WO2018060949A1 - Tryptophan hydroxylase inhibitors for use in the treatment of liver diseases - Google Patents

Tryptophan hydroxylase inhibitors for use in the treatment of liver diseases Download PDF

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Publication number
WO2018060949A1
WO2018060949A1 PCT/IB2017/056015 IB2017056015W WO2018060949A1 WO 2018060949 A1 WO2018060949 A1 WO 2018060949A1 IB 2017056015 W IB2017056015 W IB 2017056015W WO 2018060949 A1 WO2018060949 A1 WO 2018060949A1
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Prior art keywords
alkyl
cycloalkyl
aryl
independently selected
membered heterocycloalkyl
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PCT/IB2017/056015
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French (fr)
Inventor
Vishwas Paralkar
Robert J. AIELLO
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Roivant Sciences Gmbh
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Publication of WO2018060949A1 publication Critical patent/WO2018060949A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics

Definitions

  • the present invention 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), or prodrugs thereof.
  • liver diseases such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma
  • NASH non-alcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • TPH1 tryptophan hydroxylase 1
  • NASH non-alcoholic fatty liver disease
  • NAFLD non-alcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • NASH affects about 2 to 5 percent of Americans according to the National Heath Instistute. NASH can occur in people who drink little or no alcohol and is usually a silient disease with few or no symptoms. NASH can be characterized by having fat in the liver, which is not normal, as well as having inflammation and damage.
  • NASH can become severe and lead to fibrosis and cirrhosis, where the liver is permanently damaged and scarred. Diseased or damaged liver tissue caused, for example, from NASH-related cirrhosis can eventually lead to hepatocellular carcinoma.
  • Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that modulates central and peripheral functions by acting on neurons, smooth muscle, and other cell types. 5-HT is involved in the control and modulation of multiple physiological and psychological processes. Dysregulation of the peripheral 5-HT signaling system has been reported to be involved in the etiology of several conditions such as inflammatory (e.g. Margolis, K. G. 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.
  • inflammatory e.g. Margolis, K. G. 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
  • Platelet Serotonin Promotes The Recruitment Of Neutrophils To Sites Of Acute Inflammation In Mice. Blood 121, 1008-15 (2013); Li, N. et al. Serotonin Activates Dendritic Cell Function In The Context Of Gut
  • liver diseases or disorders e.g. Ebrahimkhani, M. R. 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.
  • TPH tryptophan hydrolase
  • TPHl is primarily expressed in the pineal gland and non-neuronal tissues, such as enterochromaffin (EC) cells located in the gastrointestinal (GI) tract.
  • TPH2 (the dominant form in the brain) is expressed exclusively in neuronal cells, such as dorsal raphe or myenteric plexus cells.
  • the peripheral and central systems involved in 5-HT biosynthesis are isolated, with 5-HT being unable to cross the blood-brain barrier. Therefore, the pharmacological effects of 5- HT can be modulated by agents affecting TPH in the periphery, mainly TPHl in the gut.
  • Increased 5-HT has been proposed to impact the pathophysiology of the liver through multiple mechanisms. For example, accumulation of lipids can sensitize the liver to
  • hepatic oxidation of 5-HT can generate lipid peroxide and ROS leading to mitochondrial dysfunction; and pro-fibrotic and mitogenic activity mediated through 5-HT receptor binding and TGFP signaling leads to fibrosis.
  • the present disclosure relates to methods of treating or preventing liver diseases such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma in a patient, comprising administering to the patient a therapeutically effective amount of a TPHl inhibitor, or prodrug thereof.
  • liver diseases such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma in a patient, comprising administering to the patient a therapeutically effective amount of a TPHl inhibitor, or prodrug thereof.
  • the present disclosure also relates to methods of decreasing alanine aminotransferase (ALT), aspartate aminotransferase (AST), cholesterols, triglycerides, or glucose in a patient comprising administering to the patient a therapeutically effective amount of a TPHl inhibitor, or prodrug thereof.
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • cholesterols triglycerides
  • glucose glucose
  • the present disclosure also relates to methods of reducing lipid deposits in the liver of a patient comprising administering to the patient a therapeutically effective amount of a TPH1 inhibitor, or prodrug thereof.
  • the present disclosure further relates to a TPH1 inhibitor, or prodrug thereof, for use in the treatment or prevention of liver diseases such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma in a patient.
  • liver diseases such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma in a patient.
  • the present disclosure further relates to use of a TPH1 inhibitor, or prodrug thereof, in the treatment or prevention of liver diseases such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma in a patient.
