ _- ₇ 環烷基、C₃ _- ₇ 環烷基-C₁ _- ₄ 烷基、C₆ _- ₁₀ 芳基、C₆ _- ₁₀ 芳基-C₁ _- ₄ 烷基、4-10員雜環烷基、(4-10員雜環烷基)-C₁ _- ₄ 烷基、5-10員雜芳基或(5-10員雜芳基)-C₁ _- ₄ 烷基，其中該C₁ _- ₄ 烷基、C₃ _- ₇ 環烷基、C₃ _- ₇ 環烷基-C₁ _- ₄ 烷基、C₆ _- ₁₀ 芳基、C₆ _- ₁₀ 芳基-C₁ _- ₄ 烷基、4-10員雜環烷基、(4-10員雜環烷基)-C₁ _- ₄ 烷基、5-10員雜芳基及(5-10員雜芳基)-C₁ _- ₄ 烷基各自視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基、5-6員雜芳基、CN、OR^a1 、SR^a1 、C(O)R^b1 、C(O)NR^c1 R^d1 、C(O)OR^a1 、OC(O)R^b1 、OC(O)NR^c1 R^d1 、NR^c1 R^d1 、NR^c1 C(O)R^b1 、NR^c1 C(O)NR^c1 R^d1 、NR^c1 C(O)OR^a1 、S(O)R^b1 、S(O)NR^c1 R^d1 、S(O)₂ R^b1 、NR^c1 S(O)₂ R^b1 、NR^c1 S(O)₂ NR^c1 R^d1 及S(O)₂ NR^c1 R^d1 ； R¹⁶ 為C₁ _- ₄ 烷基或NR^18a R^18b ，其中該C₁ _- ₄ 烷基視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基、5-6員雜芳基、CN、OR^a1 、SR^a1 、C(O)R^b1 、C(O)NR^c1 R^d1 、C(O)OR^a1 、OC(O)R^b1 、OC(O)NR^c1 R^d1 、NR^c1 R^d1 、NR^c1 C(O)R^b1 、NR^c1 C(O)NR^c1 R^d1 、NR^c1 C(O)OR^a1 、S(O)R^b1 、S(O)NR^c1 R^d1 、S(O)₂ R^b1 、NR^c1 S(O)₂ R^b1 、NR^c1 S(O)₂ NR^c1 R^d1 及S(O)₂ NR^c1 R^d1 ； R¹⁷ 為C₁ _- ₄ 烷基、NR^18a R^18b 或OR^18c ，其中該C₁ _- ₄ 烷基視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基、5-6員雜芳基、CN、OR^a1 、SR^a1 、C(O)R^b1 、C(O)NR^c1 R^d1 、C(O)OR^a1 、OC(O)R^b1 、OC(O)NR^c1 R^d1 、NR^c1 R^d1 、NR^c1 C(O)R^b1 、NR^c1 C(O)NR^c1 R^d1 、NR^c1 C(O)OR^a1 、S(O)R^b1 、S(O)NR^c1 R^d1 、S(O)₂ R^b1 、NR^c1 S(O)₂ R^b1 、NR^c1 S(O)₂ NR^c1 R^d1 及S(O)₂ NR^c1 R^d1 ； R^18a 及R^18b 各自獨立地選自H及C₁ _- ₄ 烷基，其中該C₁ _- ₄ 烷基視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基、5-6員雜芳基、CN、OR^a1 、SR^a1 、C(O)R^b1 、C(O)NR^c1 R^d1 、C(O)OR^a1 、OC(O)R^b1 、OC(O)NR^c1 R^d1 、NR^c1 R^d1 、NR^c1 C(O)R^b1 、NR^c1 C(O)NR^c1 R^d1 、NR^c4 C(O)OR^a1 、S(O)R^b1 、S(O)NR^c1 R^d1 、S(O)₂ R^b1 、NR^c1 S(O)₂ R^b1 、NR^c1 S(O)₂ NR^c1 R^d1 及S(O)₂ NR^c1 R^d1 ；或R^18a 及R^18b 連同其所連接之N原子形成視情況經1、2或3個獨立地選自以下之取代基取代的4員、5員、6員或7員雜環烷基：C₁ _- ₆ 烷基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基、5-6員雜芳基、鹵基、CN、OR^a1 、SR^a1 、C(O)R^b1 、C(O)NR^c1 R^d1 、C(O)OR^a1 、OC(O)R^b1 、OC(O)NR^c1 R^d1 、NR^c1 R^d1 、NR^c1 C(O)R^b1 、NR^c1 C(O)NR^c1 R^d1 、NR^c1 C(O)OR^a1 、S(O)R^b1 、S(O)NR^c1 R^d1 、S(O)₂ R^b1 、NR^c1 S(O)₂ R^b1 、NR^c1 S(O)₂ NR^c1 R^d1 及S(O)₂ NR^c1 R^d1 ，其中該C₁ _- ₆ 烷基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基及5-6員雜芳基各自視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、CN、OR^a1 、SR^a1 、C(O)R^b1 、C(O)NR^c1 R^d1 、C(O)OR^a1 、OC(O)R^b1 、OC(O)NR^c1 R^d1 、NR^c1 R^d1 、NR^c1 C(O)R^b1 、NR^c1 C(O)NR^c1 R^d1 、NR^c1 C(O)OR^a1 、S(O)R^b1 、S(O)NR^c1 R^d1 、S(O)₂ R^b1 、NR^c1 S(O)₂ R^b1 、NR^c1 S(O)₂ NR^c1 R^d1 及S(O)₂ NR^c1 R^d1 ； R^18c 為H、C₁ _- ₆ 烷基、C₃ _- ₁₀ 環烷基、C₃ _- ₇ 環烷基-C₁ _- ₄ 烷基、C₆ _- ₁₀ 芳基、C₆ _- ₁₀ 芳基-C₁ _- ₄ 烷基、4-10員雜環烷基、(4-10員雜環烷基)-C₁ _- ₄ 烷基、5-10員雜芳基或(5-10員雜芳基)-C₁ _- ₄ 烷基，其中該C₁ _- ₆ 烷基、C₃ _- ₇ 環烷基、C₃ _- ₁₀ 環烷基-C₁ _- ₄ 烷基、C₆ _- ₁₀ 芳基、C₆ _- ₁₀ 芳基-C₁ _- ₄ 烷基、4-10員雜環烷基、(4-10員雜環烷基)-C₁ _- ₄ 烷基、5-10員雜芳基及(5-10員雜芳基)-C₁ _- ₄ 烷基各自視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、C₁ _- ₄ 烷基、C₁ _- ₄ 鹵烷基、CN、NO₂ 、OR^a1 、SR^a1 、C(O)R^b1 、C(O)NR^c1 R^d1 、C(O)OR^a1 、OC(O)R^b1 、OC(O)NR^c1 R^d1 、NR^c1 R^d1 、NR^c1 C(O)R^b1 、NR^c1 C(O)OR^a1 、NR^c1 C(O)NR^c1 R^d1 、NR^c1 S(O)R^b1 、NR^c1 S(O)₂ R^b1 、NR^c1 S(O)₂ NR^c1 R^d1 、S(O)R^b1 、S(O)NR^c1 R^d1 、S(O)₂ R^b1 及S(O)₂ NR^c1 R^d1 ； R^A 為H、Cy¹ 、鹵基、C₁ _- ₆ 烷基、C₂ _- ₆ 烯基、CN、NO₂ 、OR^a2 、SR^a2 、C(O)R^b2 、C(O)NR^c2 R^d2 、C(O)OR^a2 、OC(O)R^b2 、OC(O)NR^c2 R^d2 、NR^c2 R^d2 、NR^c2 C(O)R^b2 、NR^c2 C(O)OR^a2 、NR^c2 C(O)NR^c2 R^d2 、NR^c2 S(O)R^b2 、NR^c2 S(O)₂ R^b2 、NR^c2 S(O)₂ NR^c2 R^d2 、S(O)R^b2 、S(O)NR^c2 R^d2 、S(O)₂ R^b2 或S(O)₂ NR^c2 R^d2 ，其中該C₁ _- ₆ 烷基及C₂ _- ₆ 烯基各自視情況經1、2、3、4或5個獨立地選自以下之取代基取代：Cy¹ 、鹵基、C₁ _- ₆ 烷基、C₂ _- ₆ 烯基、C₁ _- ₆ 鹵烷基、CN、NO₂ 、OR^a2 、SR^a2 、C(O)R^b2 、C(O)NR^c2 R^d2 、C(O)OR^a2 、OC(O)R^b2 、OC(O)NR^c2 R^d2 、NR^c2 R^d2 、NR^c2 C(O)R^b2 、NR^c2 C(O)OR^a2 、NR^c2 C(O)NR^c2 R^d2 、NR^c2 S(O)R^b2 、NR^c2 S(O)₂ R^b2 、NR^c2 S(O)₂ NR^c2 R^d2 、S(O)R^b2 、S(O)NR^c2 R^d2 、S(O)₂ R^b2 及S(O)₂ NR^c2 R^d2 ； R^B 為H、Cy² 、鹵基、C₁ _- ₆ 烷基、C₂ _- ₆ 烯基、C₁ _- ₆ 鹵烷基、CN、NO₂ 、OR^a3 、SR^a3 、C(O)R^b3 、C(O)NR^c3 R^d3 、C(O)OR^a3 、OC(O)R^b3 、OC(O)NR^c3 R^d3 、NR^c3 R^d3 、NR^c3 C(O)R^b3 、NR^c3 C(O)OR^a3 、NR^c3 C(O)NR^c3 R^d3 、NR^c3 S(O)R^b3 、NR^c3 S(O)₂ R^b3 、NR^c3 S(O)₂ NR^c3 R^d3 、S(O)R^b3 、S(O)NR^c3 R^d3 、S(O)₂ R^b3 或S(O)₂ NR^c3 R^d3 ，其中該C₁ _- ₆ 烷基及C₂ _- ₆ 烯基各自視情況經1、2、3、4或5個獨立地選自以下之取代基取代：Cy² 、鹵基、C₁ _- ₆ 烷基、C₂ _- ₆ 烯基、C₁ _- ₆ 鹵烷基、CN、NO₂ 、OR^a3 、SR^a3 、C(O)R^b3 、C(O)NR^c3 R^d3 、C(O)OR^a3 、OC(O)R^b3 、OC(O)NR^c3 R^d3 、NR^c3 R^d3 、NR^c3 C(O)R^b3 、NR^c3 C(O)OR^a3 、NR^c3 C(O)NR^c3 R^d3 、NR^c3 S(O)R^b3 、NR^c1 S(O)₂ R^b3 、NR^c3 S(O)₂ NR^c3 R^d3 、S(O)R^b3 、S(O)NR^c3 R^d3 、S(O)₂ R^b3 及S(O)₂ NR^c3 R^d3 ； R^C 及R^D 各自獨立地選自：H、鹵基、C₁ _- ₆ 烷基、C₂ _- ₆ 烯基、C₁ _- ₆ 鹵烷基、CN、NO₂ 、OR^a4 、SR^a4 、C(O)R^b4 、C(O)NR^c4 R^d4 、C(O)OR^a4 、OC(O)R^b4 、OC(O)NR^c4 R^d4 、NR^c4 R^d4 、NR^c4 C(O)R^b4 、NR^c4 C(O)OR^a4 、NR^c4 C(O)NR^c4 R^d4 、NR^c4 S(O)R^b4 、NR^c4 S(O)₂ R^b4 、NR^c4 S(O)₂ NR^c4 R^d4 、S(O)R^b4 、S(O)NR^c4 R^d4 、S(O)₂ R^b4 及S(O)₂ NR^c4 R^d4 ；其中該C₁ _- ₆ 烷基及C₂ _- ₆ 烯基各自視情況經1、2、3、4或5個獨立地選自以下之取代基取代：C₆ _- ₁₀ 芳基、C₃ _- ₁₀ 環烷基、5-10員雜芳基、4-10員雜環烷基、鹵基、C₁ _- ₆ 烷基、C₂ _- ₆ 烯基、C₁ _- ₆ 鹵烷基、CN、NO₂ 、OR^a4 、SR^a4 、C(O)R^b4 、C(O)NR^c4 R^d4 、C(O)OR^a4 、OC(O)R^b4 、OC(O)NR^c4 R^d4 、NR^c4 R^d4 、NR^c4 C(O)R^b4 、NR^c4 C(O)OR^a4 、NR^c4 C(O)NR^c4 R^d4 、NR^c4 S(O)R^b4 、NR^c4 S(O)₂ R^b4 、NR^c4 S(O)₂ NR^c4 R^d4 、S(O)R^b4 、S(O)NR^c4 R^d4 、S(O)₂ R^b4 及S(O)₂ NR^c4 R^d4 ； Cy¹ 及Cy² 各自獨立地選自：C₆ _- ₁₀ 芳基、C₃ _- ₁₀ 環烷基、5-10員雜芳基及4-10員雜環烷基，其各者視情況經1、2、3、4或5個獨立地選自R^Cy 之取代基取代；各R^Cy 獨立地選自：鹵基、C₁ _- ₆ 烷基、C₁ _- ₆ 鹵烷基、C₂ _- ₆ 烯基、C₆ _- ₁₀ 芳基、C₃ _- ₁₀ 環烷基、5-10員雜芳基、4-10員雜環烷基、CN、NO₂ 、OR^a5 、SR^a5 、C(O)R^b5 、C(O)NR^c5 R^d5 、C(O)OR^a5 、OC(O)R^b5 、OC(O)NR^c5 R^d5 、NR^c5 R^d5 、NR^c5 C(O)R^b5 、NR^c5 C(O)OR^a5 、NR^c5 C(O)NR^c5 R^d5 、NR^c5 S(O)R^b5 、NR^c5 S(O)₂ R^b5 、NR^c5 S(O)₂ NR^c5 R^d5 、S(O)R^b5 、S(O)NR^c5 R^d5 、S(O)₂ R^b5 及S(O)₂ NR^c5 R^d5 ，其中該C₁ _- ₆ 烷基、C₂ _- ₆ 烯基C₆ _- ₁₀ 芳基、C₃ _- ₁₀ 環烷基、5-10員雜芳基及4-10員雜環烷基各自視情況經1、2、3、4或5個獨立地選自以下之取代基取代：鹵基、C₁ _- ₆ 烷基、CN、NO₂ 、OR^a5 、SR^a5 、C(O)R^b5 、C(O)NR^c5 R^d5 、C(O)OR^a5 、OC(O)R^b5 、OC(O)NR^c5 R^d5 、NR^c5 R^d5 、NR^c5 C(O)R^b5 、NR^c5 C(O)OR^a5 、NR^c5 C(O)NR^c5 R^d5 、NR^c5 S(O)R^b5 、NR^c5 S(O)₂ R^b5 、NR^c5 S(O)₂ NR^c5 R^d5 、S(O)R^b5 、S(O)NR^c5 R^d5 、S(O)₂ R^b5 及S(O)₂ NR^c5 R^d5 ；各R^a 、R^a1 、R^a2 、R^a3 、R^a4 及R^a5 獨立地選自：H、C₁ _- ₆ 烷基、C₁ _- ₄ 鹵烷基、C₂ _- ₆ 烯基、C₆ _- ₁₀ 芳基、C₃ _- ₁₀ 環烷基、5-10員雜芳基、4-10員雜環烷基、C₆ _- ₁₀ 芳基-C₁ _- ₄ 烷基、C₃ _- ₁₀ 環烷基-C₁ _- ₄ 烷基、(5-10員雜芳基)-C₁ _- ₄ 烷基或(4-10員雜環烷基)-C₁ _- ₄ 烷基，其中該C₁ _- ₆ 烷基、C₂ _- ₆ 烯基、C₆ _- ₁₀ 芳基、C₃ _- ₁₀ 環烷基、5-10員雜芳基、4-10員雜環烷基、C₆ _- ₁₀ 芳基-C₁ _- ₄ 烷基、C₃ _- ₁₀ 環烷基-C₁ _- ₄ 烷基、(5-10員雜芳基)-C₁ _- ₄ 烷基及(4-10員雜環烷基)-C₁ _- ₄ 烷基各自視情況經1、2、3、4或5個獨立地選自以下之取代基取代：C₁ _- ₄ 烷基、鹵基、CN、OR^a6 、C(O)R^b6 、C(O)NR^c6 R^d6 、C(O)OR^a6 、OC(O)R^b6 、OC(O)NR^c6 R^d6 、NR^c6 R^d6 、NR^c6 C(O)R^b6 、NR^c6 C(O)NR^c6 R^d6 、NR^c6 C(O)OR^a6 、S(O)R^b6 、S(O)NR^c6 R^d6 、S(O)₂ R^b6 、NR^c6 S(O)₂ R^b6 、NR^c6 S(O)₂ NR^c6 R^d6 及S(O)₂ NR^c6 R^d6 ；各R^b1 、R^b2 、R^b3 、R^b4 及R^b5 獨立地選自：H、C₁ _- ₆ 烷基、C₁ _- ₄ 鹵烷基、C₂ _- ₆ 烯基、C₆ _- ₁₀ 芳基、C₃ _- ₁₀ 環烷基、5-10員雜芳基、4-10員雜環烷基、C₆ _- ₁₀ 芳基-C₁ _- ₄ 烷基、C₃ _- ₁₀ 環烷基-C₁ _- ₄ 烷基、(5-10員雜芳基)-C₁ _- ₄ 烷基或(4-10員雜環烷基)-C₁ _- ₄ 烷基，其中該C₁ _- ₆ 烷基、C₂ _- ₆ 烯基、C₆ _- ₁₀ 芳基、C₃ _- ₁₀ 環烷基、5-10員雜芳基、4-10員雜環烷基、C₆ _- ₁₀ 芳基-C₁ _- ₄ 烷基、C₃ _- ₁₀ 環烷基-C₁ _- ₄ 烷基、(5-10員雜芳基)-C₁ _- ₄ 烷基及(4-10員雜環烷基)-C₁ _- ₄ 烷基各自視情況經1、2、3、4或5個獨立地選自以下之取代基取代：C₁ _- ₄ 烷基、鹵基、CN、OR^a6 、C(O)R^b6 、C(O)NR^c6 R^d6 、C(O)OR^a6 、OC(O)R^b ⁶ 、OC(O)NR^c6 R^d6 、NR^c6 R^d6 、NR^c6 C(O)R^b6 、NR^c6 C(O)NR^c6 R^d6 、NR^c6 C(O)OR^a6 、S(O)R^b6 、S(O)NR^c6 R^d6 、S(O)₂ R^b6 、NR^c6 S(O)₂ R^b6 、NR^c6 S(O)₂ NR^c6 R^d6 及S(O)₂ NR^c6 R^d6 ；各R^c 、R^d 、R^c1 、R^d1 、R^c2 、R^d2 、R^c3 、R^d3 、R^c4 、R^d4 、R^c5 及R^d5 獨立地選自：H、C₁ _- ₆ 烷基、C₁ _- ₄ 鹵烷基、C₂ _- ₆ 烯基、C₆ _- ₁₀ 芳基、C₃ _- ₁₀ 環烷基、5-10員雜芳基、4-10員雜環烷基、C₆ _- ₁₀ 芳基-C₁ _- ₄ 烷基、C₃ _- ₁₀ 環烷基-C₁ _- ₄ 烷基、(5-10員雜芳基)-C₁ _- ₄ 烷基或(4-10員雜環烷基)-C₁ _- ₄ 烷基，其中該C₁ _- ₆ 烷基、C₂ _- ₆ 烯基、C₆ _- ₁₀ 芳基、C₃ _- ₁₀ 環烷基、5-10員雜芳基、4-10員雜環烷基、C₆ _- ₁₀ 芳基-C₁ _- ₄ 烷基、C₃ _- ₁₀ 環烷基-C₁ _- ₄ 烷基、(5-10員雜芳基)-C₁ _- ₄ 烷基及(4-10員雜環烷基)-C₁ _- ₄ 烷基各自視情況經1、2、3、4或5個獨立地選自以下之取代基取代：C₁ _- ₄ 烷基、鹵基、CN、OR^a6 、SR^a6 、C(O)R^b6 、C(O)NR^c6 R^d6 、C(O)OR^a6 、OC(O)R^b6 、OC(O)NR^c6 R^d6 、NR^c6 R^d6 、NR^c6 C(O)R^b6 、NR^c6 C(O)NR^c6 R^d6 、NR^c6 C(O)OR^a6 、S(O)R^b6 、S(O)NR^c6 R^d6 、S(O)₂ R^b6 、NR^c6 S(O)₂ R^b6 、NR^c6 S(O)₂ NR^c6 R^d6 及S(O)₂ NR^c6 R^d6 ；或任何R^c 及R^d 連同其所連接之N原子形成視情況經1、2或3個獨立地選自以下之取代基取代的4員、5員、6員或7員雜環烷基：C₁ _- ₆ 烷基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基、5-6員雜芳基、鹵基、CN、OR^a6 、SR^a6 、C(O)R^b6 、C(O)NR^c6 R^d6 、C(O)OR^a6 、OC(O)R^b6 、OC(O)NR^c6 R^d6 、NR^c6 R^d6 、NR^c6 C(O)R^b6 、NR^c6 C(O)NR^c6 R^d6 、NR^c6 C(O)OR^a6 、S(O)R^b6 、S(O)NR^c6 R^d6 、S(O)₂ R^b6 、NR^c6 S(O)₂ R^b6 、NR^c6 S(O)₂ NR^c6 R^d6 及S(O)₂ NR^c6 R^d6 ，其中該C₁ _- ₆ 烷基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基及5-6員雜芳基視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、CN、OR^a6 、SR^a6 、C(O)R^b6 、C(O)NR^c6 R^d6 、C(O)OR^a6 、OC(O)R^b6 、OC(O)NR^c6 R^d6 、NR^c6 R^d6 、NR^c6 C(O)R^b6 、NR^c6 C(O)NR^c6 R^d6 、NR^c6 C(O)OR^a6 、S(O)R^b6 、S(O)NR^c6 R^d6 、S(O)₂ R^b6 、NR^c6 S(O)₂ R^b6 、NR^c6 S(O)₂ NR^c6 R^d6 及S(O)₂ NR^c6 R^d6 ；或任何R^c1 及R^d1 連同其所連接之N原子形成視情況經1、2或3個獨立地選自以下之取代基取代的4員、5員、6員或7員雜環烷基：C₁ _- ₆ 烷基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基、5-6員雜芳基、鹵基、CN、OR^a6 、SR^a6 、C(O)R^b6 、C(O)NR^c6 R^d6 、C(O)OR^a6 、OC(O)R^b6 、OC(O)NR^c6 R^d6 、NR^c6 R^d6 、NR^c6 C(O)R^b6 、NR^c6 C(O)NR^c6 R^d6 、NR^c6 C(O)OR^a6 、S(O)R^b6 、S(O)NR^c6 R^d6 、S(O)₂ R^b6 、NR^c6 S(O)₂ R^b6 、NR^c6 S(O)₂ NR^c6 R^d6 及S(O)₂ NR^c6 R^d6 ，其中該C₁ _- ₆ 烷基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基及5-6員雜芳基各自視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、CN、OR^a6 、SR^a6 、C(O)R^b6 、C(O)NR^c6 R^d6 、C(O)OR^a6 、OC(O)R^b6 、OC(O)NR^c6 R^d6 、NR^c6 R^d6 、NR^c6 C(O)R^b6 、NR^c6 C(O)NR^c6 R^d6 、NR^c6 C(O)OR^a6 、S(O)R^b6 、S(O)NR^c6 R^d6 、S(O)₂ R^b6 、NR^c6 S(O)₂ R^b6 、NR^c6 S(O)₂ NR^c6 R^d6 及S(O)₂ NR^c6 R^d6 ；或任何R^c2 及R^d2 連同其所連接之N原子形成視情況經1、2或3個獨立地選自以下之取代基取代的4員、5員、6員或7員雜環烷基：C₁ _- ₆ 烷基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基及5-6員雜芳基、C₁ _- ₆ 鹵烷基、鹵基、CN、OR^a6 、SR^a6 、C(O)R^b6 、C(O)NR^c6 R^d6 、C(O)OR^a6 、OC(O)R^b6 、OC(O)NR^c6 R^d6 、NR^c6 R^d6 、NR^c6 C(O)R^b6 、NR^c6 C(O)NR^c6 R^d6 、NR^c6 C(O)OR^a6 、S(O)R^b6 、S(O)NR^c6 R^d6 、S(O)₂ R^b6 、NR^c6 S(O)₂ R^b6 、NR^c6 S(O)₂ NR^c6 R^d6 及S(O)₂ NR^c6 R^d6 ，其中該C₁ _- ₆ 烷基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基及5-6員雜芳基各自視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、CN、OR^a6 、SR^a6 、C(O)R^b6 、C(O)NR^c6 R^d6 、C(O)OR^a6 、OC(O)R^b6 、OC(O)NR^c6 R^d6 、NR^c6 R^d6 、NR^c6 C(O)R^b6 、NR^c6 C(O)NR^c6 R^d6 、NR^c6 C(O)OR^a6 、S(O)R^b6 、S(O)NR^c6 R^d6 、S(O)₂ R^b6 、NR^c6 S(O)₂ R^b6 、NR^c6 S(O)₂ NR^c6 R^d6 及S(O)₂ NR^c6 R^d6 ；或任何R^c3 及R^d3 連同其所連接之N原子形成視情況經1、2或3個獨立地選自以下之取代基取代的4員、5員、6員或7員雜環烷基：C₁ _- ₆ 烷基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基、5-6員雜芳基、C₁ _- ₆ 鹵烷基、鹵基、CN、OR^a6 、SR^a6 、C(O)R^b6 、C(O)NR^c6 R^d6 、C(O)OR^a6 、OC(O)R^b6 、OC(O)NR^c6 R^d6 、NR^c6 R^d6 、NR^c6 C(O)R^b6 、NR^c6 C(O)NR^c6 R^d6 、NR^c6 C(O)OR^a6 、S(O)R^b6 、S(O)NR^c6 R^d6 、S(O)₂ R^b6 、NR^c6 S(O)₂ R^b6 、NR^c6 S(O)₂ NR^c6 R^d6 及S(O)₂ NR^c6 R^d6 ，其中該C₁ _- ₆ 烷基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基及5-6員雜芳基各自視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、CN、OR^a6 、SR^a6 、C(O)R^b6 、C(O)NR^c6 R^d6 、C(O)OR^a6 、OC(O)R^b6 、OC(O)NR^c6 R^d6 、NR^c6 R^d6 、NR^c6 C(O)R^b6 、NR^c6 C(O)NR^c6 R^d6 、NR^c6 C(O)OR^a6 、S(O)R^b6 、S(O)NR^c6 R^d6 、S(O)₂ R^b6 、NR^c6 S(O)₂ R^b6 、NR^c6 S(O)₂ NR^c6 R^d6 及S(O)₂ NR^c6 R^d6 ；或任何R^c4 及R^d4 連同其所連接之N原子形成視情況經1、2或3個獨立地選自以下之取代基取代的4員、5員、6員或7員雜環烷基：C₁ _- ₆ 烷基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基、5-6員雜芳基、C₁ _- ₆ 鹵烷基、鹵基、CN、OR^a6 、SR^a6 、C(O)R^b6 、C(O)NR^c6 R^d6 、C(O)OR^a6 、OC(O)R^b ⁶ 、OC(O)NR^c6 R^d6 、NR^c6 R^d6 、NR^c6 C(O)R^b6 、NR^c6 C(O)NR^c6 R^d6 、NR^c6 C(O)OR^a6 、S(O)R^b6 、S(O)NR^c6 R^d6 、S(O)₂ R^b6 、NR^c6 S(O)₂ R^b6 、NR^c6 S(O)₂ NR^c6 R^d6 及S(O)₂ NR^c6 R^d6 ，其中該C₁ _- ₆ 烷基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基及5-6員雜芳基各自視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、CN、OR^a6 、SR^a6 、C(O)R^b6 、C(O)NR^c6 R^d6 、C(O)OR^a6 、OC(O)R^b6 、OC(O)NR^c6 R^d6 、NR^c6 R^d6 、NR^c6 C(O)R^b6 、NR^c6 C(O)NR^c6 R^d6 、NR^c6 C(O)OR^a6 、S(O)R^b6 、S(O)NR^c6 R^d6 、S(O)₂ R^b6 、NR^c6 S(O)₂ R^b6 、NR^c6 S(O)₂ NR^c6 R^d6 及S(O)₂ NR^c6 R^d6 ；或任何R^c5 及R^d5 連同其所連接之N原子形成視情況經1、2或3個獨立地選自以下之取代基取代的4員、5員、6員或7員雜環烷基：C₁ _- ₆ 烷基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基、5-6員雜芳基、C₁ _- ₆ 鹵烷基、鹵基、CN、OR^a6 、SR^a6 、C(O)R^b6 、C(O)NR^c6 R^d6 、C(O)OR^a6 、OC(O)R^b6 、OC(O)NR^c6 R^d6 、NR^c6 R^d6 、NR^c6 C(O)R^b6 、NR^c6 C(O)NR^c6 R^d6 、NR^c6 C(O)OR^a6 、S(O)R^b6 、S(O)NR^c6 R^d6 、S(O)₂ R^b6 、NR^c6 S(O)₂ R^b6 、NR^c6 S(O)₂ NR^c6 R^d6 及S(O)₂ NR^c6 R^d6 ，其中該C₁ _- ₆ 烷基、C₃ _- ₇ 環烷基、4-7員雜環烷基、C₆ _- ₁₀ 芳基及5-6員雜芳基各自視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、CN、OR^a6 、SR^a6 、C(O)R^b6 、C(O)NR^c6 R^d6 、C(O)OR^a6 、OC(O)R^b6 、OC(O)NR^c6 R^d6 、NR^c6 R^d6 、NR^c6 C(O)R^b6 、NR^c6 C(O)NR^c6 R^d6 、NR^c6 C(O)OR^a6 、S(O)R^b6 、S(O)NR^c6 R^d6 、S(O)₂ R^b6 、NR^c6 S(O)₂ R^b6 、NR^c6 S(O)₂ NR^c6 R^d6 及S(O)₂ NR^c6 R^d6 ；各R^a6 、R^b6 、R^c6 及R^d6 獨立地選自：H、C₁ _- ₄ 烷基、C₂ _- ₄ 烯基、C₃ _- ₇ 環烷基、苯基、5-6員雜芳基及4-7員雜環烷基，其中該C₁ _- ₄ 烷基、C₂ _- ₄ 烯基、C₃ _- ₇ 環烷基、苯基、5-6員雜芳基及4-7員雜環烷基各自視情況經1、2或3個獨立地選自以下之取代基取代：OH、CN、胺基、鹵基、C₁ _- ₄ 烷基、C₁ _- ₄ 烷氧基、C₁ _- ₄ 烷硫基、C₁ _- ₄ 烷胺基及二(C₁ _- ₄ 烷基)胺基； n為1或2； p為1、2或3；且 q為1或2；其中任何前述4-10員或4-7員雜環烷基視情況包含1、2或3個側氧取代基，其中存在之各側氧取代基在形成4-10員或4-7員雜環烷基之碳、氮或硫原子之環上經取代。在一些實施例中，L為O。在一些實施例中，L為NR⁴ 。在一些實施例中，W為CR⁵ ；X為N；且Y為CR⁷ 。在一些實施例中，W為N；X為N；且Y為CR⁷ 。在一些實施例中，W為CR⁵ ；X為CR⁶ ；且Y為N。在一些實施例中，W為CR⁵ ；X為CR⁶ ；且Y為CR⁷ 。在一些實施例中，W為N；X為CR⁶ ；且Y為CR⁷ 。在一些實施例中，R² 為H且R³ 為H。在一些實施例中，R² 為H且R³ 為C₁ _- ₄ 烷基。在一些實施例中，R² 為H且R³ 為甲基。在一些實施例中，R² 為H且R³ 為C₁ _- ₄ 鹵烷基。在一些實施例中，R² 為H且R³ 為三氟甲基。在一些實施例中，n為1。在一些實施例中，n為2。在一些實施例中，R¹ 為H。在一些實施例中，R¹ 為C₁ _- ₁₀ 烷基、C₃ _- ₁₀ 環烷基、苯基、-(CR⁸ R⁹ )_p OC(O)R¹⁰ 、-(CR⁸ R⁹ )_p NR¹¹ R¹² 或-(CR⁸ R⁹ )_p C(O)NR¹¹ R¹² ，其中該C₁ _- ₁₀ 烷基、C₃ _- ₁₀ 環烷基及苯基各自視情況經1、2、3、4或5個獨立地選自以下之取代基取代：F、Cl、Br、CN、C₁ _- ₄ 烷基及C₁ _- ₄ 鹵烷基。在一些實施例中，R¹ 為C₁ _- ₁₀ 烷基。在一些實施例中，R¹ 為乙基。在一些實施例中，R⁴ 為H。在一些實施例中，R⁵ 為H。在一些實施例中，R⁶ 為H。在一些實施例中，R⁷ 不為H。在一些實施例中，R⁷ 為C₁ _- ₄ 烷基、NR¹³ R¹⁴ 或OR¹⁵ 。在一些實施例中，R⁷ 為NR¹³ R¹⁴ 。在一些實施例中，R⁷ 為NH₂ 。在一些實施例中，R⁷ 為C₁ _- ₄ 烷基。在一些實施例中，R⁷ 為OR¹⁵ 。在一些實施例中，環A為C₃ _- ₁₀ 環烷基。在一些實施例中，環A為C₆ _- ₁₀ 芳基。在一些實施例中，環A為苯基。在一些實施例中，環A為4至10員雜環烷基。在一些實施例中，環A為苯基、金剛烷基、萘基、1,2,3,4-四氫喹喏啉基、3,4-二氫喹唑啉基、1,2,3,4-二氫喹唑啉基或吡啶基。在一些實施例中，環A為5至10員雜芳基。在一些實施例中，R^A 、R^B 、R^C 及R^D 中之至少一者不為氫。在一些實施例中，R^A 、R^B 、R^C 及R^D 中之至少兩者不為氫。在一些實施例中，R^A 為Cy¹ 。在一些實施例中，R^A 為C₆ _- ₁₀ 芳基或5-10員雜芳基，其各者視情況經1、2、3、4或5個獨立地選自R^Cy 之取代基取代。在一些實施例中，R^A 為視情況經1、2、3、4或5個獨立地選自R^Cy 之取代基取代的5-10員雜芳基。在一些實施例中，R^A 為視情況經1、2或3個獨立地選自R^Cy 之取代基取代的5至6員雜芳基。在一些實施例中，R^A 為視情況經1、2、3、4或5個獨立地選自R^Cy 之取代基取代的吡唑基。在一些實施例中，R^A 為3-甲基-1H-吡唑-1-基。在一些實施例中，R^A 為視情況經1、2或3個獨立地選自R^Cy 之取代基取代的C₆ _- ₁₀ 芳基。在一些實施例中，R^A 視情況經1、2或3個獨立地選自R^Cy 之取代基取代的苯基。在一些實施例中，R^B 為H。在一些實施例中，R^B 為Cy² 、鹵基、C₁ _- ₆ 烷基、C₂ _- ₆ 烯基、C₁ _- ₆ 鹵烷基、CN、NO₂ 、OR^a3 、SR^a3 、C(O)R^b3 、C(O)NR^c3 R^d3 、C(O)OR^a3 、OC(O)R^b3 、OC(O)NR^c3 R^d3 、NR^c3 R^d3 、NR^c3 C(O)R^b3 、NR^c3 C(O)OR^a3 、NR^c3 C(O)NR^c3 R^d3 、NR^c3 S(O)R^b3 、NR^c3 S(O)₂ R^b3 、NR^c3 S(O)₂ NR^c3 R^d3 、S(O)R^b3 、S(O)NR^c3 R^d3 、S(O)₂ R^b3 及S(O)₂ NR^c3 R^d3 ，其中該C₁ _- ₆ 烷基及C₂ _- ₆ 烯基各自視情況經1、2、3、4或5個獨立地選自以下之取代基取代：Cy² 、鹵基、C₁ _- ₆ 烷基、C₂ _- ₆ 烯基、C₁ _- ₆ 鹵烷基、CN、NO₂ 、OR^a3 、SR^a3 、C(O)R^b3 、C(O)NR^c3 R^d3 、C(O)OR^a3 、OC(O)R^b3 、OC(O)NR^c3 R^d3 、NR^c3 R^d3 、NR^c3 C(O)R^b3 、NR^c3 C(O)OR^a3 、NR^c3 C(O)NR^c3 R^d3 、NR^c3 S(O)R^b3 、NR^c1 S(O)₂ R^b3 、NR^c3 S(O)₂ NR^c3 R^d3 、S(O)R^b3 、S(O)NR^c3 R^d3 、S(O)₂ R^b3 及S(O)₂ NR^c3 R^d3 。在一些實施例中，R^B 為Cy² 。在一些實施例中，R^B 為C₆ _- ₁₀ 芳基或5-10員雜芳基，其各者視情況經1、2、3、4或5個獨立地選自R^Cy 之取代基取代。在一些實施例中，R^B 為鹵基、C₁ _- ₆ 烷基、C₂ _- ₆ 烯基、C₁ _- ₆ 鹵烷基、CN、NO₂ 、OR^a3 、SR^a3 、C(O)R^b3 、C(O)NR^c3 R^d3 、C(O)OR^a3 、OC(O)R^b3 、OC(O)NR^c3 R^d3 、NR^c3 R^d3 、NR^c3 C(O)R^b3 、NR^c3 C(O)OR^a3 、NR^c3 C(O)NR^c3 R^d3 、NR^c3 S(O)R^b3 、NR^c3 S(O)₂ R^b3 、NR^c3 S(O)₂ NR^c3 R^d3 、S(O)R^b3 、S(O)NR^c3 R^d3 、S(O)₂ R^b3 及S(O)₂ NR^c3 R^d3 ，其中該C₁ _- ₆ 烷基及C₂ _- ₆ 烯基各自視情況經1、2、3、4或5個獨立地選自以下之取代基取代：Cy² 、鹵基、C₁ _- ₆ 烷基、C₂ _- ₆ 烯基、C₁ _- ₆ 鹵烷基、CN、NO₂ 、OR^a3 、SR^a3 、C(O)R^b3 、C(O)NR^c3 R^d3 、C(O)OR^a3 、OC(O)R^b3 、OC(O)NR^c3 R^d3 、NR^c3 R^d3 、NR^c3 C(O)R^b3 、NR^c3 C(O)OR^a3 、NR^c3 C(O)NR^c3 R^d3 、NR^c3 S(O)R^b3 、NR^c1 S(O)₂ R^b3 、NR^c3 S(O)₂ NR^c3 R^d3 、S(O)R^b3 、S(O)NR^c3 R^d3 、S(O)₂ R^b3 及S(O)₂ NR^c3 R^d3 。在一些實施例中，R^B 為鹵基。在一些實施例中，R^C 為H。在一些實施例中，R^C 為鹵基、C₁ _- ₆ 烷基、C₂ _- ₆ 烯基、C₁ _- ₆ 鹵烷基、CN、NO₂ 、OR^a4 、SR^a4 、C(O)R^b4 、C(O)NR^c4 R^d4 、C(O)OR^a4 、OC(O)R^b4 、OC(O)NR^c4 R^d4 、NR^c4 R^d4 、NR^c4 C(O)R^b4 、NR^c4 C(O)OR^a4 、NR^c4 C(O)NR^c4 R^d4 、NR^c4 S(O)R^b4 、NR^c4 S(O)₂ R^b4 、NR^c4 S(O)₂ NR^c4 R^d4 、S(O)R^b4 、S(O)NR^c4 R^d4 、S(O)₂ R^b4 及S(O)₂ NR^c4 R^d4 ；其中該C₁ _- ₆ 烷基及C₂ _- ₆ 烯基各自視情況經1、2、3、4或5個獨立地選自以下之取代基取代：C₆ _- ₁₀ 芳基、C₃ _- ₁₀ 環烷基、5-10員雜芳基、4-10員雜環烷基、鹵基、C₁ _- ₆ 烷基、C₂ _- ₆ 烯基、C₁ _- ₆ 鹵烷基、CN、NO₂ 、OR^a4 、SR^a4 、C(O)R^b4 、C(O)NR^c4 R^d4 、C(O)OR^a4 、OC(O)R^b4 、OC(O)NR^c4 R^d4 、NR^c4 R^d4 、NR^c4 C(O)R^b4 、NR^c4 C(O)OR^a4 、NR^c4 C(O)NR^c4 R^d4 、NR^c4 S(O)R^b4 、NR^c4 S(O)₂ R^b4 、NR^c4 S(O)₂ NR^c4 R^d4 、S(O)R^b4 、S(O)NR^c4 R^d4 、S(O)₂ R^b4 及S(O)₂ NR^c4 R^d4 。在一些實施例中，R^D 為H。在一些實施例中，R^D 為鹵基、C₁ _- ₆ 烷基、C₂ _- ₆ 烯基、C₁ _- ₆ 鹵烷基、CN、NO₂ 、OR^a4 、SR^a4 、C(O)R^b4 、C(O)NR^c4 R^d4 、C(O)OR^a4 、OC(O)R^b4 、OC(O)NR^c4 R^d4 、NR^c4 R^d4 、NR^c4 C(O)R^b4 、NR^c4 C(O)OR^a4 、NR^c4 C(O)NR^c4 R^d4 、NR^c4 S(O)R^b4 、NR^c4 S(O)₂ R^b4 、NR^c4 S(O)₂ NR^c4 R^d4 、S(O)R^b4 、S(O)NR^c4 R^d4 、S(O)₂ R^b4 及S(O)₂ NR^c4 R^d4 ；其中該C₁ _- ₆ 烷基及C₂ _- ₆ 烯基各自視情況經1、2、3、4或5個獨立地選自以下之取代基取代：C₆ _- ₁₀ 芳基、C₃ _- ₁₀ 環烷基、5-10員雜芳基、4-10員雜環烷基、鹵基、C₁ _- ₆ 烷基、C₂ _- ₆ 烯基、C₁ _- ₆ 鹵烷基、CN、NO₂ 、OR^a4 、SR^a4 、C(O)R^b4 、C(O)NR^c4 R^d4 、C(O)OR^a4 、OC(O)R^b4 、OC(O)NR^c4 R^d4 、NR^c4 R^d4 、NR^c4 C(O)R^b4 、NR^c4 C(O)OR^a4 、NR^c4 C(O)NR^c4 R^d4 、NR^c4 S(O)R^b4 、NR^c4 S(O)₂ R^b4 、NR^c4 S(O)₂ NR^c4 R^d4 、S(O)R^b4 、S(O)NR^c4 R^d4 、S(O)₂ R^b4 及S(O)₂ NR^c4 R^d4 。在一些實施例中，本文所描述之化合物具有式IIa：IIa。在一些實施例中，本文所描述之化合物具有式IIb：IIb。在一些實施例中，本文所描述之化合物具有式IIc：IIc。在一些實施例中，本文所描述之化合物具有式IId：IId。在一些實施例中，本文所描述之化合物具有式IIe：IIe。在一些實施例中，在本文所描述之化合物具有式IIa、IIb、IIc、IId或IIe時，L為O。在一些實施例中，在本文所描述之化合物具有式IIa、IIb、IIc、IId或IIe時，L為NR₄ 。在一些實施例中，在本文所描述之化合物具有式IIa、IIb、IIc、IId或IIe時，R³ 為H。在一些實施例中，在本文所描述之化合物具有式IIa、IIb、IIc、IId或IIe時，R² 為CF₃ 且R³ 為H。在一些實施例中，在本文所描述之化合物具有式IIa、IIb、IIc、IId或IIe時，R¹ 為H或C₁ _- ₁₀ 烷基。在一些實施例中，在本文所描述之化合物具有式IIa、IIb、IIc、IId或IIe時，R^A 為Cy¹ 。在一些實施例中，在本文所描述之化合物具有式IIa、IIb、IIc、IId或IIe時，R^A 為C₆ _- ₁₀ 芳基或5-10員雜芳基，其各者視情況經1、2、3、4或5個獨立地選自R^Cy 之取代基取代。在一些實施例中，在本文所描述之化合物具有式IIa、IIb、IIc、IId或IIe時，R^A 為視情況經1、2、3、4或5個獨立地選自R^Cy 之取代基取代的5-10員雜芳基。在一些實施例中，在本文所描述之化合物具有式IIa、IIb、IIc、IId或IIe時，R^A 為視情況經1、2或3個獨立地選自R^Cy 之取代基取代的5至6員雜芳基。在一些實施例中，在本文所描述之化合物具有式IIa、IIb、IIc、IId或IIe時，R^A 為視情況經1、2或3個獨立地選自R^Cy 之取代基取代的C₆ _- ₁₀ 芳基。在一些實施例中，在本文所描述之化合物具有式IIa、IIb、IIc、IId或IIe時，R^A 為視情況經1、2或3個獨立地選自R^Cy 之取代基取代的苯基。在一些實施例中，在本文所描述之化合物具有式IIa、IIb、IIc、IId或IIe時，R^B 為Cy² 。在一些實施例中，在本文所描述之化合物具有式IIa、IIb、IIc、IId或IIe時，R^B 為H、鹵基、C₁ _- ₆ 烷基、C₂ _- ₆ 烯基、C₁ _- ₆ 鹵烷基、CN、OR^a3 、C(O)NR^c3 R^d3 或C(O)OR^a3 ，其中該C₁ _- ₆ 烷基及C₂ _- ₆ 烯基各自視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、C₁ _- ₆ 鹵烷基、CN、NO₂ 、OR^a3 、SR^a3 、C(O)R^b3 、C(O)NR^c3 R^d3 、C(O)OR^a3 、OC(O)R^b3 、OC(O)NR^c3 R^d3 、NR^c3 R^d3 、NR^c3 C(O)R^b3 、NR^c3 C(O)OR^a3 、NR^c3 C(O)NR^c3 R^d3 、NR^c3 S(O)R^b3 、NR^c1 S(O)₂ R^b3 、NR^c3 S(O)₂ NR^c3 R^d3 、S(O)R^b3 、S(O)NR^c3 R^d3 、S(O)₂ R^b3 及S(O)₂ NR^c3 R^d3 。在一些實施例中，在本文所描述之化合物具有式IIa、IIb、IIc、IId或IIe時，R^C 為H。在一些實施例中，在本文所描述之化合物具有式IIa、IIb、IIc、IId或IIe時，R^D 為H。在一些實施例中，在本文所描述之化合物具有式IIa、IIb、IIc、IId或IIe時，R⁵ 為H。在一些實施例中，在本文所描述之化合物具有式IIa、IIb、IIc、IId或IIe時，R⁶ 為H。在一些實施例中，本文所描述之化合物具有式IIIa或IIIb：IIIaIIIb。在一些實施例中，在本文所描述之化合物具有式IIIa或IIIb時，R² 為CF₃ 。在一些實施例中，在本文所描述之化合物具有式IIIa或IIIb時，R¹ 為H或C₁ _- ₁₀ 烷基。在一些實施例中，在本文所描述之化合物具有式IIIa或IIIb時，R^A 為Cy¹ 。在一些實施例中，在本文所描述之化合物具有式IIIa或IIIb時，R^A 為C₆ _- ₁₀ 芳基或5-10員雜芳基，其各者視情況經1、2、3、4或5個獨立地選自R^Cy 之取代基取代。在一些實施例中，在本文所描述之化合物具有式IIIa或IIIb時，R^A 為視情況經1、2、3、4或5個獨立地選自R^Cy 之取代基取代的5-10員雜芳基。在一些實施例中，在本文所描述之化合物具有式IIIa或IIIb時，R^A 為視情況經1、2或3個獨立地選自R^Cy 之取代基取代的5至6員雜芳基。在一些實施例中，在本文所描述之化合物具有式IIIa或IIIb時，R^A 為視情況經1、2或3個獨立地選自R^Cy 之取代基取代的C₆ _- ₁₀ 芳基。在一些實施例中，在本文所描述之化合物具有式IIIa或IIb時，R^A 為視情況經1、2或3個獨立地選自R^Cy 之取代基取代的苯基。在一些實施例中，在本文所描述之化合物具有式IIIa或IIIb時，R^B 為Cy² 。在一些實施例中，在本文所描述之化合物具有式IIa或IIb時，R^B 為H、鹵基、C₁ _- ₆ 烷基、C₂ _- ₆ 烯基、C₁ _- ₆ 鹵烷基、CN、OR^a3 、C(O)NR^c3 R^d3 或C(O)OR^a3 ，其中該C₁ _- ₆ 烷基及C₂ _- ₆ 烯基各自視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、C₁ _- ₆ 鹵烷基、CN、NO₂ 、OR^a3 、SR^a3 、C(O)R^b3 、C(O)NR^c3 R^d3 、C(O)OR^a3 、OC(O)R^b3 、OC(O)NR^c3 R^d3 、NR^c3 R^d3 、NR^c3 C(O)R^b3 、NR^c3 C(O)OR^a3 、NR^c3 C(O)NR^c3 R^d3 、NR^c3 S(O)R^b3 、NR^c1 S(O)₂ R^b3 、NR^c3 S(O)₂ NR^c3 R^d3 、S(O)R^b3 、S(O)NR^c3 R^d3 、S(O)₂ R^b3 及S(O)₂ NR^c3 R^d3 。在一些實施例中，在本文所描述之化合物具有式IIIa或IIIb時，R^C 為H。在一些實施例中，在本文所描述之化合物具有式IIIa或IIIb時，R^D 為H。在一些實施例中，本文所描述之化合物具有式IV：IV。在一些實施例中，在本文所描述之化合物具有式IV時，R² 為CF₃ 。在一些實施例中，在本文所描述之化合物具有式IV時，R¹ 為H或C₁ _- ₁₀ 烷基。在一些實施例中，在本文所描述之化合物具有式IV時，R^A 為Cy¹ 。在一些實施例中，在本文所描述之化合物具有式IV時，R^A 為C₆ _- ₁₀ 芳基或5-10員雜芳基，其各者視情況經1、2、3、4或5個獨立地選自R^Cy 之取代基取代。在一些實施例中，在本文所描述之化合物具有式IV時，R^A 為視情況經1、2、3、4或5個獨立地選自R^Cy 之取代基取代的5-10員雜芳基。在一些實施例中，在本文所描述之化合物具有式IV時，R^A 為視情況經1、2或3個獨立地選自R^Cy 之取代基取代的5至6員雜芳基。在一些實施例中，在本文所描述之化合物具有式IV時，R^A 為視情況經1、2或3個獨立地選自R^Cy 之取代基取代的C₆ _- ₁₀ 芳基。在一些實施例中，在本文所描述之化合物具有式IV時，R^A 為視情況經1、2或3個獨立地選自R^Cy 之取代基取代的苯基。在一些實施例中，在本文所描述之化合物具有式IV時，R^B 為Cy² 。在一些實施例中，在本文所描述之化合物具有式IV時，R^B 為H、鹵基、C₁ _- ₆ 烷基、C₂ _- ₆ 烯基、C₁ _- ₆ 鹵烷基、CN、OR^a3 、C(O)NR^c3 R^d3 或C(O)OR^a3 ，其中該C₁ _- ₆ 烷基及C₂ _- ₆ 烯基各自視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、C₁ _- ₆ 鹵烷基、CN、NO₂ 、OR^a3 、SR^a3 、C(O)R^b3 、C(O)NR^c3 R^d3 、C(O)OR^a3 、OC(O)R^b3 、OC(O)NR^c3 R^d3 、NR^c3 R^d3 、NR^c3 C(O)R^b3 、NR^c3 C(O)OR^a3 、NR^c3 C(O)NR^c3 R^d3 、NR^c3 S(O)R^b3 、NR^c1 S(O)₂ R^b3 、NR^c3 S(O)₂ NR^c3 R^d3 、S(O)R^b3 、S(O)NR^c3 R^d3 、S(O)₂ R^b3 及S(O)₂ NR^c3 R^d3 。在一些實施例中，在本文所描述之化合物具有式IV時，R^C 為H。在一些實施例中，在本文所描述之化合物具有式IV時，R^D 為H。在一些實施例中，本文所描述之化合物具有式Va：Va。在一些實施例中，在本文所描述之化合物具有式Va時，R² 為CF₃ 。在一些實施例中，在本文所描述之化合物具有式Va時，R¹ 為H或C₁ _- ₁₀ 烷基。在一些實施例中，在本文所描述之化合物具有式Va時，R^A 為Cy¹ 。在一些實施例中，在本文所描述之化合物具有式Va時，R^A 為C₆ _- ₁₀ 芳基或5-10員雜芳基，其各者視情況經1、2、3、4或5個獨立地選自R^Cy 之取代基取代。在一些實施例中，在本文所描述之化合物具有式Va時，R^A 為視情況經1、2、3、4或5個獨立地選自R^Cy 之取代基取代的5-10員雜芳基。在一些實施例中，在本文所描述之化合物具有式Va時，R^A 為視情況經1、2或3個獨立地選自R^Cy 之取代基取代的5至6員雜芳基。在一些實施例中，在本文所描述之化合物具有式Va時，R^A 為視情況經1、2或3個獨立地選自R^Cy 之取代基取代的C₆ _- ₁₀ 芳基。在一些實施例中，在本文所描述之化合物具有式Va時，R^A 為視情況經1、2或3個獨立地選自R^Cy 之取代基取代的苯基。在一些實施例中，在本文所描述之化合物具有式Va時，R^B 為Cy² 。在一些實施例中，在本文所描述之化合物具有式Va時，R^B 為H、鹵基、C₁ _- ₆ 烷基、C₂ _- ₆ 烯基、C₁ _- ₆ 鹵烷基、CN、OR^a3 、C(O)NR^c3 R^d3 或C(O)OR^a3 ，其中該C₁ _- ₆ 烷基及C₂ _- ₆ 烯基各自視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、C₁ _- ₆ 鹵烷基、CN、NO₂ 、OR^a3 、SR^a3 、C(O)R^b3 、C(O)NR^c3 R^d3 、C(O)OR^a3 、OC(O)R^b3 、OC(O)NR^c3 R^d3 、NR^c3 R^d3 、NR^c3 C(O)R^b3 、NR^c3 C(O)OR^a3 、NR^c3 C(O)NR^c3 R^d3 、NR^c3 S(O)R^b3 、NR^c1 S(O)₂ R^b3 、NR^c3 S(O)₂ NR^c3 R^d3 、S(O)R^b3 、S(O)NR^c3 R^d3 、S(O)₂ R^b3 及S(O)₂ NR^c3 R^d3 。在一些實施例中，本文所描述之化合物具有式Vb：Vb。在一些實施例中，在本文所描述之化合物具有式Vb時，R² 為CF₃ 。在一些實施例中，在本文所描述之化合物具有式Vb時，R¹ 為H或C₁ _- ₁₀ 烷基。在一些實施例中，在本文所描述之化合物具有式Vb時，R^A 為Cy¹ 。在一些實施例中，在本文所描述之化合物具有式Vb時，R^A 為C₆ _- ₁₀ 芳基或5-10員雜芳基，其各者視情況經1、2、3、4或5個獨立地選自R^Cy 之取代基取代。在一些實施例中，在本文所描述之化合物具有式Vb時，R^A 為視情況經1、2、3、4或5個獨立地選自R^Cy 之取代基取代的5-10員雜芳基。在一些實施例中，在本文所描述之化合物具有式Vb時，R^A 為視情況經1、2或3個獨立地選自R^Cy 之取代基取代的5至6員雜芳基。在一些實施例中，在本文所描述之化合物具有式Vb時，R^A 為視情況經1、2或3個獨立地選自R^Cy 之取代基取代的C₆ _- ₁₀ 芳基。在一些實施例中，在本文所描述之化合物具有式Vb時，R^A 為視情況經1、2或3個獨立地選自R^Cy 之取代基取代的苯基。在一些實施例中，在本文所描述之化合物具有式Vb時，R^B 為Cy² 。在一些實施例中，在本文所描述之化合物具有式Vb時，R^B 為H、鹵基、C₁ _- ₆ 烷基、C₂ _- ₆ 烯基、C₁ _- ₆ 鹵烷基、CN、OR^a3 、C(O)NR^c3 R^d3 或C(O)OR^a3 ，其中該C₁ _- ₆ 烷基及C₂ _- ₆ 烯基各自視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、C₁ _- ₆ 鹵烷基、CN、NO₂ 、OR^a3 、SR^a3 、C(O)R^b3 、C(O)NR^c3 R^d3 、C(O)OR^a3 、OC(O)R^b3 、OC(O)NR^c3 R^d3 、NR^c3 R^d3 、NR^c3 C(O)R^b3 、NR^c3 C(O)OR^a3 、NR^c3 C(O)NR^c3 R^d3 、NR^c3 S(O)R^b3 、NR^c1 S(O)₂ R^b3 、NR^c3 S(O)₂ NR^c3 R^d3 、S(O)R^b3 、S(O)NR^c3 R^d3 、S(O)₂ R^b3 及S(O)₂ NR^c3 R^d3 。在一些實施例中，本文所描述之化合物具有式VI：VI。在一些實施例中，在本文所描述之化合物具有式VI時，R² 為CF₃ 。在一些實施例中，在本文所描述之化合物具有式VI時，R¹ 為H或C₁ _- ₁₀ 烷基。在一些實施例中，在本文所描述之化合物具有式VI時，R^B 為Cy² 。在一些實施例中，在本文所描述之化合物具有式VI時，Cy² 為視情況經1、2或3個獨立地選自R^Cy 之取代基取代的苯基。在一些實施例中，在本文所描述之化合物具有式VI時，R^B 為H、鹵基、C₁ _- ₆ 烷基、C₂ _- ₆ 烯基、C₁ _- ₆ 鹵烷基、CN、OR^a3 、C(O)NR^c3 R^d3 或C(O)OR^a3 ，其中該C₁ _- ₆ 烷基及C₂ _- ₆ 烯基各自視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、C₁ _- ₆ 鹵烷基、CN、NO₂ 、OR^a3 、SR^a3 、C(O)R^b3 、C(O)NR^c3 R^d3 、C(O)OR^a3 、OC(O)R^b3 、OC(O)NR^c3 R^d3 、NR^c3 R^d3 、NR^c3 C(O)R^b3 、NR^c3 C(O)OR^a3 、NR^c3 C(O)NR^c3 R^d3 、NR^c3 S(O)R^b3 、NR^c1 S(O)₂ R^b3 、NR^c3 S(O)₂ NR^c3 R^d3 、S(O)R^b3 、S(O)NR^c3 R^d3 、S(O)₂ R^b3 及S(O)₂ NR^c3 R^d3 。在一些實施例中，在本文所描述之化合物具有式VI時，R^C 為H。在一些實施例中，在本文所描述之化合物具有式VI時，R^D 為H。在一些實施例中，本文所描述之化合物具有式VIA：VIA。在一些實施例中，在本文所描述之化合物具有式VIA時，R² 為CF₃ 。在一些實施例中，在本文所描述之化合物具有式VIA時，R¹ 為H或C₁ _- ₁₀ 烷基。在一些實施例中，在本文所描述之化合物具有式VIA時，R^B 為Cy² 。在一些實施例中，在本文所描述之化合物具有式VIA時，Cy² 為視情況經1、2或3個獨立地選自R^Cy 之取代基取代的苯基。在一些實施例中，在本文所描述之化合物具有式VIA時，R^B 為H、鹵基、C₁ _- ₆ 烷基、C₂ _- ₆ 烯基、C₁ _- ₆ 鹵烷基、CN、OR^a3 、C(O)NR^c3 R^d3 或C(O)OR^a3 ，其中該C₁ _- ₆ 烷基及C₂ _- ₆ 烯基各自視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、C₁ _- ₆ 鹵烷基、CN、NO₂ 、OR^a3 、SR^a3 、C(O)R^b3 、C(O)NR^c3 R^d3 、C(O)OR^a3 、OC(O)R^b3 、OC(O)NR^c3 R^d3 、NR^c3 R^d3 、NR^c3 C(O)R^b3 、NR^c3 C(O)OR^a3 、NR^c3 C(O)NR^c3 R^d3 、NR^c3 S(O)R^b3 、NR^c1 S(O)₂ R^b3 、NR^c3 S(O)₂ NR^c3 R^d3 、S(O)R^b3 、S(O)NR^c3 R^d3 、S(O)₂ R^b3 及S(O)₂ NR^c3 R^d3 。在一些實施例中，本文所描述之化合物具有式VII：VII 其中a為0、1、2或3。在一些實施例中，在本文所描述之化合物具有式VII時，R² 為CF₃ 。在一些實施例中，在本文所描述之化合物具有式VII時，R¹ 為H或C₁ _- ₁₀ 烷基。在一些實施例中，在本文所描述之化合物具有式VII時，R^B 為Cy² 。在一些實施例中，在本文所描述之化合物具有式VII時，R^B 為H、鹵基、C₁ _- ₆ 烷基、C₂ _- ₆ 烯基、C₁ _- ₆ 鹵烷基、CN、OR^a3 、C(O)NR^c3 R^d3 或C(O)OR^a3 ，其中該C₁ _- ₆ 烷基及C₂ _- ₆ 烯基各自視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、C₁ _- ₆ 鹵烷基、CN、NO₂ 、OR^a3 、SR^a3 、C(O)R^b3 、C(O)NR^c3 R^d3 、C(O)OR^a3 、OC(O)R^b3 、OC(O)NR^c3 R^d3 、NR^c3 R^d3 、NR^c3 C(O)R^b3 、NR^c3 C(O)OR^a3 、NR^c3 C(O)NR^c3 R^d3 、NR^c3 S(O)R^b3 、NR^c1 S(O)₂ R^b3 、NR^c3 S(O)₂ NR^c3 R^d3 、S(O)R^b3 、S(O)NR^c3 R^d3 、S(O)₂ R^b3 及S(O)₂ NR^c3 R^d3 。在一些實施例中，在本文所描述之化合物具有式VII時，R^B 為H或鹵基。在一些實施例中，在本文所描述之化合物具有式VII時，R^B 為鹵基。在一些實施例中，在本文所描述之化合物具有式VII時，R^C 為H。在一些實施例中，在本文所描述之化合物具有式VII時，R^D 為H。在一些實施例中，在本文所描述之化合物具有式VII時，R^Cy 為鹵基、C₁ _- ₆ 烷基、C₁ _- ₆ 鹵烷基、4-10員雜環烷基、CN、NO₂ 、OR^a5 、SR^a5 、C(O)R^b5 、C(O)NR^c5 R^d5 、C(O)OR^a5 、NR^c5 R^d5 、S(O)₂ R^b5 及S(O)₂ NR^c5 R^d5 ，其中該C₁ _- ₆ 烷基及4-10員雜環烷基各自視情況經1、2、3、4或5個獨立地選自以下之取代基取代：鹵基、C₁ _- ₆ 烷基、CN、NO₂ 、OR^a5 、SR^a5 、C(O)R^b5 、C(O)NR^c5 R^d5 、C(O)OR^a5 、OC(O)R^b5 、OC(O)NR^c5 R^d5 、NR^c5 R^d5 、NR^c5 C(O)R^b5 、NR^c5 C(O)OR^a5 、NR^c5 C(O)NR^c5 R^d5 、NR^c5 S(O)R^b5 、NR^c5 S(O)₂ R^b5 、NR^c5 S(O)₂ NR^c5 R^d5 、S(O)R^b5 、S(O)NR^c5 R^d5 、S(O)₂ R^b5 及S(O)₂ NR^c5 R^d5 。在一些實施例中，本文所描述之化合物具有式VIII：VIII 其中a為0、1、2或3。在一些實施例中，在本文所描述之化合物具有式VIII時，R² 為CF₃ 。在一些實施例中，在本文所描述之化合物具有式VIII時，R¹ 為H或C₁ _- ₁₀ 烷基。在一些實施例中，在本文所描述之化合物具有式VIII時，R^B 為Cy² 。在一些實施例中，在本文所描述之化合物具有式VIII時，R^B 為H、鹵基、C₁ _- ₆ 烷基、C₂ _- ₆ 烯基、C₁ _- ₆ 鹵烷基、CN、OR^a3 、C(O)NR^c3 R^d3 或C(O)OR^a3 ，其中該C₁ _- ₆ 烷基及C₂ _- ₆ 烯基各自視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、C₁ _- ₆ 鹵烷基、CN、NO₂ 、OR^a3 、SR^a3 、C(O)R^b3 、C(O)NR^c3 R^d3 、C(O)OR^a3 、OC(O)R^b3 、OC(O)NR^c3 R^d3 、NR^c3 R^d3 、NR^c3 C(O)R^b3 、NR^c3 C(O)OR^a3 、NR^c3 C(O)NR^c3 R^d3 、NR^c3 S(O)R^b3 、NR^c1 S(O)₂ R^b3 、NR^c3 S(O)₂ NR^c3 R^d3 、S(O)R^b3 、S(O)NR^c3 R^d3 、S(O)₂ R^b3 及S(O)₂ NR^c3 R^d3 。在一些實施例中，在本文所描述之化合物具有式VIII時，R^B 為H或鹵基。在一些實施例中，在本文所描述之化合物具有式VIII時，R^B 為鹵基。在一些實施例中，在本文所描述之化合物具有式VIII時，R^C 為H。在一些實施例中，在本文所描述之化合物具有式VIII時，R^D 為H。在一些實施例中，在本文所描述之化合物具有式VIII時，R^Cy 為鹵基、C₁ _- ₆ 烷基、C₁ _- ₆ 鹵烷基、4-10員雜環烷基、CN、NO₂ 、OR^a5 、SR^a5 、C(O)R^b5 、C(O)NR^c5 R^d5 、C(O)OR^a5 、NR^c5 R^d5 、S(O)₂ R^b5 及S(O)₂ NR^c5 R^d5 ，其中該C₁ _- ₆ 烷基及4-10員雜環烷基各自視情況經1、2、3、4或5個獨立地選自以下之取代基取代：鹵基、C₁ _- ₆ 烷基、CN、NO₂ 、OR^a5 、SR^a5 、C(O)R^b5 、C(O)NR^c5 R^d5 、C(O)OR^a5 、OC(O)R^b5 、OC(O)NR^c5 R^d5 、NR^c5 R^d5 、NR^c5 C(O)R^b5 、NR^c5 C(O)OR^a5 、NR^c5 C(O)NR^c5 R^d5 、NR^c5 S(O)R^b5 、NR^c5 S(O)₂ R^b5 、NR^c5 S(O)₂ NR^c5 R^d5 、S(O)R^b5 、S(O)NR^c5 R^d5 、S(O)₂ R^b5 及S(O)₂ NR^c5 R^d5 。在一些實施例中，在本文所描述之化合物具有式VIII時，a為0。在一些實施例中，-C(O)OR¹ 所連接之對掌性碳具有S 組態。在一些實施例中，-R² 所連接之碳為對掌性的且具有R 組態。在一些實施例中，用於本文所描述之方法之化合物為(S)-8-(2-胺基-6-((R)-1-(5-氯-[1,1'-聯苯]-2-基)-2,2,2-三氟乙氧基)嘧啶-4-基)-2,8-二氮螺[4.5]癸烷-3-羧酸乙酯，或其醫藥學上可接受之鹽。在一些實施例中，用於本文所描述之方法之化合物為(S)-8-(2-胺基-6-((R)-1-(5-氯-[1,1'-聯苯]-2-基)-2,2,2-三氟乙氧基)嘧啶-4-基)-2,8-二氮螺[4.5]癸烷-3-羧酸，或其醫藥學上可接受之鹽。在一些實施例中，用於本文所描述之方法之化合物為(S)-8-(2-胺基-6-((R)-1-(3',4'-二甲基-3-(3-甲基-1H-吡唑-1-基)-[1,1'-聯苯]-4-基)-2,2,2-三氟乙氧基)嘧啶-4-基)-2,8-二氮螺[4.5]癸烷-3-羧酸乙酯，或其醫藥學上可接受之鹽。在一些實施例中，用於本文所描述之方法之化合物為(S)-8-(2-胺基-6-((R)-1-(3',4'-二甲基-3-(3-甲基-1H-吡唑-1-基)-[1,1'-聯苯]-4-基)-2,2,2-三氟乙氧基)嘧啶-4-基)-2,8-二氮螺[4.5]癸烷-3-羧酸，或其醫藥學上可接受之鹽。在一些實施例中，用於本文所描述之方法之化合物為(S)-8-(2-胺基-6-((R)-1-(4-氯-2-(3-甲基-1H-吡唑-1-基)苯基)-2,2,2-三氟乙氧基)嘧啶-4-基)-2,8-二氮螺[4.5]癸烷-3-羧酸乙酯，或其醫藥學上可接受之鹽。在一些實施例中，用於本文所描述之方法之化合物為(S)-8-(2-胺基-6-((R)-1-(4-氯-2-(3-甲基-1H-吡唑-1-基)苯基)-2,2,2-三氟乙氧基)嘧啶-4-基)-2,8-二氮螺[4.5]癸烷-3-羧酸，或其醫藥學上可接受之鹽(參見實例34c)。在一些實施例中，用於本文所描述之方法之化合物為(S)-8-(2-胺基-6-((R)-2,2,2-三氟-1-(3'-氟-3-(3-甲基-1H-吡唑-1-基)-4'-丙氧基-[1,1'-聯苯]-4-基)乙氧基)嘧啶-4-基)-2,8-二氮螺[4.5]癸烷-3-羧酸乙酯，或其醫藥學上可接受之鹽(參見實例63i)。在一些實施例中，化合物為(S)-8-(2-胺基-6-((R)-2,2,2-三氟-1-(3'-氟-3-(3-甲基-1H-吡唑-1-基)-4'-丙氧基-[1,1'-聯苯]-4-基)乙氧基)嘧啶-4-基)-2,8-二氮螺[4.5]癸烷-3-羧酸，或其醫藥學上可接受之鹽。應瞭解，為清楚起見而在單獨實施例之上下文中所描述的本發明之某些特徵亦可於單一實施例中組合提供。相反，為了簡便起見而描述於單個實施例之上下文中之本發明的各種特徵亦可分開或以任何適合的子組合形式提供。術語「經取代」意謂原子或原子之基團形式上置換氫作為連接至另一基團之「取代基」。氫原子經形式上移除且經取代基置換。單個二價取代基(例如側氧取代基)可置換兩個氫原子。術語「視情況經取代」意謂未經取代或經取代。獨立地選擇取代基，且取代可位於任何可以化學方式接近的位置。應瞭解，既定原子處之取代受價數限制。在整個定義中，術語「C_i _- _j 」表明包括端點之範圍，其中i及j為整數且表示碳數。實例包括C₁ _- ₄ 、C₁ _- ₆ 及其類似物。若n為整數，術語「n員」通常描述部分中之成環原子之數目，其中成環原子之數目為n。舉例而言，哌啶基為6員雜環烷基環之實例，吡唑基為5員雜芳基環之實例，吡啶基為6員雜芳基環之實例，且1,2,3,4-四氫-萘為10員環烷基之實例。在本說明書中之各個位置，對各種芳基、雜芳基、環烷基及雜環烷基環加以描述。除非另外規定，否則此等環可如價數所准許在任何環成員處連接至分子之其餘部分。舉例而言，術語「吡啶環」或「吡啶基」可指吡啶-2-基、吡啶-3-基或吡啶-4-基環。對於一變數出現超過一次之本發明之化合物，各變數可為獨立地選自定義該變數之群的不同部分。舉例而言，在描述具有兩個同時存在於同一化合物上之R基團的結構時，該兩個R基團可表示獨立地選自定義R之群的不同部分。如本文所用，單獨或與其他術語組合使用之術語「C_i _- _j 烷基」係指可為直鏈或分支鏈之具有i至j個碳原子之飽和烴基。在一些實施例中，烷基含有1至10個、1至6個、1至4個或1至3個碳原子。烷基部分之實例包括但不限於化學基團，諸如甲基、乙基、正丙基、異丙基、正丁基、第二丁基及第三丁基。如本文所用，單獨或與其他術語組合使用之術語「C_i _- _j 烷氧基」係指式-O-烷基之基團，其中烷基具有i至j個碳原子。烷氧基之實例包括甲氧基、乙氧基及丙氧基(例如正丙氧基及異丙氧基)。在一些實施例中，烷基具有1至3個碳原子或1至4個碳原子。如本文所用，「C_i _- _j 烯基」係指具有一或多個雙碳-碳鍵且具有i至j個碳原子之烷基。在一些實施例中，烯基部分含有2至6個或2至4個碳原子。烯基之實例包括但不限於乙烯基、正丙烯基、異丙烯基、正丁烯基、第二丁烯基及其類似基團。如本文所用，術語「C_i _- _j 烷胺基」係指式-NH(烷基)之基團，其中烷基具有i至j個碳原子。在一些實施例中，烷基具有1至6個或1至4個碳原子。如本文所用，術語「二C_i _- _j 烷胺基」係指式-N(烷基)₂ 之基團，其中兩個烷基各分別具有i至j個碳原子。在一些實施例中，各烷基分別具有1至6個碳原子或1至4個碳原子。如本文所用，術語「硫基」係指式-SH之基團。如本文所用，術語「C_i _- _j 烷基硫基」係指式-S-烷基之基團，其中烷基具有i至j個碳原子。在一些實施例中，烷基具有1至6個或1至4個碳原子。如本文所用，術語「胺基」係指式-NH₂ 之基團。如本文所用，單獨或與其他術語組合使用之術語「C_i _- _j 芳基」係指具有i至j個成環碳原子之單環或多環(例如具有2、3、或4個稠合環)芳族烴，例如但不限於苯基、1-萘基、2-萘基、蒽基、菲基及其類似基團。在一些實施例中，芳基為C₆ _- ₁₀ 芳基。在一些實施例中，芳基為萘環或苯環。在一些實施例中，芳基為苯基。如本文所用，術語「芳基烷基」係指式-C_i _- _j 烷基-(C_i _- _j 芳基)之基團。在一些實施例中，芳基烷基為C₆ _- ₁₀ 芳基-C₁ _- ₃ 烷基。在一些實施例中，芳基烷基為C₆ _- ₁₀ 芳基-C₁ _- ₄ 烷基。在一些實施例中，芳基烷基為苄基。如本文所用，單獨或與其他術語組合使用之術語「羰基」係指-C(=O)-基團。如本文所用，術語「羧基」係指式-C(=O)OH之基團。如本文所用，單獨或與其他術語組合使用之術語「C_i _- _j 環烷基」係指具有i至j個成環碳原子之非芳環烴部分，其可視情況含有一或多個伸烯基作為環結構之一部分。環烷基可包括單環或多環(例如具有2、3或4個稠合環)系統。環烷基之定義中亦包括一或多個芳環(芳基或雜芳基)與環烷基環稠合之部分，例如環戊烷、環戊烯、環己烷及其類似物之苯并或吡啶并衍生物。在環烷基包括稠合芳環時，環烷基可在芳族或非芳族部分中之原子處發生連接。環烷基之一或多個成環碳原子可氧化以形成羰基鍵聯。在一些實施例中，環烷基為C₃ _- ₁₀ 或C₃ _- ₇ 環烷基，其可為單環或多環的。示例性環烷基包括環丙基、環丁基、環戊基、環己基、環庚基、環戊烯基、環己烯基、環己二烯基、環庚三烯基、降冰片烷基、降蒎基、降蒈烷基、金剛烷基及其類似基團。在一些實施例中，環烷基為環丙基、環丁基、環戊基或環己基。如本文所用，術語「環烷基烷基」係指式-C_i _- _j 烷基-(C_i _- _j 環烷基)之基團。在一些實施例中，環烷基烷基為C₃ _- ₇ 環烷基-C₁ _- ₃ 烷基，其中環烷基部分為單環。在一些實施例中，環烷基烷基為C₃ _- ₇ 環烷基-C₁ _- ₄ 烷基。如本文所用，「C_i _- _j 鹵烷氧基」係指具有i至j個碳原子之式-O-鹵烷基之基團。鹵烷氧基之實例為OCF₃ 。鹵烷氧基之額外實例為OCHF₂ 。在一些實施例中，烷基具有1至6個或1至4個碳原子。如本文所用，術語「鹵基」係指選自F、Cl、I或Br之鹵素原子。在一些實施例中，「鹵基」係指選自F、Cl或Br之鹵素原子。在一些實施例中，鹵基為F。如本文所用，單獨或與其他術語組合使用之術語「C_i _- _j 鹵烷基」係指具有1個鹵素原子至2s+1個可相同或不同之鹵素原子之烷基，其中「s」為烷基中之碳原子數，其中烷基具有i至j個碳原子。在一些實施例中，鹵烷基為氟甲基、二氟甲基或三氟甲基。在一些實施例中，鹵烷基為三氟甲基。在一些實施例中，鹵烷基具有1至6個或1至4個碳原子。如本文所用，單獨或與其他術語組合使用之術語「雜芳基」係指單環或多環(例如具有2、3或4個稠合環)芳族部分，其具有一或多個選自氮、硫及氧之雜原子環成員。在一些實施例中，雜芳基為5至10員雜芳基環，其為單環或雙環且其具有1、2、3或4個獨立地選自氮、硫及氧之雜原子環成員。在一些實施例中，雜芳基為5至6員雜芳基環，其為單環且具有1、2、3或4個獨立地選自氮、硫及氧之雜原子環成員。當雜芳基含有超過一個雜原子環成員時，雜原子可相同或不同。雜芳基之環中之氮原子可氧化以形成N-氧化物。雜芳基之實例包括但不限於吡啶、嘧啶、吡嗪、噠嗪、吡咯、吡唑、唑基(azolyl)、噁唑、噻唑、咪唑、呋喃、噻吩、喹啉、異喹啉、吲哚、苯并噻吩、苯并呋喃、苯并異噁唑、咪唑并[1,2-b ]噻唑、嘌呤及其類似基團。 5員雜芳基為具有5個成環原子之雜芳基，該等成環原子包含碳及一或多個(例如1、2或3個)獨立地選自N、O及S之環原子。五員雜芳基之實例包括噻吩基、呋喃基、吡咯基、咪唑基、噻唑基、噁唑基、吡唑基、異噻唑基、異噁唑基、1,2,3-三唑基、四唑基、1,2,3-噻二唑基、1,2,3-噁二唑基、1,2,4-三唑基、1,2,4-噻二唑基、1,2,4-噁二唑基、1,3,4-三唑基、1,3,4-噻二唑基及1,3,4-噁二唑基。 6員雜芳基為具有6個成環原子之雜芳基，其中一或多個(例如1、2或3個)環原子獨立地選自N、O及S。6員雜芳基之實例包括吡啶基、吡嗪基、嘧啶基、三嗪基及噠嗪基。如本文所用，術語「雜芳基烷基」係指式-C_i _- _j 烷基-(雜芳基)之基團。在一些實施例中，雜芳基烷基為5-10員雜芳基-C₁ _- ₄ 烷基，其中雜芳基部分為單環或雙環且具有1、2、3或4個獨立地選自氮、硫及氧之雜原子環成員。在一些實施例中，雜芳基烷基為5-6員雜芳基-C₁ _- ₃ 烷基或5-6員雜芳基-C₁ _- ₄ 烷基，其中雜芳基部分為單環且具有1、2、3或4個獨立地選自氮、硫及氧之雜原子環成員。如本文所用，單獨或與其他術語組合使用之術語「雜環烷基」係指非芳環或環系統，其視情況含有一或多個伸烯基作為環結構之一部分且其具有至少一個獨立地選自氮、硫及氧之雜原子環成員。當雜環烷基含有超過一個雜原子時，雜原子可相同或不同。雜環烷基可包括單環或多環(例如具有2、3或4個稠合環)環系統，包括螺環系統。雜環烷基之定義中亦包括一或多個芳環(芳基或雜芳基)與非芳環稠合之部分，例如1,2,3,4-四氫-喹啉、二氫苯并呋喃及其類似基團。在雜環烷基包括稠合芳環時，雜環烷基可在芳族或非芳族部分中之原子處發生連接。雜環烷基之環中之碳原子或雜原子可氧化(例如具有一或兩個側氧取代基)以形成羰基或磺醯基(或其他氧化鍵聯)或氮原子可四級銨化。在一些實施例中，雜環烷基為5至10員的，其可為單環或雙環且具有1、2、3或4個獨立地選自氮、硫及氧之雜原子環成員。在一些實施例中，雜環烷基為5至6員或5至7員的。雜環烷基之實例包括1,2,3,4-四氫喹啉、二氫苯并呋喃、氮雜環丁烷、氮雜環庚烷、吡咯啶、哌啶、哌嗪、嗎啉、硫代嗎啉及哌喃。雜環烷基之其他實例包括2-側氧基四氫呋喃基、2-側氧基吡咯啶基、2-側氧基咪唑啶基、1-側氧基-1,2,3,4-四氫異喹啉-6-基及2-側氧基-1,3-二氧戊環-4-基。如本文所用，術語「雜環烷基烷基」係指式-C_i _- _j 烷基-(雜環烷基)之基團。