  • liver diseases such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma in a patient.
  • the present disclosure further relates to use of a TPH1 inhibitor, or prodrug thereof, for the preparation of a medicament for the treatment or prevention of liver diseases such as nonalcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma in a patient.
  • liver diseases such as nonalcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma in a patient.
  • the present disclosure relates to methods of treating or preventing liver diseases, such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma in a patient, comprising administering to said patient a therapeutically effective amount of a TPH inhibitor, such as a TPH1 inhibitor, or a prodrug thereof.
  • a TPH inhibitor such as a TPH1 inhibitor, or a prodrug thereof.
  • the diasease is NAFLD.
  • the disease is NASH.
  • the disease is hepatocellular carcinoma.
  • the present disclosure also includes methods of treating or preventing one or more diseases or symptoms that can be associated with NAFLD, NASH, or hepatocellular carcinoma in a patient comprising administering to the patient a therapeutically effective amount of a TPH inhibitor, such as a TPH1 inhibitor, or a prodrug thereof.
  • diseases or symptoms include, for example, inflammation, fibrosis, cirrhosis, fatigue, weight loss, weakness, fluid retention, muscle wasting, bleeding from the intestines, liver failure, weight gain, obese, diabetes (e.g., type 2 diabetes or type 1 diabetes), prediabetes, lipid disorders, elevated serum lipids, elevated liver enzymers in serum, elevated cholesterol, and elevated triglycerides.
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • the methods provided herein also include reducing lipid deposits in the liver of a patient comprising administering a therapeutically effective amount of a TPH inhibitor, such as a TPHl inhibitor, or a prodrug thereof.
  • the method is a method of decreasing the concentration of ALT in a patients serum or liver.
  • the method is a method of decreasing the concentration of AST in a patients serum or liver.
  • TPHl inhibitors examples include TPHl inhibitors, and their corresponding prodrugs, that can be used according to the methods of the present invention.
  • An example prodrug that can be used according the methods of the present invention is the ester compound (S)-ethyl 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-carboxylate which can be metabolized internally by a patient to form the corresponding acid compound (S)-8-(2-amino-6-((R)-l-(5-chloro-[l,l'-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3
  • the compound that can be used according to the methods of the invention is a compound of Formula I:
  • Ring A is C3-10 cycloalkyl, C6-io aryl, 4 to 10-membered 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 ;
  • R 1 is H, Ci-10 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, -(CR 8 R 9 ) p OC(0)R 10 , -(CR 8 R 9 ) P NR U R 12 , or -(CR 8 R 9 ) p C(0)NR n R 12 , wherein said Ci-10 alkyl, C3 -10 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and phenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from F, CI, Br, CN, C1-4 alkyl, and Ci-4 haloalkyl;
  • R 2 and R 3 are each independently selected from H, C1-4 alkyl, and C1-4 haloalkyl;
  • R 4 is H or Ci- 4 alkyl
  • R 5 and R 6 are each independently selected from H, halo, and C1-4 alkyl
  • R 7 is H, Ci-4 alkyl, C2-6 alkenyl, C3 -10 cycloalkyl, C3-io cycloalkyl-Ci4 alkyl, C6-io aryl, Gs- 10 aryl-Ci-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci -4 alkyl, 5-10 membered heteroaryl, (5-10 membered heteroaryl)-Ci-4 alkyl, NR 1 R 14 , OR 15 , C(0)R 16 ,