在一些實施例中，雜環烷基烷基為5-10員雜環烷基-C₁ _- ₃ 烷基或5-10員雜環烷基-C₁ _- ₄ 烷基，其中雜環烷基部分為單環或雙環且具有1、2、3或4個獨立地選自氮、硫及氧之雜原子環成員。在一些實施例中，雜環烷基烷基為5-6員雜環烷基-C₁ _- ₄ 烷基，其中雜環烷基部分為單環且具有1、2、3或4個獨立地選自氮、硫及氧之雜原子環成員。本文所描述之化合物可為不對稱的(例如具有一或多個立體中心)。除非另外指明，否則所有立體異構體，諸如對映異構體及非對映異構體為吾人所欲。含有經不對稱取代之碳原子之本發明化合物可以光學活性或外消旋形式分離。此項技術中已知如何自光學非活性起始材料製備光學活性形式之方法，諸如解析外消旋混合物或立體選擇性合成。本文所描述之化合物中亦可存在烯烴、C=N雙鍵及其類似物之多種幾何異構體，且所有該等穩定異構體均涵蓋於本發明中。本發明化合物之順式及反式幾何異構體可以異構體之混合物形式或以分開的異構形式分離。化合物之外消旋混合物之解析可藉由諸多此項技術中已知之方法中之任一者進行。實例方法包括使用對掌性解析酸分步再結晶，該對掌性解析為光學活性成鹽有機酸。適用於分步再結晶方法之解析劑為例如光學活性酸，諸如酒石酸(tartaric acid)之D及L形式、二乙醯基酒石酸、二苯甲醯基酒石酸、杏仁酸(mandelic acid)、蘋果酸(malic acid)、乳酸或各種光學活性樟腦磺酸(camphorsulfonic acid) (諸如β-樟腦磺酸)。適用於分步結晶方法之其他解析劑包括α-甲苄胺(例如S 及R 形式或非對映異構純形式)、2-苯甘胺醇、降麻黃鹼(norephedrine)、麻黃素(ephedrine)、N-甲基麻黃素、環己基乙胺、1,2-二胺基環己烷及其類似物之立體異構純形式。外消旋混合物之解析亦可藉由用光學活性解析劑(例如二硝基苯甲醯基苯基甘胺酸)封裝之管柱溶離來進行。適合之溶離溶劑組合物可藉由熟習此項技術者來確定。本發明之化合物亦可包括互變異構形式。互變異構形式由單鍵與相鄰雙鍵之交換以及伴隨之質子遷移而產生。互變異構形式包括處於具有相同經驗式及總電荷之異構質子化狀態之質子轉移互變異構體。質子轉移互變異構體之實例包括酮-烯醇對、醯胺-亞胺酸對、內醯胺-內醯亞胺對、醯胺-亞胺對、烯胺-亞胺對及質子可佔據雜環系統之兩個或兩個以上位置之環狀形式，例如1H -咪唑及3H -咪唑、1H -1,2,4-三唑、2H -1,2,4-三唑及4H-1,2,4-三唑、1H - 異吲哚及2H -異吲哚、及1H - 吡唑及2H -吡唑。本發明之化合物亦可包括中間物或最終化合物中出現之原子之所有同位素。同位素包括原子數相同但質量數不同之彼等原子。舉例而言，氫之同位素包括氚及氘。如本文所用，術語「化合物」意謂包括所述結構之所有立體異構體、幾何異構體、互變異構體及同位素。除非另外規定，否則在本文中藉由名稱或結構鑑別為一種特定互變異構形式之化合物意欲包括其他互變異構形式。在本文中藉由名稱或結構鑑別而不指定立構中心之特定組態之化合物意欲涵蓋立構中心處之所有可能組態。舉例而言，若本發明化合物中之特定立構中心可為R或S，但化合物之名稱或結構並未指明立構中心為何者，則立構中心可為R或S。所有化合物及其醫藥學上可接受之鹽均可與諸如水及溶劑(例如水合物及溶劑合物)之其他物質一起存在或可經分離。在一些實施例中，本發明之化合物或其鹽實質上經分離。「實質上經分離」意謂該化合物至少部分或實質上與其形成或偵測所在之環境分離。部分分離可包括例如富集有本發明化合物之組合物。實質分離可包括含有至少約50重量%、至少約60重量%、至少約70重量%、至少約80重量%、至少約90重量%、至少約95重量%、至少約97重量%或至少約99重量%之本發明化合物之組合物或其鹽。用於分離化合物及其鹽之方法為此項技術中之常規方法。片語「醫藥學上可接受」在本文中用於指在合理醫學判斷範疇內，適用於與人類及動物之組織接觸而無過度毒性、刺激、過敏反應或其他問題或併發症、與合理益處/風險比相稱的彼等化合物、材料、組合物及/或劑型。如本文所用，表達「環境溫度」及「室溫」此項技術中經理解且指溫度，例如反應溫度，其約為反應進行於其中之室內溫度，例如，約20℃至約30℃之溫度。本發明亦包括本文所描述之化合物之醫藥學上可接受之鹽。如本文所用，「醫藥學上可接受之鹽」係指所揭示之化合物的衍生物，其中藉由將現有酸或鹼部分轉化為其鹽形式而修飾母體化合物。醫藥學上可接受之鹽的實例包括但不限於鹼性殘基(諸如胺)之無機酸鹽或有機酸鹽；酸性殘基(諸如羧酸)之鹼金屬鹽或有機鹽；及其類似鹽。本發明之醫藥學上可接受之鹽包括例如自無毒無機酸或有機酸形成之母體化合物的習知無毒鹽。本發明之醫藥學上可接受之鹽可藉由習知化學方法自含有鹼性或酸性部分之母體化合物合成。一般而言，該等鹽可藉由使此等化合物之游離酸或鹼形式與化學計算量之適當鹼或酸在水中或在有機溶劑中或在兩者之混合物中反應來製備；一般而言，非水介質，如醚、EtOAc、醇(例如甲醇、乙醇、異丙醇或丁醇)或乙腈(CH₃ CN)為較佳的。適合之鹽之清單發現於Remington ' s Pharmaceutical Sciences , 第17版, (Mack Publishing Company, Easton, 1985), 第1418頁, Berge等人,J . Pharm . Sci . ,1977 ,66 (1), 1-19中，且發現於Stahl等人,Handbook of Pharmaceutical Salts : Properties , Selection , and Use , (Wiley, 2002)中。如本文所用，可互換使用之術語「個體」或「患者」係指任何動物，其包括哺乳動物，較佳為小鼠、大鼠、其他嚙齒動物、兔、犬、貓、豬、牛、綿羊、馬或靈長類動物，且最佳為人類。如本文所用，片語「治療有效量」係指在組織、系統、動物、個體或人類中引起研究人員、獸醫、醫生或其他臨床醫師所尋求之生物或藥物反應的活性化合物或醫藥劑之量。如本文所用，術語「治療(treating/treatment)」係指：1)抑制疾病；例如抑制正在經歷或呈現疾病、病況或病症之病變或症狀之個體的疾病、病況或病症，(亦即使病變及/或症狀之進一步發展停滯)，或2)改善疾病；例如改善正在經歷或呈現疾病、病況或病症之病變或症狀之個體的疾病、病況或病症(亦即使病變及/或症狀逆轉)。如本文所用，術語「預防(preventing/prevention)」係指抑制疾病之發作或惡化；例如在易患疾病、病況或病症但又不經歷或呈現疾病之病變或症狀的個體中。 組合療法 本發明之治療方法可進一步包括投與至少一種額外治療劑連同TPH1抑制化合物或其前藥。額外治療劑可以單劑型與TPH1抑制劑或其前藥組合，或藥劑可以分開劑型同時或依序投與。用於組合療法之額外治療劑包括例如：ASK1抑制劑，諸如GS-4997；抗LOXL2之單株抗體，諸如辛圖珠單抗(simtuzumab)；非類固醇消炎藥(NSAID)及抗高血脂劑(例如纖維酸酯(fibrate)、士他汀(statin)、參雙鍵生育酚(tocotrienol)、菸酸(niacin)、膽酸錯隔劑(樹脂)、膽固醇吸收抑制劑、胰腺脂肪酶抑制劑及擬交感神經胺)。纖維酸酯之實例包括苯紮貝特(bezafibrate)、環丙貝特(ciprofibrate)、氯貝特(clofibrate)、吉非羅齊(gemfibrozil)及非諾貝特(fenofibrate)。膽固醇吸收抑制劑之實例包括依澤替米貝(ezetimibe)、植物甾醇(phytosterol)、固醇及固烷醇(stanol)。其他藥劑包括吡格列酮(pioglitazone)、維生素E及二甲雙胍(metformin)。額外治療方法可包括降低體重(若患者為肥胖或超重)、吃均衡及健康的飲食、增加體能活動及避免酒精。 投藥、醫藥調配物、劑型 本文所描述之方法包括以將提供預防性及/或治療效果的適當劑量向需要該治療之患者(例如動物及人類)投與本文所描述之TPH1抑制劑或其前藥。用於治療或預防任何特定疾病或病症之所需之劑量及投藥方案將通常在患者與患者之間有所不同，該方案視例如所選特定化合物或組合物、投與途徑、正在治療之病況性質、患者年齡及情況、共同作用的藥物或由患者遵循的特殊飲食及其他因素而定。適當劑量及投藥方案可由治療醫師確定。本文所描述之化合物可以含有習知無毒醫藥學上可接受之載劑、佐劑及媒劑之劑量單位調配物形式經口、皮下、局部、非經腸或經直腸進行投與。非經腸投與可包括皮下注射、靜脈內或肌肉內注射或輸注技術。用於經鼻投與或藉由吸入或吹入投與之化合物可以自加壓封裝或噴霧器之霧劑噴霧形式遞送，其中使用適合之推進劑，例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、碳氟化合物、二氧化碳或其他適合之氣體。在加壓霧劑之情況下，劑量單位可藉由提供遞送計量之量的閥來確定。可調配用於吸入器或吹入器之膠囊及藥筒(例如由明膠組成之膠囊及藥筒)使其含有化合物及諸如乳糖或澱粉之適合粉末基質之粉末混合物。治療持續時間可為治療醫師認為必要之時間長度。舉例而言，每天可投與化合物及組合物一至四次或多於四次。在一些情況下，視化合物之特性而定且視調配物而定，投與可少於每天一次，例如，每隔一天一次或每週一次。當實現所需結果(例如特定治療效果)時，可終止治療期。或治療期可無限期地繼續下去。在一些實施例中，本文所描述之方法包括向患者投與包含本文所描述之化合物、或其醫藥學上可接受之鹽及一或多種醫藥賦形劑或載劑之醫藥組合物。醫藥組合物可以用於經口投與之固體劑型(例如膠囊、錠劑、丸劑、糖衣藥丸、粉劑、粒劑及其類似劑型)來製備。錠劑可藉由壓縮或模製來製備。壓縮錠劑可包括一或多種黏合劑、潤滑劑、助滑劑、惰性稀釋劑、防腐劑、崩解劑或分散劑。錠劑及諸如膠囊、丸劑及粒劑之其他固體劑型可包括包衣，諸如腸溶衣。用於經皮投與主題組合物之劑型包括粉劑、噴霧劑、軟膏、糊劑、乳膏、洗劑、凝膠、溶液及貼片。其他適合之醫藥調配物及劑型包括吸入劑。適用於非經腸投與之本發明之醫藥組合物包括本發明化合物以及一或多種醫藥學上可接受之無菌等滲水溶液或非水溶液、分散液、懸浮液或乳液。或者，組合物可呈可在即將使用之前復原成無菌可注射溶液或分散液之無菌粉末形式。將藉助於具體實例更詳細地描述本發明。出於說明之目的提供以下實例，而不意欲以任何方式限制本發明。熟習此項技術者將容易地識別出多種可改變或修改以產生基本上相同結果之非關鍵參數。發現實例之化合物為TPH1之抑制劑。實例本文所描述之TPH1抑制劑及其前藥可基於本文中含有之教示內容及此項技術中已知之合成程序以多種方式來製備。舉例而言，實例中描述之化合物可根據美國公開案第2015/0080393號中所提供之程序來製備，其以全文引用之方式併入本文中。下文實例1u之程序可通常用於製備TPH1抑制化合物。實例 1u ： ( S )- 8 -( 2 - 胺基 - 6 -(( R )- 2 , 2 , 2 - 三氟 - 1 -( 3 -( 3 - 甲基 - 1H - 吡唑 - 1 - 基 )-[ 1 , 1 '- 聯苯 ]- 4 - 基 ) 乙氧基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸步驟 1 ：向(R)-1-(4-溴-2-(3-甲基-1H-吡唑-1-基)苯基)-2,2,2-三氟乙醇(160 mg，0.2 mmol，中間物1，參見美國公開案第2015/0080393號[0409]段)於二噁烷(2 mL)中之溶液中添加2-胺基-4,6-二氯嘧啶(100 mg，0.16 mmol)及Cs₂ CO₃ (48 g，0.16 mmol)。將反應物加熱至80℃維持16小時，冷卻至室溫且過濾。在真空中移除溶劑且將殘餘物溶解於CH₂ Cl₂ 及庚烷之混合物中，濃縮至一半體積，過濾且再次在真空中濃縮。藉由正相矽膠層析(CH₂ Cl₂ /庚烷)之純化得到呈灰白色固體狀之4-[(1R)-1-[4-溴-2-(3-甲基吡唑-1-基)苯基]-2,2,2-三氟-乙氧基]-6-氯-嘧啶-2-胺。步驟 2 ：向4-[(1R)-1-[4-溴-2-(3-甲基吡唑-1-基)苯基]-2,2,2-三氟-乙氧基]-6-氯-嘧啶-2-胺(125 mg，0.3 mmol，步驟1)於二噁烷(3 mL)中之溶液中添加(S)-2,8-二氮螺[4.5]癸烷-2,3-二羧酸-2-苄酯3-乙酯(95 mg，0.3 mmol，美國公開案第2015/0080393號[0469]段)及Na₂ CO₃ (182 mg，0.35 mmol)。將反應物加熱至90℃維持130小時，隨後冷卻至室溫，過濾且在真空中濃縮。藉由正相矽膠管柱(EtOAc/庚烷)之純化得到呈白色固體狀之(S)-(8-(2-胺基-6-((R)-1-(4-溴-2-(3-甲基-1H-吡唑-1-基)苯基)-2,2,2-三氟乙氧基)嘧啶-4-基)-2,8-二氮螺[4.5]癸烷-2,3-二羧酸-2-苄酯3-乙酯。步驟 3 ：向(S)-(8-(2-胺基-6-((R)-1-(4-溴-2-(3-甲基-1H-吡唑-1-基)苯基)-2,2,2-三氟乙氧基)嘧啶-4-基)-2,8-二氮螺[4.5]癸烷-2,3-二羧酸-2-苄酯3-乙酯(300 mg，0.4 mmol，步驟2)於乙醇(2 mL)及水(0.5 mL)中之溶液中添加苯基硼酸(143 mg，0.8 mmol)、PdCl₂ (PPh₃ )₂ (41 mg，0.058 mmol)及Cs₂ CO₃ (390 mg，1.2 mmol)。將反應物加熱至60℃維持16小時，隨後冷卻至室溫，經矽藻土過濾且在真空中濃縮。藉由正相矽膠管柱(EtOAc/庚烷)之純化得到呈白色固體狀之(S)-8-(2-胺基-6-((R)-2,2,2-三氟-1-(3-(3-甲基-1H-吡唑-1-基)-[1,1'-聯苯]-4-基)乙氧基)嘧啶-4-基)-2,8-二氮螺[4.5]癸烷-2,3-二羧酸-2-苄酯3-乙酯。步驟 4：在室溫下以1.0 mL/分鐘之流動速率使用H-Cube設備及10% (w/w) Pd/C藥筒氫化(S)-8-(2-胺基-6-((R)-2,2,2-三氟-1-(3-(3-甲基-1H-吡唑-1-基)-[1,1'-聯苯]-4-基)乙氧基)嘧啶-4-基)-2,8-二氮螺[4.5]癸烷-2,3-二羧酸-2-苄酯3-乙酯(240 mg，0.4 mmol，步驟3)於EtOAc (5 ml)中之溶液。正相矽膠上之純化(EtOAc/庚烷)得到(S)-8-(2-胺基-6-((R)-2,2,2-三氟-1-(3-(3-甲基-1H-吡唑-1-基)-[1,1'-聯苯]-4-基)乙氧基)嘧啶-4-基)-2,8-二氮螺[4.5]癸烷-3-羧酸乙酯。步驟 5：向自步驟4之(S)-8-(2-胺基-6-((R)-2,2,2-三氟-1-(3-(3-甲基-1H-吡唑-1-基)-[1,1'-聯苯]-4-基)乙氧基)嘧啶-4-基)-2,8-二氮螺[4.5]癸烷-3-羧酸乙酯(50 mg，0.08 mmol)於THF (2.0 mL)及水(0.2 mL)中之溶液中添加氫氧化鋰單一水合物(58 mg，0.05 mmol)。在室溫下攪拌反應混合物2小時，隨後用1 N HCl中和溶液且在真空中濃縮。藉由正相矽膠管柱(EtOAc/庚烷)純化得到呈灰白色固體狀之呈兩性離子形式之標題化合物。實例 1m ： ( S )- 8 -( 2 - 胺基 - 6 -(( R )- 1 -( 3 ', 4 '- 二甲基 - 3 -( 3 - 甲基 - 1H - 吡唑 - 1 - 基 )-[ 1 , 1 '- 聯苯 ]- 4 - 基 )- 2 , 2 , 2 - 三氟乙氧基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸實例 1cq ： ( S )- 8 -( 2 - 胺基 - 6 -(( R )- 2 , 2 , 2 - 三氟 - 1 -( 3 '-( 羥甲基 )- 4 '- 甲基 - 3 -( 3 - 甲基 - 1H - 吡唑 - 1 - 基 )-[ 1 , 1 '- 聯苯 ]- 4 - 基 ) 乙氧基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸實例 1cr ： ( S )- 8 -( 2 - 胺基 - 6 -(( R )- 2 , 2 , 2 - 三氟 - 1 -( 4 '-( 羥甲基 )- 3 '- 甲基 - 3 -( 3 - 甲基 - 1H - 吡唑 - 1 - 基 )-[ 1 , 1 '- 聯苯 ]- 4 - 基 ) 乙氧基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸表 1a. 實例 1cp ： ( S )- 8 -( 2 - 胺基 - 6 -(( R )- 1 -( 3 ', 4 '- 二甲基 - 3 -( 3 -( 三氟甲基 )- 1H - 吡唑 - 1 - 基 )-[ 1 , 1 '- 聯苯 ]- 4 - 基 )- 2 , 2 , 2 - 三氟乙氧基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸實例 2 ： ( S )- 8 -( 2 - 胺基 - 6 -(( R )- 2 , 2 , 2 - 三氟 - 1 -( 2 -( 3 - 甲基 - 1H - 吡唑 - 1 - 基 )- 4 -( 哌啶 - 4 - 基 ) 苯基 ) 乙氧基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸實例 3a ： ( S )- 8 -( 2 - 胺基 - 6 -(( R )- 2 , 2 , 2 - 三氟 - 1 -( 2 -( 3 - 甲基 - 1H - 吡唑 - 1 - 基 )- 4 -( 1 -( 甲磺醯基 ) 哌啶 - 4 - 基 ) 苯基 ) 乙氧基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸表 2a. 實例 4 ： ( S )- 8 -( 2 - 胺基 - 6 -(( R )- 2 , 2 , 2 - 三氟 - 1 -( 3 '- 甲氧基 - 4 '-( 甲氧羰基 )- 3 -( 3 - 甲基 - 1H - 吡唑 - 1 - 基 )-[ 1 , 1 '- 聯苯 ]- 4 - 基 ) 乙氧基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸實例 5a ： ( S )- 8 -( 2 - 胺基 - 6 -(( R )- 1 -( 3 '-( 乙氧羰基 )- 3 -( 3 - 甲基 - 1H - 吡唑 - 1 - 基 )-[ 1 , 1 '- 聯苯 ]- 4 - 基 )- 2 , 2 , 2 - 三氟乙氧基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸實例 5b ： ( S )- 8 -( 2 - 胺基 - 6 -(( R )- 1 -( 4 '-( 乙氧羰基 )- 3 -( 3 - 甲基 - 1H - 吡唑 - 1 - 基 )-[ 1 , 1 '- 聯苯 ]- 4 - 基 )- 2 , 2 , 2 - 三氟乙氧基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸實例 6 ： ( S )- 8 -( 2 - 胺基 - 6 -(( R )- 1 -( 4 -( 3 - 羧丙基 )- 2 -( 3 - 甲基 - 1H - 吡唑 - 1 - 基 ) 苯基 )- 2 , 2 , 2 - 三氟乙氧基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸實例 7 ： ( S )- 8 -( 2 - 胺基 - 6 -(( R )- 1 -( 4 -( 2 - 羧乙基 )- 2 -( 3 - 甲基 - 1H - 吡唑 - 1 - 基 ) 苯基 )- 2 , 2 , 2 - 三氟乙氧基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸實例 9 ： ( S )- 8 -( 2 - 胺基 - 6 -(( R )- 1 -( 4 -( 3 - 乙氧基 - 3 - 側氧基丙基 )- 2 -( 3 - 甲基 - 1H - 吡唑 - 1 - 基 ) 苯基 )- 2 , 2 , 2 - 三氟乙氧基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸實例 10d ： ( S )- 8 -( 2 - 胺基 - 6 -(( R )- 1 -( 4 - 氯 - 2 -( 3 - 甲基 - 1H - 吡唑 - 1 - 基 ) 苯基 )- 2 , 2 , 2 - 三氟乙氧基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸表 3a. * 下表中以名稱界定立體化學 實例 10o ： ( S )- 8 -( 2 - 胺基 - 6 -(( R )- 1 -( 4 - 溴 - 2 -( 3 - 甲基 - 1H - 吡唑 - 1 - 基 ) 苯基 )- 2 , 2 , 2 - 三氟乙氧基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸實例 10p ： ( S )- 8 -( 2 - 胺基 - 6 -(( R )- 1 -( 4 - 氯 - 2 -( 3 -( 三氟甲基 )- 1H - 吡唑 - 1 - 基 ) 苯基 )- 2 , 2 , 2 - 三氟乙氧基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸實例 10pa ： ( S )- 8 -( 2 - 胺基 - 6 -(( R )- 1 -( 2 -( 3 -( 第三丁基 )- 1H - 吡唑 - 1 - 基 )- 4 - 氯苯基 )- 2 , 2 , 2 - 三氟乙氧基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸實例 10q ： ( S )- 8 -( 2 - 胺基 - 6 -(( R )- 1 -( 4 - 氯 - 2 -( 3 - 異丙基 - 1H - 吡唑 - 1 - 基 ) 苯基 )- 2 , 2 , 2 - 三氟乙氧基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸實例 10r ： ( S )- 8 -( 2 - 胺基 - 6 -(( R )- 1 -( 4 - 氯 - 2 -( 3 - 環丙基 - 1H - 吡唑 - 1 - 基 ) 苯基 )- 2 , 2 , 2 - 三氟乙氧基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸實例 11 ： ( S )- 8 -( 2 - 胺基 - 6 -(( R )- 2 , 2 , 2 - 三氟 - 1 -( 6 - 甲基 - 2 -( 3 - 甲基 - 1H - 吡唑 - 1 - 基 ) 吡啶 - 3 - 基 ) 乙氧基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸實例12a：(S)-8-(2-胺基-6-((R)-1-(4-乙基-2-(3-甲基-1H-吡唑-1-基)苯基)-2,2,2-三氟乙氧基)嘧啶-4-基)-2,8-二氮螺[4.5]癸烷-3-羧酸表4a. 實例 13 ： ( 3S )- 8 -( 2 - 胺基 - 6 -(( 1R )- 1 -( 4 -( 1 , 2 - 二羥乙基 )- 2 -( 3 - 甲基 - 1H - 吡唑 - 1 - 基 ) 苯基 )- 2 , 2 , 2 - 三氟乙氧基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸實例 14 ： ( S )- 8 -( 2 - 胺基 - 6 -(( R )- 1 -( 4 - 氰基 - 2 -( 3 - 甲基 - 1H - 吡唑 - 1 - 基 ) 苯基 )- 2 , 2 , 2 - 三氟乙氧基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸實例 15 ： ( S )- 8 -( 2 - 胺基 - 6 -(( R )- 1 -( 4 - 胺甲醯基 - 2 -( 3 - 甲基 - 1H - 吡唑 - 1 - 基 ) 苯基 )- 2 , 2 , 2 - 三氟乙氧基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸實例 16 ： ( S )- 8 -( 2 - 胺基 - 6 -(( R )- 1 -( 4 - 羧基 - 2 -( 3 - 甲基 - 1H - 吡唑 - 1 - 基 ) 苯基 )- 2 , 2 , 2 - 三氟乙氧基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸實例 17 ： ( S )- 8 -( 2 - 胺基 - 6 -(( R )- 1 -( 4 -( 乙氧羰基 )- 2 -( 3 - 甲基 - 1H - 吡唑 - 1 - 基 ) 苯基 )- 2 , 2 , 2 - 三氟乙氧基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸實例 18a ： ( S )- 8 -( 2 - 胺基 - 6 -(( R )- 2 , 2 , 2 - 三氟 - 1 -( 4 -((( 1 , 1 , 1 , 3 , 3 , 3 - 六氟 - 2 - 甲基丙 - 2 - 基 ) 氧基 ) 羰基 )- 2 -( 3 - 甲基 - 1H - 吡唑 - 1 - 基 ) 苯基 ) 乙氧基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸表 5a. 實例 19a ： ( S )- 8 -( 2 - 胺基 - 6 -(( R )- 2 , 2 , 2 - 三氟 - 1 -( 2 -( 3 - 甲基 - 1H - 吡唑 - 1 - 基 )- 5 - 乙烯基苯基 ) 乙氧基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸表6a. 表7a. 實例 20 ： ( S )- 8 -( 2 - 胺基 - 6 -(( R )- 1 -( 2 '-( 乙氧羰基 )- 4 -( 3 - 甲基 - 1H - 吡唑 - 1 - 基 )-[ 1 , 1 '- 聯苯 ]- 3 - 基 )- 2 , 2 , 2 - 三氟乙氧基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸實例 21 ： ( S )- 8 -( 2 - 胺基 - 6 -(( R )- 1 -( 4 '-( 乙氧羰基 )- 4 -( 3 - 甲基 - 1H - 吡唑 - 1 - 基 )-[ 1 , 1 '- 聯苯 ]- 3 - 基 )- 2 , 2 , 2 - 三氟乙氧基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸實例 22a ： ( S )- 8 -( 2 - 胺基 - 6 -(( R )- 1 -( 5 - 乙基 - 2 -( 3 - 甲基 - 1H - 吡唑 - 1 - 基 ) 苯基 )- 2 , 2 , 2 - 三氟乙氧基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸表 8a. 實例 23 ： ( S )- 8 -( 2 - 胺基 - 6 -(( R )- 1 -( 5 -( 乙氧羰基 )- 2 -( 3 - 甲基 - 1H - 吡唑 - 1 - 基 ) 苯基 )- 2 , 2 , 2 - 三氟乙氧基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸實例 24 ： ( S )- 8 -( 2 - 胺基 - 6 -(( R )- 1 -( 5 - 羧基 - 2 -( 3 - 甲基 - 1H - 吡唑 - 1 - 基 ) 苯基 )- 2 , 2 , 2 - 三氟乙氧基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸實例 25 ： ( S )- 8 -( 2 - 胺基 - 6 -(( R )- 2 , 2 , 2 - 三氟 - 1 -( 4 -( 羥甲基 )- 2 -( 3 - 甲基 - 1H - 吡唑 - 1 - 基 ) 苯基 ) 乙氧基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸實例 26 ： ( S )- 8 -( 2 - 胺基 - 6 -(( R )- 1 -( 4 -(( 二甲胺基 ) 甲基 )- 2 -( 3 - 甲基 - 1H - 吡唑 - 1 - 基 ) 苯基 )- 2 , 2 , 2 - 三氟乙氧基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸實例 27 ： ( S )- 8 -( 6 -(( R )- 1 -( 4 - 溴 - 2 -( 3 - 甲基 - 1H - 吡唑 - 1 - 基 ) 苯基 )- 2 , 2 , 2 - 三氟乙氧基 )- 2 - 甲基嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸實例 28 ： ( S )- 8 -( 6 -(( R )- 1 -( 4 - 氯 - 2 -( 3 - 甲基 - 1H - 吡唑 - 1 - 基 ) 苯基 )- 2 , 2 , 2 - 三氟乙氧基 )- 2 - 甲基嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸表 9. 表 10. 實例 30a ： 8 -( 6 -(( R )- 1 -( 4 - 氯 - 2 -( 3 - 甲基 - 1H - 吡唑 - 1 - 基 ) 苯基 )- 2 , 2 , 2 - 三氟乙氧基 )- 2 - 苯氧基嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸表 11a. 實例 31 ： 8 -( 6 -(( R )- 1 -( 4 - 氯 - 2 -( 3 - 甲基 - 1H - 吡唑 - 1 - 基 ) 苯基 )- 2 , 2 , 2 - 三氟乙氧基 )- 2 -( 環己胺基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸實例 32 ： ( S )- 8 -( 6 -(( R )- 1 -( 4 - 氯 - 2 -( 3 - 甲基 - 1H - 吡唑 - 1 - 基 ) 苯基 )- 2 , 2 , 2 - 三氟乙氧基 )- 2 -( 環丁甲醯胺基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸實例 33 ： ( S )- 8 -( 2 - 胺基 - 6 -(( R )- 1 -( 4 - 氯 - 2 -( 2 - 側氧基吡咯啶 - 1 - 基 ) 苯基 )- 2 , 2 , 2 - 三氟乙氧基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸實例 34c ： ( S )- 8 -( 2 - 胺基 - 6 -(( R )- 1 -( 5 - 氯 -[ 1 , 1 '- 聯苯 ]- 2 - 基 )- 2 , 2 , 2 - 三氟乙氧基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸步驟 1 ：向(R)-1-(2-溴-4-氯苯基)-2,2,2-三氟乙醇(中間物43，參見美國公開案第2015/0080393號[0463]段) (400 mg，1.4 mmol)於二噁烷(25 mL)中之溶液中添加4,6-二氯嘧啶-2-胺(1.1 g，7 mmol)及Cs₂ CO₃ (1.3 g，4 mmol)。在80℃下加熱混合物24小時。接著使反應物冷卻至室溫且過濾。在真空中移除溶劑，隨後添加CH₂ Cl₂ 及庚烷。使溶劑體積減少直至沈澱出固體。將固體過濾且將程序重複若干次，得到呈白色固體狀之(R)-4-(1-(2-溴-4-氯苯基)-2,2,2-三氟乙氧基)-6-氯嘧啶-2-胺。步驟 2 ：向(R)-4-(1-(2-溴-4-氯苯基)-2,2,2-三氟乙氧基)-6-氯嘧啶-2-胺(100 mg，0.24 mmol，步驟1)於二噁烷(5 mL)中之溶液中添加(S)-2,8-二氮螺[4.5]癸烷-2,3-二羧酸-2-苄酯3-乙酯(100 mg，0.29 mmol，美國公開案第2015/0080393號[0469]段)及NaHCO₃ (300 mg，3.5 mmol)。5小時後，添加額外量之NaHCO₃ (300 mg，3.5 mmol)，且將反應混合物加熱至90℃維持36小時。隨後將反應物冷卻至室溫且過濾。藉由正相矽膠管柱(EtOAc/庚烷)之純化得到呈白色固體狀之(S)-8-(2-胺基-6-((R)-1-(2-溴-4-氯苯基)-2,2,2-三氟乙氧基)嘧啶-4-基)-2,8-二氮螺[4.5]癸烷-2,3-二羧酸-2-苄酯3-乙酯。步驟 3 ：向(S)-8-(2-胺基-6-((R)-1-(2-溴-4-氯苯基)-2,2,2-三氟乙氧基)嘧啶-4-基)-2,8-二氮螺[4.5]癸烷-2,3-二羧酸-2-苄酯3-乙酯(100 mg，0.13 mmol)於10:1二噁烷:水(5 mL)中之溶液中添加苯基硼酸(33 mg，0.27 mmol)、KHCO₃ (27 mg，0.3 mmol)及PdCl₂ (dppf)-CH₂ Cl₂ (6 mg，0.007 mmol)。將反應物加熱至100℃維持15小時，冷卻至室溫且在真空中濃縮。將殘餘物用水稀釋且用EtOAc萃取。將經合併之有機層經Na₂ SO₄ 乾燥，過濾，且在真空中濃縮。藉由正相矽膠管柱(EtOAc/庚烷)之純化得到呈灰白色固體狀之(S)-8-(2-胺基-6-((R)-1-(5-氯-[1,1'-聯苯]-2-基)-2,2,2-三氟乙氧基)嘧啶-4-基)-2,8-二氮螺[4.5]癸烷-2,3-二羧酸-2-苄酯3-乙酯。步驟 4 ：N-CBZ去保護藉由方法B實現，得到呈灰白色固體狀之(S)-8-(2-胺基-6-((R)-1-(5-氯-[1,1'-聯苯]-2-基)-2,2,2-三氟乙氧基)嘧啶-4-基)-2,8-二氮螺[4.5]癸烷-3-羧酸乙酯。步驟 5 ：使用LiOH通用方法水解(S)-8-(2-胺基-6-((R)-1-(5-氯-[1,1'-聯苯]-2-基)-2,2,2-三氟乙氧基)嘧啶-4-基)-2,8-二氮螺[4.5]癸烷-3-羧酸乙酯得到呈兩性離子形式之呈灰白色固體狀之標題化合物。實例 34u ： ( S )- 8 -( 2 - 胺基 - 6 -(( R )- 1 -( 5 - 氯 - 3 '- 胺磺醯基 -[ 1 , 1 '- 聯苯 ]- 2 - 基 )- 2 , 2 , 2 - 三氟乙氧基 ) 嘧啶 - 4 - 基 )- 2 , 8 - 二氮螺 [ 4 . 5 ] 癸烷 - 3 - 羧酸表 12a. * 下表中以名稱界定立體化學 實例 35 ： (S)-8-(2- 胺基 -6-((R)-1-(5- 氯 -3'-( 乙氧羰基 )-[1,1'- 聯苯 ]-2- 基 )-2,2,2- 三氟乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 36 ： (S)-8-(2- 胺基 -6-((R)-1-(4- 氯 -2-(2- 甲氧基乙氧基 ) 苯基 )-2,2,2- 三氟乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 36b ： (S)-8-(6-((R)-1-(2-(1H- 苯并 [d] 咪唑 -1- 基 )-4- 氯苯基 )-2,2,2- 三氟乙氧基 )-2- 胺基嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 36c ： (S)-8-(2- 胺基 -6-((R)-1-(4- 氯 -2-(1H- 吲唑 -1- 基 ) 苯基 )-2,2,2- 三氟乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 36d ： (S)-8-(2- 胺基 -6-((R)-1-(4- 溴 -2-( 哌嗪 -1- 基 ) 苯基 )-2,2,2- 三氟乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 36e ： (S)-8-(2- 胺基 -6-((R)-2,2,2- 三氟 -1-(4'- 異丙氧基 -3-( 哌嗪 -1- 基 )-[1,1'- 聯苯 ]-4- 基 ) 乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 36f ： (S)-8-(2- 胺基 -6-((R)-2,2,2- 三氟 -1-(4'- 異丙氧基 -3-(N- 嗎啉基 )-[1,1'- 聯苯 ]-4- 基 ) 乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 36g ： (S)-8-(6-((R)-1-([1,1'- 聯苯 ]-2- 基 )-2,2,2- 三氟乙氧基 )-2- 胺基嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 37 ： (3S)-8-(6-(1-((1r,3r,5S,7S)- 金剛烷 -2- 基 ) 乙氧基 )-2- 胺基嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 38 ： (S)-8-(6-((1r,3r,5S,7S)- 金剛烷 -2- 基甲氧基 )-2- 胺基嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 39a ： 8-(4- 胺基 -6-(( 萘 -2- 基甲基 ) 胺基 )-1,3,5- 三嗪 -2- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸表 13a. 實例 40 ： 8-(4- 胺基 -6-((R)-1-(4- 氯 -2-(3- 甲基 -1H- 吡唑 -1- 基 ) 苯基 )-2,2,2- 三氟乙氧基 )-1,3,5- 三嗪 -2- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 41a ： (S)-8-(2- 胺基 -6-((2-( 哌啶 -1- 基 ) 苄基 ) 胺基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸表 14a. 實例 42a ： (S)-8-(2- 胺基 -6-((R)-1-(3'- 氯 -[1,1'- 聯苯 ]-2- 基 )-2,2,2- 三氟乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 42b ： (S)-8-(2- 胺基 -6-((R)-2,2,2- 三氟 -1-(3'- 氟 -[1,1'- 聯苯 ]-2- 基 ) 乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 43 ： (S)-8-(5-((R)-1-(4- 氯 -2-(3- 甲基 -1H- 吡唑 -1- 基 ) 苯基 )-2,2,2- 三氟乙氧基 ) 噠嗪 -3- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 44 ： ( S)-8-(4-((R)-2,2,2- 三氟 -1-(2-(3- 甲基 -1H- 吡唑 -1- 基 ) 苯基 ) 乙氧基 ) 吡啶 -2- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸及實例 45 ： (S)-8-(4-((R)-1-(4- 氯 -2-(3- 甲基 -1H- 吡唑 -1- 基 ) 苯基 )-2,2,2- 三氟乙氧基 ) 吡啶 -2- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 46 ： 8-(4-((R)-1-(4- 氯 -2-(3- 甲基 -1H- 吡唑 -1- 基 ) 苯基 )-2,2,2- 三氟乙氧基 )-6- 苯氧基嘧啶 -2- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 47 ： (3S)-8-(2- 胺基 -6-(1-(2,6- 二溴苯基 )-2,2,2- 三氟乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 48 ： (S)-8-(2- 胺基 -6-((R)-1-(2,5- 二溴苯基 )-2,2,2- 三氟乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 49 ： ( S)-8-(2- 胺基 -6-((R)-2,2,2- 三氟 -1-(3'-( 甲磺醯基 )-4- 丙基 -[1,1'- 聯苯 ]-2- 基 ) 乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 50 ： (S)-8-(2- 胺基 -6-((R)-2,2,2- 三氟 -1-(3'-( 甲磺醯基 )-4-((E)- 丙 -1- 烯 -1- 基 )-[1,1'- 聯苯 ]-2- 基 ) 乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 51a ： (S)-8-(6-((R)-1-([1,1':4',1''- 聯三苯 ]-2'- 基 )-2,2,2- 三氟乙氧基 )-2- 胺基嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 51b ： (S)-8-(6-((R)-1-([1,1':3',1''- 聯三苯 ]-2'- 基 )-2,2,2- 三氟乙氧基 )-2- 胺基嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 52a ： (S)-8-(2- 胺基 -6-((R)-1-(3,4- 二甲基 -3''-( 甲磺醯基 )-[1,1':3',1''- 聯三苯 ]-4'- 基 )-2,2,2- 三氟乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸表 16a. 實例 53 ： (S)-8-(2- 胺基 -6-((R)-2,2,2- 三氟 -1-(3'-( 甲磺醯基 )-5-((E)- 丙 -1- 烯 -1- 基 )-[1,1'- 聯苯 ]-2- 基 ) 乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 54a ： (S)-8-(2- 胺基 -6-((R)-2,2,2- 三氟 -1-(3'-( 甲磺醯基 )-5- 丙基 -[1,1'- 聯苯 ]-2- 基 ) 乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 54b ： (S)-8-(2- 胺基 -6-((R)-2,2,2- 三氟 -1-(4- 異丙氧基 -[1,1':3',1''- 聯三苯 ]-4'- 基 ) 乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 54c ： (S)-8-(2- 胺基 -6-((R)-2,2,2- 三氟 -1-(4- 丙氧基 -[1,1':3',1''- 聯三苯 ]-4'- 基 ) 乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 54d ： (S)-8-(2- 胺基 -6-((R)-2,2,2- 三氟 -1-(5-( 甲磺醯基 )-[1,1'- 聯苯 ]-2- 基 ) 乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 54e ： (S)-8-(2- 胺基 -6-((R)-2,2,2- 三氟 -1-(3- 氟 -4- 丙氧基 -[1,1':3',1''- 聯三苯 ]-4'- 基 ) 乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 54f ： (S)-8-(2- 胺基 -6-((R)-1-(3,4- 二甲基 -[1,1':3',1''- 聯三苯 ]-4'- 基 )-2,2,2- 三氟乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 54g ： (S)-8-(6-((R)-1-([1,1':3',1''- 聯三苯 ]-4'- 基 )-2,2,2- 三氟乙氧基 )-2- 胺基嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 54h ： (R)-8-(2- 胺基 -6-((R)-1-(5- 氯 -[1,1'- 聯苯 ]-2- 基 )-2,2,2- 三氟乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 54i ： (R)-8-(2- 胺基 -6-((S)-1-(5- 氯 -[1,1'- 聯苯 ]-2- 基 )-2,2,2- 三氟乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 54j ： (S)-8-(2- 胺基 -6-((S)-1-(5- 氯 -[1,1'- 聯苯 ]-2- 基 )-2,2,2- 三氟乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 54k ： (S)-8-(2- 胺基 -6-((S)-1-(3',4'- 二甲基 -3-(3- 甲基 -1H- 吡唑 -1- 基 )-[1,1'- 聯苯 ]-4- 基 )-2,2,2- 三氟乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 54l ： (R)-8-(2- 胺基 -6-((S)-1-(3',4'- 二甲基 -3-(3- 甲基 -1H- 吡唑 -1- 基 )-[1,1'- 聯苯 ]-4- 基 )-2,2,2- 三氟乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 54m ： (R)-8-(2- 胺基 -6-((R)-1-(3',4'- 二甲基 -3-(3- 甲基 -1H- 吡唑 -1- 基 )-[1,1'- 聯苯 ]-4- 基 )-2,2,2- 三氟乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 55an ： (S)-8-(2- 胺基 -6-((R)-2,2,2- 三氟 -1-(3'- 甲氧基 -[1,1'- 聯苯 ]-4- 基 ) 乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸表 17a. 實例 56 ： (S)-8-(2- 胺基 -6-((R)-2,2,2- 三氟 -1-(4-(1,2,3,4- 四氫喹喏啉 -6- 基 ) 苯基 ) 乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 57 ： (S)-8-(2- 胺基 -6-((R)-1-(3,4- 二氫喹唑啉 -6- 基 )-2,2,2- 三氟乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 58 ： (S)-8-(2- 胺基 -6-((R)-2,2,2- 三氟 -1-(1,2,3,4- 四氫喹唑啉 -6- 基 ) 乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 59a ： (S)-8-(2- 胺基 -6-((R)-1-(4- 溴苯基 )-2,2,2- 三氟乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 59b ： (S)-8-(2- 胺基 -6-((R)-2,2,2- 三氟 -1-( 萘 -2- 基 ) 乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 59c ： (S)-8-(2- 胺基 -6-((R)-2,2,2- 三氟 -1-(4-(3- 氟喹啉 -6- 基 )-2- 甲基苯基 ) 乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 59d ： (S)-8-(2- 胺基 -6-((R)-1-(2- 乙基 -4-(3- 氟喹啉 -6- 基 ) 苯基 )-2,2,2- 三氟乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 60 ： 9-(2- 胺基 -6-((R)-1-(4- 氯 -2-(3- 甲基 -1H- 吡唑 -1- 基 ) 苯基 )-2,2,2- 三氟乙氧基 ) 嘧啶 -4- 基 )-3,9- 二氮螺 [5.5] 十一烷 -2- 羧酸實例 61 ： (S)-8-(2- 胺基 -6-((4-(3- 甲基 -1H- 吲唑 -6- 基 ) 苯氧基 ) 甲基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 62 ： (S)-8-(2- 胺基 -6-((5- 氯 -3'-( 甲磺醯基 )-[1,1'- 聯苯 ]-2- 基 ) 甲氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸實例 63bd ： (S)-8-(2- 胺基 -6-((R)-1-(3',4'- 二甲基 -3-(3- 甲基 -1H- 吡唑 -1- 基 )-[1,1'- 聯苯 ]-4- 基 )-2,2,2- 三氟乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸乙酯 實例 63kp ： (S)-8-(2- 胺基 -6-((R)-2,2,2- 三氟 -1-(3'-( 羥甲基 )-4'- 甲基 -3-(3- 甲基 -1H- 吡唑 -1- 基 )-[1,1'- 聯苯 ]-4- 基 ) 乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸乙酯 實例 63i ： (S)-8-(2- 胺基 -6-((R)-1-(5- 氯 -[1,1'- 聯苯 ]-2- 基 )-2,2,2- 三氟乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸乙酯 向(S)-8-(2-胺基-6-((R)-1-(5-氯-[1,1'-聯苯]-2-基)-2,2,2-三氟乙氧基)嘧啶-4-基)-2,8-二氮螺[4.5]癸烷-2,3-二羧酸-2-苄酯3-乙酯(自步驟3，實例34c，315 mg，0.43 mmol)於乙腈(300 mL)中之溶液中添加TMSI (0.13 mL，0.9 mmol)。隨後使反應混合物升溫至室溫再持續30-40分鐘，隨後冷卻至0-5℃，且添加含2 M HCl之乙醚(0.5 mL)。使反應混合物隨後升溫至室溫，且隨後在真空中濃縮。正相矽膠層析得到呈灰白色固體狀之標題化合物。表 18a. 實例 64a ： (S)-8-(2- 胺基 -6-((R)-1-(4- 氯 -2-(3- 甲基 -1H- 吡唑 -1- 基 ) 苯基 )-2,2,2- 三氟乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸辛酯 表 19a. 實例 65a ： (S)-8-(2- 胺基 -6-((R)-1-(4- 氯 -2-(3- 甲基 -1H- 吡唑 -1- 基 ) 苯基 )-2,2,2- 三氟乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸第三丁酯 表 20a. 實例 66a ： (S)-8-(2- 胺基 -6-((R)-1-(4- 氯 -2-(3- 甲基 -1H- 吡唑 -1- 基 ) 苯基 )-2,2,2- 三氟乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸 2-( 二甲胺基 ) 乙酯表 21a. 實例 67a ： (S)-8-(2- 胺基 -6-((R)-1-(3',4'- 二甲基 -3-(3- 甲基 -1H- 吡唑 -1- 基 )-[1,1'- 聯苯 ]-4- 基 )-2,2,2- 三氟乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸異丙酯 表 22a. 實例 68a ： (S)-8-(2- 胺基 -6-((R)-2,2,2- 三氟 -1-(4'- 異丙氧基 -3-(3- 甲基 -1H- 吡唑 -1- 基 )-[1,1'- 聯苯 ]-4- 基 ) 乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸異丙酯 表 23a. 實例 69a ： (S)-8-(2- 胺基 -6-((R)-1-(5- 氯 -[1,1'- 聯苯 ]-2- 基 )-2,2,2- 三氟乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸異丙酯 表 24a. 實例 70 ： (S)-8-(2- 胺基 -6-((R)-1-(5- 氯 -3'-( 甲磺醯基 )-[1,1'- 聯苯 ]-2- 基 )-2,2,2- 三氟乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸甲酯 實例 71 ： (S)-8-(2- 胺基 -6-((R)-1-(5- 氯 -3'- 胺磺醯基 -[1,1'- 聯苯 ]-2- 基 )-2,2,2- 三氟乙氧基 ) 嘧啶 -4- 基 )-2,8- 二氮螺 [4.5] 癸烷 -3- 羧酸甲酯 根據本發明適用的其他TPH1抑制化合物、其前藥及劑型包括特羅司他(telotristat)及其鹽，包括特羅司他愛替普瑞特(telotristat etiprate) (LX1032)。參見例如美國專利公開案第2008/0153852號、第2009/0029993號、第2009/0088447號、第2010/0240906號、第2012/0316171號、第2013/0137635號、第2013/0172376號、第2013/0303763號及PCT公開案第WO 2010/065333號及第WO 2014/082034號。實例 A . 用缺乏甲硫胺酸 - 膽鹼 ( MCD ) 飲食之 NASH C57bl6 小鼠之鼠模型 此研究經設計以研究本發明之化合物對用MCD飲食之NASH C57bl6小鼠之鼠模型的影響。以200 mg/kg之化合物63i (亦稱為實例63i之化合物)之口服劑量誘發對NASH之鼠模型中之等離子體及肝脂質以及肝功能酶的積極影響。NASH模型藉由讓C57bL6小鼠食用損害VLDL總成的MCD飲食誘發，導致肝三酸甘油酯分泌破壞及肝內連續脂肪積聚(Rizki G,等人, J Lipid Res. 2006；2280-2290)。用MCD餵養之小鼠經4週每天一次經口投與200 mg/kg化合物63i。用化合物63i進行之處理顯著逆轉以血清脂質及肝三酸甘油酯餵養的MCD之影響，使濃度回到未處理、食物餵養對照小鼠中觀測到之濃度。化合物63i亦顯著降低丙胺酸轉胺酶(ALT)及天冬胺酸轉胺酶(AST)血清濃度，表明相比於MCD餵養媒劑對照，TPH1抑制改善肝功能。用於此研究之化學品為：triton X-100 (Sigma - Cat #X100)、膽固醇檢定套組(Wako Diagnostics - Cat #439-17501)、三酸甘油酯檢定套組(Wako Diagnostics - Cat #461-08992及Cat #461-09092)、三酸甘油酯標準(Wako Diagnostics - Cat #464-01601)、丙胺酸轉胺酶(ALT)檢定(Cayman Chemical - Cat #700260)、天冬胺酸轉胺酶(AST)檢定(Sigma - Cat #MAK055)、磷酸鹽緩衝鹽水(Sigma - Cat#P3813)、蔗糖(Sigma - Cat #S7903)、阿拉伯膠(gum Arabic) (Sigma - Cat #G9752)、含油紅O之0.5%丙二醇(Polyscientific - Cat #s1848)及OCT化合物(Tissue Tek - Cat #4583)。對照飲食為經輻射之嚙齒動物飲食18%蛋白質(Envigo #2918)。挑戰飲食為MCD飲食(Envigo #TD90262)。 200 mg/kg化合物63i (作為游離鹼)之口服劑量在水中製備之0.5%甲基纖維素媒劑中製備。在投藥日將媒劑添加至化合物中，且將混合物經短暫超音波處理隨後混合約20分鐘直至獲得均相懸浮液。藉由經口管飼按體重之10 mL/kg投與劑量。用於研究之動物描述於下文中。雄性小鼠(每組n=10)在28-30 g時到達設施，且在玉米芯墊料上每籠5隻進行圈養。研究開始前使動物適應處理7-10天。暗循環開始前經4週每天一次向小鼠投與單口服劑量之媒劑(0.5%甲基纖維素水溶液)或200 mg/kg化合物63i。在投藥期期間，經媒劑及化合物63i處理之小鼠用正常飲食或MCD飲食餵養。在第4週，血液樣品自餵養之小鼠收集以量測經分離之血清中之膽固醇、三酸甘油酯、丙胺酸轉胺酶(ALT)及天冬胺酸轉胺酶(AST)。用10 mL PBS在原位之整個身體灌注後，將肝之中葉移除且固定在4%多聚甲醛中用於組織學量測。將額外肝樣品(100 mg)急速冷凍於液氮中以量測肝三酸甘油酯。血液收集在第4週，藉由連續吸入將小鼠用以含2%之氧投與的異氟醚麻醉。全血樣品(800 µL)藉由心臟穿刺獲得，且使其在室溫下結塊30分鐘。血清藉由在7000 rpm下離心分離20分鐘，且在-80℃下儲存以量測膽固醇、三酸甘油酯、丙胺酸轉胺酶及天冬胺酸轉胺酶。血清膽固醇根據套組說明書使用比色檢定(Wako Diagnostics)在血清中量測膽固醇濃度。簡言之，將3 µL各標準品或樣品添加至96孔透明底板之孔中。標準品藉由將200 mg/dL儲備液稀釋於水中來製備。反應藉由添加300 µL檢定試劑且在37℃下保溫5分鐘而實現。用分光光度計在600 nm處讀取吸收率。血清三酸甘油酯根據套組說明書使用比色檢定(Wako Diagnostics)在血清中量測三酸甘油酯濃度。簡言之，將4 µL各標準品或樣品添加至96孔透明底板之孔中。標準品藉由將98 mg/dL儲備液稀釋於水中來製備。反應藉由添加180 µL第一檢定試劑且在37℃下保溫5分鐘而實現。反應藉由添加60 µL第二檢定試劑且在37℃下再保溫5分鐘而繼續。用分光光度計在600 nm處讀取吸收率。血清丙胺酸轉胺酶如上文中所描述分離血清，且根據套組說明書使用比色檢定藉由量測血清中之丙胺酸轉胺酶(ALT)濃度評估肝功能。簡言之，將20 µL血清樣品或標準品添加至具有150 µL基質及20 µL輔因子之透明底96孔板中。將樣品在37℃保溫15分鐘後，反應藉由添加20 µL ALT引發劑起始。經5分鐘每分鐘用分光光度計在340 nm處立即讀取吸收率。吸收率之變化(ΔA₃₄₀ /分鐘)藉由在曲線之線性部分上之2點處計算吸收率之變化來測定(a)，且ALT活性(U/mL)使用(b)中之方程式來計算： (a)b)血清天冬胺酸轉胺酶如上文中所描述分離血清，且根據套組說明書使用比色檢定藉由量測血清中之天冬胺酸轉胺酶(AST)濃度評估肝功能。簡言之，將5 µL血清樣品或標準品添加至具有45µL AST分析緩衝液之透明底96孔板中。標準品藉由將1 mM麩胺酸儲備液稀釋於AST分析緩衝液中來製備。反應藉由添加100 µL含有80 µL緩衝液+2 µL酶+8 µL顯影劑+10 µL基質且在37℃下保溫3分鐘而實現。用分光光度計在450 nm處讀取初始吸收率[AST]_初始。樣品保溫在37℃下繼續且每5分鐘在450 nm處讀取吸收率。當活性最強樣品之值比最高標準品大時，反應完成[AST]_最終。對於各樣品，產生之麩胺酸濃度(nmoL)或Δ[AST]按以下測定： [AST]_最終 - [AST]_起始 AST活性(nmoL/分鐘/mL)或在37℃下每分鐘將產生1 µmoL麩胺酸之酶的濃度按以下計算：Δ [ AST ] × 樣品稀釋因子 (反應時間) × V 其中，反應時間(分鐘) = T_最終 - T_起始 V (mL) = 添加至孔中之體積肝收集血液收集後，根據the Guide for the Care and Use of Laboratory Animals中之規定將小鼠在麻醉下藉由放血處死，且整個身體灌注用10 mL PBS實現。將肝樣品在液體N₂ 中急速冷凍且在-80℃下儲存直至處理以用於三酸甘油酯量測。處理以用於組織學量測前將肝之中葉移除且固定於4%多聚甲醛中24小時。肝三酸甘油酯將冷凍肝樣品(50 mg)轉移至含有含1 mm高衝擊鋯珠粒(Benchmark Scientific)及500 µL之5% Triton X-100之磷酸鹽緩衝鹽水的管中。將樣品在Bead Bug微管均質器(Benchmark Scientific)上均質化2分鐘直至完全溶解，且在4℃下以13,000 rpm離心5分鐘。檢定前，將樣品在5% Triton X-100中按1:4進一步稀釋。根據套組說明書使用比色檢定(Wako Diagnostics)量測肝三酸甘油酯濃度。簡言之，將4 µL樣品或標準品添加至透明底96孔板之孔中。標準品藉由將98 mg/dL儲備液稀釋於5% Triton X-100中來製備。反應藉由添加180 µL第一檢定試劑且在37℃下保溫5分鐘而實現。反應藉由添加60 µL第二檢定試劑且在37℃下再保溫5分鐘而繼續。用分光光度計在600 nm處讀取吸收率。肝脂質沈積在嵌入於-18℃下之低溫恆溫器腔室中之OCT化合物中之前，固定肝組織樣品之福馬林(formalin)之隨機選擇的子組在4℃下用30%蔗糖+1%阿拉伯膠溶液浸潤24-48小時。將肝樣品以10 µM進行低溫切片，且用含油紅O之0.5%丙二醇染色以評估脂質沈積。統計分析方差分析(analysis of variance，ANOVA)用於檢驗基團之間之顯著差異。事後Bonferroni多個比較試驗分析用於測定均值中之顯著差異。使用Graph Pad Prism 5軟體實現所有統計分析。結果概述於以下中。表 A1. 化合物63i對餵MCD飲食4週的雄性C57bL6小鼠中之血清膽固醇及三酸甘油酯之影響經口投與200 mg/kg化合物63i 4週後，血清從自MCD飲食餵養之C57bL6小鼠收集之血液樣品中分離。膽固醇及三酸甘油酯濃度藉由比色檢定量測。在經化合物63i處理之小鼠中觀測到血清膽固醇中及血清三酸甘油酯中朝向正常之顯著改善，相對於MCD餵養媒劑對照組之顯著性，*P＜0.05且****P＜0.0001。表 A2. 化合物63i對餵MCD飲食4週的雄性C57bL6小鼠之肝三酸甘油酯之影響經口投與200 mg/kg化合物63i 4週後，肝組織樣品自MCD飲食餵養之C57bL6小鼠收集。三酸甘油酯濃度藉由比色檢定量測。在經化合物63i處理之小鼠中觀測到朝向正常之肝三酸甘油酯中之非顯著改善。相對於MCD餵養媒劑對照組，**P＜0.01顯著性。表 A3. 化合物63i對餵MCD飲食4週的雄性C57bL6小鼠中之血清丙胺酸轉胺酶(ALT)之影響經口投與200 mg/kg化合物63i 4週後，血清從自MCD飲食餵養之C57bL6小鼠收集之血液樣品中分離。丙胺酸轉胺酶(ALT)濃度藉由比色檢定量測。¹ ΔA₃₄₀ /分鐘= (A₃₄₀ 時間1 - A₃₄₀ 時間2)/ 5分鐘。² ALT活性= (ΔA₃₄₀ /分鐘× 0.21 mL) / (4.11 mM^-1 × 0.02mL)。在經化合物63i處理之小鼠中觀測到朝向正常之血清ALT中之顯著改善。相對於MCD餵養媒劑對照組，***P＜0.001顯著性。表 A4. 化合物63i對餵MCD飲食4週的雄性C57bL6小鼠中之血清天冬胺酸轉胺酶(AST)之影響經口投與200 mg/kg化合物63i 4週後，血清從自MCD飲食餵養之C57bL6小鼠收集之血液樣品中分離。AST濃度藉由比色檢定量測。AST活性= Δ[AST] /反應時間×樣品體積。在經化合物63i處理之小鼠中觀測到朝向正常之血清AST中之顯著改善。相對於MCD餵養媒劑對照組，***P＜0.001及****P＜0.0001顯著性。經口投與200 mg/kg化合物63i 4週後(結果未展示)，在自MCD餵養之C57bL6小鼠收集之肝組織中觀測到脂質沈積顯著減少。實例 B . 用高脂飲食之 NASH ApoE 基因剔除小鼠之鼠模型 此研究經設計以研究本發明之化合物對用高脂飲食之NASH ApoE基因剔除小鼠之鼠模型的影響。以200 mg/kg之口服劑量之化合物63i(亦稱作實例63i之化合物)誘發對NASH之鼠模型中之肝病理生理學的積極影響。NASH模型藉由讓ApoE基因剔除小鼠食用高脂飲食誘發。用高脂餵養之小鼠經8週每天一次經口投與200 mg/kg化合物63i。相比於高脂餵養之媒劑對照，用化合物63i進行之處理顯著逆轉以肝脂質沈積物及肝架構餵養的高脂之影響。在用化合物63i處理之小鼠中觀測到血清血清素顯著減少而無對血清膽固醇、三酸甘油酯或葡萄糖之影響。此研究中使用之材料描述於下表中。對照飲食為經輻射之嚙齒動物飲食18%蛋白質(Envigo #2918)。挑戰飲食為具有自椰子油之1.25%膽固醇及21%脂肪之高脂飲食(研究飲食#D15100301)。測試化合物為實例63i之化合物(亦稱作化合物63i)。其用作游離鹼。口服劑量之200 mg/kg化合物63i在水中製備之0.5%甲基纖維素中製備。在投藥日將媒劑添加至化合物中，且將混合物經短暫超音波處理隨後混合約20分鐘直至獲得均相懸浮液。藉由經口管飼按體重之10 mL/kg投與劑量。研究中使用之動物描述於下表中。雄性小鼠(每組n=10)在28-30 g時到達設施，且在玉米芯墊料上每籠4隻進行圈養。研究開始前使動物適應處理7-10天。暗循環開始前經8週每天一次向小鼠投與單口服劑量之媒劑(0.5%甲基纖維素水溶液)或200 mg/kg化合物63i。在投藥期期間，經媒劑及化合物63i處理之小鼠用正常飲食或含有自椰子油的1.25%膽固醇及21%脂肪之高脂飲食餵養。在第8週，血液樣品自餵養之小鼠收集以量測經分離之血清中之血清素、膽固醇、三酸甘油酯及葡萄糖。用10 mL PBS在原位之整個身體灌注後，將肝之中葉移除且固定在4%多聚甲醛中用於組織學量測。血液收集在第8週，藉由連續吸入將小鼠用以含2%之氧投與的異氟醚麻醉。全血樣品(800 µL)藉由心臟穿刺獲得，且使其在室溫下結塊30分鐘。血清藉由以7000 rpm離心20分鐘分離且在-80℃下儲存以量測血清素、膽固醇、三酸甘油酯及葡萄糖。血清血清素量測在三氯乙酸(TCA)均勻化緩衝液中萃取血清樣品。簡言之，將100 µL TCA緩衝液添加至1.5 mL微離心管中之50 µL血清中。樣品在緩衝液中渦動且在4℃下以13,000 rpm離心30分鐘。將上澄液謹慎移除且轉移至玻璃管中以使用上文所描述之條件用螢光偵測器量測血清素。高效液相層析法(HPLC)條件 HPLC均勻化緩衝液如下製備： HPLC量測使用配備有螢光偵測器及經含水C18管柱驗證之Brownlee(3 µm，50 × 2.1 mm；Perkin Elmer)之Perkin Elmer Flexar HPLC系統進行。所用之移動相為100 mM乙酸鈉，pH 3.5。在280 nm之激勵波長及330 nm之發射波長下實現偵測。血清膽固醇根據套組說明書使用比色檢定(Wako Diagnostics)在血清中量測膽固醇濃度。簡言之，將3 µL各標準品或樣品添加至96孔透明底板之孔中。標準品藉由將200 mg/dL儲備液稀釋於水中來製備。反應藉由添加300 µL檢定試劑且在37℃下保溫5分鐘而實現。用分光光度計在600 nm處讀取吸收率。血清三酸甘油酯根據套組說明書使用比色檢定(Wako Diagnostics)在血清中量測三酸甘油酯濃度。簡言之，將4 µL各標準品或樣品添加至96孔透明底板之孔中。標準品藉由將98 mg/dL儲備液稀釋於水中來製備。反應藉由添加180 µL第一檢定試劑且在37℃下保溫5分鐘而實現。反應藉由添加60 µL第二檢定試劑且在37℃下再保溫5分鐘而繼續。用分光光度計在600 nm處讀取吸收率。血清葡萄糖根據套組說明書使用比色檢定(Cayman)在血清中量測葡萄糖氧化酶濃度。簡言之，將15 µL各標準品或樣品添加至各自含有85 µL由供應商提供之分析緩衝液的96孔透明底板之孔中。標準品藉由將100 mg/dL儲備液稀釋於分析緩衝液中來製備。反應藉由添加100 µL酶試劑且在37℃下保溫10分鐘而實現。用分光光度計在500-520 nm處讀取吸收率。肝收集血液收集後，根據the Guide for the Care and Use of Laboratory Animals中之規定將小鼠在麻醉下藉由放血處死，且整個身體灌注用10 mL PBS實現。處理以用於組織學量測前將肝之中葉移除且固定於4%多聚甲醛中24小時。組織學分析在嵌入於-18℃下之低溫恆溫器腔室中之OCT化合物中之前，固定肝組織樣品之福馬林之隨機選擇的子組在4℃下用30%蔗糖+1%阿拉伯膠溶液浸潤24-48小時。將肝樣品以10 µM進行低溫切片，且用含油紅O之0.5%丙二醇染色以評估脂質沈積。將一部分肝處理，嵌入於石蠟中且以5 µm切片，以染色馬洛里小體(Mallory Body)，且結構隨色變劑-苯胺藍變化。統計分析方差分析(ANOVA)用於檢驗基團之間之顯著差異。事後Bonferroni多個比較試驗分析用於測定均值中之顯著差異。使用Graph Pad Prism 5軟體實現所有統計分析。結果概述於以下中。表 B1. 化合物63i對餵高脂或飲食8週的雄性ApoE基因剔除小鼠中之血清血清素之影響經口投與200 mg/kg化合物63i同時餵高脂或飲食8週後，血清從自ApoE基因剔除小鼠收集之血液樣品中分離。血清素(5-HT)藉由高效液相層析法量測。在同時用食物及脂肪飲食之用化合物63i處理之小鼠中觀測到血清5-HT顯著減少。相對於高脂或食物餵養之媒劑對照組分別為****p＜0.0001及††††p＜0.0001顯著性。表B2.化合物 63i 對餵 高脂或飲食 8 週的雄性 ApoE 基因剔除小鼠中之血清膽固醇、三酸甘油酯及葡萄糖之影響 經口投與200 mg/kg化合物63i同時餵高脂或飲食8週後，血清從自ApoE基因剔除小鼠收集之血液樣品中分離。膽固醇、三酸甘油酯及葡萄糖濃度藉由比色檢定量測。無論飲食，觀測不到膽固醇、三酸甘油酯或葡萄糖之顯著變化。經口投與200 mg/kg化合物63i 8週後，在自高脂餵養之ApoE基因剔除小鼠收集之肝組織中評估脂質沈積。脂質沈積物藉由暗紅色油紅O染色表示，其表明相比於用媒劑處理之小鼠，用化合物63i處理之脂肪餵養之小鼠中之脂質沈積的定性減少。經口投與200 mg/kg化合物63i 8週後，在自高脂餵養之ApoE基因剔除小鼠收集之肝組織中觀測到肝架構之改善。相比於用200 mg/kg化合物63i處理之小鼠，主要容器附近之液泡出現增加及結構完整性崩潰藉由用媒劑處理之小鼠中之色變劑2B-苯胺藍染色展現。實例 C . 用缺乏甲硫胺酸膽鹼 ( MCD ) 或高脂飲食之 NASH LDLr 基因剔除小鼠之鼠模型 此研究經設計以研究本發明之化合物對用高脂飲食之NASH LDLr基因剔除小鼠之鼠模型的影響。以200 mg/kg之口服劑量之化合物63i(亦稱作實例63i之化合物)誘發對兩個NASH之鼠模型中之肝病理生理學的積極影響。首先，NASH模型藉由讓LDLr基因剔除小鼠食用損害VLDL總成的MCD飲食誘發，導致肝三酸甘油酯分泌破壞及肝內連續脂肪積聚(Rizki G.,等人, J Lipid Res. 2006；2280-2290)。第二，NASH模型藉由讓LDLr基因剔除小鼠食用含有自椰子油之1.25%膽固醇及21%脂肪的高脂飲食誘發。分別經3週及8週每天一次向MCD或脂肪餵養之小鼠經口投與200 mg/kg化合物63i。相比於高脂餵養之媒劑對照，用化合物63i進行之處理顯著逆轉以肝脂質沈積物及肝架構餵養的高脂之影響。在用化合物63i處理之小鼠中觀測到血清血清素顯著減少而無對血清膽固醇、三酸甘油酯或葡萄糖之影響。用於此研究之化學品描述如下：對照飲食為經輻射之嚙齒動物飲食18%蛋白質(Envigo #2918)。挑戰飲食為MCD飲食(Envigo #TD90262)及具有自椰子油之1.25%膽固醇及21%脂肪之高脂飲食(研究飲食#D15100301)。口服劑量之200 mg/kg化合物63i (游離鹼)在水中製備之0.5%甲基纖維素中製備。在投藥日將媒劑添加至化合物中，且將混合物經短暫超音波處理隨後混合約20分鐘直至獲得均相懸浮液。藉由經口管飼按體重之10 mL/kg投與劑量。研究中使用之動物描述於下表中。雄性小鼠(每組n=10)在28-30 g時到達設施，且在玉米芯墊料上每籠4隻進行圈養。研究開始前使動物適應處理7-10天。分別向小鼠餵MCD飲食或含有自椰子油之1.25%膽固醇及21%脂肪之高脂飲食3週及8週。用飲食時，暗循環開始前每天一次向小鼠投與單口服劑量之媒劑(0.5%甲基纖維素水溶液)或200 mg/kg化合物63i。在投藥期結束時，自餵養之小鼠收集血液樣品以由外部承包人內部量測血清血清素且量測血清膽固醇、三酸甘油酯、葡萄糖、丙胺酸轉胺酶(ALT)或天冬胺酸轉胺酶(AST)。用10 mL PBS在原位之整個身體灌注後，將肝之中葉移除且固定在4%多聚甲醛中用於組織學量測。收集腸黏膜樣品以藉由高效液相層析法量測血清素。血液收集在投藥期結束時，藉由連續吸入將小鼠用以含2%之氧投與的異氟醚麻醉。全血樣品(1 mL)藉由心臟穿刺獲得，且使其在室溫下結塊30分鐘。血清藉由以6000 rpm離心20分鐘分離且50 µL樣品在-80℃下儲存以量測血清素。將其餘血清運送至Charles River (Shrewsbury，Mass)以量測血清膽固醇、三酸甘油酯、葡萄糖及肝功能酶(ALT及AST)。血清血清素量測在三氯乙酸(TCA)均勻化緩衝液中萃取血清樣品。