  • R 8 and R 9 are each independently selected from H and C1-4 alkyl
  • R 10 is Ci-6 alkyl optionally substituted by 1, 2 or 3 substituents independently selected from Ci-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 Ci-6 alkyl
  • R 13 is H or C1-4 alkyl;
  • R is H, Ci-4 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-Ci alkyl, C6-io aryl, C6-io aryl-Ci-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, 5-10 membered heteroaryl, or (5-10 membered heteroaryl)-Ci- 4 alkyl, C(0)R bl , C(0)OR al ,
  • R 13 and R 14 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7- membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents
  • R 15 is H, Ci-4 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-Ci-4 alkyl, Gs-io aryl, C6-io aryl-Ci-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci4 alkyl, 5-10 membered heteroaryl, or (5-10 membered heteroaryl)-Ci-4 alkyl, wherein said CM alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-Ci-4 alkyl, Gs-io aryl, G5-10 aryl-Ci4 alkyl, 4-10 membered
  • heterocycloalkyl (4-10 membered heterocycloalkyl)-Ci- 4 alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl)-Ci4 alkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Gs-io aryl, 5-6 membered heteroaryl, CN, OR al , SR al , C(0)R bl , C(0)NR cl R dl , C(0)OR al , OC(0)R bl , OC(0)NR cl R dl , NR cl R dl , NR cl C(0)R bl , NR cl C(0)NR cl R dl , NR cl C(0)OR al , S(0)R bl ,
  • R 16 is Ci4 alkyl or NR 18a R 18b wherein said C1-4 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, 5-6 membered heteroaryl, CN, OR al , SR al , C(0)R bl , C(0)NR cl R dl , C(0)OR al , OC(0)R bl , OC(0)NR cl R dl , NR cl R dl , NR cl C(0)R bl , NR cl C(0)NR cl R dl , NR cl C(0)OR al , S(0)R bl , S(0)NR cl R dl , S(0) 2 R bl , NR cl S(0) 2 R bl , NR cl S(0) 2 NR cl R d
  • R 17 is Ci-4 alkyl, NR 18a R 18b , or OR 18c , wherein said C1-4 alkyl is optionally substituted by 1 , 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, 5-6 membered heteroaryl, CN, OR al , SR al , C(0)R bl , C(0)NR cl R dl , C(0)OR al , OC(0)R bl , OC(0)NR cl R dl , NR cl R dl , NR cl C(0)R bl , NR cl C(0)NR cl R dl ,
  • R 18a and R 18b are each independently selected from H and C1-4 alkyl wherein said C1-4 alkyl is optionally substituted by 1 , 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, 5-6 membered heteroaryl, CN, OR al , SR al , C(0)R bl , C(0)NR cl R dl , C(0)OR al , OC(0)R bl , OC(0)NR cl R dl , NR cl R dl , NR cl C(0)R bl , NR cl C(0)NR cl R dl , NR c4 C(0)OR al , S(0)R bl , S(0)NR cl R dl , S(0) 2 R bl , NR cl S(0) 2 R bl , NR cl S(0) 2 R
  • R 18a and R 18b together with the N atom to which they are attached form a 4-, 5-, 6-, or
  • R c is H, Ci-6 alkyl, C3-io cycloalkyl, C3-7 cycloalkyl-Ci-4 alkyl, Gs-io aryl, C6-io aryl-Ci-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci- 4 alkyl, 5-10 membered heteroaryl, or (5-10 membered heteroaryl)-Ci- 4 alkyl, wherein said Ci-6 alkyl, C3-7 cycloalkyl, C3-io cycloalkyl-Ci alkyl, Gs-io aryl, C6-io aryl-Ci alkyl, wherein said Ci-6 alkyl, C3-7 cycloalkyl, C3-io cycloalkyl-Ci alkyl, Gs-io aryl, C6-io aryl-Ci alkyl, wherein said Ci-6
  • heterocycloalkyl (4-10 membered heterocycloalkyl)-Ci4 alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl)-Ci- 4 alkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CM alkyl, CM haloalkyl, CN, N0 2 , OR al , SR al , C(0)R bl , C(0)NR cl R dl , C(0)OR al , OC(0)R bl , OC(0)NR cl R dl , NR cl R dl , NR cl C(0)R bl , NR cl C(0)OR al , NR cl C(0)NR cl R dl , NR cl S(0)R bl , NR cl S(0) 2 R bl , NR cl S(0) 2 NR cl R dl , S(0)
  • R A is H, Cy 1 , halo, Ci -6 alkyl, C2-6 alkenyl, CN, N0 2 , OR a2 , SR a2 , C(0)R b2 , C(0)NR c2 R d2 , C(0)OR a2 , OC(0)R b2 , OC(0)NR c2 R d2 , NR ⁇ R ⁇ , NR c2 C(0)R b2 , NR c2 C(0)OR a2 ,