簡言之，將100 µL TCA緩衝液添加至1.5 mL微離心管中之50 µL血清中。樣品在緩衝液中渦動且在4℃下以13,000 rpm離心30分鐘。將上澄液謹慎移除且轉移至玻璃管中以使用上文所描述之條件用螢光偵測器量測血清素。高效液相層析法(HPLC)條件 HPLC均勻化緩衝液根據下表製備。 HPLC量測使用配備有螢光偵測器及經含水C18管柱驗證之Brownlee(3 µm，50 × 2.1 mm；Perkin Elmer)之Perkin Elmer Flexar HPLC系統進行。所用之移動相為100 mM乙酸鈉，pH 3.5。在280 nm之激勵波長及330 nm之發射波長下實現偵測。腸黏膜收集血液收集後，根據the Guide for the Care and Use of Laboratory Animals中之規定將小鼠在麻醉下藉由放血處死，且整個身體灌注用10 mL PBS實現。胃大致位於以幽門括約肌(pyloric sphincter，十二指腸)為起點之腸之6-8 cm處，且移除相鄰6-8 cm (空腸)。捨棄十二指腸，且使用連接至填充有PBS之10 cc 針筒的投藥針沖洗空腸之腸內容物。隨後沿在顯微鏡玻璃載片上平坦敞開之片段之單側進行縱向切割。將腸黏膜使用第二顯微鏡載片自內腔表面刮下，且在2 mL平底微離心管中收集。大約50 mg之各樣品轉移至第二個2 mL平底微離心管中以用於萃取及血清素量測。腸黏膜血清素量測在三氯乙酸(TCA)均勻化緩衝液中萃取腸黏膜樣品。簡言之，將300 µL TCA緩衝液添加至2 mL平底微離心管中之50-75 mg之組織中。組織在緩衝液中均質化且在4℃下以13,000 rpm離心30分鐘。將上澄液謹慎移除且轉移至玻璃管中以使用上文所描述之條件用螢光偵測器量測血清素。完全自組織離心塊移除任何殘餘上澄液後，蛋白質量測前將在0.1 N氫氧化鈉(NaOH)中製備之1200 µL之5%十二烷基硫酸鈉緩衝液(SDS)添加至各微離心管中，且將樣品溶解於37℃烘爐中隔夜。腸黏膜蛋白質根據套組說明書使用比色檢定(Pierce BCA Protein，Fisher)在消化黏膜組織離心塊中量測腸黏膜蛋白質濃度。簡言之，將5 µL樣品稀釋於具有在0.1 N NaOH中製備的20 µL之5% SDS緩衝液之透明底96孔板中。標準品藉由將2 mg/mL蛋白儲備液稀釋於5% SDS緩衝液中來製備。反應藉由添加200 µL BCA蛋白質試劑且在37℃下保溫30分鐘而實現。用分光光度計在562 nm處讀取吸收率。肝收集血液收集後，根據the Guide for the Care and Use of Laboratory Animals中之規定將小鼠在麻醉下藉由放血處死，且整個身體灌注用10 mL PBS實現。處理以用於組織學量測前將肝之中葉移除且固定於4%多聚甲醛中24小時。組織學分析在嵌入於-18℃下之低溫恆溫器腔室中之OCT化合物中之前，固定肝組織樣品之福馬林之隨機選擇的子組在4℃下用30%蔗糖+1%阿拉伯膠溶液浸潤24-48小時。將肝樣品以10 µM進行低溫切片，且用含油紅O之0.5%丙二醇染色以評估脂質沈積。統計分析方差分析(ANOVA)用於檢驗基團之間之顯著差異。事後Bonferroni多個比較試驗分析用於測定均值中之顯著差異。使用Graph Pad Prism 5軟體實現所有統計分析。結果概述於以下中。表C1.化合物 63i 對餵 MCD 飲食或高脂飲食的雄性 LDLr 基因剔除小鼠中之血清血清素之影響 經口投與200 mg/kg化合物63i同時分別餵MCD飲食或高脂飲食3週及8週後，血清從自LDLr基因剔除小鼠之血液樣品中分離。血清素(5-HT)藉由高效液相層析法量測。在同時用無論何種飲食之用化合物63i處理之小鼠中觀測到血清5-HT顯著減少。相對於高脂或MCD餵養之媒劑對照組分別為****p＜0.0001及††††p＜0.0001顯著性。表B2.化合物 63i 對餵 MCD 飲食或高脂飲食的雄性 LDLr 基因剔除小鼠中之黏膜血清素之影響 經口投與200 mg/kg化合物63i同時分別餵MCD飲食或高脂飲食3週及8週後，在自LDLr基因剔除小鼠之腸黏膜中量測血清素(5-HT)。5-HT藉由高效液相層析法量測。在同時用無論何種飲食之用化合物63i處理之小鼠中觀測到腸黏膜5-HT顯著減少。相對於高脂或MCD餵養之媒劑對照組分別為****p＜0.0001及††††p＜0.0001顯著性。表 C3. 化合物63i對餵MCD飲食或高脂飲食之雄性LDLr基因剔除小鼠中之血清膽固醇、三酸甘油酯及葡萄糖之影響經口投與200 mg/kg化合物63i同時分別餵MCD飲食或高脂飲食3週及8週後，血清從自LDLr基因剔除小鼠之血液樣品中分離。將樣品隔夜運送至Charles River實驗室(Shrewsbury，Mass)以量測膽固醇、三酸甘油酯及葡萄糖濃度。相對於高脂或MCD餵養之媒劑對照組分別為**p＜0.01及†p＜0.05顯著性。表 C4. 化合物63i對餵MCD飲食或高脂飲食的雄性LDLr基因剔除小鼠中之肝功能酶丙胺酸轉胺酶(ALT)及天冬胺酸轉胺酶(AST)之影響經口投與200 mg/kg化合物63i同時分別餵MCD飲食或高脂飲食3週及8週後，血清從自LDLr基因剔除小鼠之血液樣品中分離。將樣品隔夜運送至Charles River實驗室(Shrewsbury，Mass)以量測肝功能酶ALT及AST。經口投與200 mg/kg化合物63i 3週後，在自MCD飲食餵養之LDLr基因剔除小鼠收集之肝組織中評估脂質沈積。脂質沈積物藉由暗紅色油紅O染色表示，其表明相比於用媒劑處理之小鼠，用化合物63i處理之MCD飲食餵養之小鼠中之脂質沈積的定性減少。經口投與200 mg/kg化合物63i 8週後，在自高脂餵養之LDLr基因剔除小鼠收集之肝組織中評估脂質沈積。脂質沈積物藉由暗紅色油紅O染色表示，其表明相比於用媒劑處理之小鼠，用化合物63i處理之脂肪餵養之小鼠中之脂質沈積的定性減少。除本文所述之彼等修改以外，根據前述描述，本發明之各種修改對熟習此項技術者而言將為顯而易見的。該等修改亦意欲屬於所附申請專利範圍之範疇內。本發明申請案中所引用之各參考文獻(包括所有專利、專利申請案及公開案)係以全文引用的方式併入本文中。The present invention relates to a method for treating or preventing liver diseases such as nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatosis hepatitis (NASH) and hepatocellular carcinoma in a patient, the method comprising administering to the patient a therapeutically effective amount A TPH inhibitor, such as a TPHl inhibitor or a prodrug thereof. In some embodiments, the disease is NAFLD. In some embodiments, the disease is NASH. In some embodiments, the disease is hepatocellular carcinoma. The invention also encompasses methods of treating or preventing one or more diseases or conditions associated with NAFLD, NASH or hepatocellular carcinoma in a patient, the methods comprising administering to the patient a therapeutically effective amount of a TPH inhibitor, such as a TPHl inhibitor Or its prodrug. Such diseases or conditions include, for example, inflammation, fibrosis, cirrhosis, fatigue, weight loss, weakness, fluid retention, muscle wasting, intestinal bleeding, liver failure, weight gain, obesity, diabetes (eg, type 2 diabetes or type 1) Diabetes), pre-diabetes, lipid disorders, elevated serum lipids, elevated liver enzymes in serum, elevated cholesterol, and elevated triglycerides. Also provided herein are methods for reducing alanine transaminase (ALT), aspartate transaminase (AST), cholesterol, triglyceride or glucose in a patient (eg, patient serum concentration and/or liver), Such methods comprise administering to the patient a therapeutically effective amount of a TPH inhibitor, such as a TPHl inhibitor or a prodrug thereof. In some embodiments, the methods provided herein also include reducing lipid deposits in the liver of a patient, the methods comprising administering a therapeutically effective amount of a TPH inhibitor, such as a TPHl inhibitor or a prodrug thereof. In some embodiments, the method is a method of reducing ALT concentration in a patient's serum or liver. In some embodiments, the method is a method of reducing the AST concentration in a patient's serum or liver. Examples of TPH1 inhibitors and their corresponding prodrugs that can be used in accordance with the methods of the present invention are described, for example, in U.S. Patent Publication No. 2016/0272655, No. 2016/0096836, No. 2015/0366865, No. 2015/00080393 No. 2014/0378489, 2014/0303197, 2014/0017677, 2013/0137635, 2013/0274261, 2013/0303763, 2013/0338176, 2013/0316924, 2013/0053343, 2012/0316171, 2011/0112094, 2011/0281899, 2011/0152220, 2010/0317664, 2009/0054308, 2009/0029993, 2009 /0005382, No. 2009/0005, 381, and No. 2008/0108077, and are hereby incorporated by reference in its entirety in its entirety in the entire disclosure of the entire disclosure of the disclosure of the disclosure of the disclosure of the disclosure of An example prodrug that can be used in accordance with the methods of the present invention is the ester compound (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-)- 2-ethyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid ethyl ester, which can be metabolized by the patient Formation of the corresponding acid compound (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2 -Trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid, which is a TPH1 inhibitor. In some embodiments, the compound that can be used in accordance with the methods of the invention is a compound of formula I:I or a pharmaceutically acceptable salt thereof, wherein: Ring A is C₃ _- ₁₀ Cycloalkyl, C₆ _- ₁₀ Aryl, 4 to 10 membered heterocycloalkyl or 5 to 10 membered heteroaryl; L is O or NR⁴ ; W is N or CR⁵ ; X is N or CR⁶ ; Y is N or CR⁷ Where only one of X and Y is N; R¹ For H, C₁ _- ₁₀ Alkyl, C₃ _- ₁₀ Cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, -(CR⁸ R⁹ )_p OC(O)R¹⁰ ,-(CR⁸ R⁹ )_p NR¹¹ R¹² Or - (CR⁸ R⁹ )_p C(O)NR¹¹ R¹² Where the C₁ _- ₁₀ Alkyl, C₃ _- ₁₀ The cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl and phenyl are each independently selected from 1, 2, 3, 4 or 5, independently selected from the group consisting of F, Cl, Br, CN, C.₁ _- ₄ Alkyl and C₁ _- ₄ Substituted by a haloalkyl group; R² And R³ Each is independently selected from H, C₁ _- ₄ Alkyl and C₁ _- ₄ Haloalkyl; R⁴ For H or C₁ _- ₄ Alkyl; R⁵ And R⁶ Each independently selected from H, halo and C₁ _- ₄ Alkyl; R⁷ For H, C₁ _- ₄ Alkyl, C₂ _- ₆ Alkenyl, C₃ _- ₁₀ Cycloalkyl, C₃ _- ₁₀ cycloalkyl-C₁ _- ₄ Alkyl, C₆ _- ₁₀ Aryl, C₆ _- ₁₀ aryl-C₁ _- ₄ Alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C₁ _- ₄ Alkyl, 5-10 membered heteroaryl, (5-10 membered heteroaryl)-C₁ _- ₄ Alkyl, NR¹³ R¹⁴ OR¹⁵ , C(O)R¹⁶ , S(O)_q R¹⁷ Where the C₁ _- ₄ Alkyl, C₂ _- ₆ Alkenyl, C₃ _- ₁₀ Cycloalkyl, C₃ _- ₁₀ cycloalkyl-C₁ _- ₄ Alkyl, C₆ _- ₁₀ Aryl, C₆ _- ₁₀ aryl-C₁ _- ₄ Alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C₁ _- ₄ Alkyl, 5-10 membered heteroaryl and (5-10 membered heteroaryl)-C₁ _- ₄ The alkyl groups are each optionally substituted by 1, 2 or 3 substituents selected from the group consisting of halo, C₁ _- ₄ Alkyl, C₂ _- ₆ Alkenyl, amine, C₁ _- ₄ Alkylamine, C₂ _- ₈ Dialkylamine, hydroxyl and C₁ _- ₄ Alkoxy; R⁸ And R⁹ Each is independently selected from H and C₁ _- ₄ Alkyl; R¹⁰ For C₁ _- ₆ Alkyl, optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of C:₁ _- ₆ Haloalkyl, C₃ _- ₁₀ Cycloalkyl, OR^a And NR^c R^d ; R¹¹ And R¹² Each is independently selected from H and C₁ _- ₆ Alkyl; R¹³ For H or C₁ _- ₄ Alkyl; R¹⁴ For H, C₁ _- ₄ Alkyl, C₃ _- ₇ Cycloalkyl, C₃ _- ₇ cycloalkyl-C₁ _- ₄ Alkyl, C₆ _- ₁₀ Aryl, C₆ _- ₁₀ aryl-C₁ _- ₄ Alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C₁ _- ₄ Alkyl, 5-10 membered heteroaryl or (5-10 membered heteroaryl)-C₁ _- ₄ Alkyl, C(O)R^B1 , C(O)OR^A1 , C(O)NR^C1 R^D1 , S(O)R^B1 , S(O)₂ R^B1 Or S(O)₂ NR^C1 R^D1 Where the C₁ _- ₄ Alkyl, C₃ _- ₇ Cycloalkyl, C₃ _- ₇ cycloalkyl-C₁ _- ₄ Alkyl, C₆ _- ₁₀ Aryl, C₆ _- ₁₀ aryl-C₁ _- ₄ Alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C₁ _- ₄ Alkyl, 5-10 membered heteroaryl and (5-10 membered heteroaryl)-C₁ _- ₄ The alkyl groups are each optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, C₁ _- ₄ Alkyl, C₁ _- ₄ Haloalkyl, CN, NO₂ OR^A1 , SR^A1 , C(O)R^B1 , C(O)NR^C1 R^D1 , C(O)OR^A1 , OC(O)R^B1 , OC(O)NR^C1 R^D1 NR^C1 R^D1 NR^C1 C(O)R^B1 NR^C1 C(O)OR^A1 NR^C1 C(O)NR^C1 R^D1 NR^C1 S(O)R^B1 NR^C1 S(O)₂ R^B1 NR^C1 S(O)₂ NR^C1 R^D1 , S(O)R^B1 , S(O)NR^C1 R^D1 , S(O)₂ R^B1 And S(O)₂ NR^C1 R^D1 ; or R¹³ And R¹⁴ Together with the N atom to which it is attached, a 4 member, 5 member, 6 member or 7 membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents selected from: C₁ _- ₆ Alkyl, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ Aryl, 5-6 membered heteroaryl, halo, CN, OR^A1 , SR^A1 , C(O)R^B1 , C(O)NR^C1 R^D1 , C(O)OR^A1 , OC(O)R^B1 , OC(O)NR^C1 R^D1 NR^C1 R^D1 NR^C1 C(O)R^B1 NR^C1 C(O)NR^C1 R^D1 NR^C1 C(O)OR^A1 , S(O)R^B1 , S(O)NR^C1 R^D1 , S(O)₂ R^B1 NR^C1 S(O)₂ R^B1 NR^C1 S(O)₂ NR^C1 R^D1 And S(O)₂ NR^C1 R^D1 Where the C₁ _- ₆ Alkyl, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ The aryl group and the 5-6 membered heteroaryl group are each optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, CN, OR.^A1 , SR^A1 , C(O)R^B1 , C(O)NR^C1 R^D1 , C(O)OR^A1 , OC(O)R^B1 , OC(O)NR^C1 R^D1 NR^C1 R^D1 NR^C1 C(O)R^B1 NR^C1 C(O)NR^C1 R^D1 NR^C1 C(O)OR^A1 , S(O)R^B1 , S(O)NR^C1 R^D1 , S(O)₂ R^B1 NR^C1 S(O)₂ R^B1 NR^C1 S(O)₂ NR^C1 R^D1 And S(O)₂ NR^C1 R^D1 ; R¹⁵ For H, C₁ _- ₄ Alkyl, C₃ _- ₇ Cycloalkyl, C₃ _- ₇ cycloalkyl-C₁ _- ₄ Alkyl, C₆ _- ₁₀ Aryl, C₆ _- ₁₀ aryl-C₁ _- ₄ Alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C₁ _- ₄ Alkyl, 5-10 membered heteroaryl or (5-10 membered heteroaryl)-C₁ _- ₄ Alkyl, where the C₁ _- ₄ Alkyl, C₃ _- ₇ Cycloalkyl, C₃ _- ₇ cycloalkyl-C₁ _- ₄ Alkyl, C₆ _- ₁₀ Aryl, C₆ _- ₁₀ aryl-C₁ _- ₄ Alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C₁ _- ₄ Alkyl, 5-10 membered heteroaryl and (5-10 membered heteroaryl)-C₁ _- ₄ The alkyl groups are each optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ Aryl, 5-6 membered heteroaryl, CN, OR^A1 , SR^A1 , C(O)R^B1 , C(O)NR^C1 R^D1 , C(O)OR^A1 , OC(O)R^B1 , OC(O)NR^C1 R^D1 NR^C1 R^D1 NR^C1 C(O)R^B1 NR^C1 C(O)NR^C1 R^D1 NR^C1 C(O)OR^A1 , S(O)R^B1 , S(O)NR^C1 R^D1 , S(O)₂ R^B1 NR^C1 S(O)₂ R^B1 NR^C1 S(O)₂ NR^C1 R^D1 And S(O)₂ NR^C1 R^D1 ; R¹⁶ For C₁ _- ₄ Alkyl or NR^18a R^18b Where the C₁ _- ₄ The alkyl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ Aryl, 5-6 membered heteroaryl, CN, OR^A1 , SR^A1 , C(O)R^B1 , C(O)NR^C1 R^D1 , C(O)OR^A1 , OC(O)R^B1 , OC(O)NR^C1 R^D1 NR^C1 R^D1 NR^C1 C(O)R^B1 NR^C1 C(O)NR^C1 R^D1 NR^C1 C(O)OR^A1 , S(O)R^B1 , S(O)NR^C1 R^D1 , S(O)₂ R^B1 NR^C1 S(O)₂ R^B1 NR^C1 S(O)₂ NR^C1 R^D1 And S(O)₂ NR^C1 R^D1 ; R¹⁷ For C₁ _- ₄ Alkyl, NR^18a R^18b Or OR^18c Where the C₁ _- ₄ The alkyl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ Aryl, 5-6 membered heteroaryl, CN, OR^A1 , SR^A1 , C(O)R^B1 , C(O)NR^C1 R^D1 , C(O)OR^A1 , OC(O)R^B1 , OC(O)NR^C1 R^D1 NR^C1 R^D1 NR^C1 C(O)R^B1 NR^C1 C(O)NR^C1 R^D1 NR^C1 C(O)OR^A1 , S(O)R^B1 , S(O)NR^C1 R^D1 , S(O)₂ R^B1 NR^C1 S(O)₂ R^B1 NR^C1 S(O)₂ NR^C1 R^D1 And S(O)₂ NR^C1 R^D1 ; R^18a And R^18b Each is independently selected from H and C₁ _- ₄ Alkyl, where the C₁ _- ₄ The alkyl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ Aryl, 5-6 membered heteroaryl, CN, OR^A1 , SR^A1 , C(O)R^B1 , C(O)NR^C1 R^D1 , C(O)OR^A1 , OC(O)R^B1 , OC(O)NR^C1 R^D1 NR^C1 R^D1 NR^C1 C(O)R^B1 NR^C1 C(O)NR^C1 R^D1 NR^C4 C(O)OR^A1 , S(O)R^B1 , S(O)NR^C1 R^D1 , S(O)₂ R^B1 NR^C1 S(O)₂ R^B1 NR^C1 S(O)₂ NR^C1 R^D1 And S(O)₂ NR^C1 R^D1 ; or R^18a And R^18b Together with the N atom to which it is attached, a 4 member, 5 member, 6 member or 7 membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents selected from: C₁ _- ₆ Alkyl, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ Aryl, 5-6 membered heteroaryl, halo, CN, OR^A1 , SR^A1 , C(O)R^B1 , C(O)NR^C1 R^D1 , C(O)OR^A1 , OC(O)R^B1 , OC(O)NR^C1 R^D1 NR^C1 R^D1 NR^C1 C(O)R^B1 NR^C1 C(O)NR^C1 R^D1 NR^C1 C(O)OR^A1 , S(O)R^B1 , S(O)NR^C1 R^D1 , S(O)₂ R^B1 NR^C1 S(O)₂ R^B1 NR^C1 S(O)₂ NR^C1 R^D1 And S(O)₂ NR^C1 R^D1 Where the C₁ _- ₆ Alkyl, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ The aryl group and the 5-6 membered heteroaryl group are each optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, CN, OR.^A1 , SR^A1 , C(O)R^B1 , C(O)NR^C1 R^D1 , C(O)OR^A1 , OC(O)R^B1 , OC(O)NR^C1 R^D1 NR^C1 R^D1 NR^C1 C(O)R^B1 NR^C1 C(O)NR^C1 R^D1 NR^C1 C(O)OR^A1 , S(O)R^B1 , S(O)NR^C1 R^D1 , S(O)₂ R^B1 NR^C1 S(O)₂ R^B1 NR^C1 S(O)₂ NR^C1 R^D1 And S(O)₂ NR^C1 R^D1 ; R^18c For H, C₁ _- ₆ Alkyl, C₃ _- ₁₀ Cycloalkyl, C₃ _- ₇ cycloalkyl-C₁ _- ₄ Alkyl, C₆ _- ₁₀ Aryl, C₆ _- ₁₀ aryl-C₁ _- ₄ Alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C₁ _- ₄ Alkyl, 5-10 membered heteroaryl or (5-10 membered heteroaryl)-C₁ _- ₄ Alkyl, where the C₁ _- ₆ Alkyl, C₃ _- ₇ Cycloalkyl, C₃ _- ₁₀ cycloalkyl-C₁ _- ₄ Alkyl, C₆ _- ₁₀ Aryl, C₆ _- ₁₀ aryl-C₁ _- ₄ Alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C₁ _- ₄ Alkyl, 5-10 membered heteroaryl and (5-10 membered heteroaryl)-C₁ _- ₄ The alkyl groups are each optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, C₁ _- ₄ Alkyl, C₁ _- ₄ Haloalkyl, CN, NO₂ OR^A1 , SR^A1 , C(O)R^B1 , C(O)NR^C1 R^D1 , C(O)OR^A1 , OC(O)R^B1 , OC(O)NR^C1 R^D1 NR^C1 R^D1 NR^C1 C(O)R^B1 NR^C1 C(O)OR^A1 NR^C1 C(O)NR^C1 R^D1 NR^C1 S(O)R^B1 NR^C1 S(O)₂ R^B1 NR^C1 S(O)₂ NR^C1 R^D1 , S(O)R^B1 , S(O)NR^C1 R^D1 , S(O)₂ R^B1 And S(O)₂ NR^C1 R^D1 ; R^A For H, Cy¹ Halogen, C₁ _- ₆ Alkyl, C₂ _- ₆ Alkenyl, CN, NO₂ OR^A2 , SR^A2 , C(O)R^B2 , C(O)NR^C2 R^D2 , C(O)OR^A2 , OC(O)R^B2 , OC(O)NR^C2 R^D2 NR^C2 R^D2 NR^C2 C(O)R^B2 NR^C2 C(O)OR^A2 NR^C2 C(O)NR^C2 R^D2 NR^C2 S(O)R^B2 NR^C2 S(O)₂ R^B2 NR^C2 S(O)₂ NR^C2 R^D2 , S(O)R^B2 , S(O)NR^C2 R^D2 , S(O)₂ R^B2 Or S(O)₂ NR^C2 R^D2 Where the C₁ _- ₆ Alkyl and C₂ _- ₆ The alkenyl groups are each substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of: Cy¹ Halogen, C₁ _- ₆ Alkyl, C₂ _- ₆ Alkenyl, C₁ _- ₆ Haloalkyl, CN, NO₂ OR^A2 , SR^A2 , C(O)R^B2 , C(O)NR^C2 R^D2 , C(O)OR^A2 , OC(O)R^B2 , OC(O)NR^C2 R^D2 NR^C2 R^D2 NR^C2 C(O)R^B2 NR^C2 C(O)OR^A2 NR^C2 C(O)NR^C2 R^D2 NR^C2 S(O)R^B2 NR^C2 S(O)₂ R^B2 NR^C2 S(O)₂ NR^C2 R^D2 , S(O)R^B2 , S(O)NR^C2 R^D2 , S(O)₂ R^B2 And S(O)₂ NR^C2 R^D2 ; R^B For H, Cy² Halogen, C₁ _- ₆ Alkyl, C₂ _- ₆ Alkenyl, C₁ _- ₆ Haloalkyl, CN, NO₂ OR^A3 , SR^A3 , C(O)R^B3 , C(O)NR^C3 R^D3 , C(O)OR^A3 , OC(O)R^B3 , OC(O)NR^C3 R^D3 NR^C3 R^D3 NR^C3 C(O)R^B3 NR^C3 C(O)OR^A3 NR^C3 C(O)NR^C3 R^D3 NR^C3 S(O)R^B3 NR^C3 S(O)₂ R^B3 NR^C3 S(O)₂ NR^C3 R^D3 , S(O)R^B3 , S(O)NR^C3 R^D3 , S(O)₂ R^B3 Or S(O)₂ NR^C3 R^D3 Where the C₁ _- ₆ Alkyl and C₂ _- ₆ The alkenyl groups are each substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of: Cy² Halogen, C₁ _- ₆ Alkyl, C₂ _- ₆ Alkenyl, C₁ _- ₆ Haloalkyl, CN, NO₂ OR^A3 , SR^A3 , C(O)R^B3 , C(O)NR^C3 R^D3 , C(O)OR^A3 , OC(O)R^B3 , OC(O)NR^C3 R^D3 NR^C3 R^D3 NR^C3 C(O)R^B3 NR^C3 C(O)OR^A3 NR^C3 C(O)NR^C3 R^D3 NR^C3 S(O)R^B3 NR^C1 S(O)₂ R^B3 NR^C3 S(O)₂ NR^C3 R^D3 , S(O)R^B3 , S(O)NR^C3 R^D3 , S(O)₂ R^B3 And S(O)₂ NR^C3 R^D3 ; R^C And R^D Each is independently selected from: H, halo, C₁ _- ₆ Alkyl, C₂ _- ₆ Alkenyl, C₁ _- ₆ Haloalkyl, CN, NO₂ OR^A4 , SR^A4 , C(O)R^B4 , C(O)NR^C4 R^D4 , C(O)OR^A4 , OC(O)R^B4 , OC(O)NR^C4 R^D4 NR^C4 R^D4 NR^C4 C(O)R^B4 NR^C4 C(O)OR^A4 NR^C4 C(O)NR^C4 R^D4 NR^C4 S(O)R^B4 NR^C4 S(O)₂ R^B4 NR^C4 S(O)₂ NR^C4 R^D4 , S(O)R^B4 , S(O)NR^C4 R^D4 , S(O)₂ R^B4 And S(O)₂ NR^C4 R^D4 Where the C₁ _- ₆ Alkyl and C₂ _- ₆ The alkenyl groups are each substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of C:₆ _- ₁₀ Aryl, C₃ _- ₁₀ Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, C₁ _- ₆ Alkyl, C₂ _- ₆ Alkenyl, C₁ _- ₆ Haloalkyl, CN, NO₂ OR^A4 , SR^A4 , C(O)R^B4 , C(O)NR^C4 R^D4 , C(O)OR^A4 , OC(O)R^B4 , OC(O)NR^C4 R^D4 NR^C4 R^D4 NR^C4 C(O)R^B4 NR^C4 C(O)OR^A4 NR^C4 C(O)NR^C4 R^D4 NR^C4 S(O)R^B4 NR^C4 S(O)₂ R^B4 NR^C4 S(O)₂ NR^C4 R^D4 , S(O)R^B4 , S(O)NR^C4 R^D4 , S(O)₂ R^B4 And S(O)₂ NR^C4 R^D4 ; Cy¹ And Cy² Each is independently selected from: C₆ _- ₁₀ Aryl, C₃ _- ₁₀ a cycloalkyl group, a 5-10 membered heteroaryl group, and a 4-10 membered heterocycloalkyl group, each of which is independently selected from 1, 2, 3, 4 or 5, optionally R.^Cy Replacement of substituents; each R^Cy Independently selected from: halogen, C₁ _- ₆ Alkyl, C₁ _- ₆ Haloalkyl, C₂ _- ₆ Alkenyl, C₆ _- ₁₀ Aryl, C₃ _- ₁₀ Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂ OR^A5 , SR^A5 , C(O)R^B5 , C(O)NR^C5 R^D5 , C(O)OR^A5 , OC(O)R^B5 , OC(O)NR^C5 R^D5 NR^C5 R^D5 NR^C5 C(O)R^B5 NR^C5 C(O)OR^A5 NR^C5 C(O)NR^C5 R^D5 NR^C5 S(O)R^B5 NR^C5 S(O)₂ R^B5 NR^C5 S(O)₂ NR^C5 R^D5 , S(O)R^B5 , S(O)NR^C5 R^D5 , S(O)₂ R^B5 And S(O)₂ NR^C5 R^D5 Where the C₁ _- ₆ Alkyl, C₂ _- ₆ Alkenyl C₆ _- ₁₀ Aryl, C₃ _- ₁₀ The cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of halo, C₁ _- ₆ Alkyl, CN, NO₂ OR^A5 , SR^A5 , C(O)R^B5 , C(O)NR^C5 R^D5 , C(O)OR^A5 , OC(O)R^B5 , OC(O)NR^C5 R^D5 NR^C5 R^D5 NR^C5 C(O)R^B5 NR^C5 C(O)OR^A5 NR^C5 C(O)NR^C5 R^D5 NR^C5 S(O)R^B5 NR^C5 S(O)₂ R^B5 NR^C5 S(O)₂ NR^C5 R^D5 , S(O)R^B5 , S(O)NR^C5 R^D5 , S(O)₂ R^B5 And S(O)₂ NR^C5 R^D5 ; each R^a , R^A1 , R^A2 , R^A3 , R^A4 And R^A5 Independently selected from: H, C₁ _- ₆ Alkyl, C₁ _- ₄ Haloalkyl, C₂ _- ₆ Alkenyl, C₆ _- ₁₀ Aryl, C₃ _- ₁₀ Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆ _- ₁₀ aryl-C₁ _- ₄ Alkyl, C₃ _- ₁₀ cycloalkyl-C₁ _- ₄ Alkyl, (5-10 membered heteroaryl)-C₁ _- ₄ Alkyl or (4-10 membered heterocycloalkyl)-C₁ _- ₄ Alkyl, where the C₁ _- ₆ Alkyl, C₂ _- ₆ Alkenyl, C₆ _- ₁₀ Aryl, C₃ _- ₁₀ Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆ _- ₁₀ aryl-C₁ _- ₄ Alkyl, C₃ _- ₁₀ cycloalkyl-C₁ _- ₄ Alkyl, (5-10 membered heteroaryl)-C₁ _- ₄ Alkyl and (4-10 membered heterocycloalkyl)-C₁ _- ₄ The alkyl groups are each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of C:₁ _- ₄ Alkyl, halogen, CN, OR^A6 , C(O)R^B6 , C(O)NR^C6 R^D6 , C(O)OR^A6 , OC(O)R^B6 , OC(O)NR^C6 R^D6 NR^C6 R^D6 NR^C6 C(O)R^B6 NR^C6 C(O)NR^C6 R^D6 NR^C6 C(O)OR^A6 , S(O)R^B6 , S(O)NR^C6 R^D6 , S(O)₂ R^B6 NR^C6 S(O)₂ R^B6 NR^C6 S(O)₂ NR^C6 R^D6 And S(O)₂ NR^C6 R^D6 ; each R^B1 , R^B2 , R^B3 , R^B4 And R^B5 Independently selected from: H, C₁ _- ₆ Alkyl, C₁ _- ₄ Haloalkyl, C₂ _- ₆ Alkenyl, C₆ _- ₁₀ Aryl, C₃ _- ₁₀ Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆ _- ₁₀ aryl-C₁ _- ₄ Alkyl, C₃ _- ₁₀ cycloalkyl-C₁ _- ₄ Alkyl, (5-10 membered heteroaryl)-C₁ _- ₄ Alkyl or (4-10 membered heterocycloalkyl)-C₁ _- ₄ Alkyl, where the C₁ _- ₆ Alkyl, C₂ _- ₆ Alkenyl, C₆ _- ₁₀ Aryl, C₃ _- ₁₀ Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆ _- ₁₀ aryl-C₁ _- ₄ Alkyl, C₃ _- ₁₀ cycloalkyl-C₁ _- ₄ Alkyl, (5-10 membered heteroaryl)-C₁ _- ₄ Alkyl and (4-10 membered heterocycloalkyl)-C₁ _- ₄ The alkyl groups are each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of C:₁ _- ₄ Alkyl, halogen, CN, OR^A6 , C(O)R^B6 , C(O)NR^C6 R^D6 , C(O)OR^A6 , OC(O)R^B6 , OC(O)NR^C6 R^D6 NR^C6 R^D6 NR^C6 C(O)R^B6 NR^C6 C(O)NR^C6 R^D6 NR^C6 C(O)OR^A6 , S(O)R^B6 , S(O)NR^C6 R^D6 , S(O)₂ R^B6 NR^C6 S(O)₂ R^B6 NR^C6 S(O)₂ NR^C6 R^D6 And S(O)₂ NR^C6 R^D6 ; each R^c , R^d , R^C1 , R^D1 , R^C2 , R^D2 , R^C3 , R^D3 , R^C4 , R^D4 , R^C5 And R^D5 Independently selected from: H, C₁ _- ₆ Alkyl, C₁ _- ₄ Haloalkyl, C₂ _- ₆ Alkenyl, C₆ _- ₁₀ Aryl, C₃ _- ₁₀ Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆ _- ₁₀ aryl-C₁ _- ₄ Alkyl, C₃ _- ₁₀ cycloalkyl-C₁ _- ₄ Alkyl, (5-10 membered heteroaryl)-C₁ _- ₄ Alkyl or (4-10 membered heterocycloalkyl)-C₁ _- ₄ Alkyl, where the C₁ _- ₆ Alkyl, C₂ _- ₆ Alkenyl, C₆ _- ₁₀ Aryl, C₃ _- ₁₀ Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆ _- ₁₀ aryl-C₁ _- ₄ Alkyl, C₃ _- ₁₀ cycloalkyl-C₁ _- ₄ Alkyl, (5-10 membered heteroaryl)-C₁ _- ₄ Alkyl and (4-10 membered heterocycloalkyl)-C₁ _- ₄ The alkyl groups are each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of C:₁ _- ₄ Alkyl, halogen, CN, OR^A6 , SR^A6 , C(O)R^B6 , C(O)NR^C6 R^D6 , C(O)OR^A6 , OC(O)R^B6 , OC(O)NR^C6 R^D6 NR^C6 R^D6 NR^C6 C(O)R^B6 NR^C6 C(O)NR^C6 R^D6 NR^C6 C(O)OR^A6 , S(O)R^B6 , S(O)NR^C6 R^D6 , S(O)₂ R^B6 NR^C6 S(O)₂ R^B6 NR^C6 S(O)₂ NR^C6 R^D6 And S(O)₂ NR^C6 R^D6 ; or any R^c And R^d Together with the N atom to which it is attached, a 4 member, 5 member, 6 member or 7 membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents selected from: C₁ _- ₆ Alkyl, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ Aryl, 5-6 membered heteroaryl, halo, CN, OR^A6 , SR^A6 , C(O)R^B6 , C(O)NR^C6 R^D6 , C(O)OR^A6 , OC(O)R^B6 , OC(O)NR^C6 R^D6 NR^C6 R^D6 NR^C6 C(O)R^B6 NR^C6 C(O)NR^C6 R^D6 NR^C6 C(O)OR^A6 , S(O)R^B6 , S(O)NR^C6 R^D6 , S(O)₂ R^B6 NR^C6 S(O)₂ R^B6 NR^C6 S(O)₂ NR^C6 R^D6 And S(O)₂ NR^C6 R^D6 Where the C₁ _- ₆ Alkyl, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ The aryl group and the 5-6 membered heteroaryl group are optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, CN, OR.^A6 , SR^A6 , C(O)R^B6 , C(O)NR^C6 R^D6 , C(O)OR^A6 , OC(O)R^B6 , OC(O)NR^C6 R^D6 NR^C6 R^D6 NR^C6 C(O)R^B6 NR^C6 C(O)NR^C6 R^D6 NR^C6 C(O)OR^A6 , S(O)R^B6 , S(O)NR^C6 R^D6 , S(O)₂ R^B6 NR^C6 S(O)₂ R^B6 NR^C6 S(O)₂ NR^C6 R^D6 And S(O)₂ NR^C6 R^D6 ; or any R^C1 And R^D1 Together with the N atom to which it is attached, a 4 member, 5 member, 6 member or 7 membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents selected from: C₁ _- ₆ Alkyl, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ Aryl, 5-6 membered heteroaryl, halo, CN, OR^A6 , SR^A6 , C(O)R^B6 , C(O)NR^C6 R^D6 , C(O)OR^A6 , OC(O)R^B6 , OC(O)NR^C6 R^D6 NR^C6 R^D6 NR^C6 C(O)R^B6 NR^C6 C(O)NR^C6 R^D6 NR^C6 C(O)OR^A6 , S(O)R^B6 , S(O)NR^C6 R^D6 , S(O)₂ R^B6 NR^C6 S(O)₂ R^B6 NR^C6 S(O)₂ NR^C6 R^D6 And S(O)₂ NR^C6 R^D6 Where the C₁ _- ₆ Alkyl, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ The aryl group and the 5-6 membered heteroaryl group are each optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, CN, OR.^A6 , SR^A6 , C(O)R^B6 , C(O)NR^C6 R^D6 , C(O)OR^A6 , OC(O)R^B6 , OC(O)NR^C6 R^D6 NR^C6 R^D6 NR^C6 C(O)R^B6 NR^C6 C(O)NR^C6 R^D6 NR^C6 C(O)OR^A6 , S(O)R^B6 , S(O)NR^C6 R^D6 , S(O)₂ R^B6 NR^C6 S(O)₂ R^B6 NR^C6 S(O)₂ NR^C6 R^D6 And S(O)₂ NR^C6 R^D6 ; or any R^C2 And R^D2 Together with the N atom to which it is attached, a 4 member, 5 member, 6 member or 7 membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents selected from: C₁ _- ₆ Alkyl, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ Aryl and 5-6 membered heteroaryl, C₁ _- ₆ Haloalkyl, halo, CN, OR^A6 , SR^A6 , C(O)R^B6 , C(O)NR^C6 R^D6 , C(O)OR^A6 , OC(O)R^B6 , OC(O)NR^C6 R^D6 NR^C6 R^D6 NR^C6 C(O)R^B6 NR^C6 C(O)NR^C6 R^D6 NR^C6 C(O)OR^A6 , S(O)R^B6 , S(O)NR^C6 R^D6 , S(O)₂ R^B6 NR^C6 S(O)₂ R^B6 NR^C6 S(O)₂ NR^C6 R^D6 And S(O)₂ NR^C6 R^D6 Where the C₁ _- ₆ Alkyl, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ The aryl group and the 5-6 membered heteroaryl group are each optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, CN, OR.^A6 , SR^A6 , C(O)R^B6 , C(O)NR^C6 R^D6 , C(O)OR^A6 , OC(O)R^B6 , OC(O)NR^C6 R^D6 NR^C6 R^D6 NR^C6 C(O)R^B6 NR^C6 C(O)NR^C6 R^D6 NR^C6 C(O)OR^A6 , S(O)R^B6 , S(O)NR^C6 R^D6 , S(O)₂ R^B6 NR^C6 S(O)₂ R^B6 NR^C6 S(O)₂ NR^C6 R^D6 And S(O)₂ NR^C6 R^D6 ; or any R^C3 And R^D3 Together with the N atom to which it is attached, a 4 member, 5 member, 6 member or 7 membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents selected from: C₁ _- ₆ Alkyl, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ Aryl, 5-6 membered heteroaryl, C₁ _- ₆ Haloalkyl, halo, CN, OR^A6 , SR^A6 , C(O)R^B6 , C(O)NR^C6 R^D6 , C(O)OR^A6 , OC(O)R^b ⁶ , OC(O)NR^C6 R^D6 NR^C6 R^D6 NR^C6 C(O)R^B6 NR^C6 C(O)NR^C6 R^D6 NR^C6 C(O)OR^A6 , S(O)R^B6 , S(O)NR^C6 R^D6 , S(O)₂ R^B6 NR^C6 S(O)₂ R^B6 NR^C6 S(O)₂ NR^C6 R^D6 And S(O)₂ NR^C6 R^D6 Where the C₁ _- ₆ Alkyl, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ The aryl group and the 5-6 membered heteroaryl group are each optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, CN, OR.^A6 , SR^A6 , C(O)R^B6 , C(O)NR^C6 R^D6 , C(O)OR^A6 , OC(O)R^B6 , OC(O)NR^C6 R^D6 NR^C6 R^D6 NR^C6 C(O)R^B6 NR^C6 C(O)NR^C6 R^D6 NR^C6 C(O)OR^A6 , S(O)R^B6 , S(O)NR^C6 R^D6 , S(O)₂ R^B6 NR^C6 S(O)₂ R^B6 NR^C6 S(O)₂ NR^C6 R^D6 And S(O)₂ NR^C6 R^D6 ; or any R^C4 And R^D4 Together with the N atom to which it is attached, a 4 member, 5 member, 6 member or 7 membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents selected from: C₁ _- ₆ Alkyl, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ Aryl, 5-6 membered heteroaryl, C₁ _- ₆ Haloalkyl, halo, CN, OR^A6 , SR^A6 , C(O)R^B6 , C(O)NR^C6 R^D6 , C(O)OR^A6 , OC(O)R^B6 , OC(O)NR^C6 R^D6 NR^C6 R^D6 NR^C6 C(O)R^B6 NR^C6 C(O)NR^C6 R^D6 NR^C6 C(O)OR^A6 , S(O)R^B6 , S(O)NR^C6 R^D6 , S(O)₂ R^B6 NR^C6 S(O)₂ R^B6 NR^C6 S(O)₂ NR^C6 R^D6 And S(O)₂ NR^C6 R^D6 Where the C₁ _- ₆ Alkyl, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ The aryl group and the 5-6 membered heteroaryl group are each optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, CN, OR.^A6 , SR^A6 , C(O)R^B6 , C(O)NR^C6 R^D6 , C(O)OR^A6 , OC(O)R^B6 , OC(O)NR^C6 R^D6 NR^C6 R^D6 NR^C6 C(O)R^B6 NR^C6 C(O)NR^C6 R^D6 NR^C6 C(O)OR^A6 , S(O)R^B6 , S(O)NR^C6 R^D6 , S(O)₂ R^B6 NR^C6 S(O)₂ R^B6 NR^C6 S(O)₂ NR^C6 R^D6 And S(O)₂ NR^C6 R^D6 ; or any R^C5 And R^D5 Together with the N atom to which it is attached, a 4 member, 5 member, 6 member or 7 membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents selected from: C₁ _- ₆ Alkyl, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ Aryl, 5-6 membered heteroaryl, C₁ _- ₆ Haloalkyl, halo, CN, OR^A6 , SR^A6 , C(O)R^B6 , C(O)NR^C6 R^D6 , C(O)OR^A6 , OC(O)R^b ⁶ , OC(O)NR^C6 R^D6 NR^C6 R^D6 NR^C6 C(O)R^B6 NR^C6 C(O)NR^C6 R^D6 NR^C6 C(O)OR^A6 , S(O)R^B6 , S(O)NR^C6 R^D6 , S(O)₂ R^B6 NR^C6 S(O)₂ R^B6 NR^C6 S(O)₂ NR^C6 R^D6 And S(O)₂ NR^C6 R^D6 Where the C₁ _- ₆ Alkyl, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ The aryl group and the 5-6 membered heteroaryl group are each optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, CN, OR.^A6 , SR^A6 , C(O)R^B6 , C(O)NR^C6 R^D6 , C(O)OR^A6 , OC(O)R^B6 , OC(O)NR^C6 R^D6 NR^C6 R^D6 NR^C6 C(O)R^B6 NR^C6 C(O)NR^C6 R^D6 NR^C6 C(O)OR^A6 , S(O)R^B6 , S(O)NR^C6 R^D6 , S(O)₂ R^B6 NR^C6 S(O)₂ R^B6 NR^C6 S(O)₂ NR^C6 R^D6 And S(O)₂ NR^C6 R^D6 ; each R^A6 , R^B6 , R^C6 And R^D6 Independently selected from: H, C₁ _- ₄ Alkyl, C₂ _- ₄ Alkenyl, C₃ _- ₇ a cycloalkyl group, a phenyl group, a 5-6 membered heteroaryl group, and a 4-7 membered heterocycloalkyl group, wherein the C₁ _- ₄ Alkyl, C₂ _- ₄ Alkenyl, C₃ _- ₇ The cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of OH, CN, amine, Halogen, C₁ _- ₄ Alkyl, C₁ _- ₄ Alkoxy, C₁ _- ₄ Alkylthio, C₁ _- ₄ Alkylamine and II (C₁ _- ₄ Alkylamino; n is 1 or 2; p is 1, 2 or 3; and q is 1 or 2; wherein any of the aforementioned 4-10 member or 4-7 membered heterocycloalkyl group optionally comprises 1, 2 or Three pendant oxygen substituents in which the pendant oxygen substituents are substituted on the ring forming the carbon, nitrogen or sulfur atom of a 4-10 member or 4-7 membered heterocycloalkyl group. In some embodiments, the TPH-inhibiting compound described herein is a compound of Formula I:I or a pharmaceutically acceptable salt thereof, wherein: Ring A is C₃ _- ₁₀ Cycloalkyl, C₆ _- ₁₀ Aryl, 4 to 10 membered heterocycloalkyl or 5 to 10 membered heteroaryl; L is O or NR⁴ ; W is N or CR⁵ ; X is N or CR⁶ ; Y is N or CR⁷ Where only one of X and Y is N; R¹ For H, C₁ _- ₁₀ Alkyl, C₃ _- ₁₀ Cycloalkyl, phenyl, -(CR⁸ R⁹ )_p OC(O)R¹⁰ ,-(CR⁸ R⁹ )_p NR¹¹ R¹² Or - (CR⁸ R⁹ )_p C(O)NR¹¹ R¹² Where the C₁ _- ₁₀ Alkyl, C₃ _- ₁₀ The cycloalkyl and phenyl groups are each substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of F, Cl, Br, CN, C.₁ _- ₄ Alkyl and C₁ _- ₄ Haloalkyl; R² And R³ Each is independently selected from H, C₁ _- ₄ Alkyl and C₁ _- ₄ Haloalkyl; R⁴ For H or C₁ _- ₄ Alkyl; R⁵ And R⁶ Each independently selected from H, halo and C₁ _- ₄ Alkyl; R⁷ For H, C₁ _- ₄ Alkyl, C₂ _- ₆ Alkenyl, C₃ _- ₁₀ Cycloalkyl, C₃ _- ₁₀ cycloalkyl-C₁ _- ₄ Alkyl, C₆ _- ₁₀ Aryl, C₆ _- ₁₀ aryl-C₁ _- ₄ Alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C₁ _- ₄ Alkyl, 5-10 membered heteroaryl, (5-10 membered heteroaryl)-C₁ _- ₄ Alkyl, NR¹³ R¹⁴ OR¹⁵ , C(O)R¹⁶ , S(O)_q R¹⁷ Where the C₁ _- ₄ Alkyl, C₂ _- ₆ Alkenyl, C₃ _- ₁₀ Cycloalkyl, C₃ _- ₁₀ cycloalkyl-C₁ _- ₄ Alkyl, C₆ _- ₁₀ Aryl, C₆ _- ₁₀ aryl-C₁ _- ₄ Alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C₁ _- ₄ Alkyl, 5-10 membered heteroaryl and (5-10 membered heteroaryl)-C₁ _- ₄ The alkyl groups are each optionally substituted by 1, 2 or 3 substituents selected from the group consisting of halo, C₁ _- ₄ Alkyl, C₂ _- ₆ Alkenyl, amine, C₁ _- ₄ Alkylamine, C₂ _- ₈ Dialkylamine, hydroxyl and C₁ _- ₄ Alkoxy; R⁸ And R⁹ Each is independently selected from H and C₁ _- ₄ Alkyl; R¹⁰ For C₁ _- ₆ Alkyl, optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of C:₁ _- ₆ Haloalkyl, C₃ _- ₁₀ Cycloalkyl, OR^a And NR^c R^d ; R¹¹ And R¹² Each is independently selected from H and C₁ _- ₆ Alkyl; R¹³ For H or C₁ _- ₄ Alkyl; R¹⁴ For H, C₁ _- ₄ Alkyl, C₃ _- ₇ Cycloalkyl, C₃ _- ₇ cycloalkyl-C₁ _- ₄ Alkyl, C₆ _- ₁₀ Aryl, C₆ _- ₁₀ aryl-C₁ _- ₄ Alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C₁ _- ₄ Alkyl, 5-10 membered heteroaryl or (5-10 membered heteroaryl)-C₁ _- ₄ Alkyl, C(O)R^B1 , C(O)OR^A1 , C(O)NR^C1 R^D1 , S(O)R^B1 , S(O)₂ R^B1 Or S(O)₂ NR^C1 R^D1 Where the C₁ _- ₄ Alkyl, C₃ _- ₇ Cycloalkyl, C₃ _- ₇ cycloalkyl-C₁ _- ₄ Alkyl, C₆ _- ₁₀ Aryl, C₆ _- ₁₀ aryl-C₁ _- ₄ Alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C₁ _- ₄ Alkyl, 5-10 membered heteroaryl and (5-10 membered heteroaryl)-C₁ _- ₄ The alkyl groups are each optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, C₁ _- ₄ Alkyl, C₁ _- ₄ Haloalkyl, CN, NO₂ OR^A1 , SR^A1 , C(O)R^B1 , C(O)NR^C1 R^D1 , C(O)OR^A1 , OC(O)R^B1 , OC(O)NR^C1 R^D1 NR^C1 R^D1 NR^C1 C(O)R^B1 NR^C1 C(O)OR^A1 NR^C1 C(O)NR^C1 R^D1 NR^C1 S(O)R^B1 NR^C1 S(O)₂ R^B1 NR^C1 S(O)₂ NR^C1 R^D1 , S(O)R^B1 , S(O)NR^C1 R^D1 , S(O)₂ R^B1 And S(O)₂ NR^C1 R^D1 ; or R¹³ And R¹⁴ Together with the N atom to which it is attached, a 4 member, 5 member, 6 member or 7 membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents selected from: C₁ _- ₆ Alkyl, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ Aryl, 5-6 membered heteroaryl, halo, CN, OR^A1 , SR^A1 , C(O)R^B1 , C(O)NR^C1 R^D1 , C(O)OR^A1 , OC(O)R^B1 , OC(O)NR^C1 R^d ¹ NR^C1 R^D1 NR^C1 C(O)R^B1 NR^C1 C(O)NR^C1 R^D1 NR^C1 C(O)OR^A1 , S(O)R^B1 , S(O)NR^C1 R^D1 , S(O)₂ R^B1 NR^C1 S(O)₂ R^B1 NR^C1 S(O)₂ NR^C1 R^D1 And S(O)₂ NR^C1 R^D1 Where the C₁ _- ₆ Alkyl, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ The aryl group and the 5-6 membered heteroaryl group are each optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, CN, OR.^A1 , SR^A1 , C(O)R^B1 , C(O)NR^C1 R^D1 , C(O)OR^A1 , OC(O)R^B1 , OC(O)NR^C1 R^D1 NR^C1 R^D1 NR^C1 C(O)R^B1 NR^C1 C(O)NR^C1 R^D1 NR^C1 C(O)OR^A1 , S(O)R^B1 , S(O)NR^C1 R^D1 , S(O)₂ R^B1 NR^C1 S(O)₂ R^B1 NR^C1 S(O)₂ NR^C1 R^D1 And S(O)₂ NR^C1 R^D1 ; R¹⁵ For H, C₁ _- ₄ Alkyl, C₃ _- ₇ Cycloalkyl, C₃ _- ₇ cycloalkyl-C₁ _- ₄ Alkyl, C₆ _- ₁₀ Aryl, C₆ _- ₁₀ aryl-C₁ _- ₄ Alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C₁ _- ₄ Alkyl, 5-10 membered heteroaryl or (5-10 membered heteroaryl)-C₁ _- ₄ Alkyl, where the C₁ _- ₄ Alkyl, C₃ _- ₇ Cycloalkyl, C₃ _- ₇ cycloalkyl-C₁ _- ₄ Alkyl, C₆ _- ₁₀ Aryl, C₆ _- ₁₀ aryl-C₁ _- ₄ Alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C₁ _- ₄ Alkyl, 5-10 membered heteroaryl and (5-10 membered heteroaryl)-C₁ _- ₄ The alkyl groups are each optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ Aryl, 5-6 membered heteroaryl, CN, OR^A1 , SR^A1 , C(O)R^B1 , C(O)NR^C1 R^D1 , C(O)OR^A1 , OC(O)R^B1 , OC(O)NR^C1 R^D1 NR^C1 R^D1 NR^C1 C(O)R^B1 NR^C1 C(O)NR^C1 R^D1 NR^C1 C(O)OR^A1 , S(O)R^B1 , S(O)NR^C1 R^D1 , S(O)₂ R^B1 NR^C1 S(O)₂ R^B1 NR^C1 S(O)₂ NR^C1 R^D1 And S(O)₂ NR^C1 R^D1 ; R¹⁶ For C₁ _- ₄ Alkyl or NR^18a R^18b Where the C₁ _- ₄ The alkyl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ Aryl, 5-6 membered heteroaryl, CN, OR^A1 , SR^A1 , C(O)R^B1 , C(O)NR^C1 R^D1 , C(O)OR^A1 , OC(O)R^B1 , OC(O)NR^C1 R^D1 NR^C1 R^D1 NR^C1 C(O)R^B1 NR^C1 C(O)NR^C1 R^D1 NR^C1 C(O)OR^A1 , S(O)R^B1 , S(O)NR^C1 R^D1 , S(O)₂ R^B1 NR^C1 S(O)₂ R^B1 NR^C1 S(O)₂ NR^C1 R^D1 And S(O)₂ NR^C1 R^D1 ; R¹⁷ For C₁ _- ₄ Alkyl, NR^18a R^18b Or OR^18c Where the C₁ _- ₄ The alkyl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ Aryl, 5-6 membered heteroaryl, CN, OR^A1 , SR^A1 , C(O)R^B1 , C(O)NR^C1 R^D1 , C(O)OR^A1 , OC(O)R^B1 , OC(O)NR^C1 R^D1 NR^C1 R^D1 NR^C1 C(O)R^B1 NR^C1 C(O)NR^C1 R^D1 NR^C1 C(O)OR^A1 , S(O)R^B1 , S(O)NR^C1 R^D1 , S(O)₂ R^B1 NR^C1 S(O)₂ R^B1 NR^C1 S(O)₂ NR^C1 R^D1 And S(O)₂ NR^C1 R^D1 ; R^18a And R^18b Each is independently selected from H and C₁ _- ₄ Alkyl, where the C₁ _- ₄ The alkyl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ Aryl, 5-6 membered heteroaryl, CN, OR^A1 , SR^A1 , C(O)R^B1 , C(O)NR^C1 R^D1 , C(O)OR^A1 , OC(O)R^B1 , OC(O)NR^C1 R^D1 NR^C1 R^D1 NR^C1 C(O)R^B1 NR^C1 C(O)NR^C1 R^D1 NR^C4 C(O)OR^A1 , S(O)R^B1 , S(O)NR^C1 R^D1 , S(O)₂ R^B1 NR^C1 S(O)₂ R^B1 NR^C1 S(O)₂ NR^C1 R^D1 And S(O)₂ NR^C1 R^D1 ; or R^18a And R^18b Together with the N atom to which it is attached, a 4 member, 5 member, 6 member or 7 membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents selected from: C₁ _- ₆ Alkyl, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ Aryl, 5-6 membered heteroaryl, halo, CN, OR^A1 , SR^A1 , C(O)R^B1 , C(O)NR^C1 R^D1 , C(O)OR^A1 , OC(O)R^B1 , OC(O)NR^C1 R^D1 NR^C1 R^D1 NR^C1 C(O)R^B1 NR^C1 C(O)NR^C1 R^D1 NR^C1 C(O)OR^A1 , S(O)R^B1 , S(O)NR^C1 R^D1 , S(O)₂ R^B1 NR^C1 S(O)₂ R^B1 NR^C1 S(O)₂ NR^C1 R^D1 And S(O)₂ NR^C1 R^D1 Where the C₁ _- ₆ Alkyl, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ The aryl group and the 5-6 membered heteroaryl group are each optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, CN, OR.^A1 , SR^A1 , C(O)R^B1 , C(O)NR^C1 R^D1 , C(O)OR^A1 , OC(O)R^B1 , OC(O)NR^C1 R^D1 NR^C1 R^D1 NR^C1 C(O)R^B1 NR^C1 C(O)NR^C1 R^D1 NR^C1 C(O)OR^A1 , S(O)R^B1 , S(O)NR^C1 R^D1 , S(O)₂ R^B1 NR^C1 S(O)₂ R^B1 NR^C1 S(O)₂ NR^C1 R^D1 And S(O)₂ NR^C1 R^D1 ; R^18c For H, C₁ _- ₆ Alkyl, C₃ _- ₁₀ Cycloalkyl, C₃ _- ₇ cycloalkyl-C₁ _- ₄ Alkyl, C₆ _- ₁₀ Aryl, C₆ _- ₁₀ aryl-C₁ _- ₄ Alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C₁ _- ₄ Alkyl, 5-10 membered heteroaryl or (5-10 membered heteroaryl)-C₁ _- ₄ Alkyl, where the C₁ _- ₆ Alkyl, C₃ _- ₇ Cycloalkyl, C₃ _- ₁₀ cycloalkyl-C₁ _- ₄ Alkyl, C₆ _- ₁₀ Aryl, C₆ _- ₁₀ aryl-C₁ _- ₄ Alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C₁ _- ₄ Alkyl, 5-10 membered heteroaryl and (5-10 membered heteroaryl)-C₁ _- ₄ The alkyl groups are each optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, C₁ _- ₄ Alkyl, C₁ _- ₄ Haloalkyl, CN, NO₂ OR^A1 , SR^A1 , C(O)R^B1 , C(O)NR^C1 R^D1 , C(O)OR^A1 , OC(O)R^B1 , OC(O)NR^C1 R^D1 NR^C1 R^D1 NR^C1 C(O)R^B1 NR^C1 C(O)OR^A1 NR^C1 C(O)NR^C1 R^D1 NR^C1 S(O)R^B1 NR^C1 S(O)₂ R^B1 NR^C1 S(O)₂ NR^C1 R^D1 , S(O)R^B1 , S(O)NR^C1 R^D1 , S(O)₂ R^B1 And S(O)₂ NR^C1 R^D1 ; R^A For H, Cy¹ Halogen, C₁ _- ₆ Alkyl, C₂ _- ₆ Alkenyl, CN, NO₂ OR^A2 , SR^A2 , C(O)R^B2 , C(O)NR^C2 R^D2 , C(O)OR^A2 , OC(O)R^B2 , OC(O)NR^C2 R^D2 NR^C2 R^D2 NR^C2 C(O)R^B2 NR^C2 C(O)OR^A2 NR^C2 C(O)NR^C2 R^D2 NR^C2 S(O)R^B2 NR^C2 S(O)₂ R^B2 NR^C2 S(O)₂ NR^C2 R^D2 , S(O)R^B2 , S(O)NR^C2 R^D2 , S(O)₂ R^B2 Or S(O)₂ NR^C2 R^D2 Where the C₁ _- ₆ Alkyl and C₂ _- ₆ The alkenyl groups are each substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of: Cy¹ Halogen, C₁ _- ₆ Alkyl, C₂ _- ₆ Alkenyl, C₁ _- ₆ Haloalkyl, CN, NO₂ OR^A2 , SR^A2 , C(O)R^B2 , C(O)NR^C2 R^D2 , C(O)OR^A2 , OC(O)R^B2 , OC(O)NR^C2 R^D2 NR^C2 R^D2 NR^C2 C(O)R^B2 NR^C2 C(O)OR^A2 NR^C2 C(O)NR^C2 R^D2 NR^C2 S(O)R^B2 NR^C2 S(O)₂ R^B2 NR^C2 S(O)₂ NR^C2 R^D2 , S(O)R^B2 , S(O)NR^C2 R^D2 , S(O)₂ R^B2 And S(O)₂ NR^C2 R^D2 ; R^B For H, Cy² Halogen, C₁ _- ₆ Alkyl, C₂ _- ₆ Alkenyl, C₁ _- ₆ Haloalkyl, CN, NO₂ OR^A3 , SR^A3 , C(O)R^B3 , C(O)NR^C3 R^D3 , C(O)OR^A3 , OC(O)R^B3 , OC(O)NR^C3 R^D3 NR^C3 R^D3 NR^C3 C(O)R^B3 NR^C3 C(O)OR^A3 NR^C3 C(O)NR^C3 R^D3 NR^C3 S(O)R^B3 NR^C3 S(O)₂ R^B3 NR^C3 S(O)₂ NR^C3 R^D3 , S(O)R^B3 , S(O)NR^C3 R^D3 , S(O)₂ R^B3 Or S(O)₂ NR^C3 R^D3 Where the C₁ _- ₆ Alkyl and C₂ _- ₆ The alkenyl groups are each substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of: Cy² Halogen, C₁ _- ₆ Alkyl, C₂ _- ₆ Alkenyl, C₁ _- ₆ Haloalkyl, CN, NO₂ OR^A3 , SR^A3 , C(O)R^B3 , C(O)NR^C3 R^D3 , C(O)OR^A3 , OC(O)R^B3 , OC(O)NR^C3 R^D3 NR^C3 R^D3 NR^C3 C(O)R^B3 NR^C3 C(O)OR^A3 NR^C3 C(O)NR^C3 R^D3 NR^C3 S(O)R^B3 NR^C1 S(O)₂ R^B3 NR^C3 S(O)₂ NR^C3 R^D3 , S(O)R^B3 , S(O)NR^C3 R^D3 , S(O)₂ R^B3 And S(O)₂ NR^C3 R^D3 ; R^C And R^D Each is independently selected from: H, halo, C₁ _- ₆ Alkyl, C₂ _- ₆ Alkenyl, C₁ _- ₆ Haloalkyl, CN, NO₂ OR^A4 , SR^A4 , C(O)R^B4 , C(O)NR^C4 R^D4 , C(O)OR^A4 , OC(O)R^B4 , OC(O)NR^C4 R^D4 NR^C4 R^D4 NR^C4 C(O)R^B4 NR^C4 C(O)OR^A4 NR^C4 C(O)NR^C4 R^D4 NR^C4 S(O)R^B4 NR^C4 S(O)₂ R^B4 NR^C4 S(O)₂ NR^C4 R^D4 , S(O)R^B4 , S(O)NR^C4 R^D4 , S(O)₂ R^B4 And S(O)₂ NR^C4 R^D4 Where the C₁ _- ₆ Alkyl and C₂ _- ₆ The alkenyl groups are each substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of C:₆ _- ₁₀ Aryl, C₃ _- ₁₀ Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, C₁ _- ₆ Alkyl, C₂ _- ₆ Alkenyl, C₁ _- ₆ Haloalkyl, CN, NO₂ OR^A4 , SR^A4 , C(O)R^B4 , C(O)NR^C4 R^D4 , C(O)OR^A4 , OC(O)R^B4 , OC(O)NR^C4 R^D4 NR^C4 R^D4 NR^C4 C(O)R^B4 NR^C4 C(O)OR^A4 NR^C4 C(O)NR^C4 R^D4 NR^C4 S(O)R^B4 NR^C4 S(O)₂ R^B4 NR^C4 S(O)₂ NR^C4 R^D4 , S(O)R^B4 , S(O)NR^C4 R^D4 , S(O)₂ R^B4 And S(O)₂ NR^C4 R^D4 ; Cy¹ And Cy² Each is independently selected from: C₆ _- ₁₀ Aryl, C₃ _- ₁₀ a cycloalkyl group, a 5-10 membered heteroaryl group, and a 4-10 membered heterocycloalkyl group, each of which is independently selected from 1, 2, 3, 4 or 5, optionally R.^Cy Replacement of substituents; each R^Cy Independently selected from: halogen, C₁ _- ₆ Alkyl, C₁ _- ₆ Haloalkyl, C₂ _- ₆ Alkenyl, C₆ _- ₁₀ Aryl, C₃ _- ₁₀ Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂ OR^A5 , SR^A5 , C(O)R^B5 , C(O)NR^C5 R^D5 , C(O)OR^A5 , OC(O)R^B5 , OC(O)NR^C5 R^D5 NR^C5 R^D5 NR^C5 C(O)R^B5 NR^C5 C(O)OR^A5 NR^C5 C(O)NR^C5 R^D5 NR^C5 S(O)R^B5 NR^C5 S(O)₂ R^B5 NR^C5 S(O)₂ NR^C5 R^D5 , S(O)R^B5 , S(O)NR^C5 R^D5 , S(O)₂ R^B5 And S(O)₂ NR^C5 R^D5 Where the C₁ _- ₆ Alkyl, C₂ _- ₆ Alkenyl C₆ _- ₁₀ Aryl, C₃ _- ₁₀ The cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of halo, C₁ _- ₆ Alkyl, CN, NO₂ OR^A5 , SR^A5 , C(O)R^B5 , C(O)NR^C5 R^D5 , C(O)OR^A5 , OC(O)R^B5 , OC(O)NR^C5 R^D5 NR^C5 R^D5 NR^C5 C(O)R^B5 NR^C5 C(O)OR^A5 NR^C5 C(O)NR^C5 R^D5 NR^C5 S(O)R^B5 NR^C5 S(O)₂ R^B5 NR^C5 S(O)₂ NR^C5 R^D5 , S(O)R^B5 , S(O)NR^C5 R^D5 , S(O)₂ R^B5 And S(O)₂ NR^C5 R^D5 ; each R^a , R^A1 , R^A2 , R^A3 , R^A4 And R^A5 Independently selected from: H, C₁ _- ₆ Alkyl, C₁ _- ₄ Haloalkyl, C₂ _- ₆ Alkenyl, C₆ _- ₁₀ Aryl, C₃ _- ₁₀ Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆ _- ₁₀ aryl-C₁ _- ₄ Alkyl, C₃ _- ₁₀ cycloalkyl-C₁ _- ₄ Alkyl, (5-10 membered heteroaryl)-C₁ _- ₄ Alkyl or (4-10 membered heterocycloalkyl)-C₁ _- ₄ Alkyl, where the C₁ _- ₆ Alkyl, C₂ _- ₆ Alkenyl, C₆ _- ₁₀ Aryl, C₃ _- ₁₀ Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆ _- ₁₀ aryl-C₁ _- ₄ Alkyl, C₃ _- ₁₀ cycloalkyl-C₁ _- ₄ Alkyl, (5-10 membered heteroaryl)-C₁ _- ₄ Alkyl and (4-10 membered heterocycloalkyl)-C₁ _- ₄ The alkyl groups are each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of C:₁ _- ₄ Alkyl, halogen, CN, OR^A6 , C(O)R^B6 , C(O)NR^C6 R^D6 , C(O)OR^A6 , OC(O)R^B6 , OC(O)NR^C6 R^D6 NR^C6 R^D6 NR^C6 C(O)R^B6 NR^C6 C(O)NR^C6 R^D6 NR^C6 C(O)OR^A6 , S(O)R^B6 , S(O)NR^C6 R^D6 , S(O)₂ R^B6 NR^C6 S(O)₂ R^B6 NR^C6 S(O)₂ NR^C6 R^D6 And S(O)₂ NR^C6 R^D6 ; each R^B1 , R^B2 , R^B3 , R^B4 And R^B5 Independently selected from: H, C₁ _- ₆ Alkyl, C₁ _- ₄ Haloalkyl, C₂ _- ₆ Alkenyl, C₆ _- ₁₀ Aryl, C₃ _- ₁₀ Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆ _- ₁₀ aryl-C₁ _- ₄ Alkyl, C₃ _- ₁₀ cycloalkyl-C₁ _- ₄ Alkyl, (5-10 membered heteroaryl)-C₁ _- ₄ Alkyl or (4-10 membered heterocycloalkyl)-C₁ _- ₄ Alkyl, where the C₁ _- ₆ Alkyl, C₂ _- ₆ Alkenyl, C₆ _- ₁₀ Aryl, C₃ _- ₁₀ Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆ _- ₁₀ aryl-C₁ _- ₄ Alkyl, C₃ _- ₁₀ cycloalkyl-C₁ _- ₄ Alkyl, (5-10 membered heteroaryl)-C₁ _- ₄ Alkyl and (4-10 membered heterocycloalkyl)-C₁ _- ₄ The alkyl groups are each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of C:₁ _- ₄ Alkyl, halogen, CN, OR^A6 , C(O)R^B6 , C(O)NR^C6 R^D6 , C(O)OR^A6 , OC(O)R^b ⁶ , OC(O)NR^C6 R^D6 NR^C6 R^D6 NR^C6 C(O)R^B6 NR^C6 C(O)NR^C6 R^D6 NR^C6 C(O)OR^A6 , S(O)R^B6 , S(O)NR^C6 R^D6 , S(O)₂ R^B6 NR^C6 S(O)₂ R^B6 NR^C6 S(O)₂ NR^C6 R^D6 And S(O)₂ NR^C6 R^D6 ; each R^c , R^d , R^C1 , R^D1 , R^C2 , R^D2 , R^C3 , R^D3 , R^C4 , R^D4 , R^C5 And R^D5 Independently selected from: H, C₁ _- ₆ Alkyl, C₁ _- ₄ Haloalkyl, C₂ _- ₆ Alkenyl, C₆ _- ₁₀ Aryl, C₃ _- ₁₀ Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆ _- ₁₀ aryl-C₁ _- ₄ Alkyl, C₃ _- ₁₀ cycloalkyl-C₁ _- ₄ Alkyl, (5-10 membered heteroaryl)-C₁ _- ₄ Alkyl or (4-10 membered heterocycloalkyl)-C₁ _- ₄ Alkyl, where the C₁ _- ₆ Alkyl, C₂ _- ₆ Alkenyl, C₆ _- ₁₀ Aryl, C₃ _- ₁₀ Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆ _- ₁₀ aryl-C₁ _- ₄ Alkyl, C₃ _- ₁₀ cycloalkyl-C₁ _- ₄ Alkyl, (5-10 membered heteroaryl)-C₁ _- ₄ Alkyl and (4-10 membered heterocycloalkyl)-C₁ _- ₄ The alkyl groups are each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of C:₁ _- ₄ Alkyl, halogen, CN, OR^A6 , SR^A6 , C(O)R^B6 , C(O)NR^C6 R^D6 , C(O)OR^A6 , OC(O)R^B6 , OC(O)NR^C6 R^D6 NR^C6 R^D6 NR^C6 C(O)R^B6 NR^C6 C(O)NR^C6 R^D6 NR^C6 C(O)OR^A6 , S(O)R^B6 , S(O)NR^C6 R^D6 , S(O)₂ R^B6 NR^C6 S(O)₂ R^B6 NR^C6 S(O)₂ NR^C6 R^D6 And S(O)₂ NR^C6 R^D6 ; or any R^c And R^d Together with the N atom to which it is attached, a 4 member, 5 member, 6 member or 7 membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents selected from: C₁ _- ₆ Alkyl, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ Aryl, 5-6 membered heteroaryl, halo, CN, OR^A6 , SR^A6 , C(O)R^B6 , C(O)NR^C6 R^D6 , C(O)OR^A6 , OC(O)R^B6 , OC(O)NR^C6 R^D6 NR^C6 R^D6 NR^C6 C(O)R^B6 NR^C6 C(O)NR^C6 R^D6 NR^C6 C(O)OR^A6 , S(O)R^B6 , S(O)NR^C6 R^D6 , S(O)₂ R^B6 NR^C6 S(O)₂ R^B6 NR^C6 S(O)₂ NR^C6 R^D6 And S(O)₂ NR^C6 R^D6 Where the C₁ _- ₆ Alkyl, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ The aryl group and the 5-6 membered heteroaryl group are optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, CN, OR.^A6 , SR^A6 , C(O)R^B6 , C(O)NR^C6 R^D6 , C(O)OR^A6 , OC(O)R^B6 , OC(O)NR^C6 R^D6 NR^C6 R^D6 NR^C6 C(O)R^B6 NR^C6 C(O)NR^C6 R^D6 NR^C6 C(O)OR^A6 , S(O)R^B6 , S(O)NR^C6 R^D6 , S(O)₂ R^B6 NR^C6 S(O)₂ R^B6 NR^C6 S(O)₂ NR^C6 R^D6 And S(O)₂ NR^C6 R^D6 ; or any R^C1 And R^D1 Together with the N atom to which it is attached, a 4 member, 5 member, 6 member or 7 membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents selected from: C₁ _- ₆ Alkyl, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ Aryl, 5-6 membered heteroaryl, halo, CN, OR^A6 , SR^A6 , C(O)R^B6 , C(O)NR^C6 R^D6 , C(O)OR^A6 , OC(O)R^B6 , OC(O)NR^C6 R^D6 NR^C6 R^D6 NR^C6 C(O)R^B6 NR^C6 C(O)NR^C6 R^D6 NR^C6 C(O)OR^A6 , S(O)R^B6 , S(O)NR^C6 R^D6 , S(O)₂ R^B6 NR^C6 S(O)₂ R^B6 NR^C6 S(O)₂ NR^C6 R^D6 And S(O)₂ NR^C6 R^D6 Where the C₁ _- ₆ Alkyl, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ The aryl group and the 5-6 membered heteroaryl group are each optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, CN, OR.^A6 , SR^A6 , C(O)R^B6 , C(O)NR^C6 R^D6 , C(O)OR^A6 , OC(O)R^B6 , OC(O)NR^C6 R^D6 NR^C6 R^D6 NR^C6 C(O)R^B6 NR^C6 C(O)NR^C6 R^D6 NR^C6 C(O)OR^A6 , S(O)R^B6 , S(O)NR^C6 R^D6 , S(O)₂ R^B6 NR^C6 S(O)₂ R^B6 NR^C6 S(O)₂ NR^C6 R^D6 And S(O)₂ NR^C6 R^D6 ; or any R^C2 And R^D2 Together with the N atom to which it is attached, a 4 member, 5 member, 6 member or 7 membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents selected from: C₁ _- ₆ Alkyl, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ Aryl and 5-6 membered heteroaryl, C₁ _- ₆ Haloalkyl, halo, CN, OR^A6 , SR^A6 , C(O)R^B6 , C(O)NR^C6 R^D6 , C(O)OR^A6 , OC(O)R^B6 , OC(O)NR^C6 R^D6 NR^C6 R^D6 NR^C6 C(O)R^B6 NR^C6 C(O)NR^C6 R^D6 NR^C6 C(O)OR^A6 , S(O)R^B6 , S(O)NR^C6 R^D6 , S(O)₂ R^B6 NR^C6 S(O)₂ R^B6 NR^C6 S(O)₂ NR^C6 R^D6 And S(O)₂ NR^C6 R^D6 Where the C₁ _- ₆ Alkyl, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ The aryl group and the 5-6 membered heteroaryl group are each optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, CN, OR.^A6 , SR^A6 , C(O)R^B6 , C(O)NR^C6 R^D6 , C(O)OR^A6 , OC(O)R^B6 , OC(O)NR^C6 R^D6 NR^C6 R^D6 NR^C6 C(O)R^B6 NR^C6 C(O)NR^C6 R^D6 NR^C6 C(O)OR^A6 , S(O)R^B6 , S(O)NR^C6 R^D6 , S(O)₂ R^B6 NR^C6 S(O)₂ R^B6 NR^C6 S(O)₂ NR^C6 R^D6 And S(O)₂ NR^C6 R^D6 ; or any R^C3 And R^D3 Together with the N atom to which it is attached, a 4 member, 5 member, 6 member or 7 membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents selected from: C₁ _- ₆ Alkyl, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ Aryl, 5-6 membered heteroaryl, C₁ _- ₆ Haloalkyl, halo, CN, OR^A6 , SR^A6 , C(O)R^B6 , C(O)NR^C6 R^D6 , C(O)OR^A6 , OC(O)R^B6 , OC(O)NR^C6 R^D6 NR^C6 R^D6 NR^C6 C(O)R^B6 NR^C6 C(O)NR^C6 R^D6 NR^C6 C(O)OR^A6 , S(O)R^B6 , S(O)NR^C6 R^D6 , S(O)₂ R^B6 NR^C6 S(O)₂ R^B6 NR^C6 S(O)₂ NR^C6 R^D6 And S(O)₂ NR^C6 R^D6 Where the C₁ _- ₆ Alkyl, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ The aryl group and the 5-6 membered heteroaryl group are each optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, CN, OR.^A6 , SR^A6 , C(O)R^B6 , C(O)NR^C6 R^D6 , C(O)OR^A6 , OC(O)R^B6 , OC(O)NR^C6 R^D6 NR^C6 R^D6 NR^C6 C(O)R^B6 NR^C6 C(O)NR^C6 R^D6 NR^C6 C(O)OR^A6 , S(O)R^B6 , S(O)NR^C6 R^D6 , S(O)₂ R^B6 NR^C6 S(O)₂ R^B6 NR^C6 S(O)₂ NR^C6 R^D6 And S(O)₂ NR^C6 R^D6 ; or any R^C4 And R^D4 Together with the N atom to which it is attached, a 4 member, 5 member, 6 member or 7 membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents selected from: C₁ _- ₆ Alkyl, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ Aryl, 5-6 membered heteroaryl, C₁ _- ₆ Haloalkyl, halo, CN, OR^A6 , SR^A6 , C(O)R^B6 , C(O)NR^C6 R^D6 , C(O)OR^A6 , OC(O)R^b ⁶ , OC(O)NR^C6 R^D6 NR^C6 R^D6 NR^C6 C(O)R^B6 NR^C6 C(O)NR^C6 R^D6 NR^C6 C(O)OR^A6 , S(O)R^B6 , S(O)NR^C6 R^D6 , S(O)₂ R^B6 NR^C6 S(O)₂ R^B6 NR^C6 S(O)₂ NR^C6 R^D6 And S(O)₂ NR^C6 R^D6 Where the C₁ _- ₆ Alkyl, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ The aryl group and the 5-6 membered heteroaryl group are each optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, CN, OR.^A6 , SR^A6 , C(O)R^B6 , C(O)NR^C6 R^D6 , C(O)OR^A6 , OC(O)R^B6 , OC(O)NR^C6 R^D6 NR^C6 R^D6 NR^C6 C(O)R^B6 NR^C6 C(O)NR^C6 R^D6 NR^C6 C(O)OR^A6 , S(O)R^B6 , S(O)NR^C6 R^D6 , S(O)₂ R^B6 NR^C6 S(O)₂ R^B6 NR^C6 S(O)₂ NR^C6 R^D6 And S(O)₂ NR^C6 R^D6 ; or any R^C5 And R^D5 Together with the N atom to which it is attached, a 4 member, 5 member, 6 member or 7 membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents selected from: C₁ _- ₆ Alkyl, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ Aryl, 5-6 membered heteroaryl, C₁ _- ₆ Haloalkyl, halo, CN, OR^A6 , SR^A6 , C(O)R^B6 , C(O)NR^C6 R^D6 , C(O)OR^A6 , OC(O)R^B6 , OC(O)NR^C6 R^D6 NR^C6 R^D6 NR^C6 C(O)R^B6 NR^C6 C(O)NR^C6 R^D6 NR^C6 C(O)OR^A6 , S(O)R^B6 , S(O)NR^C6 R^D6 , S(O)₂ R^B6 NR^C6 S(O)₂ R^B6 NR^C6 S(O)₂ NR^C6 R^D6 And S(O)₂ NR^C6 R^D6 Where the C₁ _- ₆ Alkyl, C₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C₆ _- ₁₀ The aryl group and the 5-6 membered heteroaryl group are each optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, CN, OR.^A6 , SR^A6 , C(O)R^B6 , C(O)NR^C6 R^D6 , C(O)OR^A6 , OC(O)R^B6 , OC(O)NR^C6 R^D6 NR^C6 R^D6 NR^C6 C(O)R^B6 NR^C6 C(O)NR^C6 R^D6 NR^C6 C(O)OR^A6 , S(O)R^B6 , S(O)NR^C6 R^D6 , S(O)₂ R^B6 NR^C6 S(O)₂ R^B6 NR^C6 S(O)₂ NR^C6 R^D6 And S(O)₂ NR^C6 R^D6 ; each R^A6 , R^B6 , R^C6 And R^D6 Independently selected from: H, C₁ _- ₄ Alkyl, C₂ _- ₄ Alkenyl, C₃ _- ₇ a cycloalkyl group, a phenyl group, a 5-6 membered heteroaryl group, and a 4-7 membered heterocycloalkyl group, wherein the C₁ _- ₄ Alkyl, C₂ _- ₄ Alkenyl, C₃ _- ₇ The cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of OH, CN, amine, Halogen, C₁ _- ₄ Alkyl, C₁ _- ₄ Alkoxy, C₁ _- ₄ Alkylthio, C₁ _- ₄ Alkylamine and II (C₁ _- ₄ Alkylamino; n is 1 or 2; p is 1, 2 or 3; and q is 1 or 2; wherein any of the aforementioned 4-10 member or 4-7 membered heterocycloalkyl group optionally comprises 1, 2 or Three pendant oxygen substituents in which the pendant oxygen substituents are substituted on the ring forming the carbon, nitrogen or sulfur atom of a 4-10 member or 4-7 membered heterocycloalkyl group. In some embodiments, L is O. In some embodiments, L is NR⁴ . In some embodiments, W is CR⁵ ; X is N; and Y is CR⁷ . In some embodiments, W is N; X is N; and Y is CR⁷ . In some embodiments, W is CR⁵ ;X is CR⁶ ; and Y is N. In some embodiments, W is CR⁵ ;X is CR⁶ ; and Y is CR⁷ . In some embodiments, W is N; X is CR⁶ ; and Y is CR⁷ . In some embodiments, R² H and R³ H. In some embodiments, R² H and R³ For C₁ _- ₄ alkyl. In some embodiments, R² H and R³ Is a methyl group. In some embodiments, R² H and R³ For C₁ _- ₄ Haloalkyl. In some embodiments, R² H and R³ It is a trifluoromethyl group. In some embodiments, n is one. In some embodiments, n is 2. In some embodiments, R¹ H. In some embodiments, R¹ For C₁ _- ₁₀ Alkyl, C₃ _- ₁₀ Cycloalkyl, phenyl, -(CR⁸ R⁹ )_p OC(O)R¹⁰ ,-(CR⁸ R⁹ )_p NR¹¹ R¹² Or - (CR⁸ R⁹ )_p C(O)NR¹¹ R¹² Where the C₁ _- ₁₀ Alkyl, C₃ _- ₁₀ The cycloalkyl and phenyl groups are each substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of F, Cl, Br, CN, C.₁ _- ₄ Alkyl and C₁ _- ₄ Haloalkyl. In some embodiments, R¹ For C₁ _- ₁₀ alkyl. In some embodiments, R¹ It is an ethyl group. In some embodiments, R⁴ H. In some embodiments, R⁵ H. In some embodiments, R⁶ H. In some embodiments, R⁷ Not H. In some embodiments, R⁷ For C₁ _- ₄ Alkyl, NR¹³ R¹⁴ Or OR¹⁵ . In some embodiments, R⁷ For NR¹³ R¹⁴ . In some embodiments, R⁷ For NH₂ . In some embodiments, R⁷ For C₁ _- ₄ alkyl. In some embodiments, R⁷ For OR¹⁵ . In some embodiments, ring A is C₃ _- ₁₀ Cycloalkyl. In some embodiments, ring A is C₆ _- ₁₀ Aryl. In some embodiments, Ring A is phenyl. In some embodiments, Ring A is a 4 to 10 membered heterocycloalkyl. In some embodiments, Ring A is phenyl, adamantyl, naphthyl, 1,2,3,4-tetrahydroquinoxalinyl, 3,4-dihydroquinazolinyl, 1,2,3 , 4-dihydroquinazolinyl or pyridyl. In some embodiments, Ring A is 5 to 10 membered heteroaryl. In some embodiments, R^A , R^B , R^C And R^D At least one of them is not hydrogen. In some embodiments, R^A , R^B , R^C And R^D At least two of them are not hydrogen. In some embodiments, R^A Cy¹ . In some embodiments, R^A For C₆ _- ₁₀ Aryl or 5-10 membered heteroaryl, each of which is independently selected from R, 1, 2, 3, 4 or 5, as appropriate^Cy The substituent is substituted. In some embodiments, R^A 1, 2, 3, 4 or 5 independently selected from R as appropriate^Cy Substituent substituted 5-10 membered heteroaryl. In some embodiments, R^A 1, 2 or 3 independently selected from R as appropriate^Cy A 5- to 6-membered heteroaryl group substituted with a substituent. In some embodiments, R^A 1, 2, 3, 4 or 5 independently selected from R as appropriate^Cy Substituent substituted pyrazolyl. In some embodiments, R^A It is 3-methyl-1H-pyrazol-1-yl. In some embodiments, R^A 1, 2 or 3 independently selected from R as appropriate^Cy Substituent substituted C₆ _- ₁₀ Aryl. In some embodiments, R^A 1, 2 or 3 independently selected from R as appropriate^Cy Substituent substituted phenyl. In some embodiments, R^B H. In some embodiments, R^B Cy² Halogen, C₁ _- ₆ Alkyl, C₂ _- ₆ Alkenyl, C₁ _- ₆ Haloalkyl, CN, NO₂ OR^A3 , SR^A3 , C(O)R^B3 , C(O)NR^C3 R^D3 , C(O)OR^A3 , OC(O)R^B3 , OC(O)NR^C3 R^D3 NR^C3 R^D3 NR^C3 C(O)R^B3 NR^C3 C(O)OR^A3 NR^C3 C(O)NR^C3 R^D3 NR^C3 S(O)R^B3 NR^C3 S(O)₂ R^B3 NR^C3 S(O)₂ NR^C3 R^D3 , S(O)R^B3 , S(O)NR^C3 R^D3 , S(O)₂ R^B3 And S(O)₂ NR^C3 R^D3 Where the C₁ _- ₆ Alkyl and C₂ _- ₆ The alkenyl groups are each substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of: Cy² Halogen, C₁ _- ₆ Alkyl, C₂ _- ₆ Alkenyl, C₁ _- ₆ Haloalkyl, CN, NO₂ OR^A3 , SR^A3 , C(O)R^B3 , C(O)NR^C3 R^D3 , C(O)OR^A3 , OC(O)R^B3 , OC(O)NR^C3 R^D3 NR^C3 R^D3 NR^C3 C(O)R^B3 NR^C3 C(O)OR^A3 NR^C3 C(O)NR^C3 R^D3 NR^C3 S(O)R^B3 NR^C1 S(O)₂ R^B3 NR^C3 S(O)₂ NR^C3 R^D3 , S(O)R^B3 , S(O)NR^C3 R^D3 , S(O)₂ R^B3 And S(O)₂ NR^C3 R^D3 . In some embodiments, R^B Cy² . In some embodiments, R^B For C₆ _- ₁₀ Aryl or 5-10 membered heteroaryl, each of which is independently selected from R, 1, 2, 3, 4 or 5, as appropriate^Cy The substituent is substituted. In some embodiments, R^B Halogen, C₁ _- ₆ Alkyl, C₂ _- ₆ Alkenyl, C₁ _- ₆ Haloalkyl, CN, NO₂ OR^A3 , SR^A3 , C(O)R^B3 , C(O)NR^C3 R^D3 , C(O)OR^A3 , OC(O)R^B3 , OC(O)NR^C3 R^D3 NR^C3 R^D3 NR^C3 C(O)R^B3 NR^C3 C(O)OR^A3 NR^C3 C(O)NR^C3 R^D3 NR^C3 S(O)R^B3 NR^C3 S(O)₂ R^B3 NR^C3 S(O)₂ NR^C3 R^D3 , S(O)R^B3 , S(O)NR^C3 R^D3 , S(O)₂ R^B3 And S(O)₂ NR^C3 R^D3 Where the C₁ _- ₆ Alkyl and C₂ _- ₆ The alkenyl groups are each substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of: Cy² Halogen, C₁ _- ₆ Alkyl, C₂ _- ₆ Alkenyl, C₁ _- ₆ Haloalkyl, CN, NO₂ OR^A3 , SR^A3 , C(O)R^B3 , C(O)NR^C3 R^D3 , C(O)OR^A3 , OC(O)R^B3 , OC(O)NR^C3 R^D3 NR^C3 R^D3 NR^C3 C(O)R^B3 NR^C3 C(O)OR^A3 NR^C3 C(O)NR^C3 R^D3 NR^C3 S(O)R^B3 NR^C1 S(O)₂ R^B3 NR^C3 S(O)₂ NR^C3 R^D3 , S(O)R^B3 , S(O)NR^C3 R^D3 , S(O)₂ R^B3 And S(O)₂ NR^C3 R^D3 . In some embodiments, R^B It is a halogen group. In some embodiments, R^C H. In some embodiments, R^C Halogen, C₁ _- ₆ Alkyl, C₂ _- ₆ Alkenyl, C₁ _- ₆ Haloalkyl, CN, NO₂ OR^A4 , SR^A4 , C(O)R^B4 , C(O)NR^C4 R^D4 , C(O)OR^A4 , OC(O)R^B4 , OC(O)NR^C4 R^D4 NR^C4 R^D4 NR^C4 C(O)R^B4 NR^C4 C(O)OR^A4 NR^C4 C(O)NR^C4 R^D4 NR^C4 S(O)R^B4 NR^C4 S(O)₂ R^B4 NR^C4 S(O)₂ NR^C4 R^D4 , S(O)R^B4 , S(O)NR^C4 R^D4 , S(O)₂ R^B4 And S(O)₂ NR^C4 R^D4 Where the C₁ _- ₆ Alkyl and C₂ _- ₆ The alkenyl groups are each substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of C:₆ _- ₁₀ Aryl, C₃ _- ₁₀ Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, C₁ _- ₆ Alkyl, C₂ _- ₆ Alkenyl, C₁ _- ₆ Haloalkyl, CN, NO₂ OR^A4 , SR^A4 , C(O)R^B4 , C(O)NR^C4 R^D4 , C(O)OR^A4 , OC(O)R^B4 , OC(O)NR^C4 R^D4 NR^C4 R^D4 NR^C4 C(O)R^B4 NR^C4 C(O)OR^A4 NR^C4 C(O)NR^C4 R^D4 NR^C4 S(O)R^B4 NR^C4 S(O)₂ R^B4 NR^C4 S(O)₂ NR^C4 R^D4 , S(O)R^B4 , S(O)NR^C4 R^D4 , S(O)₂ R^B4 And S(O)₂ NR^C4 R^D4 . In some embodiments, R^D H. In some embodiments, R^D Halogen, C₁ _- ₆ Alkyl, C₂ _- ₆ Alkenyl, C₁ _- ₆ Haloalkyl, CN, NO₂ OR^A4 , SR^A4 , C(O)R^B4 , C(O)NR^C4 R^D4 , C(O)OR^A4 , OC(O)R^B4 , OC(O)NR^C4 R^D4 NR^C4 R^D4 NR^C4 C(O)R^B4 NR^C4 C(O)OR^A4 NR^C4 C(O)NR^C4 R^D4 NR^C4 S(O)R^B4 NR^C4 S(O)₂ R^B4 NR^C4 S(O)₂ NR^C4 R^D4 , S(O)R^B4 , S(O)NR^C4 R^D4 , S(O)₂ R^B4 And S(O)₂ NR^C4 R^D4 Where the C₁ _- ₆ Alkyl and C₂ _- ₆ The alkenyl groups are each substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of C:₆ _- ₁₀ Aryl, C₃ _- ₁₀ Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, C₁ _- ₆ Alkyl, C₂ _- ₆ Alkenyl, C₁ _- ₆ Haloalkyl, CN, NO₂ OR^A4 , SR^A4 , C(O)R^B4 , C(O)NR^C4 R^D4 , C(O)OR^A4 , OC(O)R^B4 , OC(O)NR^C4 R^D4 NR^C4 R^D4 NR^C4 C(O)R^B4 NR^C4 C(O)OR^A4 NR^C4 C(O)NR^C4 R^D4 NR^C4 S(O)R^B4 NR^C4 S(O)₂ R^B4 NR^C4 S(O)₂ NR^C4 R^D4 , S(O)R^B4 , S(O)NR^C4 R^D4 , S(O)₂ R^B4 And S(O)₂ NR^C4 R^D4 . In some embodiments, the compounds described herein have Formula IIa:IIa. In some embodiments, the compounds described herein have Formula IIb:IIb. In some embodiments, the compounds described herein have Formula IIc:IIc. In some embodiments, the compounds described herein have Formula IId:IId. In some embodiments, the compounds described herein have Formula IIe:IIe. In some embodiments, when the compound described herein has Formula IIa, IIb, IIc, IId, or IIe, L is O. In some embodiments, when the compound described herein has Formula IIa, IIb, IIc, IId, or IIe, L is NR₄ . In some embodiments, when a compound described herein has Formula IIa, IIb, IIc, IId, or IIe, R³ H. In some embodiments, when a compound described herein has Formula IIa, IIb, IIc, IId, or IIe, R² For CF₃ And R³ H. In some embodiments, when a compound described herein has Formula IIa, IIb, IIc, IId, or IIe, R¹ For H or C₁ _- ₁₀ alkyl. In some embodiments, when a compound described herein has Formula IIa, IIb, IIc, IId, or IIe, R^A Cy¹ . In some embodiments, when a compound described herein has Formula IIa, IIb, IIc, IId, or IIe, R^A For C₆ _- ₁₀ Aryl or 5-10 membered heteroaryl, each of which is independently selected from R, 1, 2, 3, 4 or 5, as appropriate^Cy The substituent is substituted. In some embodiments, when a compound described herein has Formula IIa, IIb, IIc, IId, or IIe, R^A 1, 2, 3, 4 or 5 independently selected from R as appropriate^Cy Substituent substituted 5-10 membered heteroaryl. In some embodiments, when a compound described herein has Formula IIa, IIb, IIc, IId, or IIe, R^A 1, 2 or 3 independently selected from R as appropriate^Cy A 5- to 6-membered heteroaryl group substituted with a substituent. In some embodiments, when a compound described herein has Formula IIa, IIb, IIc, IId, or IIe, R^A 1, 2 or 3 independently selected from R as appropriate^Cy Substituent substituted C₆ _- ₁₀ Aryl. In some embodiments, when a compound described herein has Formula IIa, IIb, IIc, IId, or IIe, R^A 1, 2 or 3 independently selected from R as appropriate^Cy Substituent substituted phenyl. In some embodiments, when a compound described herein has Formula IIa, IIb, IIc, IId, or IIe, R^B Cy² . In some embodiments, when a compound described herein has Formula IIa, IIb, IIc, IId, or IIe, R^B H, halo, C₁ _- ₆ Alkyl, C₂ _- ₆ Alkenyl, C₁ _- ₆ Haloalkyl, CN, OR^A3 , C(O)NR^C3 R^D3 Or C(O)OR^A3 Where the C₁ _- ₆ Alkyl and C₂ _- ₆ Alkenyl groups are each optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, C₁ _- ₆ Haloalkyl, CN, NO₂ OR^A3 , SR^A3 , C(O)R^B3 , C(O)NR^C3 R^D3 , C(O)OR^A3 , OC(O)R^B3 , OC(O)NR^C3 R^D3 NR^C3 R^D3 NR^C3 C(O)R^B3 NR^C3 C(O)OR^A3 NR^C3 C(O)NR^C3 R^D3 NR^C3 S(O)R^B3 NR^C1 S(O)₂ R^B3 NR^C3 S(O)₂ NR^C3 R^D3 , S(O)R^B3 , S(O)NR^C3 R^D3 , S(O)₂ R^B3 And S(O)₂ NR^C3 R^D3 . In some embodiments, when a compound described herein has Formula IIa, IIb, IIc, IId, or IIe, R^C H. In some embodiments, when a compound described herein has Formula IIa, IIb, IIc, IId, or IIe, R^D H. In some embodiments, when a compound described herein has Formula IIa, IIb, IIc, IId, or IIe, R⁵ H. In some embodiments, when a compound described herein has Formula IIa, IIb, IIc, IId, or IIe, R⁶ H. In some embodiments, the compounds described herein have Formula IIIa or IIIb:IIIaIIIb. In some embodiments, when the compound described herein has Formula IIIa or IIIb, R² For CF₃ . In some embodiments, when the compound described herein has Formula IIIa or IIIb, R¹ For H or C₁ _- ₁₀ alkyl. In some embodiments, when the compound described herein has Formula IIIa or IIIb, R^A Cy¹ . In some embodiments, when the compound described herein has Formula IIIa or IIIb, R^A For C₆ _- ₁₀ Aryl or 5-10 membered heteroaryl, each of which is independently selected from R, 1, 2, 3, 4 or 5, as appropriate^Cy The substituent is substituted. In some embodiments, when the compound described herein has Formula IIIa or IIIb, R^A 1, 2, 3, 4 or 5 independently selected from R as appropriate^Cy Substituent substituted 5-10 membered heteroaryl. In some embodiments, when the compound described herein has Formula IIIa or IIIb, R^A 1, 2 or 3 independently selected from R as appropriate^Cy A 5- to 6-membered heteroaryl group substituted with a substituent. In some embodiments, when the compound described herein has Formula IIIa or IIIb, R^A 1, 2 or 3 independently selected from R as appropriate^Cy Substituent substituted C₆ _- ₁₀ Aryl. In some embodiments, when the compound described herein has Formula IIIa or IIb, R^A 1, 2 or 3 independently selected from R as appropriate^Cy Substituent substituted phenyl. In some embodiments, when the compound described herein has Formula IIIa or IIIb, R^B Cy² . In some embodiments, when the compound described herein has Formula IIa or IIb, R^B H, halo, C₁ _- ₆ Alkyl, C₂ _- ₆ Alkenyl, C₁ _- ₆ Haloalkyl, CN, OR^A3 , C(O)NR^C3 R^D3 Or C(O)OR^A3 Where the C₁ _- ₆ Alkyl and C₂ _- ₆ Alkenyl groups are each optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, C₁ _- ₆ Haloalkyl, CN, NO₂ OR^A3 , SR^A3 , C(O)R^B3 , C(O)NR^C3 R^D3 , C(O)OR^A3 , OC(O)R^B3 , OC(O)NR^C3 R^D3 NR^C3 R^D3 NR^C3 C(O)R^B3 NR^C3 C(O)OR^A3 NR^C3 C(O)NR^C3 R^D3 NR^C3 S(O)R^B3 NR^C1 S(O)₂ R^B3 NR^C3 S(O)₂ NR^C3 R^D3 , S(O)R^B3 , S(O)NR^C3 R^D3 , S(O)₂ R^B3 And S(O)₂ NR^C3 R^D3 . In some embodiments, when the compound described herein has Formula IIIa or IIIb, R^C H. In some embodiments, when the compound described herein has Formula IIIa or IIIb, R^D H. In some embodiments, the compounds described herein have Formula IV:IV. In some embodiments, when the compound described herein has Formula IV, R² For CF₃ . In some embodiments, when the compound described herein has Formula IV, R¹ For H or C₁ _- ₁₀ alkyl. In some embodiments, when the compound described herein has Formula IV, R^A Cy¹ . In some embodiments, when the compound described herein has Formula IV, R^A For C₆ _- ₁₀ Aryl or 5-10 membered heteroaryl, each of which is independently selected from R, 1, 2, 3, 4 or 5, as appropriate^Cy The substituent is substituted. In some embodiments, when the compound described herein has Formula IV, R^A 1, 2, 3, 4 or 5 independently selected from R as appropriate^Cy Substituent substituted 5-10 membered heteroaryl. In some embodiments, when the compound described herein has Formula IV, R^A 1, 2 or 3 independently selected from R as appropriate^Cy A 5- to 6-membered heteroaryl group substituted with a substituent. In some embodiments, when the compound described herein has Formula IV, R^A 1, 2 or 3 independently selected from R as appropriate^Cy Substituent substituted C₆ _- ₁₀ Aryl. In some embodiments, when the compound described herein has Formula IV, R^A 1, 2 or 3 independently selected from R as appropriate^Cy Substituent substituted phenyl. In some embodiments, when the compound described herein has Formula IV, R^B Cy² . In some embodiments, when the compound described herein has Formula IV, R^B H, halo, C₁ _- ₆ Alkyl, C₂ _- ₆ Alkenyl, C₁ _- ₆ Haloalkyl, CN, OR^A3 , C(O)NR^C3 R^D3 Or C(O)OR^A3 Where the C₁ _- ₆ Alkyl and C₂ _- ₆ Alkenyl groups are each optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, C₁ _- ₆ Haloalkyl, CN, NO₂ OR^A3 , SR^A3 , C(O)R^B3 , C(O)NR^C3 R^D3 , C(O)OR^A3 , OC(O)R^B3 , OC(O)NR^C3 R^D3 NR^C3 R^D3 NR^C3 C(O)R^B3 NR^C3 C(O)OR^A3 NR^C3 C(O)NR^C3 R^D3 NR^C3 S(O)R^B3 NR^C1 S(O)₂ R^B3 NR^C3 S(O)₂ NR^C3 R^D3 , S(O)R^B3 , S(O)NR^C3 R^D3 , S(O)₂ R^B3 And S(O)₂ NR^C3 R^D3 . In some embodiments, when the compound described herein has Formula IV, R^C H. In some embodiments, when the compound described herein has Formula IV, R^D H. In some embodiments, the compounds described herein have the formula Va:Va. In some embodiments, when the compound described herein has Formula Va, R² For CF₃ . In some embodiments, when the compound described herein has Formula Va, R¹ For H or C₁ _- ₁₀ alkyl. In some embodiments, when the compound described herein has Formula Va, R^A Cy¹ . In some embodiments, when the compound described herein has Formula Va, R^A For C₆ _- ₁₀ Aryl or 5-10 membered heteroaryl, each of which is independently selected from R, 1, 2, 3, 4 or 5, as appropriate^Cy The substituent is substituted. In some embodiments, when the compound described herein has Formula Va, R^A 1, 2, 3, 4 or 5 independently selected from R as appropriate^Cy Substituent substituted 5-10 membered heteroaryl. In some embodiments, when the compound described herein has Formula Va, R^A 1, 2 or 3 