  • Ci -6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy 1 , halo, Ci-6 alkyl, C 2- 6 alkenyl, Ci -6 haloalkyl, CN, N0 2 , OR a2 , SR a2 , C(0)R b2 , C(0)NR c2 R d2 , C(0)OR a2 , OC(0)R b2 , OC(0)NR c2 R d2 , NR c2 R d2 , NR c2 R d2
  • R B is H, Cy 2 , halo, Ci -6 alkyl, C2-6 alkenyl, Ct-s haloalkyl, CN, N0 2 , OR a3 , SR a3 , C(0)R b3 , C(0)NR c R d3 , C(0)OR a3 , OC(0)R b3 , OC(0)NR c R d3 , NR c R d3 , NR c C(0)R b3 , NR c C(0)OR a3 , NR c C(0)NR c R d3 , NR c S(0)R b3 , NR c S(0) 2 R b3 , NR c S(0) 2 R b3 , NR c S(0) 2 NR c R d3 , S(0)R b3 , S(0)NR c R d3 , S(0)R b3 , or S(0) 2 NR c R d3 , where
  • R c and R D are each independently selected from H, halo, Ci-6 alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, N0 2 , OR a4 , SR a4 , C(0)R b4 , C(0)NR c4 R d4 , C(0)OR a4 , OC(0)R b4 , OC(0)NR c4 R d4 , NR c4 R d4 , NR c4 C(0)R b4 , NR c4 C(0)OR a4 , NR c4 C(0)NR c4 R d4 , NR c4 S(0)R b4 , NR c4 S(0) 2 R b4 , NR c4 S(0) 2 NR c4 R d4 , S(0)R b4 , S(0)NR c4 R d4 , S(0)R b4 , S(0)NR c4 R d4 , S(0)R
  • Cy 1 and Cy 2 are each independently selected from C6-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted by 1 , 2, 3, 4, or 5 substituents independently selected from R Cy ;
  • each R ⁇ is independently selected from halo, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, G5-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO2, OR a5 , SR a5 , C(0)R b5 , C(0)NR c5 R d5 , C(0)OR a5 , OC(0)R b5 , OC(0)NR c5 R d5 , NR c5 R d5 ,
  • NR c5 C(0)R b5 NR c5 C(0)OR a5 , NR c5 C(0)NR c5 R d5 , NR c5 S(0)R b5 , NR c5 S(0) 2 R b5 ,
  • each R a , R al , R a2 , R a3 , R a4 , and R a5 is independently selected from H, Ci- 6 alkyl, Ci- 4 haloalkyl, C2-6 alkenyl, Gs-io aryl, C3 -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-io aryl-Ci -4 alkyl, C3-io cycloalkyl-Ci -4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, or (4-10 membered heterocycloalkyl)-Ci -4 alkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, Gs- lo aryl, C3 -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Gs-io aryl- Ci4 alkyl,
  • each R bl , R b2 , R b3 , R b4 , and R b5 is independently selected from H, Ci -6 alkyl, Ci -4 haloalkyl, C2-6 alkenyl, C6-io aryl, C3 -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-io aryl-Ci -4 alkyl, C3-10 cycloalkyl-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, or (4-10 membered heterocycloalky
  • each R c , R d , R cl , R dl , R c2 , R ⁇ , R c3 , R d3 , R c4 , R d4 , R c5 , and R d5 is independently selected from H, Ci-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C6-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-io aryl-Ci -4 alkyl, C3-io cycloalkyl-Ci -4 alkyl, (5- 10 membered heteroaryl)-Ci- 4 alkyl, or (4- 10 membered heterocycloalkyl)-Ci- 4 alkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, C6-io aryl, C3-10 cycloalkyl, 5-10 member
  • R c and R d together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, 5-6 membered heteroaryl, halo, CN, OR a6 , SR a6 , C(0)R b6 , C(0)NR c6 R d6 , C(0)OR a6 , OC(0)R b6 , OC(0)NR c6 R d6 , NR c6 R d6 , NR c6 C(0)R b6 , NR c6 C(0)NR c6 R d6 , NR c6 C(0)OR b6 , NR c6 C(0)NR c6 R d6 , NR c6 C(0)OR b6 ,
  • Ci-6 alkyl, C3 -7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, and 5-6 membered heteroaryl are optionally substituted by 1 , 2, or 3 substituents independently selected from halo, CN, OR a6 , SR a6 , C(0)R b6 , C(0)NR c6 R d6 , C(0)OR a6 , OC(0)R b6 , OC(0)NR c6 R d6 , NR C R d , NR c6 C(0)R b6 , NR c6 C(0)NR c6 R d6 , NR
  • R cl and R dl together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, 5-6 membered heteroaryl, halo, CN, OR a6 , SR a6 , C(0)R b6 , C(0)NR c6 R d6 , C(0)OR a6 , OC(0)R b6 , OC(0)NR c6 R d6 , NR c6 R d6 , NR c6 C(0)R b6 , NR c6 C(0)NR c6 R d6 , NR c6 C(0)OR b6 , NR c6 C(0)NR c6 R d6 , NR c6 C(0)OR b6