independently selected from R as appropriate^Cy A 5- to 6-membered heteroaryl group substituted with a substituent. In some embodiments, when the compound described herein has Formula Va, R^A 1, 2 or 3 independently selected from R as appropriate^Cy Substituent substituted C₆ _- ₁₀ Aryl. In some embodiments, when the compound described herein has Formula Va, R^A 1, 2 or 3 independently selected from R as appropriate^Cy Substituent substituted phenyl. In some embodiments, when the compound described herein has Formula Va, R^B Cy² . In some embodiments, when the compound described herein has Formula Va, R^B H, halo, C₁ _- ₆ Alkyl, C₂ _- ₆ Alkenyl, C₁ _- ₆ Haloalkyl, CN, OR^A3 , C(O)NR^C3 R^D3 Or C(O)OR^A3 Where the C₁ _- ₆ Alkyl and C₂ _- ₆ Alkenyl groups are each optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, C₁ _- ₆ Haloalkyl, CN, NO₂ OR^A3 , SR^A3 , C(O)R^B3 , C(O)NR^C3 R^D3 , C(O)OR^A3 , OC(O)R^B3 , OC(O)NR^C3 R^D3 NR^C3 R^D3 NR^C3 C(O)R^B3 NR^C3 C(O)OR^A3 NR^C3 C(O)NR^C3 R^D3 NR^C3 S(O)R^B3 NR^C1 S(O)₂ R^B3 NR^C3 S(O)₂ NR^C3 R^D3 , S(O)R^B3 , S(O)NR^C3 R^D3 , S(O)₂ R^B3 And S(O)₂ NR^C3 R^D3 . In some embodiments, the compounds described herein have the formula Vb:Vb. In some embodiments, when the compound described herein has Formula Vb, R² For CF₃ . In some embodiments, when the compound described herein has Formula Vb, R¹ For H or C₁ _- ₁₀ alkyl. In some embodiments, when the compound described herein has Formula Vb, R^A Cy¹ . In some embodiments, when the compound described herein has Formula Vb, R^A For C₆ _- ₁₀ Aryl or 5-10 membered heteroaryl, each of which is independently selected from R, 1, 2, 3, 4 or 5, as appropriate^Cy The substituent is substituted. In some embodiments, when the compound described herein has Formula Vb, R^A 1, 2, 3, 4 or 5 independently selected from R as appropriate^Cy Substituent substituted 5-10 membered heteroaryl. In some embodiments, when the compound described herein has Formula Vb, R^A 1, 2 or 3 independently selected from R as appropriate^Cy A 5- to 6-membered heteroaryl group substituted with a substituent. In some embodiments, when the compound described herein has Formula Vb, R^A 1, 2 or 3 independently selected from R as appropriate^Cy Substituent substituted C₆ _- ₁₀ Aryl. In some embodiments, when the compound described herein has Formula Vb, R^A 1, 2 or 3 independently selected from R as appropriate^Cy Substituent substituted phenyl. In some embodiments, when the compound described herein has Formula Vb, R^B Cy² . In some embodiments, when the compound described herein has Formula Vb, R^B H, halo, C₁ _- ₆ Alkyl, C₂ _- ₆ Alkenyl, C₁ _- ₆ Haloalkyl, CN, OR^A3 , C(O)NR^C3 R^D3 Or C(O)OR^A3 Where the C₁ _- ₆ Alkyl and C₂ _- ₆ Alkenyl groups are each optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, C₁ _- ₆ Haloalkyl, CN, NO₂ OR^A3 , SR^A3 , C(O)R^B3 , C(O)NR^C3 R^D3 , C(O)OR^A3 , OC(O)R^B3 , OC(O)NR^C3 R^D3 NR^C3 R^D3 NR^C3 C(O)R^B3 NR^C3 C(O)OR^A3 NR^C3 C(O)NR^C3 R^D3 NR^C3 S(O)R^B3 NR^C1 S(O)₂ R^B3 NR^C3 S(O)₂ NR^C3 R^D3 , S(O)R^B3 , S(O)NR^C3 R^D3 , S(O)₂ R^B3 And S(O)₂ NR^C3 R^D3 . In some embodiments, the compounds described herein have Formula VI:VI. In some embodiments, when the compound described herein has Formula VI, R² For CF₃ . In some embodiments, when the compound described herein has Formula VI, R¹ For H or C₁ _- ₁₀ alkyl. In some embodiments, when the compound described herein has Formula VI, R^B Cy² . In some embodiments, when the compound described herein has Formula VI, Cy² 1, 2 or 3 independently selected from R as appropriate^Cy Substituent substituted phenyl. In some embodiments, when the compound described herein has Formula VI, R^B H, halo, C₁ _- ₆ Alkyl, C₂ _- ₆ Alkenyl, C₁ _- ₆ Haloalkyl, CN, OR^A3 , C(O)NR^C3 R^D3 Or C(O)OR^A3 Where the C₁ _- ₆ Alkyl and C₂ _- ₆ Alkenyl groups are each optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, C₁ _- ₆ Haloalkyl, CN, NO₂ OR^A3 , SR^A3 , C(O)R^B3 , C(O)NR^C3 R^D3 , C(O)OR^A3 , OC(O)R^B3 , OC(O)NR^C3 R^D3 NR^C3 R^D3 NR^C3 C(O)R^B3 NR^C3 C(O)OR^A3 NR^C3 C(O)NR^C3 R^D3 NR^C3 S(O)R^B3 NR^C1 S(O)₂ R^B3 NR^C3 S(O)₂ NR^C3 R^D3 , S(O)R^B3 , S(O)NR^C3 R^D3 , S(O)₂ R^B3 And S(O)₂ NR^C3 R^D3 . In some embodiments, when the compound described herein has Formula VI, R^C H. In some embodiments, when the compound described herein has Formula VI, R^D H. In some embodiments, the compounds described herein have Formula VIA:VIA. In some embodiments, when the compound described herein has Formula VIA, R² For CF₃ . In some embodiments, when the compound described herein has Formula VIA, R¹ For H or C₁ _- ₁₀ alkyl. In some embodiments, when the compound described herein has Formula VIA, R^B Cy² . In some embodiments, when the compound described herein has Formula VIA, Cy² 1, 2 or 3 independently selected from R as appropriate^Cy Substituent substituted phenyl. In some embodiments, when the compound described herein has Formula VIA, R^B H, halo, C₁ _- ₆ Alkyl, C₂ _- ₆ Alkenyl, C₁ _- ₆ Haloalkyl, CN, OR^A3 , C(O)NR^C3 R^D3 Or C(O)OR^A3 Where the C₁ _- ₆ Alkyl and C₂ _- ₆ Alkenyl groups are each optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, C₁ _- ₆ Haloalkyl, CN, NO₂ OR^A3 , SR^A3 , C(O)R^B3 , C(O)NR^C3 R^D3 , C(O)OR^A3 , OC(O)R^B3 , OC(O)NR^C3 R^D3 NR^C3 R^D3 NR^C3 C(O)R^B3 NR^C3 C(O)OR^A3 NR^C3 C(O)NR^C3 R^D3 NR^C3 S(O)R^B3 NR^C1 S(O)₂ R^B3 NR^C3 S(O)₂ NR^C3 R^D3 , S(O)R^B3 , S(O)NR^C3 R^D3 , S(O)₂ R^B3 And S(O)₂ NR^C3 R^D3 . In some embodiments, the compounds described herein have Formula VII:VII where a is 0, 1, 2 or 3. In some embodiments, when the compound described herein has Formula VII, R² For CF₃ . In some embodiments, when the compound described herein has Formula VII, R¹ For H or C₁ _- ₁₀ alkyl. In some embodiments, when the compound described herein has Formula VII, R^B Cy² . In some embodiments, when the compound described herein has Formula VII, R^B H, halo, C₁ _- ₆ Alkyl, C₂ _- ₆ Alkenyl, C₁ _- ₆ Haloalkyl, CN, OR^A3 , C(O)NR^C3 R^D3 Or C(O)OR^A3 Where the C₁ _- ₆ Alkyl and C₂ _- ₆ Alkenyl groups are each optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, C₁ _- ₆ Haloalkyl, CN, NO₂ OR^A3 , SR^A3 , C(O)R^B3 , C(O)NR^C3 R^D3 , C(O)OR^A3 , OC(O)R^B3 , OC(O)NR^C3 R^D3 NR^C3 R^D3 NR^C3 C(O)R^B3 NR^C3 C(O)OR^A3 NR^C3 C(O)NR^C3 R^D3 NR^C3 S(O)R^B3 NR^C1 S(O)₂ R^B3 NR^C3 S(O)₂ NR^C3 R^D3 , S(O)R^B3 , S(O)NR^C3 R^D3 , S(O)₂ R^B3 And S(O)₂ NR^C3 R^D3 . In some embodiments, when the compound described herein has Formula VII, R^B Is H or a halogen group. In some embodiments, when the compound described herein has Formula VII, R^B It is a halogen group. In some embodiments, when the compound described herein has Formula VII, R^C H. In some embodiments, when the compound described herein has Formula VII, R^D H. In some embodiments, when the compound described herein has Formula VII, R^Cy Halogen, C₁ _- ₆ Alkyl, C₁ _- ₆ Haloalkyl, 4-10 membered heterocycloalkyl, CN, NO₂ OR^A5 , SR^A5 , C(O)R^B5 , C(O)NR^C5 R^D5 , C(O)OR^A5 NR^C5 R^D5 , S(O)₂ R^B5 And S(O)₂ NR^C5 R^D5 Where the C₁ _- ₆ The alkyl group and the 4-10 membered heterocycloalkyl group are each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of halo, C₁ _- ₆ Alkyl, CN, NO₂ OR^A5 , SR^A5 , C(O)R^B5 , C(O)NR^C5 R^D5 , C(O)OR^A5 , OC(O)R^B5 , OC(O)NR^C5 R^D5 NR^C5 R^D5 NR^C5 C(O)R^B5 NR^C5 C(O)OR^A5 NR^C5 C(O)NR^C5 R^D5 NR^C5 S(O)R^B5 NR^C5 S(O)₂ R^B5 NR^C5 S(O)₂ NR^C5 R^D5 , S(O)R^B5 , S(O)NR^C5 R^D5 , S(O)₂ R^B5 And S(O)₂ NR^C5 R^D5 . In some embodiments, the compounds described herein have Formula VIII:VIII where a is 0, 1, 2 or 3. In some embodiments, when the compound described herein has Formula VIII, R² For CF₃ . In some embodiments, when the compound described herein has Formula VIII, R¹ For H or C₁ _- ₁₀ alkyl. In some embodiments, when the compound described herein has Formula VIII, R^B Cy² . In some embodiments, when the compound described herein has Formula VIII, R^B H, halo, C₁ _- ₆ Alkyl, C₂ _- ₆ Alkenyl, C₁ _- ₆ Haloalkyl, CN, OR^A3 , C(O)NR^C3 R^D3 Or C(O)OR^A3 Where the C₁ _- ₆ Alkyl and C₂ _- ₆ Alkenyl groups are each optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, C₁ _- ₆ Haloalkyl, CN, NO₂ OR^A3 , SR^A3 , C(O)R^B3 , C(O)NR^C3 R^D3 , C(O)OR^A3 , OC(O)R^B3 , OC(O)NR^C3 R^D3 NR^C3 R^D3 NR^C3 C(O)R^B3 NR^C3 C(O)OR^A3 NR^C3 C(O)NR^C3 R^D3 NR^C3 S(O)R^B3 NR^C1 S(O)₂ R^B3 NR^C3 S(O)₂ NR^C3 R^D3 , S(O)R^B3 , S(O)NR^C3 R^D3 , S(O)₂ R^B3 And S(O)₂ NR^C3 R^D3 . In some embodiments, when the compound described herein has Formula VIII, R^B Is H or a halogen group. In some embodiments, when the compound described herein has Formula VIII, R^B It is a halogen group. In some embodiments, when the compound described herein has Formula VIII, R^C H. In some embodiments, when the compound described herein has Formula VIII, R^D H. In some embodiments, when the compound described herein has Formula VIII, R^Cy Halogen, C₁ _- ₆ Alkyl, C₁ _- ₆ Haloalkyl, 4-10 membered heterocycloalkyl, CN, NO₂ OR^A5 , SR^A5 , C(O)R^B5 , C(O)NR^C5 R^D5 , C(O)OR^A5 NR^C5 R^D5 , S(O)₂ R^B5 And S(O)₂ NR^C5 R^D5 Where the C₁ _- ₆ The alkyl group and the 4-10 membered heterocycloalkyl group are each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of halo, C₁ _- ₆ Alkyl, CN, NO₂ OR^A5 , SR^A5 , C(O)R^B5 , C(O)NR^C5 R^D5 , C(O)OR^A5 , OC(O)R^B5 , OC(O)NR^C5 R^D5 NR^C5 R^D5 NR^C5 C(O)R^B5 NR^C5 C(O)OR^A5 NR^C5 C(O)NR^C5 R^D5 NR^C5 S(O)R^B5 NR^C5 S(O)₂ R^B5 NR^C5 S(O)₂ NR^C5 R^D5 , S(O)R^B5 , S(O)NR^C5 R^D5 , S(O)₂ R^B5 And S(O)₂ NR^C5 R^D5 . In some embodiments, a is 0 when the compound described herein has Formula VIII. In some embodiments, -C(O)OR¹ Connected to the palm carbonS configuration. In some embodiments, -R² The carbon to be connected is palmar and hasR configuration. In some embodiments, the compound used in the methods described herein is (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl) ]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid ethyl ester, or its medicinal Acceptable salt. In some embodiments, the compound used in the methods described herein is (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl) ]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid, or a pharmaceutically acceptable Accept the salt. In some embodiments, the compound used in the methods described herein is (S)-8-(2-amino-6-((R)-1-(3',4'-dimethyl-3-) (3-Methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- Ethyl 2,8-diazaspiro[4.5]decane-3-carboxylate, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound used in the methods described herein is (S)-8-(2-amino-6-((R)-1-(3',4'-dimethyl-3-) (3-Methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound used in the methods described herein is (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-)- 1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid An ester, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound used in the methods described herein is (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-)- 1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid, Or a pharmaceutically acceptable salt thereof (see Example 34c). In some embodiments, the compound used in the methods described herein is (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-) Fluor-3-(3-methyl-1H-pyrazol-1-yl)-4'-propoxy-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl Ethyl-2,8-diazaspiro[4.5]decane-3-carboxylate, or a pharmaceutically acceptable salt thereof (see Example 63i). In some embodiments, the compound is (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-fluoro-3-(3-) -1H-pyrazol-1-yl)-4'-propoxy-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diaza Spiro[4.5]decane-3-carboxylic acid, or a pharmaceutically acceptable salt thereof. It will be appreciated that certain features of the invention which are described in the <RTI ID=0.0> Conversely, various features of the invention that are described in the context of a single embodiment for the sake of brevity may be provided separately or in any suitable sub-combination. The term "substituted" means that the atom or atomic group is formally substituted for hydrogen as a "substituent" attached to another group. The hydrogen atom is formally removed and replaced with a substituent. A single divalent substituent (eg, a pendant oxygen substituent) can replace two hydrogen atoms. The term "optionally substituted" means unsubstituted or substituted. The substituents are independently selected and the substitutions can be located at any position that is chemically accessible. It should be understood that the substitution at a given atom is limited by the valence. Throughout the definition, the term "C_i _- _j "Indicates a range including endpoints, where i and j are integers and represent carbon numbers. Examples include C₁ _- ₄ , C₁ _- ₆ And its analogues. If n is an integer, the term "n-member" generally describes the number of ring-forming atoms in a moiety, where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1, 2, 3, 4-Tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group. Various aryl, heteroaryl, cycloalkyl and heterocycloalkyl rings are described at various positions throughout the specification. Unless otherwise specified, such rings may be attached to the remainder of the molecule at any ring member as permitted by the valence. For example, the term "pyridine ring" or "pyridyl" may refer to pyridin-2-yl, pyridin-3-yl or pyridin-4-yl ring. For a compound of the invention in which a variable occurs more than once, each variable may be independently selected from a different portion of the population defining the variable. For example, when describing a structure having two R groups co-present on the same compound, the two R groups can be represented independently from different portions of the group defining R. As used herein, the term "C, alone or in combination with other terms._i _- _j "Alkyl" means a saturated hydrocarbon group having from i to j carbon atoms which may be a straight or branched chain. In some embodiments, an alkyl group contains from 1 to 10, from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, and tert-butyl. As used herein, the term "C, alone or in combination with other terms._i _- _j Alkoxy" refers to a radical of the formula -O-alkyl wherein alkyl has from 1 to j carbon atoms. Examples of alkoxy groups include methoxy, ethoxy, and propoxy groups (e.g., n-propoxy and isopropoxy). In some embodiments, an alkyl group has from 1 to 3 carbon atoms or from 1 to 4 carbon atoms. As used herein, "C_i _- _j "Alkenyl" means an alkyl group having one or more double carbon-carbon bonds and having from i to j carbon atoms. In some embodiments, the alkenyl moiety contains 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, second butenyl, and the like. As used herein, the term "C_i _- _j "Alkylamino" refers to a radical of the formula -NH(alkyl) wherein alkyl has from 1 to j carbon atoms. In some embodiments, an alkyl group has from 1 to 6 or from 1 to 4 carbon atoms. As used herein, the term "two C_i _- _j "Alkylamino" means a formula -N(alkyl)₂ a group in which two alkyl groups each have from i to j carbon atoms. In some embodiments, each alkyl group has from 1 to 6 carbon atoms or from 1 to 4 carbon atoms, respectively. As used herein, the term "thio" refers to a radical of the formula -SH. As used herein, the term "C_i _- _j "Alkylthio" refers to a radical of the formula -S-alkyl wherein alkyl has from 1 to j carbon atoms. In some embodiments, an alkyl group has from 1 to 6 or from 1 to 4 carbon atoms. As used herein, the term "amine group" refers to the formula -NH.₂ The group. As used herein, the term "C, alone or in combination with other terms._i _- _j "Aryl" means a monocyclic or polycyclic (eg, having 2, 3, or 4 fused ring) aromatic hydrocarbons having from i to j ring-forming carbon atoms such as, but not limited to, phenyl, 1-naphthyl, 2-naphthyl, anthracenyl, phenanthryl and the like. In some embodiments, the aryl group is C₆ _- ₁₀ Aryl. In some embodiments, the aryl group is a naphthalene ring or a benzene ring. In some embodiments, the aryl group is a phenyl group. As used herein, the term "arylalkyl" refers to the formula -C._i _- _j Alkyl-(C_i _- _j a group of aryl). In some embodiments, the arylalkyl group is C₆ _- ₁₀ aryl-C₁ _- ₃ alkyl. In some embodiments, the arylalkyl group is C₆ _- ₁₀ aryl-C₁ _- ₄ alkyl. In some embodiments, the arylalkyl group is a benzyl group. As used herein, the term "carbonyl", alone or in combination with other terms, refers to a -C(=O)- group. As used herein, the term "carboxy" refers to a radical of the formula -C(=O)OH. As used herein, the term "C, alone or in combination with other terms._i _- _j "Cycloalkyl" means a non-aromatic cyclic hydrocarbon moiety having from i to j ring-forming carbon atoms, which may optionally contain one or more alkenyl groups as part of the ring structure. Cycloalkyl groups can include monocyclic or polycyclic (eg, having 2, 3, or 4 fused rings) systems. The definition of cycloalkyl also includes a moiety in which one or more aromatic rings (aryl or heteroaryl) are fused to a cycloalkyl ring, such as benzene of cyclopentane, cyclopentene, cyclohexane, and the like. And or a pyridine derivative. Where the cycloalkyl group comprises a fused aromatic ring, the cycloalkyl group can be attached at the atom in the aromatic or non-aromatic moiety. One or more ring-forming carbon atoms of the cycloalkyl group can be oxidized to form a carbonyl linkage. In some embodiments, the cycloalkyl group is C₃ _- ₁₀ Or C₃ _- ₇ A cycloalkyl group which may be monocyclic or polycyclic. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornane Base, norbornyl, norbornyl, adamantyl and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. As used herein, the term "cycloalkylalkyl" refers to the formula -C._i _- _j Alkyl-(C_i _- _j a group of a cycloalkyl group. In some embodiments, the cycloalkylalkyl group is C₃ _- ₇ cycloalkyl-C₁ _- ₃ An alkyl group in which the cycloalkyl moiety is a single ring. In some embodiments, the cycloalkylalkyl group is C₃ _- ₇ cycloalkyl-C₁ _- ₄ alkyl. As used herein, "C_i _- _j "Haloalkoxy" means a group of the formula -O-haloalkyl having from i to j carbon atoms. An example of a haloalkoxy group is OCF₃ . An additional example of a haloalkoxy group is OCHF₂ . In some embodiments, an alkyl group has from 1 to 6 or from 1 to 4 carbon atoms. As used herein, the term "halo" refers to a halogen atom selected from F, Cl, I or Br. In some embodiments, "halo" refers to a halogen atom selected from F, Cl or Br. In some embodiments, the halo group is F. As used herein, the term "C, alone or in combination with other terms._i _- _j "Haloalkyl" means an alkyl group having 1 halogen atom to 2s+1 halogen atoms which may be the same or different, wherein "s" is the number of carbon atoms in the alkyl group, wherein the alkyl group has from i to j carbon atoms . In some embodiments, the haloalkyl group is fluoromethyl, difluoromethyl or trifluoromethyl. In some embodiments, the haloalkyl group is a trifluoromethyl group. In some embodiments, haloalkyl has from 1 to 6 or from 1 to 4 carbon atoms. As used herein, the term "heteroaryl", alone or in combination with other terms, refers to a monocyclic or polycyclic (eg, having 2, 3 or 4 fused rings) aromatic moiety having one or more selected from one or more A hetero atom ring member of nitrogen, sulfur, and oxygen. And X. . In some embodiments, a heteroaryl is a 5 to 6 membered heteroaryl ring which is monocyclic and has 1, 2, 3 or 4 heteroatom ring members independently selected from the group consisting of nitrogen, sulfur and oxygen. When a heteroaryl contains more than one heteroatom ring member, the heteroatoms may be the same or different. The nitrogen atom in the ring of the heteroaryl group can be oxidized to form an N-oxide. Examples of heteroaryl groups include, but are not limited to, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, azolyl, oxazole, thiazole, imidazole, furan, thiophene, quinoline, isoquinoline, anthracene , benzothiophene, benzofuran, benzisoxazole, imidazo[1,2-b Thiazole, hydrazine and the like. A 5-membered heteroaryl group is a heteroaryl group having 5 ring-forming atoms, the ring-forming atoms comprising carbon and one or more (eg 1, 2 or 3) ring atoms independently selected from N, O and S . Examples of the five-membered heteroaryl group include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, Tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2 4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl. The 6-membered heteroaryl group is a heteroaryl group having 6 ring-forming atoms, wherein one or more (for example, 1, 2 or 3) ring atoms are independently selected from N, O and S. Examples of the 6-membered heteroaryl group include a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a triazinyl group, and a pyridazinyl group. As used herein, the term "heteroarylalkyl" refers to the formula -C._i _- _j A group of an alkyl-(heteroaryl) group. In some embodiments, the heteroarylalkyl group is a 5-10 membered heteroaryl-C₁ _- ₄ An alkyl group wherein the heteroaryl moiety is monocyclic or bicyclic and has 1, 2, 3 or 4 heteroatom ring members independently selected from the group consisting of nitrogen, sulfur and oxygen. In some embodiments, the heteroarylalkyl group is a 5-6 membered heteroaryl-C₁ _- ₃ Alkyl or 5-6 membered heteroaryl-C₁ _- ₄ An alkyl group wherein the heteroaryl moiety is monocyclic and has 1, 2, 3 or 4 heteroatom ring members independently selected from the group consisting of nitrogen, sulfur and oxygen. The term "heterocycloalkyl" as used herein, alone or in combination with other terms, refers to a non-aromatic ring or ring system which optionally contains one or more alkenyl groups as part of the ring structure and which has at least one independent It is selected from the group consisting of nitrogen, sulfur and oxygen. When a heterocycloalkyl contains more than one heteroatom, the heteroatoms may be the same or different. Heterocycloalkyl groups can include monocyclic or polycyclic (eg, having 2, 3, or 4 fused rings) ring systems, including spiro ring systems. The definition of heterocycloalkyl also includes a moiety in which one or more aromatic rings (aryl or heteroaryl) are fused to a non-aromatic ring, such as 1,2,3,4-tetrahydro-quinoline, dihydrobenzene. And furan and its like. When a heterocycloalkyl group includes a fused aromatic ring, the heterocycloalkyl group can be attached at the atom in the aromatic or non-aromatic moiety. The carbon or heteroatom in the ring of the heterocycloalkyl group can be oxidized (e.g., having one or two pendant oxygen substituents) to form a carbonyl or sulfonyl group (or other oxidative linkage) or the nitrogen atom can be quaternized. In some embodiments, a heterocycloalkyl group is 5 to 10 membered members which may be monocyclic or bicyclic and have 1, 2, 3 or 4 heteroatom ring members independently selected from the group consisting of nitrogen, sulfur and oxygen. In some embodiments, the heterocycloalkyl group is 5 to 6 members or 5 to 7 members. Examples of heterocycloalkyl groups include 1,2,3,4-tetrahydroquinoline, dihydrobenzofuran, azetidine, azepane, pyrrolidine, piperidine, piperazine, morpholine, Thiomorpholine and piper. Other examples of heterocycloalkyl groups include 2-sided oxytetrahydrofuranyl, 2-sided oxypyrrolidinyl, 2-sided oxyimidazolidinyl, 1-sided oxy-1,2,3,4-tetrahydrol Isoquinolin-6-yl and 2-sided oxy-1,3-dioxolan-4-yl. As used herein, the term "heterocycloalkylalkyl" refers to the formula -C._i _- _j a group of an alkyl-(heterocycloalkyl group). In some embodiments, a heterocycloalkylalkyl group is a 5-10 membered heterocycloalkyl-C₁ _- ₃ Alkyl or 5-10 membered heterocycloalkyl-C₁ _- ₄ An alkyl group wherein the heterocycloalkyl moiety is monocyclic or bicyclic and has 1, 2, 3 or 4 heteroatom ring members independently selected from the group consisting of nitrogen, sulfur and oxygen. In some embodiments, a heterocycloalkylalkyl group is a 5-6 membered heterocycloalkyl-C₁ _- ₄ An alkyl group wherein the heterocycloalkyl moiety is monocyclic and has 1, 2, 3 or 4 heteroatom ring members independently selected from the group consisting of nitrogen, sulfur and oxygen. The compounds described herein can be asymmetric (e.g., have one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are intended. Compounds of the invention containing asymmetrically substituted carbon atoms can be separated in optically active or racemic forms. Methods for preparing optically active forms from optically inactive starting materials, such as analytical racemic mixtures or stereoselective synthesis, are known in the art. A wide variety of geometric isomers of olefins, C=N double bonds, and analogs thereof may also be present in the compounds described herein, and all such stable isomers are encompassed by the present invention. The cis and trans geometric isomers of the compounds of the invention may be isolated as a mixture of isomers or in separate isomeric forms. The resolution of the racemic mixture of the compound can be carried out by any of a number of methods known in the art. An example method involves stepwise recrystallization using a palmitic acid, which resolves to an optically active salt-forming organic acid. Analytical agents suitable for use in the step-wise recrystallization process are, for example, optically active acids such as D and L forms of tartaric acid, diethyl tartaric acid, benzhydryl tartaric acid, mandelic acid, malic acid (malic acid), lactic acid or various optically active camphorsulfonic acid (such as β-camphorsulfonic acid). Other resolving agents suitable for use in the fractional crystallization process include alpha-methylbenzylamine (egS andR Form or diastereomeric form), 2-phenylglycolol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2- Stereoisomerically pure form of diaminocyclohexane and its analogs. The resolution of the racemic mixture can also be carried out by dissolving the column packed with an optically active resolving agent such as dinitrobenzimidylglycolic acid. Suitable dissolving solvent compositions can be determined by those skilled in the art. The compounds of the invention may also include tautomeric forms. The tautomeric form is produced by the exchange of a single bond with an adjacent double bond and the accompanying proton transfer. Tautomeric forms include proton transfer tautomers in an isomerized state having the same empirical formula and total charge. Examples of proton transfer tautomers include keto-enol pairs, guanamine-imidic acid pairs, indoleamine-indoline pairs, indoleamine-imine pairs, enamine-imine pairs, and protons can occupy a cyclic form of two or more positions of a heterocyclic ring system, for example1H -Imidazole and3H -imidazole,1H -1,2,4-triazole,2H -1,2,4-triazole and 4H-1,2,4-triazole,1H - Different2H - different, and1H - Pyrazole and2H -pyrazole. The compounds of the invention may also include all isotopes of the atoms present in the intermediate or final compound. Isotopes include those atoms that have the same number of atoms but different mass numbers. For example, isotopes of hydrogen include deuterium and tritium. As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structure. Unless otherwise specified, a compound identified by a name or structure herein as a particular tautomeric form is intended to include other tautomeric forms. Compounds that are identified by name or structure herein without specifying a particular configuration of the stereocenter are intended to cover all possible configurations at the stereocenter. For example, if a particular stereocenter in a compound of the invention can be R or S, but the name or structure of the compound does not indicate the stereocenter, then the stereocenter can be R or S. All of the compounds and their pharmaceutically acceptable salts can be present together with or separated from other materials such as water and solvents such as hydrates and solvates. In some embodiments, a compound of the invention or a salt thereof is substantially isolated. "Substantially separated" means that the compound is at least partially or substantially separated from the environment in which it is formed or detected. Partial separation can include, for example, a composition enriched with a compound of the invention. Substantial separation can include at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99. A composition by weight of a compound of the invention or a salt thereof. The method for isolating the compound and its salt is a conventional method in the art. The phrase "pharmaceutically acceptable" is used herein to mean that it is suitable for contact with human and animal tissues without reasonable toxicity, irritation, allergic reactions or other problems or complications, and reasonable benefits within the scope of sound medical judgment. /The compounds, materials, compositions and/or dosage forms that are commensurate with the risk ratio. As used herein, the expression "ambient temperature" and "room temperature" is understood in the art and refers to a temperature, such as a reaction temperature, which is about the temperature at which the reaction is carried out, for example, a temperature of from about 20 ° C to about 30 ° C. . The invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salt" refers to a derivative of the disclosed compound wherein the parent compound is modified by converting the existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali metal or organic salts of acidic residues such as carboxylic acids; and the like. . The pharmaceutically acceptable salts of the present invention include, for example, the conventional non-toxic salts of the parent compound formed from a non-toxic inorganic or organic acid. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. In general, the salts can be prepared by reacting the free acid or base forms of such compounds with a stoichiometric amount of a suitable base or acid in water or in an organic solvent or a mixture of the two; , non-aqueous medium such as ether, EtOAc, alcohol (eg methanol, ethanol, isopropanol or butanol) or acetonitrile (CH₃ CN) is preferred. A list of suitable salts was found inRemington ' s Pharmaceutical Sciences , 17th ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al.J . Pharm . Sci . ,1977 ,66 (1), 1-19, and found in Stahl et al.Handbook Of Pharmaceutical Salts : Properties , Selection , And Use , (Wiley, 2002). As used herein, the terms "individual" or "patient" are used interchangeably to refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep. , horse or primate, and best for humans. As used herein, the phrase "therapeutically effective amount" refers to an amount of an active compound or pharmaceutical agent that elicits a biological or pharmaceutical response sought by a researcher, veterinarian, doctor, or other clinician in a tissue, system, animal, individual, or human. . As used herein, the term "treating/treatment" refers to: 1) inhibiting a disease; for example, inhibiting a disease, condition or condition of an individual who is experiencing or presenting a disease or condition of the disease, condition or condition, (even if the lesion and / or further development of the symptoms are stagnant), or 2) to ameliorate the disease; for example to improve the disease, condition or condition of an individual who is experiencing or presenting a disease or condition of the disease, condition or condition (even if the lesion and/or symptoms are reversed). As used herein, the term "preventing/prevention" refers to inhibiting the onset or worsening of a disease; for example, in an individual susceptible to a disease, condition or condition without experiencing or presenting a disease or condition of the disease. Combination therapy The method of treatment of the invention may further comprise administering at least one additional therapeutic agent together with a TPHl inhibitory compound or a prodrug thereof. The additional therapeutic agent may be combined with the TPHl inhibitor or a prodrug thereof in a single dosage form, or the agent may be administered simultaneously or sequentially in separate dosage forms. Additional therapeutic agents for combination therapies include, for example, ASK1 inhibitors such as GS-4997; monoclonal antibodies against LOXL2, such as simtuzumab; non-steroidal anti-inflammatory drugs (NSAIDs) and anti-hyperlipidemic agents ( For example, fibrate, statin, tocotrienol, niacin, bile acid spacer (resin), cholesterol absorption inhibitor, pancreatic lipase inhibitor and Sympathetic amine). Examples of the fibrous acid ester include bezafibrate, ciprofibrate, clofibrate, gemfibrozil, and fenofibrate. Examples of cholesterol absorption inhibitors include ezetimibe, phytosterol, sterols, and stanol. Other agents include pioglitazone, vitamin E, and metformin. Additional treatments may include weight loss (if the patient is obese or overweight), eating a balanced and healthy diet, increasing physical activity and avoiding alcohol. Administration, pharmaceutical formulation, dosage form The methods described herein comprise administering to a patient in need of such treatment (e.g., an animal and a human) a TPHl inhibitor or a prodrug thereof as described herein, in an appropriate dosage that will provide a prophylactic and/or therapeutic effect. The dosages and dosing regimens required to treat or prevent any particular disease or condition will generally vary from patient to patient, depending, for example, on the particular compound or composition selected, the route of administration, the condition being treated The nature, the age and condition of the patient, the combination of drugs or the particular diet followed by the patient and other factors. The appropriate dosage and dosage regimen can be determined by the treating physician. The compounds described herein can be administered orally, subcutaneously, topically, parenterally or rectally in the form of a dosage unit formulation containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Parenteral administration can include subcutaneous injections, intravenous or intramuscular injection or infusion techniques. The compound for nasal administration or administration by inhalation or insufflation may be delivered as an aerosol spray from a pressurized pack or nebulizer using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, Dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or other suitable gases. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve that delivers a metered amount. Capsules and cartridges (e.g., capsules and cartridges of gelatin) for use in an inhaler or insufflator can be formulated to contain a powder mixture of the compound and a suitable powder base such as lactose or starch. The duration of treatment can be the length of time that the treating physician deems necessary. For example, the compounds and compositions can be administered one to four times or more than four times per day. In some cases, depending on the nature of the compound and depending on the formulation, the administration may be less than once a day, for example, once every other day or once a week. The treatment period can be terminated when the desired result (eg, a particular therapeutic effect) is achieved. Or the treatment period can continue indefinitely. In some embodiments, the methods described herein comprise administering to a patient a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutical excipients or carriers. The pharmaceutical compositions can be prepared for oral administration of solid dosage forms such as capsules, lozenges, pills, dragees, powders, granules and the like. Tablets can be prepared by compression or molding. Compressed tablets may include one or more binders, lubricants, slip agents, inert diluents, preservatives, disintegrating agents or dispersing agents. Tablets and other solid dosage forms such as capsules, pills, and granules can include coatings such as enteric coatings. Dosage forms for transdermal administration of the subject compositions include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches. Other suitable pharmaceutical formulations and dosage forms include inhalants. Pharmaceutical compositions suitable for parenteral administration of the present invention include the compounds of the present invention together with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions. Alternatively, the compositions may be in the form of a sterile powder which can be reconstituted in a sterile injectable solution or dispersion, ready for use. The invention will be described in more detail by means of specific examples. The following examples are provided for illustrative purposes and are not intended to limit the invention in any way. Those skilled in the art will readily recognize a variety of non-critical parameters that can be changed or modified to produce substantially the same results. The compound of the example was found to be an inhibitor of TPH1.Instance The TPHl inhibitors and prodrugs thereof described herein can be prepared in a variety of ways based on the teachings contained herein and synthetic procedures known in the art. For example, the compounds described in the Examples can be prepared according to the procedures provided in US Publication No. 2015/0080393, which is incorporated herein by reference in its entirety. The procedure of Example 1u below can be generally used to prepare TPH1 inhibiting compounds.Instance 1u : ( S )- 8 -( 2 - Amine - 6 -(( R )- 2 , 2 , 2 - Trifluoro - 1 -( 3 -( 3 - methyl - 1H - Pyrazole - 1 - base )-[ 1 , 1 '- Biphenyl ]- 4 - base ) Ethoxy ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid step 1 :(R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol (160 mg, 0.2 mmol, Addition of 2-amino-4,6-dichloropyrimidine (100 mg, 0.16 mmol) to a solution of the intermediate 1, see US Publication No. 2015/0080393 [0409] in dioxane (2 mL) And Cs₂ CO₃ (48 g, 0.16 mmol). The reaction was heated to 80 ° C for 16 hours, cooled to room temperature and filtered. Remove the solvent in vacuo and dissolve the residue in CH₂ Cl₂ In a mixture of heptane, concentrated to half volume, filtered and concentrated again in vacuo. Normal phase gel chromatography (CH)₂ Cl₂ Purification of /[heptane) afforded 4-[(1R)-1-[4-bromo-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2- Trifluoro-ethoxy]-6-chloro-pyrimidin-2-amine.step 2 : to 4-[(1R)-1-[4-bromo-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoro-ethoxy]-6- Add (S)-2,8-diazaspiro[4.5]nonane-2,3 to a solution of chloro-pyrimidin-2-amine (125 mg, 0.3 mmol, step 1) in dioxane (3 mL) -dibenzyl 2-benzyl ester 3-ethyl ester (95 mg, 0.3 mmol, US Publication No. 2015/0080393 [0469]) and Na₂ CO₃ (182 mg, 0.35 mmol). The reaction was heated to 90 <0>C for 130 h then cooled to rt, filtered and concentrated in vacuo. (S)-(8-(2-Amino-6-((R)-1-(4-bromo-2-)) was obtained as a white solid as a white solid. (3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane 2-2,3-dicarboxylic acid-2-benzyl ester 3-ethyl ester.step 3 : to (S)-(8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-) 2,2,2-Trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylic acid-2-benzyl ester 3-ethyl ester (300 Mg, 0.4 mmol, step 2) Add phenylboronic acid (143 mg, 0.8 mmol), PdCl to a solution of ethanol (2 mL) and water (0.5 mL)₂ (PPh₃ )₂ (41 mg, 0.058 mmol) and Cs₂ CO₃ (390 mg, 1.2 mmol). The reaction was heated to 60 <0>C for 16 h then cooled to rt. filtered over EtOAc EtOAc. (S)-8-(2-Amino-6-((R)-2,2,2-trifluoro-1) was obtained as a white solid as a white solid. -(3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-di Nitrospiro[4.5]decane-2,3-dicarboxylic acid-2-benzyl ester 3-ethyl ester.step 4: Hydrogenation of (S)-8-(2-amino-6-(R) using H-Cube equipment and 10% (w/w) Pd/C cartridge at a flow rate of 1.0 mL/min at room temperature -2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)ethoxy) Pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylic acid-2-benzyl ester 3-ethyl ester (240 mg, 0.4 mmol, step 3) in EtOAc (5 Solution in ml). Purification on ruthenium ruthenium (EtOAc/heptane) afforded (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-) -1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- Ethyl 3-carboxylate.step 5: (S)-8-(2-Amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazole)) -1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid ethyl ester (50 mg, 0.08 mmol) was added a solution of lithium hydroxide monohydrate (58 mg, 0.05 mmol) in THF (2.0 mL) and water (0.2 mL). The reaction mixture was stirred at room temperature for 2 hr then neutralized with 1 N HCI and concentrated in vacuo. The title compound was obtained as a white solid in the form of a white solid.Instance 1m : ( S )- 8 -( 2 - Amine - 6 -(( R )- 1 -( 3 ', 4 '- Dimethyl - 3 -( 3 - methyl - 1H - Pyrazole - 1 - base )-[ 1 , 1 '- Biphenyl ]- 4 - base )- 2 , 2 , 2 - Trifluoroethoxy ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid Instance 1cq : ( S )- 8 -( 2 - Amine - 6 -(( R )- 2 , 2 , 2 - Trifluoro - 1 -( 3 '-( Hydroxymethyl )- 4 '- methyl - 3 -( 3 - methyl - 1H - Pyrazole - 1 - base )-[ 1 , 1 '- Biphenyl ]- 4 - base ) Ethoxy ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid Instance 1cr : ( S )- 8 -( 2 - Amine - 6 -(( R )- 2 , 2 , 2 - Trifluoro - 1 -( 4 '-( Hydroxymethyl )- 3 '- methyl - 3 -( 3 - methyl - 1H - Pyrazole - 1 - base )-[ 1 , 1 '- Biphenyl ]- 4 - base ) Ethoxy ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid table 1a. Instance 1cp : ( S )- 8 -( 2 - Amine - 6 -(( R )- 1 -( 3 ', 4 '- Dimethyl - 3 -( 3 -( Trifluoromethyl )- 1H - Pyrazole - 1 - base )-[ 1 , 1 '- Biphenyl ]- 4 - base )- 2 , 2 , 2 - Trifluoroethoxy ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid Instance 2 : ( S )- 8 -( 2 - Amine - 6 -(( R )- 2 , 2 , 2 - Trifluoro - 1 -( 2 -( 3 - methyl - 1H - Pyrazole - 1 - base )- 4 -( Piperidine - 4 - base ) Phenyl ) Ethoxy ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid Instance 3a : ( S )- 8 -( 2 - Amine - 6 -(( R )- 2 , 2 , 2 - Trifluoro - 1 -( 2 -( 3 - methyl - 1H - Pyrazole - 1 - base )- 4 -( 1 -( Methanesulfonyl ) Piperidine - 4 - base ) Phenyl ) Ethoxy ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid table 2a. Instance 4 : ( S )- 8 -( 2 - Amine - 6 -(( R )- 2 , 2 , 2 - Trifluoro - 1 -( 3 '- Methoxy - 4 '-( Methoxycarbonyl )- 3 -( 3 - methyl - 1H - Pyrazole - 1 - base )-[ 1 , 1 '- Biphenyl ]- 4 - base ) Ethoxy ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid Instance 5a : ( S )- 8 -( 2 - Amine - 6 -(( R )- 1 -( 3 '-( Ethoxycarbonyl )- 3 -( 3 - methyl - 1H - Pyrazole - 1 - base )-[ 1 , 1 '- Biphenyl ]- 4 - base )- 2 , 2 , 2 - Trifluoroethoxy ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid Instance 5b : ( S )- 8 -( 2 - Amine - 6 -(( R )- 1 -( 4 '-( Ethoxycarbonyl )- 3 -( 3 - methyl - 1H - Pyrazole - 1 - base )-[ 1 , 1 '- Biphenyl ]- 4 - base )- 2 , 2 , 2 - Trifluoroethoxy ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid Instance 6 : ( S )- 8 -( 2 - Amine - 6 -(( R )- 1 -( 4 -( 3 - Carboxypropyl )- 2 -( 3 - methyl - 1H - Pyrazole - 1 - base ) Phenyl )- 2 , 2 , 2 - Trifluoroethoxy ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid Instance 7 : ( S )- 8 -( 2 - Amine - 6 -(( R )- 1 -( 4 -( 2 - Carboxyethyl )- 2 -( 3 - methyl - 1H - Pyrazole - 1 - base ) Phenyl )- 2 , 2 , 2 - Trifluoroethoxy ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid Instance 9 : ( S )- 8 -( 2 - Amine - 6 -(( R )- 1 -( 4 -( 3 - Ethoxy - 3 - Oxyloxypropyl )- 2 -( 3 - methyl - 1H - Pyrazole - 1 - base ) Phenyl )- 2 , 2 , 2 - Trifluoroethoxy ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid Instance 10d : ( S )- 8 -( 2 - Amine - 6 -(( R )- 1 -( 4 - chlorine - 2 -( 3 - methyl - 1H - Pyrazole - 1 - base ) Phenyl )- 2 , 2 , 2 - Trifluoroethoxy ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid table 3a. * The three-dimensional chemistry is defined by name in the table below. Instance 10o : ( S )- 8 -( 2 - Amine - 6 -(( R )- 1 -( 4 - bromine - 2 -( 3 - methyl - 1H - Pyrazole - 1 - base ) Phenyl )- 2 , 2 , 2 - Trifluoroethoxy ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid Instance 10p : ( S )- 8 -( 2 - Amine - 6 -(( R )- 1 -( 4 - chlorine - 2 -( 3 -( Trifluoromethyl )- 1H - Pyrazole - 1 - base ) Phenyl )- 2 , 2 , 2 - Trifluoroethoxy ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid Instance 10pa : ( S )- 8 -( 2 - Amine - 6 -(( R )- 1 -( 2 -( 3 -( Third butyl )- 1H - Pyrazole - 1 - base )- 4 - Chlorophenyl )- 2 , 2 , 2 - Trifluoroethoxy ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid Instance 10q : ( S )- 8 -( 2 - Amine - 6 -(( R )- 1 -( 4 - chlorine - 2 -( 3 - Isopropyl - 1H - Pyrazole - 1 - base ) Phenyl )- 2 , 2 , 2 - Trifluoroethoxy ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid Instance 10r : ( S )- 8 -( 2 - Amine - 6 -(( R )- 1 -( 4 - chlorine - 2 -( 3 - Cyclopropyl - 1H - Pyrazole - 1 - base ) Phenyl )- 2 , 2 , 2 - Trifluoroethoxy ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid Instance 11 : ( S )- 8 -( 2 - Amine - 6 -(( R )- 2 , 2 , 2 - Trifluoro - 1 -( 6 - methyl - 2 -( 3 - methyl - 1H - Pyrazole - 1 - base ) Pyridine - 3 - base ) Ethoxy ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid Example 12a: (S)-8-(2-Amino-6-((R)-1-(4-ethyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl) -2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acidTable 4a. Instance 13 : ( 3S )- 8 -( 2 - Amine - 6 -(( 1R )- 1 -( 4 -( 1 , 2 - Dihydroxyethyl )- 2 -( 3 - methyl - 1H - Pyrazole - 1 - base ) Phenyl )- 2 , 2 , 2 - Trifluoroethoxy ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid Instance 14 : ( S )- 8 -( 2 - Amine - 6 -(( R )- 1 -( 4 - Cyano - 2 -( 3 - methyl - 1H - Pyrazole - 1 - base ) Phenyl )- 2 , 2 , 2 - Trifluoroethoxy ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid Instance 15 : ( S )- 8 -( 2 - Amine - 6 -(( R )- 1 -( 4 - Aminomethyl sulfhydryl - 2 -( 3 - methyl - 1H - Pyrazole - 1 - base ) Phenyl )- 2 , 2 , 2 - Trifluoroethoxy ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid Instance 16 : ( S )- 8 -( 2 - Amine - 6 -(( R )- 1 -( 4 - carboxyl - 2 -( 3 - methyl - 1H - Pyrazole - 1 - base ) Phenyl )- 2 , 2 , 2 - Trifluoroethoxy ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid Instance 17 : ( S )- 8 -( 2 - Amine - 6 -(( R )- 1 -( 4 -( Ethoxycarbonyl )- 2 -( 3 - methyl - 1H - Pyrazole - 1 - base ) Phenyl )- 2 , 2 , 2 - Trifluoroethoxy ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid Instance 18a : ( S )- 8 -( 2 - Amine - 6 -(( R )- 2 , 2 , 2 - Trifluoro - 1 -( 4 -((( 1 , 1 , 1 , 3 , 3 , 3 - Hexafluoro - 2 - Methyl propyl - 2 - base ) Oxyl ) Carbonyl )- 2 -( 3 - methyl - 1H - Pyrazole - 1 - base ) Phenyl ) Ethoxy ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid table 5a. Instance 19a : ( S )- 8 -( 2 - Amine - 6 -(( R )- 2 , 2 , 2 - Trifluoro - 1 -( 2 -( 3 - methyl - 1H - Pyrazole - 1 - base )- 5 - Vinyl phenyl ) Ethoxy ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid Table 6a. Table 7a. Instance 20 : ( S )- 8 -( 2 - Amine - 6 -(( R )- 1 -( 2 '-( Ethoxycarbonyl )- 4 -( 3 - methyl - 1H - Pyrazole - 1 - base )-[ 1 , 1 '- Biphenyl ]- 3 - base )- 2 , 2 , 2 - Trifluoroethoxy ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid Instance twenty one : ( S )- 8 -( 2 - Amine - 6 -(( R )- 1 -( 4 '-( Ethoxycarbonyl )- 4 -( 3 - methyl - 1H - Pyrazole - 1 - base )-[ 1 , 1 '- Biphenyl ]- 3 - base )- 2 , 2 , 2 - Trifluoroethoxy ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid Instance 22a : ( S )- 8 -( 2 - Amine - 6 -(( R )- 1 -( 5 - Ethyl - 2 -( 3 - methyl - 1H - Pyrazole - 1 - base ) Phenyl )- 2 , 2 , 2 - Trifluoroethoxy ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid table 8a. Instance twenty three : ( S )- 8 -( 2 - Amine - 6 -(( R )- 1 -( 5 -( Ethoxycarbonyl )- 2 -( 3 - methyl - 1H - Pyrazole - 1 - base ) Phenyl )- 2 , 2 , 2 - Trifluoroethoxy ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid Instance twenty four : ( S )- 8 -( 2 - Amine - 6 -(( R )- 1 -( 5 - carboxyl - 2 -( 3 - methyl - 1H - Pyrazole - 1 - base ) Phenyl )- 2 , 2 , 2 - Trifluoroethoxy ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid Instance 25 : ( S )- 8 -( 2 - Amine - 6 -(( R )- 2 , 2 , 2 - Trifluoro - 1 -( 4 -( Hydroxymethyl )- 2 -( 3 - methyl - 1H - Pyrazole - 1 - base ) Phenyl ) Ethoxy ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid Instance 26 : ( S )- 8 -( 2 - Amine - 6 -(( R )- 1 -( 4 -(( Dimethylamino ) methyl )- 2 -( 3 - methyl - 1H - Pyrazole - 1 - base ) Phenyl )- 2 , 2 , 2 - Trifluoroethoxy ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid Instance 27 : ( S )- 8 -( 6 -(( R )- 1 -( 4 - bromine - 2 -( 3 - methyl - 1H - Pyrazole - 1 - base ) Phenyl )- 2 , 2 , 2 - Trifluoroethoxy )- 2 - Methyl pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid Instance 28 : ( S )- 8 -( 6 -(( R )- 1 -( 4 - chlorine - 2 -( 3 - methyl - 1H - Pyrazole - 1 - base ) Phenyl )- 2 , 2 , 2 - Trifluoroethoxy )- 2 - Methyl pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid table 9. table 10. Instance 30a : 8 -( 6 -(( R )- 1 -( 4 - chlorine - 2 -( 3 - methyl - 1H - Pyrazole - 1 - base ) Phenyl )- 2 , 2 , 2 - Trifluoroethoxy )- 2 - Phenoxypyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid table 11a. Instance 31 : 8 -( 6 -(( R )- 1 -( 4 - chlorine - 2 -( 3 - methyl - 1H - Pyrazole - 1 - base ) Phenyl )- 2 , 2 , 2 - Trifluoroethoxy )- 2 -( Cyclohexylamine ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid Instance 32 : ( S )- 8 -( 6 -(( R )- 1 -( 4 - chlorine - 2 -( 3 - methyl - 1H - Pyrazole - 1 - base ) Phenyl )- 2 , 2 , 2 - Trifluoroethoxy )- 2 -( Cyclobutylidene ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid Instance 33 : ( S )- 8 -( 2 - Amine - 6 -(( R )- 1 -( 4 - chlorine - 2 -( 2 - Side oxypyrrolidine - 1 - base ) Phenyl )- 2 , 2 , 2 - Trifluoroethoxy ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid Instance 34c : ( S )- 8 -( 2 - Amine - 6 -(( R )- 1 -( 5 - chlorine -[ 1 , 1 '- Biphenyl ]- 2 - base )- 2 , 2 , 2 - Trifluoroethoxy ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid step 1 : to (R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethanol (Intermediate 43, see US Publication No. 2015/0080393 [0463]) (400 Add 4,6-dichloropyrimidin-2-amine (1.1 g, 7 mmol) and Cs to a solution of di-methane (25 mL)₂ CO₃ (1.3 g, 4 mmol). The mixture was heated at 80 ° C for 24 hours. The reaction was then cooled to room temperature and filtered. Remove solvent in vacuum, then add CH₂ Cl₂ And heptane. The solvent volume is reduced until a solid precipitates. The solid is filtered and the procedure is repeated several times to give (R)-4-(1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy) as a white solid. 6-chloropyrimidin-2-amine.step 2 :(R)-4-(1-(2-Bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)-6-chloropyrimidin-2-amine (100 mg, 0.24 mmol Step 1) Add (S)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylic acid-2-benzyl ester 3-ethyl ester to a solution of dioxane (5 mL) (100 mg, 0.29 mmol, US Publication No. 2015/0080393 [0469]) and NaHCO₃ (300 mg, 3.5 mmol). After 5 hours, add an additional amount of NaHCO₃ (300 mg, 3.5 mmol) and the reaction mixture was heated to 90 ° C for 36 h. The reaction was then cooled to room temperature and filtered. Purification of the (S)-8-(2-amino-6-((R)-1-(2-bromo-4-) chloride as a white solid as a white solid. Phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylic acid-2-benzyl ester 3- Ethyl ester.step 3 :(S)-8-(2-Amino-6-((R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)pyrimidine-4 -yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylic acid-2-benzyl ester 3-ethyl ester (100 mg, 0.13 mmol) in 10:1 dioxane: water ( Add phenylboronic acid (33 mg, 0.27 mmol), KHCO to the solution in 5 mL)₃ (27 mg, 0.3 mmol) and PdCl₂ (dppf)-CH₂ Cl₂ (6 mg, 0.007 mmol). The reaction was heated to 100 ° C for 15 h, cooled to rt and concentrated in vacuo. The residue was diluted with water and extracted with EtOAc. The combined organic layer is passed through Na₂ SO₄ Dry, filter, and concentrate in vacuo. Purification of the (S)-8-(2-amino-6-((R)-1-(5-chloro-[1, 1'-Biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxyl Acid-2-benzyl ester 3-ethyl ester.step 4 :N-CBZ deprotection was achieved by Method B to give (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1'-) as an off-white solid. Ethylbiphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate.step 5 : Hydrolysis of (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2 using LiOH General Method Ethyl 2-fluorotrifluoro)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate gave the title compound as a white solid.Instance 34u : ( S )- 8 -( 2 - Amine - 6 -(( R )- 1 -( 5 - chlorine - 3 '- Amine sulfonyl -[ 1 , 1 '- Biphenyl ]- 2 - base )- 2 , 2 , 2 - Trifluoroethoxy ) Pyrimidine - 4 - base )- 2 , 8 - Diazo snail [ 4 . 5 ] Decane - 3 - carboxylic acid table 12a. * The three-dimensional chemistry is defined by name in the table below. Instance 35 : (S)-8-(2- Amine -6-((R)-1-(5- chlorine -3'-( Ethoxycarbonyl )-[1,1'- Biphenyl ]-2- base )-2,2,2- Trifluoroethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 36 : (S)-8-(2- Amine -6-((R)-1-(4- chlorine -2-(2- Methoxyethoxy ) Phenyl )-2,2,2- Trifluoroethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 36b : (S)-8-(6-((R)-1-(2-(1H-) Benzo [d] Imidazole -1- base )-4- Chlorophenyl )-2,2,2- Trifluoroethoxy )-2- Amine Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 36c : (S)-8-(2- Amine -6-((R)-1-(4- chlorine -2-(1H- Carbazole -1- base ) Phenyl )-2,2,2- Trifluoroethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 36d : (S)-8-(2- Amine -6-((R)-1-(4- bromine -2-( Piperazine -1- base ) Phenyl )-2,2,2- Trifluoroethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 36e : (S)-8-(2- Amine -6-((R)-2,2,2- Trifluoro -1-(4'- Isopropoxy -3-( Piperazine -1- base )-[1,1'- Biphenyl ]-4- base ) Ethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 36f : (S)-8-(2- Amine -6-((R)-2,2,2- Trifluoro -1-(4'- Isopropoxy -3-(N- Morpholinyl )-[1,1'- Biphenyl ]-4- base ) Ethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 36g : (S)-8-(6-((R)-1-([1,1'-- Biphenyl ]-2- base )-2,2,2- Trifluoroethoxy )-2- Amine Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 37 : (3S)-8-(6-(1-((1r,3r,5S,7S)- Adamantane -2- base ) Ethoxy )-2- Aminopyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 38 : (S)-8-(6-((1r,3r,5S,7S)- Adamantane -2- Methoxy )-2- Aminopyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 39a : 8-(4- Amine -6-(( Naphthalene -2- Methyl ) Amine )-1,3,5- Triazine -2- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid table 13a. Instance 40 : 8-(4- Amine -6-((R)-1-(4- chlorine -2-(3- methyl -1H- Pyrazole -1- base ) Phenyl )-2,2,2- Trifluoroethoxy )-1,3,5- Triazine -2- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 41a : (S)-8-(2- Amine -6-((2-( Piperidine -1- base ) Benzyl ) Amine ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid table 14a. Instance 42a : (S)-8-(2- Amine -6-((R)-1-(3'- chlorine -[1,1'- Biphenyl ]-2- base )-2,2,2- Trifluoroethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 42b : (S)-8-(2- Amine -6-((R)-2,2,2- Trifluoro -1-(3'- fluorine -[1,1'- Biphenyl ]-2- base ) Ethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 43 : (S)-8-(5-((R)-1-(4- chlorine -2-(3- methyl -1H- Pyrazole -1- base ) Phenyl )-2,2,2- Trifluoroethoxy ) Pyridazine -3- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 44 : ( S)-8-(4-((R)-2,2,2- Trifluoro -1-(2-(3- methyl -1H- Pyrazole -1- base ) Phenyl ) Ethoxy ) Pyridine -2- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid and Instance 45 : (S)-8-(4-((R)-1-(4-) chlorine -2-(3- methyl -1H- Pyrazole -1- base ) Phenyl )-2,2,2- Trifluoroethoxy ) Pyridine -2- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 46 : 8-(4-((R)-1-(4-) chlorine -2-(3- methyl -1H- Pyrazole -1- base ) Phenyl )-2,2,2- Trifluoroethoxy )-6- Phenoxypyrimidine -2- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 47 : (3S)-8-(2- Amine -6-(1-(2,6- Dibromophenyl )-2,2,2- Trifluoroethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 48 : (S)-8-(2- Amine -6-((R)-1-(2,5- Dibromophenyl )-2,2,2- Trifluoroethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 49 : ( S)-8-(2- Amine -6-((R)-2,2,2- Trifluoro -1-(3'-( Methanesulfonyl )-4- Propyl -[1,1'- Biphenyl ]-2- base ) Ethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 50 : (S)-8-(2- Amine -6-((R)-2,2,2- Trifluoro -1-(3'-( Methanesulfonyl )-4-((E)- C -1- Alkene -1- base )-[1,1'- Biphenyl ]-2- base ) Ethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 51a : (S)-8-(6-((R)-1-([1,1':4',1''-- Triphenylene ]-2'- base )-2,2,2- Trifluoroethoxy )-2- Aminopyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 51b : (S)-8-(6-((R)-1-([1,1':3',1''-- Triphenylene ]-2'- base )-2,2,2- Trifluoroethoxy )-2- Aminopyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 52a : (S)-8-(2- Amine -6-((R)-1-(3,4- Dimethyl -3''-( Methanesulfonyl )-[1,1':3',1''- Triphenylene ]-4'- base )-2,2,2- Trifluoroethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid table 16a. Instance 53 : (S)-8-(2- Amine -6-((R)-2,2,2- Trifluoro -1-(3'-( Methanesulfonyl )-5-((E)- C -1- Alkene -1- base )-[1,1'- Biphenyl ]-2- base ) Ethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 54a : (S)-8-(2- Amine -6-((R)-2,2,2- Trifluoro -1-(3'-( Methanesulfonyl )-5- Propyl -[1,1'- Biphenyl ]-2- base ) Ethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 54b : (S)-8-(2- Amine -6-((R)-2,2,2- Trifluoro -1-(4- Isopropoxy -[1,1':3',1''- Triphenylene ]-4'- base ) Ethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 54c : (S)-8-(2- Amine -6-((R)-2,2,2- Trifluoro -1-(4- Propoxy -[1,1':3',1''- Triphenylene ]-4'- base ) Ethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 54d : (S)-8-(2- Amine -6-((R)-2,2,2- Trifluoro -1-(5-( Methanesulfonyl )-[1,1'- Biphenyl ]-2- base ) Ethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 54e : (S)-8-(2- Amine -6-((R)-2,2,2- Trifluoro -1-(3- fluorine -4- Propoxy -[1,1':3',1''- Triphenylene ]-4'- base ) Ethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 54f : (S)-8-(2- Amine -6-((R)-1-(3,4- Dimethyl -[1,1':3',1''- Triphenylene ]-4'- base )-2,2,2- Trifluoroethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 54g : (S)-8-(6-((R)-1-([1,1':3',1''-- Triphenylene ]-4'- base )-2,2,2- Trifluoroethoxy )-2- Aminopyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 54h : (R)-8-(2- Amine -6-((R)-1-(5- chlorine -[1,1'- Biphenyl ]-2- base )-2,2,2- Trifluoroethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 54i : (R)-8-(2- Amine -6-((S)-1-(5- chlorine -[1,1'- Biphenyl ]-2- base )-2,2,2- Trifluoroethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 54j : (S)-8-(2- Amine -6-((S)-1-(5- chlorine -[1,1'- Biphenyl ]-2- base )-2,2,2- Trifluoroethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 54k : (S)-8-(2- Amine -6-((S)-1-(3',4'- Dimethyl -3-(3- methyl -1H- Pyrazole -1- base )-[1,1'- Biphenyl ]-4- base )-2,2,2- Trifluoroethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 54l : (R)-8-(2- Amine -6-((S)-1-(3',4'- Dimethyl -3-(3- methyl -1H- Pyrazole -1- base )-[1,1'- Biphenyl ]-4- base )-2,2,2- Trifluoroethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 54m : (R)-8-(2- Amine -6-((R)-1-(3',4'- Dimethyl -3-(3- methyl -1H- Pyrazole -1- base )-[1,1'- Biphenyl ]-4- base )-2,2,2- Trifluoroethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 55an : (S)-8-(2- Amine -6-((R)-2,2,2- Trifluoro -1-(3'- Methoxy -[1,1'- Biphenyl ]-4- base ) Ethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid table 17a. Instance 56 : (S)-8-(2- Amine -6-((R)-2,2,2- Trifluoro -1-(4-(1,2,3,4- Tetrahydroquinoxaline -6- base ) Phenyl ) Ethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 57 : (S)-8-(2- Amine -6-((R)-1-(3,4- Dihydroquinazoline -6- base )-2,2,2- Trifluoroethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 58 : (S)-8-(2- Amine -6-((R)-2,2,2- Trifluoro -1-(1,2,3,4- Tetrahydroquinazoline -6- base ) Ethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 59a : (S)-8-(2- Amine -6-((R)-1-(4- Bromophenyl )-2,2,2- Trifluoroethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 59b : (S)-8-(2- Amine -6-((R)-2,2,2- Trifluoro -1-( Naphthalene -2- base ) Ethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 59c : (S)-8-(2- Amine -6-((R)-2,2,2- Trifluoro -1-(4-(3- Fluoroquinoline -6- base )-2- Methyl phenyl ) Ethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 59d : (S)-8-(2- Amine -6-((R)-1-(2- Ethyl -4-(3- Fluoroquinoline -6- base ) Phenyl )-2,2,2- Trifluoroethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 60 : 9-(2- Amine -6-((R)-1-(4- chlorine -2-(3- methyl -1H- Pyrazole -1- base ) Phenyl )-2,2,2- Trifluoroethoxy ) Pyrimidine -4- base )-3,9- Diazo snail [5.5] Undecane -2- carboxylic acid Instance 61 : (S)-8-(2- Amine -6-((4-(3- methyl -1H- Carbazole -6- base ) Phenoxy ) methyl ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 62 : (S)-8-(2- Amine -6-((5- chlorine -3'-( Methanesulfonyl )-[1,1'- Biphenyl ]-2- base ) Methoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid Instance 63bd : (S)-8-(2- Amine -6-((R)-1-(3',4'- Dimethyl -3-(3- methyl -1H- Pyrazole -1- base )-[1,1'- Biphenyl ]-4- base )-2,2,2- Trifluoroethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- Ethyl carboxylate Instance 63kp : (S)-8-(2- Amine -6-((R)-2,2,2- Trifluoro -1-(3'-( Hydroxymethyl )-4'- methyl -3-(3- methyl -1H- Pyrazole -1- base )-[1,1'- Biphenyl ]-4- base ) Ethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- Ethyl carboxylate Instance 63i : (S)-8-(2- Amine -6-((R)-1-(5- chlorine -[1,1'- Biphenyl ]-2- base )-2,2,2- Trifluoroethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- Ethyl carboxylate To (S)-8-(2-Amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoro Ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylic acid-2-benzyl ester 3-ethyl ester (from step 3, example 34c, 315 mg , 0.43 mmol) TMS (0.13 mL, 0.9 mmol) was added to a solution in acetonitrile (300 mL). The reaction mixture was then allowed to warm to room temperature for a further 30-40 min then cooled to 0-5 <0>C and diethyl ether (0.5 mL) EtOAc. The reaction mixture was then allowed to warm to room temperature and then concentrated in vacuo. The title compound was obtained as a white solid.table 18a. Instance 64a : (S)-8-(2- Amine -6-((R)-1-(4- chlorine -2-(3- methyl -1H- Pyrazole -1- base ) Phenyl )-2,2,2- Trifluoroethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- Octyl carboxylic acid table 19a. Instance 65a : (S)-8-(2- Amine -6-((R)-1-(4- chlorine -2-(3- methyl -1H- Pyrazole -1- base ) Phenyl )-2,2,2- Trifluoroethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- Tert-butyl carboxylate table 20a. Instance 66a : (S)-8-(2- Amine -6-((R)-1-(4- chlorine -2-(3- methyl -1H- Pyrazole -1- base ) Phenyl )-2,2,2- Trifluoroethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- carboxylic acid 2-( Dimethylamino ) Ethyl ester table 21a. Instance 67a : (S)-8-(2- Amine -6-((R)-1-(3',4'- Dimethyl -3-(3- methyl -1H- Pyrazole -1- base )-[1,1'- Biphenyl ]-4- base )-2,2,2- Trifluoroethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- Isopropyl carboxylate table 22a. Instance 68a : (S)-8-(2- Amine -6-((R)-2,2,2- Trifluoro -1-(4'- Isopropoxy -3-(3- methyl -1H- Pyrazole -1- base )-[1,1'- Biphenyl ]-4- base ) Ethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- Isopropyl carboxylate table 23a. Instance 69a : (S)-8-(2- Amine -6-((R)-1-(5- chlorine -[1,1'- Biphenyl ]-2- base )-2,2,2- Trifluoroethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- Isopropyl carboxylate table 24a. Instance 70 : (S)-8-(2- Amine -6-((R)-1-(5- chlorine -3'-( Methanesulfonyl )-[1,1'- Biphenyl ]-2- base )-2,2,2- Trifluoroethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- Methyl carboxylate Instance 71 : (S)-8-(2- Amine -6-((R)-1-(5- chlorine -3'- Amine sulfonyl -[1,1'- Biphenyl ]-2- base )-2,2,2- Trifluoroethoxy ) Pyrimidine -4- base )-2,8- Diazo snail [4.5] Decane -3- Methyl carboxylate Other TPHl inhibitory compounds, prodrugs and dosage forms thereof suitable for use in accordance with the present invention include telotristat and its salts, including telotristat etiprate (LX1032). See, for example, U.S. Patent Publication No. 2008/0153852, No. 2009/0029993, No. 2009/0088447, No. 2010/0240906, No. 2012/0316171, No. 2013/0137635, No. 2013/0172376, No. 2013 /0303763 and PCT Publication Nos. WO 2010/065333 and WO 2014/082034.Instance A . Lack of methionine - choline ( MCD ) Diet NASH C57bl6 Mouse model This study was designed to investigate the effect of the compounds of the invention on a murine model of NASH C57bl6 mice on a MCD diet. The oral dose of 200 mg/kg of compound 63i (also known as the compound of Example 63i) induced a positive effect on plasma and liver lipids and liver function enzymes in a mouse model of NASH. The NASH model was induced by the consumption of MCD diet that impaired the VLDL assembly in C57bL6 mice, resulting in destruction of hepatic triglyceride secretion and continuous intrahepatic fat accumulation (Rizki G, et al, J Lipid Res. 2006; 2280-2290). MCD-fed mice were orally administered with 200 mg/kg of compound 63i once a day for 4 weeks. Treatment with Compound 63i significantly reversed the effects of serum lipids and hepatic triglyceride-fed MCD, returning the concentration back to the concentration observed in untreated, food-fed control mice. Compound 63i also significantly reduced alanine transaminase (ALT) and aspartate transaminase (AST) serum concentrations, indicating that TPHl inhibition improved liver function compared to MCD-fed vehicle control. The chemicals used in this study were: triton X-100 (Sigma - Cat #X100), cholesterol assay kit (Wako Diagnostics - Cat #439-17501), triglyceride assay kit (Wako Diagnostics - Cat #461 -08992 and Cat #461-09092), triglyceride standard (Wako Diagnostics - Cat #464-01601), alanine transaminase (ALT) assay (Cayman Chemical - Cat #700260), aspartate transamin Enzyme (AST) assay (Sigma - Cat #MAK055), phosphate buffered saline (Sigma - Cat #P3813), sucrose (Sigma - Cat #S7903), gum arabic (Sigma - Cat #G9752), oil red 0.5% propylene glycol (Polyscientific - Cat #s1848) and OCT compound (Tissue Tek - Cat #4583). The control diet was 18% protein in a irradiated rodent diet (Envigo #2918). The challenge diet is the MCD diet (Envigo #TD90262). An oral dose of 200 mg/kg of compound 63i (as the free base) was prepared in 0.5% methylcellulose vehicle prepared in water. The vehicle was added to the compound on the day of administration and the mixture was briefly subjected to ultrasonic treatment followed by mixing for about 20 minutes until a homogeneous suspension was obtained. The dose was administered by oral gavage at a dose of 10 mL/kg. The animals used for the study are described below. Male mice (n=10 per group) arrived at the facility at 28-30 g and were housed in cages on corn cobs. Animals were acclimated for 7-10 days prior to the start of the study. Mice were administered a single oral dose of vehicle (0.5% aqueous methylcellulose solution) or 200 mg/kg of compound 63i once daily for 4 weeks prior to the start of the dark cycle. During the dosing period, mice treated with vehicle and compound 63i were fed a normal diet or MCD diet. At week 4, blood samples were collected from the fed mice to measure cholesterol, triglycerides, alanine transaminase (ALT), and aspartate transaminase (AST) in the separated serum. After infusion of whole body in situ with 10 mL PBS, the mid-hepatic lobe was removed and fixed in 4% paraformaldehyde for histological measurements. Additional liver samples (100 mg) were snap frozen in liquid nitrogen to measure hepatic triglyceride. Blood Collection At week 4, mice were anesthetized with isoflurane administered with 2% oxygen by continuous inhalation. Whole blood samples (800 μL) were obtained by cardiac puncture and allowed to agglomerate for 30 minutes at room temperature. The serum was centrifuged at 7000 rpm for 20 minutes and stored at -80 ° C to measure cholesterol, triglyceride, alanine transaminase, and aspartate transaminase. Serum Cholesterol The cholesterol concentration was measured in serum using a colorimetric assay (Wako Diagnostics) according to the kit instructions. Briefly, 3 μL of each standard or sample was added to the well of a 96-well clear substrate. Standards were prepared by diluting a 200 mg/dL stock solution in water. The reaction was achieved by adding 300 μL of assay reagent and incubating at 37 ° C for 5 minutes. The absorbance was read at 600 nm using a spectrophotometer. Serum triglyceride Triglyceride concentration was measured in serum using a colorimetric assay (Wako Diagnostics) according to the kit instructions. Briefly, 4 μL of each standard or sample was added to the well of a 96-well clear substrate. Standards were prepared by diluting a 98 mg/dL stock solution in water. The reaction was achieved by adding 180 μL of the first assay reagent and incubating at 37 ° C for 5 minutes. The reaction was continued by the addition of 60 μL of the second assay reagent and incubation for an additional 5 minutes at 37 °C. The absorbance was read at 600 nm using a spectrophotometer. Serum alanine transaminase Serum was isolated as described above and liver function was assessed by measuring the concentration of alanine transaminase (ALT) in the serum using a colorimetric assay according to the kit instructions. Briefly, 20 μL of serum sample or standard was added to a clear bottom 96-well plate with 150 μL of matrix and 20 μL of cofactor. After the sample was incubated at 37 ° C for 15 minutes, the reaction was initiated by the addition of 20 μL of ALT initiator. The absorbance was read immediately at 340 nm using a spectrophotometer for 5 minutes per minute. Absorption rate change (ΔA₃₄₀ /min) Determine (a) by calculating the change in absorbance at 2 points on the linear portion of the curve, and ALT activity (U/mL) is calculated using the equation in (b): (a)b)Serum aspartate transaminase serum was isolated as described above and liver function was assessed by measuring the concentration of aspartate transaminase (AST) in serum using a colorimetric assay according to the kit instructions. Briefly, 5 μL of serum sample or standard was added to a clear bottom 96-well plate with 45 μL of AST assay buffer. Standards were prepared by diluting 1 mM glutamate stock solution in AST assay buffer. The reaction was achieved by adding 100 μL of a medium containing 80 μL of buffer + 2 μL of enzyme + 8 μL of developer + 10 μL of the substrate and incubating at 37 ° C for 3 minutes. Reading the initial absorption rate at 450 nm with a spectrophotometer [AST]_initial . Sample incubation was continued at 37 ° C and the absorbance was read at 450 nm every 5 minutes. When the value of the most active sample is greater than the highest standard, the reaction is completed [AST]_finally . For each sample, the glutamic acid concentration (nmoL) or Δ[AST] produced was determined as follows: [AST]_finally - [AST]_Start The AST activity (nmoL/min/mL) or the concentration of enzyme producing 1 μmol of glutamic acid per minute at 37 ° C is calculated as follows:Δ [ AST ] × Sample dilution factor (reaction time) × V where reaction time (minutes) = T_finally - T_Start V (mL) = volume added to the well. After collection of blood, the mice were sacrificed by anesthesia under anesthesia according to the guidelines for the Care and Use of Laboratory Animals, and the entire body was perfused with 10 mL of PBS. achieve. Liver sample in liquid N₂ It was rapidly frozen and stored at -80 °C until processing for triglyceride measurement. The mid-hepatic lobe was removed and fixed in 4% paraformaldehyde for 24 hours prior to treatment for histological measurements. Hepatic Triglyceride A frozen liver sample (50 mg) was transferred to a tube containing phosphate buffered saline containing 1 mm high impact zirconium beads (Benchmark Scientific) and 500 μL of 5% Triton X-100. Samples were homogenized on a Bead Bug microtube homogenizer (Benchmark Scientific) for 2 minutes until completely dissolved, and centrifuged at 13,000 rpm for 5 minutes at 4 °C. Samples were further diluted 1:4 in 5% Triton X-100 prior to assay. The liver triglyceride concentration was measured using a colorimetric assay (Wako Diagnostics) according to the kit instructions. Briefly, 4 μL of sample or standard was added to the well of a clear bottom 96-well plate. Standards were prepared by diluting a 98 mg/dL stock solution in 5% Triton X-100. The reaction was achieved by adding 180 μL of the first assay reagent and incubating at 37 ° C for 5 minutes. The reaction was continued by the addition of 60 μL of the second assay reagent and incubation for an additional 5 minutes at 37 °C. The absorbance was read at 600 nm using a spectrophotometer. Liver lipid deposition Prior to insertion into OCT compounds in cryostat chambers at -18 °C, randomly selected subgroups of formalin fixed liver tissue samples were incubated with 30% sucrose at 4 °C The gum arabic solution is infiltrated for 24-48 hours. Liver samples were cryosectioned at 10 μM and stained with 0.5% propylene glycol containing oil red O to assess lipid deposition. Statistical Analysis Analysis of variance (ANOVA) was used to test for significant differences between groups. Post-Bonferroni multiple comparative test analyses were used to determine significant differences in mean. All statistical analyses were performed using the Graph Pad Prism 5 software. The results are summarized in the following.table A1. Effect of Compound 63i on Serum Cholesterol and Triglyceride in Male C57bL6 Mice fed MCD Diet for 4 Weeks Four weeks after oral administration of 200 mg/kg of compound 63i, serum was separated from blood samples collected from MCD diet-fed C57bL6 mice. Cholesterol and triglyceride concentrations were quantified by colorimetric assay. A significant improvement in normality in serum cholesterol and serum triglyceride was observed in mice treated with compound 63i, relative to the significance of the MCD-fed vehicle control group, *P<0.05 and ****P< 0.0001.table A2. Effect of Compound 63i on Hepatic Triglyceride in Male C57bL6 Mice fed MCD Diet for 4 Weeks Four weeks after oral administration of 200 mg/kg of compound 63i, liver tissue samples were collected from MCD diet-fed C57bL6 mice. The triglyceride concentration was quantified by colorimetric examination. A non-significant improvement in normal liver triglycerides was observed in mice treated with compound 63i. **P < 0.01 was significant compared to the MCD feeding vehicle control group.table A3. Effect of Compound 63i on Serum Alanine Transaminase (ALT) in Male C57bL6 Mice fed MCD Diet for 4 Weeks Four weeks after oral administration of 200 mg/kg of compound 63i, serum was separated from blood samples collected from MCD diet-fed C57bL6 mice. The alanine transaminase (ALT) concentration was quantified by colorimetric assay.¹ ΔA₃₄₀ /min = (A₃₄₀ Time 1 - A₃₄₀ Time 2) / 5 minutes.² ALT activity = (ΔA₃₄₀ /min × 0.21 mL) / (4.11 mM^-1 × 0.02 mL). A significant improvement in normal serum ALT was observed in mice treated with compound 63i. ***P < 0.001 was significant compared to the MCD feeding vehicle control group.table A4. Effect of Compound 63i on Serum Aspartate Transaminase (AST) in Male C57bL6 Mice fed MCD Diet for 4 Weeks Four weeks after oral administration of 200 mg/kg of compound 63i, serum was separated from blood samples collected from MCD diet-fed C57bL6 mice. The AST concentration was quantified by colorimetric examination. AST activity = Δ [AST] / reaction time x sample volume. A significant improvement in normal serum AST was observed in mice treated with compound 63i. ***P<0.001 and ****P<0.0001 were significant compared to the MCD-fed vehicle control group. After 4 weeks of oral administration of 200 mg/kg of compound 63i (results not shown), a significant reduction in lipid deposition was observed in liver tissue collected from MCD-fed C57bL6 mice.Instance B . Using a high-fat diet NASH ApoE Mouse model of knockout mice This study was designed to investigate the effect of the compounds of the invention on a murine model of NASH ApoE knockout mice on a high fat diet. Compound 63i (also referred to as the compound of Example 63i) at an oral dose of 200 mg/kg induced a positive effect on liver pathophysiology in a murine model of NASH. The NASH model was induced by letting ApoE knockout mice eat a high-fat diet. Mice fed with high fat were orally administered with 200 mg/kg of compound 63i once a day for 8 weeks. Treatment with Compound 63i significantly reversed the effects of high lipids fed by liver lipid deposits and liver architecture compared to high fat fed vehicle controls. A significant reduction in serum serotonin was observed in mice treated with compound 63i without effect on serum cholesterol, triglycerides or glucose. The materials used in this study are described in the table below. The control diet was 18% protein in a irradiated rodent diet (Envigo #2918). The challenge diet is a high-fat diet with 1.25% cholesterol and 21% fat from coconut oil (Study Diet #D15100301). The test compound was the compound of Example 63i (also known as compound 63i). It is used as a free base. An oral dose of 200 mg/kg of Compound 63i was prepared in 0.5% methylcellulose prepared in water. The vehicle was added to the compound on the day of administration and the mixture was briefly subjected to ultrasonic treatment followed by mixing for about 20 minutes until a homogeneous suspension was obtained. The dose was administered by oral gavage at a dose of 10 mL/kg. The animals used in the study are described in the table below. Male mice (n=10 per group) arrived at the facility at 28-30 g and were housed in cages on corn cobs. Animals were acclimated for 7-10 days prior to the start of the study. The mice were administered a single oral dose of vehicle (0.5% aqueous methylcellulose solution) or 200 mg/kg of compound 63i once daily for 8 weeks prior to the start of the dark cycle. During the dosing period, mice treated with vehicle and compound 63i were fed a normal diet or a high fat diet containing 1.25% cholesterol and 21% fat from coconut oil. At week 8, blood samples were collected from the fed mice to measure serotonin, cholesterol, triglycerides, and glucose in the separated serum. After infusion of whole body in situ with 10 mL PBS, the mid-hepatic lobe was removed and fixed in 4% paraformaldehyde for histological measurements. Blood Collection At week 8, mice were anesthetized with isoflurane administered with 2% oxygen by continuous inhalation. Whole blood samples (800 μL) were obtained by cardiac puncture and allowed to agglomerate for 30 minutes at room temperature. Serum was separated by centrifugation at 7000 rpm for 20 minutes and stored at -80 °C to measure serotonin, cholesterol, triglyceride and glucose. Serum serotonin measurement Serum samples were extracted in trichloroacetic acid (TCA) homogenization buffer. Briefly, 100 μL of TCA buffer was added to 50 μL of serum in a 1.5 mL microcentrifuge tube. The sample was vortexed in buffer and centrifuged at 13,000 rpm for 30 minutes at 4 °C. The supernatant was carefully removed and transferred to a glass tube to measure serotonin using a fluorescence detector using the conditions described above. High Performance Liquid Chromatography (HPLC) Conditions HPLC homogenization buffer was prepared as follows: HPLC measurements were performed using a Perkin Elmer Flexar HPLC system equipped with a fluorescence detector and Brownlee (3 μm, 50 x 2.1 mm; Perkin Elmer) verified with an aqueous C18 column. The mobile phase used was 100 mM sodium acetate, pH 3.5. Detection is achieved at an excitation wavelength of 280 nm and an emission wavelength of 330 nm. Serum Cholesterol The cholesterol concentration was measured in serum using a colorimetric assay (Wako Diagnostics) according to the kit instructions. Briefly, 3 μL of each standard or sample was added to the well of a 96-well clear substrate. Standards were prepared by diluting a 200 mg/dL stock solution in water. The reaction was achieved by adding 300 μL of assay reagent and incubating at 37 ° C for 5 minutes. The absorbance was read at 600 nm using a spectrophotometer. Serum triglyceride Triglyceride concentration was measured in serum using a colorimetric assay (Wako Diagnostics) according to the kit instructions. Briefly, 4 μL of each standard or sample was added to the well of a 96-well clear substrate. Standards were prepared by diluting a 98 mg/dL stock solution in water. The reaction was achieved by adding 180 μL of the first assay reagent and incubating at 37 ° C for 5 minutes. The reaction was continued by the addition of 60 μL of the second assay reagent and incubation for an additional 5 minutes at 37 °C. The absorbance was read at 600 nm using a spectrophotometer. Serum Glucose Glucose oxidase concentration was measured in serum using a colorimetric assay (Cayman) according to the kit instructions. Briefly, 15 μL of each standard or sample was added to a well containing a 96-well clear bottom plate each containing 85 μL of assay buffer supplied by the supplier. Standards were prepared by diluting a 100 mg/dL stock solution in assay buffer. The reaction was achieved by adding 100 μL of enzyme reagent and incubating at 37 ° C for 10 minutes. The absorbance was read at 500-520 nm using a spectrophotometer. Liver Collection After blood collection, the mice were sacrificed by exsanguination under anesthesia according to the guidelines in the Guide for the Care and Use of Laboratory Animals, and the entire body perfusion was achieved with 10 mL of PBS. The mid-hepatic lobe was removed and fixed in 4% paraformaldehyde for 24 hours prior to treatment for histological measurements. Histological analysis Prior to embedding in OCT compounds in cryostat chambers at -18 °C, randomly selected subgroups of formalin-fixed liver tissue samples were treated with 30% sucrose + 1% gum arabic solution at 4 °C. Infiltrate for 24-48 hours. Liver samples were cryosectioned at 10 μM and stained with 0.5% propylene glycol containing oil red O to assess lipid deposition. A portion of the liver was treated, embedded in paraffin and sectioned at 5 μm to stain the Mallory Body, and the structure varied with the color change agent-aniline blue. Statistical Analysis Analysis of variance (ANOVA) was used to test for significant differences between groups. Post-Bonferroni multiple comparative test analyses were used to determine significant differences in mean. All statistical analyses were performed using the Graph Pad Prism 5 software. The results are summarized in the following.table B1. Effect of compound 63i on serum serotonin in male ApoE knockout mice fed high fat or 8 weeks diet Serum was isolated from blood samples collected from ApoE knockout mice after oral administration of 200 mg/kg of compound 63i simultaneously with high fat or diet for 8 weeks. Serotonin (5-HT) was measured by high performance liquid chromatography. A significant decrease in serum 5-HT was observed in mice treated with Compound 63i for both food and fat diets. The vehicle control group relative to high fat or food feeding was ****p<0.0001 and ††††p<0.0001 significant, respectively. Table B2.Compound 63i Correct Hey High fat or diet 8 Male of the week ApoE Effects of serum cholesterol, triglyceride and glucose in knockout mice Serum was isolated from blood samples collected from ApoE knockout mice after oral administration of 200 mg/kg of compound 63i simultaneously with high fat or diet for 8 weeks. Cholesterol, triglyceride and glucose concentrations were quantified by colorimetric assay. No significant changes in cholesterol, triglycerides or glucose were observed regardless of diet. After 8 weeks of oral administration of 200 mg/kg of compound 63i, lipid deposition was assessed in liver tissue collected from high fat fed ApoE knockout mice. Lipid deposits were expressed by dark red oil red O staining, which indicates a qualitative decrease in lipid deposition in fat-fed mice treated with compound 63i compared to vehicle treated mice. Eight weeks after oral administration of 200 mg/kg of compound 63i, an improvement in liver architecture was observed in liver tissue collected from high-fat-fed ApoE knockout mice. The increase in vacuoles near the main container and the collapse of structural integrity were demonstrated by the color change agent 2B-aniline blue staining in mice treated with vehicle compared to mice treated with 200 mg/kg compound 63i.Instance C . Lack of choline methionine ( MCD ) Or high fat diet NASH LDLr Mouse model of knockout mice This study was designed to investigate the effect of the compounds of the invention on a murine model of NASH LDLr knockout mice on a high fat diet. Compound 63i (also referred to as the compound of Example 63i) at an oral dose of 200 mg/kg induced a positive effect on liver pathophysiology in two mouse models of NASH. First, the NASH model was induced by letting the LDLr knockout mice eat the MCD diet that impaired the VLDL assembly, resulting in the destruction of hepatic triglyceride secretion and continuous intrahepatic fat accumulation (Rizki G., et al, J Lipid Res. 2006; 2280-2290). Second, the NASH model was induced by letting LDLr knockout mice consume a high-fat diet containing 1.25% cholesterol and 21% fat from coconut oil. MCD or fat-fed mice were orally administered with 200 mg/kg of compound 63i once daily for 3 weeks and 8 weeks, respectively. Treatment with Compound 63i significantly reversed the effects of high lipids fed by liver lipid deposits and liver architecture compared to high fat fed vehicle controls. A significant reduction in serum serotonin was observed in mice treated with compound 63i without effect on serum cholesterol, triglycerides or glucose. The chemicals used in this study are described below: The control diet was 18% protein in a irradiated rodent diet (Envigo #2918). The challenge diet was the MCD diet (Envigo #TD90262) and a high-fat diet with 1.25% cholesterol and 21% fat from coconut oil (Study Diet #D15100301). An oral dose of 200 mg/kg of compound 63i (free base) was prepared in 0.5% methylcellulose prepared in water. The vehicle was added to the compound on the day of administration and the mixture was briefly subjected to ultrasonic treatment followed by mixing for about 20 minutes until a homogeneous suspension was obtained. The dose was administered by oral gavage at a dose of 10 mL/kg. The animals used in the study are described in the table below. Male mice (n=10 per group) arrived at the facility at 28-30 g and were housed in cages on corn cobs. Animals were acclimated for 7-10 days prior to the start of the study. The mice were fed a MCD diet or a high-fat diet containing 1.25% cholesterol and 21% fat from coconut oil for 3 weeks and 8 weeks, respectively. At the time of diet, a single oral dose of vehicle (0.5% aqueous methylcellulose solution) or 200 mg/kg of compound 63i was administered to the mice once daily before the start of the dark cycle. At the end of the dosing period, blood samples are taken from the fed mice to measure serum serotonin from external contractors and measure serum cholesterol, triglycerides, glucose, alanine transaminase (ALT) or aspartame Acid transaminase (AST). After infusion of whole body in situ with 10 mL PBS, the mid-hepatic lobe was removed and fixed in 4% paraformaldehyde for histological measurements. Intestinal mucosa samples were collected for measurement of serotonin by high performance liquid chromatography. Blood Collection At the end of the dosing period, mice were anesthetized with isoflurane administered with 2% oxygen by continuous inhalation. Whole blood samples (1 mL) were obtained by cardiac puncture and allowed to agglomerate for 30 minutes at room temperature. Serum was measured by centrifugation at 6000 rpm for 20 minutes and 50 μL of sample at -80 °C to measure serotonin. The remaining serum was shipped to Charles River (Shrewsbury, Mass) to measure serum cholesterol, triglycerides, glucose, and liver function enzymes (ALT and AST). Serum serotonin measurement Serum samples were extracted in trichloroacetic acid (TCA) homogenization buffer. Briefly, 100 μL of TCA buffer was added to 50 μL of serum in a 1.5 mL microcentrifuge tube. The sample was vortexed in buffer and centrifuged at 13,000 rpm for 30 minutes at 4 °C. The supernatant was carefully removed and transferred to a glass tube to measure serotonin using a fluorescence detector using the conditions described above. High Performance Liquid Chromatography (HPLC) Conditions HPLC homogenization buffer was prepared according to the table below. HPLC measurements were performed using a Perkin Elmer Flexar HPLC system equipped with a fluorescence detector and Brownlee (3 μm, 50 x 2.1 mm; Perkin Elmer) verified with an aqueous C18 column. The mobile phase used was 100 mM sodium acetate, pH 3.5. Detection is achieved at an excitation wavelength of 280 nm and an emission wavelength of 330 nm. Intestinal Mucosal Collection After blood collection, the mice were sacrificed by exsanguination under anesthesia according to the guidelines in the Guide for the Care and Use of Laboratory Animals, and the whole body perfusion was achieved with 10 mL of PBS. The stomach is located approximately 6-8 cm from the intestine starting from the pyloric sphincter (duodenum) and the adjacent 6-8 cm (jejunum) is removed. The duodenum was discarded and the contents of the jejunum were rinsed with a needle attached to a 10 cc syringe filled with PBS. The longitudinal cut is then performed along one side of the flat open section on the microscope glass slide. The intestinal mucosa was scraped from the lumen surface using a second microscope slide and collected in a 2 mL flat bottom microcentrifuge tube. Approximately 50 mg of each sample was transferred to a second 2 mL flat-bottom microcentrifuge tube for extraction and serotonin measurements. Intestinal Mucosal Serotonin Measurements Intestinal mucosa samples were extracted in trichloroacetic acid (TCA) homogenization buffer. Briefly, 300 μL of TCA buffer was added to 50-75 mg of tissue in a 2 mL flat-bottom microcentrifuge tube. The tissue was homogenized in buffer and centrifuged at 13,000 rpm for 30 minutes at 4 °C. The supernatant was carefully removed and transferred to a glass tube to measure serotonin using a fluorescence detector using the conditions described above. After removing any residual supernatant from the fully self-organized centrifugation block, add 1200 μL of 5% sodium dodecyl sulfate buffer (SDS) prepared in 0.1 N sodium hydroxide (NaOH) to each before protein measurement. The tube was centrifuged and the sample was dissolved in an oven at 37 ° C overnight. Intestinal Mucosal Protein The intestinal mucosal protein concentration was measured in a digested mucosal tissue centrifugation block using a Pierce BCA Protein (Fisher) according to the kit instructions. Briefly, 5 μL of the sample was diluted in a clear bottom 96-well plate with 20 μL of 5% SDS buffer prepared in 0.1 N NaOH. Standards were prepared by diluting 2 mg/mL protein stock in 5% SDS buffer. The reaction was achieved by adding 200 μL of BCA protein reagent and incubating at 37 ° C for 30 minutes. The absorbance was read at 562 nm using a spectrophotometer. Liver Collection After blood collection, the mice were sacrificed by exsanguination under anesthesia according to the guidelines in the Guide for the Care and Use of Laboratory Animals, and the entire body perfusion was achieved with 10 mL of PBS. The mid-hepatic lobe was removed and fixed in 4% paraformaldehyde for 24 hours prior to treatment for histological measurements. Histological analysis Prior to embedding in OCT compounds in cryostat chambers at -18 °C, randomly selected subgroups of formalin-fixed liver tissue samples were treated with 30% sucrose + 1% gum arabic solution at 4 °C. Infiltrate for 24-48 hours. Liver samples were cryosectioned at 10 μM and stained with 0.5% propylene glycol containing oil red O to assess lipid deposition. Statistical Analysis Analysis of variance (ANOVA) was used to test for significant differences between groups. Post-Bonferroni multiple comparative test analyses were used to determine significant differences in mean. All statistical analyses were performed using the Graph Pad Prism 5 software. The results are summarized in the following. Table C1.Compound 63i Correct Hey MCD Male diet or high fat diet LDLr Effect of serum serotonin in knockout mice Serum was isolated from blood samples from LDLr knockout mice by oral administration of 200 mg/kg compound 63i at the same time as MCD diet or high fat diet for 3 and 8 weeks, respectively. Serotonin (5-HT) was measured by high performance liquid chromatography. A significant decrease in serum 5-HT was observed in mice treated with compound 63i regardless of diet. The vehicle control group fed with high fat or MCD was ****p<0.0001 and ††††p<0.0001 significant, respectively. Table B2.Compound 63i Correct Hey MCD Male diet or high fat diet LDLr Effect of mucosal serotonin in knockout mice Serotonin (5-HT) was measured in the intestinal mucosa of LDLr knockout mice by oral administration of 200 mg/kg compound 63i at 3 and 8 weeks after feeding MCD diet or high fat diet, respectively. 5-HT was measured by high performance liquid chromatography. A significant reduction in 5-HT of the intestinal mucosa was observed in mice treated with compound 63i regardless of diet. The vehicle control group fed with high fat or MCD was ****p<0.0001 and ††††p<0.0001 significant, respectively.table C3. Effect of Compound 63i on Serum Cholesterol, Triglyceride and Glucose in Male LDLr Knockout Mice Feeded on MCD Diet or High Fat Diet Serum was isolated from blood samples from LDLr knockout mice by oral administration of 200 mg/kg compound 63i at the same time as MCD diet or high fat diet for 3 and 8 weeks, respectively. Samples were shipped overnight to Charles River Laboratories (Shrewsbury, Mass) to measure cholesterol, triglyceride and glucose concentrations. The vehicle control group fed with high fat or MCD was **p<0.01 and †p<0.05 significant, respectively.table C4. Effects of Compound 63i on Liver Function Enzymes Alanine Transaminase (ALT) and Aspartate Transaminase (AST) in Male LDLr-killed Mice fed MCD Diet or High-fat Diet Serum was isolated from blood samples from LDLr knockout mice by oral administration of 200 mg/kg compound 63i at the same time as MCD diet or high fat diet for 3 and 8 weeks, respectively. Samples were shipped overnight to Charles River Laboratories (Shrewsbury, Mass) to measure liver function enzymes ALT and AST. After 3 weeks of oral administration of 200 mg/kg of compound 63i, lipid deposition was assessed in liver tissue collected from MCD diet-fed LDLr knockout mice. Lipid deposits were expressed by dark red oil red O staining, which showed a qualitative decrease in lipid deposition in MCD diet-fed mice treated with compound 63i compared to vehicle treated mice. After 8 weeks of oral administration of 200 mg/kg of compound 63i, lipid deposition was assessed in liver tissue collected from high fat fed LDLr knockout mice. Lipid deposits were expressed by dark red oil red O staining, which indicates a qualitative decrease in lipid deposition in fat-fed mice treated with compound 63i compared to vehicle treated mice. Various modifications of the invention in addition to those described herein will be apparent to those skilled in the art. Such modifications are also intended to fall within the scope of the appended claims. Each of the references (including all patents, patent applications, and publications) cited in the present application is hereby incorporated by reference.

Claims

A method for treating or preventing a disease in a patient, wherein the disease is nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatosis hepatitis (NASH) or hepatocellular carcinoma, the method comprising administering to the patient a therapeutically effective amount TPH1 inhibitor or a prodrug thereof.

The method of claim 1, wherein the disease is NAFLD.

The method of claim 1, wherein the disease is NASH.

The method of claim 1, wherein the disease is hepatocellular carcinoma.

A method of reducing serum or liver concentration of alanine transaminase (ALT), aspartate transaminase (AST), cholesterol, triglyceride or glucose in a patient, the method comprising administering to the patient An effective amount of a TPH1 inhibitor or a prodrug thereof.

A method of reducing lipid deposits in a patient's liver, the method comprising administering to the patient a therapeutically effective amount of a TPHl inhibitor or a prodrug thereof.

A method of treating or preventing one or more diseases or conditions associated with nonalcoholic fatty liver disease (NAFLD), NASH or hepatocellular carcinoma, the one or more diseases or conditions being selected from the group consisting of inflammation, fibrosis, cirrhosis, Fatigue, weight loss, weakness, fluid retention, muscle atrophy, intestinal bleeding, liver failure, weight gain, obesity, diabetes, pre-diabetes, lipid disorders, elevated serum lipids, elevated cholesterol, and elevated triglycerides The method comprises administering to the patient a therapeutically effective amount of a TPHl inhibitor or a prodrug thereof.

The method of any one of claims 1 to 7, wherein the TPH1 inhibitor or a prodrug thereof is a compound of formula I: I or a pharmaceutically acceptable salt thereof, wherein: Ring A is C ₃ _- ₁₀ cycloalkyl, C ₆ _- ₁₀ aryl, 4-10 heterocycloalkyl or 5 to 10 membered heteroaryl; L is O or NR ^4; W is N or CR ^5; X is N or CR ^6; Y is N or CR ^7; wherein X and Y is one of only N; R ¹ is H, C ₁ _- ₁₀ alkyl, C ₃ _- ₁₀ cycloalkyl, ^{^{phenyl, - (CR 8 R 9)}} p OC (O) R 10, - (CR 8 R 9) p NR 11 R 12 or ^{^{_{- (CR 8 R 9) p}}} C (O ) NR ¹¹ R ^12, wherein the C ₁ _- ₁₀ alkyl, C ₃ _- ₁₀ cycloalkyl, and phenyl are each optionally substituted with 1,2,3,4 or 5 substituents independently selected from the substituents: F , Cl, Br, CN, C 1 - 4 alkyl and C ₁ _- ₄ halo alkyl; R ² and R ³ are each independently selected from H, C ₁ _- ₄ alkyl and C ₁ _- ₄ halo alkyl; R ^is H or C ₁ _- ₄ alkyl group; R ⁵ and R ⁶ are each independently selected from H, halo and C ₁ _- ₄ alkyl; R ⁷ is H, C ₁ _- ₄ alkyl, C ₂ _- ₆ alkenyl group, C ₃ _- ₁₀ cycloalkyl, C ₃ _- ₁₀ cycloalkyl, -C ₁ _- ₄ alkyl, C ₆ _- ₁₀ aryl group, C ₆ _- ₁₀ aryl group -C ₁ _- ₄ alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl) -C ₁ _- ₄ alkyl, 5-10 membered heteroaryl, (5-10 membered heteroaryl) -C ₁ _- ₄ alkyl, NR ¹³ R ¹⁴ ^{OR 15, C (O) R} 16, S (O) q R 17, wherein the C ₁ _- ₄ alkyl, C ₂ _- ₆ alkenyl, C ₃ _- ₁₀ cycloalkyl, C ₃ _- ₁₀ cycloalkyl - C ₁ _- ₄ alkyl, C ₆ _- ₁₀ aryl group, C ₆ _- ₁₀ aryl group -C ₁ _- ₄ alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl) -C ₁ _{_--4} alkyl, 5-10 membered heteroaryl and (5-10 membered heteroaryl) -C ₁ _- ₄ alkyl each optionally substituted with 1, 2 or 3 substituents selected from the substituent group: halo, C ₁ _- ₄ alkyl, C ₂ _- ₆ alkenyl, amino, C ₁ _- ₄ alkylamino, C ₂ _- ₈ dialkylamino, hydroxy and C ₁ _- ₄ alkoxy group; R ⁸ and R ⁹ are each is independently selected from H and C ₁ _- ₄ alkyl; R ¹⁰ is a C ₁ _- ₆ alkyl, optionally substituted with 1, 2 or 3 substituents independently selected from the substituents: C ₁ _- ₆ haloalkyl, C ₃ _- ₁₀ cycloalkyl, oR ^a and NR ^c R ^d; R ¹¹ and R ¹² are each independently selected from H and C ₁ _- ₆ alkyl group; R ¹³ is H or C _{_₁₄} alkyl; R ¹⁴ is H, C ₁ _- ₄ alkyl, C ₃ _- ₇ cycloalkyl, C ₃ _- ₇ cycloalkyl, -C ₁ _- ₄ alkyl, C ₆ _- ₁₀ aryl group, C ₆ _- ₁₀ aryl group -C ₁ _- ₄ alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl) -C ₁ _- ₄ alkyl, 5-10 membered heteroaryl, or (5-10 membered heteroaryl) -C ₁ _- ₄ alkyl, C(O)R ^{^{b1, C (O) OR a1}} , C (O) NR c1 R d1, S (O) R b1, S (O) 2 R b1 , or _{^{S (O) 2 NR c1 R}} d1, wherein the C ₁ _- ₄ alkoxy group, C ₃ _- ₇ cycloalkyl, C ₃ _- ₇ cycloalkyl, -C ₁ _- ₄ alkyl, C ₆ _- ₁₀ aryl group, C ₆ _- ₁₀ aryl group -C ₁ _- ₄ alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl) -C ₁ _- ₄ alkyl, 5-10 membered heteroaryl and (5-10 membered heteroaryl) -C ₁ _- ₄ alkyl each optionally 1, 2 or 3 substituents independently selected from the substituents: halo, C ₁ _- ₄ alkyl, C ₁ _- ₄ _{^{haloalkyl, CN, NO 2, oR a1}} , SR a1, C (O) R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 , OC(O)R ^b1 , OC(O)NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 C(O)R ^b1 , NR ^C1 C(O)OR ^a1 , NR ^c1 C(O)NR ^c1 R ^d1 , NR ^c1 S(O)R ^b1 , NR ^c1 S(O) ₂ R ^b1 , NR ^c1 S(O) ₂ NR ^c1 R ^d1 , S(O)R ^b1 , S(O)NR ^c1 R ^d1 , S(O) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 ; or R ¹³ and R ¹⁴ together with the N atom to which they are attached form 4, 5, 6 or 7 membered heterocycloalkyl substituted by 1, 2 or 3 substituents independently selected from C ₁ _- ₆ alkyl, C ₃ _- ₇ cycloalkyl, 4 7 heterocycloalkyl, C ₆ _- ₁₀ aryl, 5-6 membered heteroaryl, halo ^{^{, CN, OR a1, SR a1}} , C (O) R b1, C (O) NR c1 R d1, C (O) OR a1, OC (O) R b1, OC (O) NR c1 R d1, NR c1 R ^d1 , NR ^c1 C(O)R ^b1 , NR ^c1 C(O)NR ^c1 R ^d1 , NR ^c1 C(O)OR ^a1 , S(O)R ^b1 , S(O)NR ^c1 R ^d1 , S( O) ₂ R ^b1 , NR ^c1 S(O) ₂ R ^b1 , NR ^c1 S(O) ₂ NR ^c1 R ^d1 and S(O) ₂ NR ^c1 R ^d1 , wherein the C ₁ _- ₆ alkyl group, C ₃ _- _{The 7} cycloalkyl, 4-7 membered heterocycloalkyl, C ₆ _- ₁₀ aryl and 5-6 membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo , CN, OR ^a1 , SR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 , OC(O)R ^b1 , OC(O)NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 C(O)R ^b1 , NR ^c1 C(O)NR ^c1 R ^d1 , NR ^c1 C(O)OR ^a1 , S(O)R ^b1 , S(O)NR ^c1 R ^d1 , S( _{^{^{O) 2 R b1, NR c1}}} S (O) 2 R b1, NR c1 S (O) 2 NR c1 R d1 and _{^{S (O) 2 NR c1 R}} d1; R 15 is H, C ₁ _- ₄ alkyl, C ₃ _- ₇ cycloalkyl, C ₃ _- ₇ cycloalkyl, -C ₁ _- ₄ alkyl, C ₆ _- ₁₀ aryl group, C ₆ _- ₁₀ aryl group -C ₁ _- ₄ alkyl, 4-10 membered heterocyclic ring alkyl, (4-10 membered heterocycloalkyl) -C ₁ _- ₄ alkyl, 5-10 membered heteroaryl, or (5-10 membered heteroaryl) -C ₁ _- ₄ alkyl, which The C ₁ _- ₄ alkyl, C ₃ _- ₇ cycloalkyl, C ₃ _- ₇ cycloalkyl, -C ₁ _- ₄ alkyl, C ₆ _- ₁₀ aryl group, C ₆ _- ₁₀ aryl group -C ₁ _- ₄ alkyl groups, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl) -C ₁ _- ₄ alkyl, 5-10 membered heteroaryl and (5-10 membered heteroaryl) -C ₁ _- ₄ alkyl each optionally substituted with 1, 2 or 3 substituents independently selected from the substituents: halo, C ₃ _- ₇ cycloalkyl, 4-7 membered heterocycloalkyl, C ₆ _- ₁₀ aryl group, 5-6 member heteroaryl, CN, OR ^a1 , SR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 , OC(O)R ^b1 , OC(O) NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 C(O)R ^b1 , NR ^c1 C(O)NR ^c1 R ^d1 , NR ^c1 C(O)OR ^a1 , S(O)R ^b1 , S(O) NR ^c1 R ^d1 , S(O) ₂ R ^b1 , NR ^c1 S(O) ₂ R ^b1 , NR ^c1 S(O) ₂ NR ^c1 R ^d1 and S(O) ₂ NR ^c1 R ^d1 ; R ¹⁶ is C ₁ _{_--4} alkyl, or NR ^18a R ^18b, wherein the C ₁ _- ₄ alkyl optionally substituted with 1, 2 or 3 substituents independently selected from the substituents: halo, C ₃ _- ₇ cycloalkyl, 4- 7-membered heterocycloalkyl, C ₆ _- ₁₀ aryl, 5-6 membered heteroaryl, CN, OR ^a1 , SR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O) OR ^a1 , OC(O)R ^b1 , OC(O)NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^C1 C(O)R ^b1 , NR ^c1 C(O)NR ^c1 R ^d1 , NR ^c1 C(O)OR ^a1 , S(O)R ^b1 , S(O)NR ^c1 R ^d1 , S(O) ₂ R ^{^{b1, NR c1 S (O)}} 2 R b1, NR c1 S (O) 2 NR c1 R d1 and _{^{S (O) 2 NR c1 R}} d1; R 17 is C ₁ _- ₄ alkyl, NR ^18a R ^18b, or oR ^18c, wherein the C ₁ _- ₄ alkyl optionally substituted with 1, 2 or 3 substituents independently selected from the substituents: halo, C ₃ _- ₇ cycloalkyl, 4-7 membered heterocycloalkyl, C ₆ _- ₁₀ aryl, 5-6 membered heteroaryl, CN, OR ^a1 , SR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 , OC(O)R ^B1 , OC(O)NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 C(O)R ^b1 , NR ^c1 C(O)NR ^c1 R ^d1 , NR ^c1 C(O)OR ^a1 , S(O)R ^B1 , S(O)NR ^c1 R ^d1 , S(O) ₂ R ^b1 , NR ^c1 S(O) ₂ R ^b1 , NR ^c1 S(O) ₂ NR ^c1 R ^d1 and S(O) ₂ NR ^c1 R ^d1 ; R ^18a and R ^18b are each independently selected from H and C ₁ _- ₄ alkyl, wherein the C ₁ _- ₄ alkyl optionally substituted with 1, 2 or 3 substituents independently selected from the substituents: halo, C ₃ _- ₇ cycloalkyl, 4-7 membered heterocycloalkyl, C ₆ _- ₁₀ aryl, 5-6 membered ^{^{heteroaryl, CN, OR a1, SR a1}} , C (O) R b1, C (O )NR ^c1 R ^d1 , C(O)OR ^a1 , OC(O)R ^b1 , OC(O)NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 C(O)R ^b1 , NR ^c1 C(O)NR ^c1 R ^d1 , NR ^c4 C(O)OR ^a1 , S(O)R ^b1 , S(O)NR ^c1 R ^d1 , S(O) ₂ R ^b1 , NR ^c1 S(O) ₂ R ^b1 , NR ^c1 S(O) ₂ NR ^c1 R ^d1 and S(O) ₂ NR ^c1 R ^d1 ; or R ^18a and R ^18b together with The N atom to be bonded forms a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 substituents selected from C ₁ _- ₆ alkyl, C ₃ _- ₇ cycloalkyl, 4-7 membered heterocycloalkyl, C ₆ _- ₁₀ aryl, 5-6 membered heteroaryl, halo, CN, OR ^a1 , SR ^a1 , C(O)R ^b1 , C(O ) NR ^c1 R ^d1 , C(O)OR ^a1 , OC(O)R ^b1 , OC(O)NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 C(O)R ^b1 , NR ^c1 C(O)NR ^C1 R ^d1 , NR ^c1 C(O)OR ^a1 , S(O)R ^b1 , S(O)NR ^c1 R ^d1 , S(O) ₂ R ^b1 , NR ^c1 S(O) ₂ R ^b1 , NR ^c1 S (O) ₂ NR ^c1 R ^d1 and _{^{S (O) 2 NR c1 R}} d1, wherein the C ₁ _- ₆ alkyl, C ₃ _- ₇ cycloalkyl, 4-7 membered heterocycloalkyl, C ₆ _- ₁₀ aryl And 5-6 membered heteroaryl groups are each substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, CN, OR ^a1 , SR ^a1 , C(O)R ^b1 , C(O )NR ^c1 R ^d1 , C(O)OR ^a1 , OC(O)R ^b1 , OC(O)NR ^C1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 C(O)R ^b1 , NR ^c1 C(O)NR ^c1 R ^d1 , NR ^c1 C(O)OR ^a1 , S(O)R ^b1 , S(O)NR ^C1 R ^d1 , S(O) ₂ R ^b1 , NR ^c1 S(O) ₂ R ^b1 , NR ^c1 S(O) ₂ NR ^c1 R ^d1 and S(O) ₂ NR ^c1 R ^d1 ; R ^18c is H, C _{_{_1--6}} alkyl, C ₃ _- ₁₀ cycloalkyl, C ₃ _- ₇ cycloalkyl, -C ₁ _- ₄ alkyl, C ₆ _- ₁₀ aryl group, C ₆ _- ₁₀ aryl group -C ₁ _- ₄ alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl) -C ₁ _- ₄ alkyl, 5-10 membered heteroaryl, or (5-10 membered heteroaryl) -C ₁ _- ₄ alkyl group, wherein the C ₁ _- ₆ alkyl, C ₃ _- ₇ cycloalkyl, C ₃ _- ₁₀ cycloalkyl, -C ₁ _- ₄ alkyl, C ₆ _- ₁₀ aryl group, C ₆ _- ₁₀ aryl -C ₁ _- _C4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl) -C ₁ _- ₄ alkyl, 5-10 membered heteroaryl and (5-10 membered heteroaryl) - C ₁ _- ₄ alkyl each optionally substituted with 1, 2 or 3 substituents independently selected from the substituents: halo, C ₁ _- ₄ alkyl, C ₁ _- ₄ haloalkyl, CN, NO _2, oR ^A1 , SR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 , OC(O)R ^b1 , OC(O)NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^C1 C(O)R ^b1 , NR ^c1 C(O)OR ^a1 , NR ^c1 C(O)NR ^c1 R ^d1 , NR ^c1 S(O)R ^b1 , NR ^c1 S(O) ₂ R ^b1 , NR ^c1 S(O) ₂ NR ^c1 R ^d1 , S(O)R ^b1 , S(O)NR ^c1 R ^d1 , S(O) ₂ R ^b1 and S(O) ₂ NR ^C1 R ^d1 ; R ^A is H, Cy ¹ , halo, C ₁ _- ₆ alkyl, C ₂ _- ₆ alkenyl, CN, NO ₂ , OR ^a2 , SR ^a2 , C(O)R ^b2 , C(O )NR ^c2 R ^d2 , C(O)OR ^a2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^A2 , NR ^c2 C(O)NR ^c2 R ^d2 , NR ^c2 S(O)R ^b2 , NR ^c2 S(O) ₂ R ^b2 , NR ^c2 S(O) ₂ NR ^c2 R ^d2 , S(O)R ^b2 , S(O)NR ^c2 R ^d2 , S(O) ₂ R ^b2 or S(O) ₂ NR ^c2 R ^d2 , wherein the C ₁ _- ₆ alkyl group and the C ₂ _- ₆ alkenyl group are respectively 1, 2 as the case may be. , 3, 4 or 5 substituents independently selected from the group consisting of Cy ¹ , halo, C ₁ _- ₆ alkyl, C ₂ _- ₆ alkenyl, C ₁ _- ₆ haloalkyl, CN, NO ₂ , OR ^a2 , SR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 , NR ^c2 C(O)NR ^c2 R ^d2 , NR ^c2 S(O)R ^b2 , NR ^c2 S(O) ₂ R ^b2 , NR ^c2 S(O) ₂ NR ^c2 R ^d2 , S(O)R ^b2 , S(O)NR ^c2 R ^d2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 ; R ^B is H, Cy ² , halogen , C ₁ _- ₆ alkyl, C ₂ _- ₆ alkenyl, C ₁ _- ₆ haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C (O)NR ^c3 R ^d3 , NR ^c3 S(O)R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S(O) NR ^c3 R ^d3 , S(O) ₂ R ^b3 or S(O) ₂ NR ^c3 R ^d3 , wherein the C ₁ _- ₆ alkyl group and the C ₂ _- ₆ alkenyl group are each 1, 2, 3, 4 or Substituted by five substituents independently selected from the group consisting of Cy ² , halo, C ₁ _- ₆ alkyl, C ₂ _- ₆ alkenyl, C ₁ _- ₆ haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , NR ^c3 S(O)R ^b3 , NR ^c1 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 ; R ^C and R ^D are each independently selected from: H, halo, C ₁ _- ₆ alkyl, C ₂ _- ₆ alkenyl, C ₁ _- ₆ haloalkyl, CN, NO ₂ , OR ^a4 , SR ^a4 , C(O) R ^b4 , C(O)NR ^c4 R ^d4 , C(O)OR ^a4 , OC(O)R ^b4 , OC(O)NR ^c4 R ^d4 , NR ^c4 R ^d4 , NR ^c4 C(O)R ^b4 , NR ^{^{c4 C (O) OR a4,}} NR c4 C (O) NR c4 R d4, NR c4 S (O) R b4, NR c4 S (O) 2 R b4, NR c4 S (O) 2 NR c4 R d4, S(O)R ^b4 , S(O)NR ^c4 R ^d4 , S(O) ₂ R ^b4 and S(O) ₂ NR ^c4 R ^d4 ; wherein the C ₁ _- ₆ alkyl group and the C ₂ _- ₆ alkenyl group are each optionally substituted with 4 or 5 substituents independently selected from the substituents: C ₆ _- ₁₀ aryl, C ₃ _- ₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, C ₁ _- ₆ alkyl, C ₂ _- ₆ alkenyl, C ₁ _- ₆ _{^{haloalkyl, CN, NO 2, OR a4}} , SR a4, C (O) R b4, C ( O) NR ^c4 R ^d4 , C(O)OR ^a4 , OC(O)R ^b4 , OC(O)NR ^c4 R ^d4 , NR ^c4 R ^d4 , NR ^c4 C(O)R ^b4 , NR ^c4 C(O) OR ^a4 , NR ^c4 C(O)NR ^c4 R ^d4 , NR ^c4 S(O)R ^b4 , NR ^c4 S(O) ₂ R ^b4 , NR ^c4 S(O) ₂ NR ^c4 R ^d4 , S(O)R ^B4 , S(O)NR ^c4 R ^d4 , S(O) ₂ R ^b4 and S(O) ₂ NR ^c4 R ^d4 ; Cy ¹ and Cy ² are each independently selected from: C ₆ _- ₁₀ aryl, C ₃ _- ₁₀ cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl, each of which is 1, 2, 3, 4 or 5, as appropriate R ^Cy is independently selected from the substituents; R ^Cy each independently selected from: halo, C ₁ _- ₆ alkyl, C ₁ _- ₆ haloalkyl, C ₂ _- ₆ alkenyl, C ₆ _- ₁₀ aryl , C ₃ _- ₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered _{^{heterocycloalkyl, CN, NO 2, OR a5}} , SR a5, C (O) R b5, C (O) NR c5 R ^d5 , C(O)OR ^a5 , OC(O)R ^b5 , OC(O)NR ^c5 R ^d5 , NR ^c5 R ^d5 , NR ^c5 C(O)R ^b5 , NR ^c5 C(O)OR ^a5 , NR ^C5 C(O)NR ^c5 R ^d5 , NR ^c5 S(O)R ^b5 , NR ^c5 S(O) ₂ R ^b5 , NR ^c5 S(O) ₂ NR ^c5 R ^d5 , S(O)R ^b5 , S( O) NR ^c5 R ^d5 , S(O) ₂ R ^b5 and S(O) ₂ NR ^c5 R ^d5 , wherein the C ₁ _- ₆ alkyl group, C ₂ _- ₆ alkenyl C ₆ _- ₁₀ aryl group, C ₃ _- _{The 10} cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of halo, C ₁ _- ₆ alkyl, CN, NO ₂ , OR ^a5 , SR ^a5 , C(O)R ^b5 , C(O)NR ^c5 R ^d5 , C(O)OR ^a5 , OC(O)R ^b5 , OC(O) NR ^c5 R ^d5 , NR ^c5 R ^d5 , NR ^c5 C(O)R ^b5 , NR ^c5 C(O)OR ^a5 , NR ^c5 C(O)NR ^c5 R ^d5 , NR ^c5 S(O)R ^b5 , NR ^c5 S(O) ₂ R ^b5 , NR ^c5 S(O) ₂ NR ^c5 R ^d5 , S(O)R ^b5 , S(O)NR ^C5 R ^d5 , S(O) ₂ R ^b5 and S(O) ₂ NR ^c5 R ^d5 ; each R ^a , R ^a1 , R ^a2 , R ^a3 , R ^a4 and R ^{a5 are} independently selected from: H, C ₁ _- ₆ alkyl, C ₁ _- ₄ haloalkyl, C ₂ _- ₆ alkenyl, C ₆ _- ₁₀ aryl, C ₃ _- ₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl , C ₆ _- ₁₀ aryl group -C ₁ _- ₄ alkyl, C ₃ _- ₁₀ cycloalkyl, -C ₁ _- ₄ alkyl, (5-10 membered heteroaryl) -C ₁ _- ₄ alkyl or (4- 10 heterocycloalkyl) -C ₁ _- ₄ alkyl, wherein the C ₁ _- ₆ alkyl, C ₂ _- ₆ alkenyl, C ₆ _- ₁₀ aryl, C ₃ _- ₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C ₆ _- ₁₀ aryl group -C ₁ _- ₄ alkyl, C ₃ _- ₁₀ cycloalkyl, -C ₁ _- ₄ alkyl, (5-10 membered heteroaryl ) -C ₁ _- ₄ alkyl, and (4-10 membered heterocycloalkyl) -C ₁ _- ₄ alkyl each optionally substituted 3, 4 or 5 substituents independently selected from the substituents: C ₁ _- ₄ alkyl, ^{halo, CN, OR a6, C (} O) R b6, C (O) NR c6 R d6, C (O) OR a6, OC (O) R b6, OC (O) NR ^C6 R ^d6 , NR ^c6 R ^d6 , NR ^c6 C(O)R ^b6 , NR ^c6 C(O)NR ^c6 R ^d6 , NR ^c6 C(O)OR ^a6 , S(O)R ^b6 , S(O)NR ^C6 R ^d6 , S(O) ₂ R ^b6 , NR ^c6 S(O) ₂ R ^b6 , NR ^c6 S(O) ₂ NR ^c6 R ^d6 and S(O) ₂ NR ^c6 R ^d6 ; each R ^b1 , R ^b2 , R ^b3 , R ^b4 and R ^{b5 are} independently selected from: H, C ₁ _- ₆ alkyl, C ₁ _- ₄ haloalkyl, C ₂ _- ₆ alkenyl, C ₆ _- ₁₀ aryl, C ₃ _- ₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C ₆ _- ₁₀ aryl group -C ₁ _- ₄ alkyl, C ₃ _- ₁₀ cycloalkyl -C ₁ _- ₄ alkyl, (5-10 membered heteroaryl) -C ₁ _- ₄ alkyl or (4-10 membered heterocycloalkyl) -C ₁ _- ₄ alkyl, wherein the C ₁ _- ₆ alkyl, C ₂ _- ₆ alkenyl, C ₆ _- ₁₀ aryl, C ₃ _- ₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C ₆ _- ₁₀ aryl -C ₁ _- ₄ alkyl, C ₃ _- ₁₀ cycloalkyl, -C ₁ _- ₄ alkyl, (5-10 membered heteroaryl) -C ₁ _- ₄ alkyl, and (4-10 membered heterocycloalkyl) -C ₁ _- ₄ alkyl each optionally substituted 3, 4 or 5 substituents independently selected from the substituents: C ₁ _- ₄ alkyl, ^{halo, CN, oR a6, C (} O) R ^b6 , C(O)NR ^c6 R ^d6 , C(O)OR ^a6 , OC(O)R ^b6 , OC(O)NR ^c6 R ^d6 , NR ^c6 R ^d6 , NR ^c6 C(O)R ^b6 , NR ^C6 C(O)NR ^c6 R ^d6 , NR ^c6 C(O)OR ^a6 , S(O)R ^b6 , S(O)NR ^c6 R ^d6 , S(O) ₂ R ^b6 , NR ^c6 S(O) ₂ R ^b6 , NR ^c6 S(O) ₂ NR ^c6 R ^d6 and S(O) ₂ NR ^c6 R ^d6 ; each R ^c , R ^d , R ^C1 , R ^d1 , R ^c2 , R ^d2 , R ^c3 , R ^d3 , R ^c4 , R ^d4 , R ^c5 and R ^{d5 are} independently selected from the group consisting of: H, C ₁ _- ₆ alkyl, C ₁ _- ₄ haloalkyl, C ₂ _- ₆ alkenyl, C ₆ _- ₁₀ aryl, C ₃ _- ₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C ₆ _- ₁₀ aryl group -C ₁ _- ₄ alkyl group, C ₃ _- ₁₀ cycloalkyl, -C ₁ _- ₄ alkyl, (5-10 membered heteroaryl) -C ₁ _- ₄ alkyl or (4-10 membered heterocycloalkyl) -C ₁ _- ₄ alkyl, wherein the C ₁ _- ₆ alkyl, C ₂ _- ₆ alkenyl, C ₆ _- ₁₀ aryl, C ₃ _- ₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl , C ₆ _- ₁₀ aryl group -C ₁ _- ₄ alkyl, C ₃ _- ₁₀ cycloalkyl, -C ₁ _- ₄ alkyl, (5-10 membered heteroaryl) -C ₁ _- ₄ alkyl and (4- 10 heterocycloalkyl) -C ₁ _- each optionally substituted, 4 or 5 substituents selected from the group ₄ are independently: C ₁ _- ₄ alkyl, halo, CN, OR ^a6 , SR ^a6 , C(O)R ^b6 , C(O)NR ^c6 R ^d6 , C(O)OR ^a6 , OC(O)R ^b6 , OC(O)NR ^c6 R ^d6 , NR ^c6 R ^d6 , NR ^c6 C(O)R ^b6 , NR ^c6 C(O)NR ^c6 R ^d6 , NR ^c6 C(O)OR ^a6 , S(O)R ^b6 , S(O)NR ^c6 R ^d6 , S(O) ₂ R ^b6 , NR ^c6 S(O) ₂ R ^b6 , NR ^c6 S(O) ₂ NR ^c6 R ^d6 and S(O) ₂ NR ^c6 R ^d6 ; or any R ^c and R ^d together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocyclic ring, optionally substituted with 1, 2 or 3 substituents independently selected from alkyl: C ₁ _- ₆ alkyl, C ₃ _- ₇ cycloalkyl, 4-7 membered heterocycloalkyl, C ₆ _- ₁₀ aryl, 5-6 membered heteroaryl, halo, CN, OR ^a6, SR ^a6 , C(O)R ^b6 , C(O)NR ^c6 R ^d6 , C(O)OR ^a6 , OC(O)R ^b6 , OC(O)NR ^c6 R ^d6 , NR ^c6 R ^d6 , NR ^c6 C (O) R ^b6 , NR ^c6 C(O)NR ^c6 R ^d6 , NR ^c6 C(O)OR ^a6 , S(O)R ^b6 , S(O)NR ^c6 R ^d6 , S(O) ₂ R ^b6 , NR ^c6 S(O) ₂ R ^b6 , NR ^c6 S(O) ₂ NR ^c6 R ^d6 and S(O) ₂ NR ^c6 R ^d6 , wherein the C ₁ _- ₆ alkyl group, C ₃ _- ₇ cycloalkyl group, 4 The -7 membered heterocycloalkyl, C ₆ _- ₁₀ aryl and 5-6 membered heteroaryl are optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, CN, OR ^a6 , SR ^A6 , C(O)R ^b6 , C(O)NR ^c6 R ^d6 , C(O)OR ^a6 , OC(O)R ^b6 , OC(O)NR ^c6 R ^d6 , NR ^c6 R ^d6 , NR ^c6 C( O) R ^b6 , NR ^c6 C(O)NR ^c6 R ^d6 , NR ^c6 C(O)OR ^a6 , S(O)R ^b6 , S(O)NR ^c6 R ^d6 , S(O) ₂ R ^b6 , NR ^C6 S(O) ₂ R ^b6 , NR ^c6 S(O) ₂ NR ^c6 R ^d6 and S(O) ₂ NR ^C6 R ^d6 ; or any R ^c1 and R ^d1 together with the N atom to which they are attached form 4, 5, 6 or 7 members which are optionally substituted by 1, 2 or 3 substituents selected from the following: Cycloalkyl: C ₁ _- ₆ alkyl, C ₃ _- ₇ cycloalkyl, 4-7 membered heterocycloalkyl, C ₆ _- ₁₀ aryl, 5-6 membered heteroaryl, halo, CN, OR ^a6 , SR ^a6 , C(O)R ^b6 , C(O)NR ^c6 R ^d6 , C(O)OR ^a6 , OC(O)R ^b6 , OC(O)NR ^c6 R ^d6 , NR ^c6 R ^d6 , NR ^c6 C(O)R ^b6 , NR ^c6 C(O)NR ^c6 R ^d6 , NR ^c6 C(O)OR ^a6 , S(O)R ^b6 , S(O)NR ^c6 R ^d6 , S(O) ₂ R ^b6 NR ^c6 S(O) ₂ R ^b6 , NR ^c6 S(O) ₂ NR ^c6 R ^d6 and S(O) ₂ NR ^c6 R ^d6 , wherein the C ₁ _- ₆ alkyl group, C ₃ _- ₇ cycloalkyl group, 4-7 membered heterocycloalkyl, C ₆ _- ₁₀ aryl, and 5-6 membered heteroaryl, each optionally substituted with 1, 2 or 3 substituents independently selected from the substituents: halo, CN, oR ^a6 , SR ^a6 , C(O)R ^b6 , C(O)NR ^c6 R ^d6 , C(O)OR ^a6 , OC(O)R ^b6 , OC(O)NR ^c6 R ^d6 , NR ^c6 R ^d6 , NR ^c6 C(O)R ^b6 , NR ^c6 C(O)NR ^c6 R ^d6 , NR ^c6 C(O)OR ^a6 , S(O)R ^b6 , S(O)NR ^c6 R ^d6 , S(O) ₂ R ^b6 ^{_{, NR c6 S (O) 2}} R b6, NR c6 S (O) 2 NR c6 R d6 _{^{S (O) 2 NR c6 R}} d6; or any of R ^c2 and R ^d2 together with the N atom to which they are attached form an optionally substituted with 1, 2, or 3 substituents independently selected from the group of substituted 4, 5, 6 or 7 membered heterocycloalkyl: C ₁ _- ₆ alkyl, C ₃ _- ₇ cycloalkyl, 4-7 membered heterocycloalkyl, C ₆ _- ₁₀ aryl and 5-6 membered heteroaryl, C ₁ _- ₆ haloalkyl, halo, CN, OR ^a6 , SR ^a6 , C(O)R ^b6 , C(O)NR ^c6 R ^d6 , C(O)OR ^a6 , OC(O)R ^b6 , OC( O) NR ^c6 R ^d6 , NR ^c6 R ^d6 , NR ^c6 C(O)R ^b6 , NR ^c6 C(O)NR ^c6 R ^d6 , NR ^c6 C(O)OR ^a6 , S(O)R ^b6 , S( O) NR ^c6 R ^d6 , S(O) ₂ R ^b6 , NR ^c6 S(O) ₂ R ^b6 , NR ^c6 S(O) ₂ NR ^c6 R ^d6 and S(O) ₂ NR ^c6 R ^d6 , wherein the C ₁ _- ₆ alkyl, C ₃ _- ₇ cycloalkyl, 4-7 membered heterocycloalkyl, C ₆ _- ₁₀ aryl and 5-6 membered heteroaryl are each independently selected 1, 2 or 3 Substituted from the following substituents: halo, CN, OR ^a6 , SR ^a6 , C(O)R ^b6 , C(O)NR ^c6 R ^d6 , C(O)OR ^a6 , OC(O)R ^b6 , OC ( O) NR ^c6 R ^d6 , NR ^c6 R ^d6 , NR ^c6 C(O)R ^b6 , NR ^c6 C(O)NR ^c6 R ^d6 , NR ^c6 C(O)OR ^a6 , S(O)R ^b6 , S( O) NR ^c6 R ^d6 , S(O) ₂ R ^b6 , NR ^c6 S(O) ₂ R ^{b 6.} NR ^c6 S(O) ₂ NR ^c6 R ^d6 and S(O) ₂ NR ^c6 R ^d6 ; or any R ^c3 and R ^d3 together with the N atom to which they are attached form 1, 2 or 3 independently substituents selected from the group of substituted 4, 5, 6 or 7-membered heterocycloalkyl group: C ₁ _- ₆ alkyl, C ₃ _- ₇ cycloalkyl, 4-7 membered heterocycloalkyl, C ₆ _{_--10} aryl, 5-6 membered heteroaryl, C ₁ _- ₆ haloalkyl, ^{^{halo, CN, OR a6, SR a6}} , C (O) R b6, C (O) NR c6 R d6, C ( O) OR ^a6 , OC(O)R ^b6 , OC(O)NR ^c6 R ^d6 , NR ^c6 R ^d6 , NR ^c6 C(O)R ^b6 , NR ^c6 C(O)NR ^c6 R ^d6 , NR ^c6 C( O) OR ^a6 , S(O)R ^b6 , S(O)NR ^c6 R ^d6 , S(O) ₂ R ^b6 , NR ^c6 S(O) ₂ R ^b6 , NR ^c6 S(O) ₂ NR ^c6 R ^d6 and _{^{S (O) 2 NR c6 R}} d6, wherein the C ₁ _- ₆ alkyl, C ₃ _- ₇ cycloalkyl, 4-7 membered heterocycloalkyl, C ₆ _- ₁₀ aryl, 5-6 membered heteroaryl and The groups are each substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, CN, OR ^a6 , SR ^a6 , C(O)R ^b6 , C(O)NR ^c6 R ^d6 , C ( O) OR ^a6 , OC(O)R ^b6 , OC(O)NR ^c6 R ^d6 , NR ^c6 R ^d6 , NR ^c6 C(O)R ^b6 , NR ^c6 C(O)NR ^c6 R ^d6 , NR ^c6 C( O) OR ^a6 , S(O)R ^b6 , S(O)NR ^c6 R ^d6 , S (O) ₂ R ^b6 , NR ^c6 S(O) ₂ R ^b6 , NR ^c6 S(O) ₂ NR ^c6 R ^d6 and S(O) ₂ NR ^c6 R ^d6 ; or any R ^c4 and R ^d4 together with The N atom forms a 4-membered, 5-membered, 6-membered or 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 substituents selected from C ₁ _- ₆ alkyl, C ₃ _- ₇ Cycloalkyl, 4-7 membered heterocycloalkyl, C ₆ _- ₁₀ aryl, 5-6 membered heteroaryl, C ₁ _- ₆ haloalkyl, halo, CN, OR ^a6 , SR ^a6 , C(O R ^b6 , C(O)NR ^c6 R ^d6 , C(O)OR ^a6 , OC(O)R ^b6 , OC(O)NR ^c6 R ^d6 , NR ^c6 R ^d6 , NR ^c6 C(O)R ^b6 , NR ^c6 C(O)NR ^c6 R ^d6 , NR ^c6 C(O)OR ^a6 , S(O)R ^b6 , S(O)NR ^c6 R ^d6 , S(O) ₂ R ^b6 , NR ^c6 S(O) _{^{^{2 R b6, NR c6 S (}}} O) 2 NR c6 R d6 and _{^{S (O) 2 NR c6 R}} d6, wherein the C ₁ _- ₆ alkyl, C ₃ _- ₇ cycloalkyl, 4-7 membered heterocycloalkyl group, C ₆ _- ₁₀ aryl, and 5-6 membered heteroaryl, each optionally substituted with 1, 2 or 3 substituents independently selected from the substituents: ^{^{halo, CN, oR a6, SR a6}} , C (O R ^b6 , C(O)NR ^c6 R ^d6 , C(O)OR ^a6 , OC(O)R ^b6 , OC(O)NR ^c6 R ^d6 , NR ^c6 R ^d6 , NR ^c6 C(O)R ^b6 , NR ^c6 C(O)NR ^c6 R ^d6 , NR ^c6 C(O)OR ^a6 , S (O)R ^b6 , S(O)NR ^c6 R ^d6 , S(O) ₂ R ^b6 , NR ^c6 S(O) ₂ R ^b6 , NR ^c6 S(O) ₂ NR ^c6 R ^d6 and S(O) ₂ NR ^c6 R ^d6 ; or any R ^c5 and R ^d5 together with the N atom to which they are attached form 4, 5, 6 or 7 members which are optionally substituted with 1, 2 or 3 substituents independently selected from the following: Heterocycloalkyl: C ₁ _- ₆ alkyl, C ₃ _- ₇ cycloalkyl, 4-7 membered heterocycloalkyl, C ₆ _- ₁₀ aryl, 5-6 membered heteroaryl, C ₁ _- ₆ halo Base, halo, CN, OR ^a6 , SR ^a6 , C(O)R ^b6 , C(O)NR ^c6 R ^d6 , C(O)OR ^a6 , OC(O)R ^b6 , OC(O)NR ^c6 R ^D6 , NR ^c6 R ^d6 , NR ^c6 C(O)R ^b6 , NR ^c6 C(O)NR ^c6 R ^d6 , NR ^c6 C(O)OR ^a6 , S(O)R ^b6 , S(O)NR ^c6 R ^D6 , S(O) ₂ R ^b6 , NR ^c6 S(O) ₂ R ^b6 , NR ^c6 S(O) ₂ NR ^c6 R ^d6 and S(O) ₂ NR ^c6 R ^d6 , wherein the C ₁ _- ₆ alkyl group , C ₃ _- ₇ cycloalkyl, 4-7 membered heterocycloalkyl, C ₆ _- ₁₀ aryl, and 5-6 membered heteroaryl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group Substitution: halo, CN, OR ^a6 , SR ^a6 , C(O)R ^b6 , C(O)NR ^c6 R ^d6 , C(O)OR ^a6 , OC(O)R ^b6 , OC(O)NR ^c6 R ^D6 , NR ^c6 R ^d6 , NR ^c6 C(O)R ^b6 , NR ^c6 C(O)NR ^{c 6} R ^d6 , NR ^c6 C(O)OR ^a6 , S(O)R ^b6 , S(O)NR ^c6 R ^d6 , S(O) ₂ R ^b6 , NR ^c6 S(O) ₂ R ^b6 , NR ^c6 S (O) ₂ NR ^c6 R ^d6 and _{^{S (O) 2 NR c6 R}} d6; each R ^a6, R ^b6, R ^c6 and R ^d6 are independently selected from: H, C ₁ _- ₄ alkyl, C ₂ _- ₄ alkenyl group, C ₃ _- ₇ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl, wherein the C ₁ _- ₄ alkyl, C ₂ _- ₄ alkenyl, C ₃ _- ₇ The cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of OH, CN, amine, halo, C ₁ _- ₄ alkyl, C ₁ _- ₄ alkoxy, C ₁ _- ₄ alkylthio, C ₁ _- ₄ alkoxy group and two (C ₁ _- ₄ alkyl) amino; n is 1 or 2; p is 1, 2 or 3; and q is 1 or 2; wherein any of the aforementioned 4-10 member or 4-7 membered heterocycloalkyl optionally contains 1, 2 or 3 pendant oxygen substituents, wherein Each side oxygen substituent is substituted on the ring forming the carbon, nitrogen or sulfur atom of the 4-10 member or 4-7 membered heterocycloalkyl.

The method of claim 8, wherein the compound is a compound of formula IIa: IIa.

The method of claim 8 or 9, wherein L is O.

The compound of any one of claims 8 to 10, wherein R ³ is H.

The method of any one of clauses 8 to 11, wherein R ² is CF ₃ and R ³ is H.

The requested item 8 to 12. A method according to any one of wherein R ¹ is H or C ₁ _- ₁₀ alkyl.

The method of any one of claims 8 to 13, wherein R ^A is a C ₆ _- ₁₀ aryl group optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R ^Cy .

The method of any one of claims 8 to 14, wherein R ^A is a phenyl group optionally substituted with 1, 2 or 3 substituents independently selected from R ^Cy .

The method of any one of clauses 8 to 15, wherein R ^C is H.

The method of any one of clauses 8 to 16, wherein R ^D is H.

The method of any one of clauses 8 to 17, wherein R ⁵ is H.

The method of any one of claims 8 and 12, wherein the compound is a compound of formula IV: IV.

The method of any one of claims 8 and 12, wherein the compound is a compound of formula Va: Va.

The method of any one of claims 8 and 12, wherein the compound is a compound of formula VII: VII where a is 0, 1, 2 or 3.

The method of any one of clauses 8 to 21, wherein the palmitic carbon coupled to -C(O)OR ¹ has an S configuration.

The method of any one of clauses 8 to 22, wherein the carbon connected to -R ² has an R configuration.

The method of any one of claims 1 to 7, wherein the TPH1 inhibitor or a prodrug thereof is (S)-8-(2-amino-6-((R)-1-(5-chloro-[ 1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid Ethyl ester or a pharmaceutically acceptable salt thereof.

The method of any one of claims 1 to 7, wherein the TPH1 inhibitor or a prodrug thereof is (S)-8-(2-amino-6-((R)-1-(5-chloro-[ 1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid Ethyl ester.

The method of any one of claims 1 to 7, wherein the TPH1 inhibitor or a prodrug thereof is (S)-8-(2-amino-6-((R)-1-(5-chloro-[ 1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid Or a pharmaceutically acceptable salt thereof.

The method of any one of claims 1 to 7, wherein the TPH1 inhibitor or a prodrug thereof is (S)-8-(2-amino-6-((R)-1-(5-chloro-[ 1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid .

A method of treating non-alcoholic fatty liver disease (NAFLD), nonalcoholic steatosis hepatitis (NASH) or hepatocellular carcinoma in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound, which is metabolized to form (S 8-(2-Amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy) Pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid.

A method of reducing serum levels of alanine transaminase (ALT), aspartate transaminase (AST), cholesterol, triglyceride or glucose in a patient, the method comprising administering to the patient a therapeutically effective amount a compound which is metabolized to form (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2, 2,2-Trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid.

A method of reducing lipid deposits in a patient's liver, the method comprising administering to the patient a therapeutically effective amount of a compound that is metabolized to form (S)-8-(2-amino-6-((R)-1) -(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diaza snail [4.5] Decane-3-carboxylic acid.

A method of treating or preventing one or more diseases or conditions associated with nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatosis hepatitis (NASH) or hepatocellular carcinoma in a patient, the one or more diseases or symptoms selected from the group consisting of Inflammation, fibrosis, cirrhosis, fatigue, weight loss, weakness, fluid retention, muscle atrophy, intestinal bleeding, liver failure, weight gain, obesity, diabetes, pre-diabetes, lipid disorders, elevated serum lipids, elevated cholesterol And elevated triglyceride, the method comprising administering to the patient a therapeutically effective amount of a compound that is metabolized to form (S)-8-(2-amino-6-((R)-1-(5) -Chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylic acid.

The method of any one of claims 28 to 31, wherein the metabolism is carried out to form (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1'-linked) This compound of phenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid is (S 8-(2-Amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy) Pyrimidine-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid ethyl ester or a pharmaceutically acceptable salt thereof.