  • R c2 and K 02 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1 , 2, or 3 substituents independently selected from Ci-6 alkyl, C3 -7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, and 5-6 membered heteroaryl, Ci-e haloalkyl, halo, CN, OR a6 , SR a6 , C(0)R b6 , C(0)NR c6 R d6 , C(0)OR a6 , OC(0)R b6 , OC(0)NR c6 R d6 , NR c6 R d6 , NR c6 C(0)R b6 , NR c6 C(0)NR c6 R d6 ,
  • Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, OR a6 , SR a6 , C(0)R b6 , C(0)NR c6 R d6 , C(0)OR a6 ,
  • R c3 and R d3 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, 5-6 membered heteroaryl, Ci-e haloalkyl, halo, CN, OR a6 , SR a6 , C(0)R b6 , C(0)NR c6 R d6 , C(0)OR a6 , OC(0)R b6 , OC(0)NR c6 R d6 , NR c6 R d6 , NR c6 C(0)R b6 , NR c6 C(0)NR c6 R d6 ,
  • Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, and 5-6 membered heteroaryl are each optionally substituted by 1 , 2, or 3 substituents independently selected from halo, CN, OR a6 , SR a6 , C(0)R b6 , C(0)NR c6 R d6 , C(0)OR a6 ,
  • R c4 and R d4 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1 , 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, 5-6 membered heteroaryl, Ct-s haloalkyl, halo, CN, OR a6 , SR a6 , C(0)R b6 , C(0)NR c6 R d6 , C(0)OR a6 , OC(0)R b6 , OC(0)NR c6 R d6 , NR c6 R d6 , NR c6 C(0)R b6 , NR c6 C(0)NR c6 R d6 ,
  • Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, and 5-6 membered heteroaryl are each optionally substituted by 1 , 2, or 3 substituents independently selected from halo, CN, OR a6 , SR a6 , C(0)R b6 , C(0)NR c6 R d6 , C(0)OR a6 ,
  • R c5 and R d5 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, 5-6 membered heteroaryl, Ci -6 haloalkyl, halo, CN, OR a6 , SR a6 , C(0)R b6 , C(0)NR c6 R d6 , C(0)OR a6 , OC(0)R b6 , OC(0)NR c6 R d6 , NR c6 R d6 , NR c6 C(0)R b6 , NR c6 C(0)NR c6 R d6 ,
  • Ci-6 alkyl, C3 -7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, OR a6 , SR a6 , C(0)R b6 , C(0)NR c6 R d6 , C(0)OR a6 ,
  • each R a6 , R b6 , R c6 , and R d6 is independently selected from H, C1-4 alkyl, C 2-4 alkenyl, C3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein said Ci-4 alkyl, C 2-4 alkenyl, C3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, Ci alkyl, Ci alkoxy, Ci-4 alkylthio, Ci-4 alkylamino, and di(Ci4 alkyl)amino;
  • n 1 or 2;
  • p is 1, 2, or 3;
  • q 1 or 2;
  • any aforementioned 4-10 or 4-7 membered heterocycloalkyl group optionally comprises 1, 2, or 3 oxo substituents, wherein each oxo substituent that is present is substituted on a ring- forming carbon, nitrogen, or sulfur atom of the 4-10 or 4-7 membered heterocycloalkyl group.
  • the TPH-inhibiting compound described herein is a compound of Formula I:
  • Ring A is C3-10 cycloalkyl, C6-io aryl, 4 to 10-membered 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 ;
  • R 1 is H, Ci-10 alkyl, C 3 -10 cycloalkyl, phenyl, -(CR 8 R 9 ) p OC(0)R 10 , -(CR 8 R 9 ) p NR n R 12 , or -(CR 8 R 9 )pC(0)NR n R 12 , wherein said Ci-10 alkyl, C3-10 cycloalkyl, and phenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from F, CI, Br, CN, C14 alkyl, and Ci4 haloalkyl; R 2 and R 3 are each independently selected from H, C1-4 alkyl, and C1-4 haloalkyl;
  • R 4 is H or CM alkyl
  • R 5 and R 6 are each independently selected from H, halo, and C1-4 alkyl
  • R 7 is H, Ci-4 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C3-io cycloalkyl-Ci4 alkyl, C6-io aryl, C 6 - 10 aryl-Ci-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, 5-10 membered heteroaryl, (5-10 membered heteroaryl)-Ci -4 alkyl, NR 1 R 14 , OR 15 , C(0)R 16 , S(0) q R 17 , wherein said C1-4 alkyl, C2-6 alkenyl, C3 -10 cycloalkyl, C3-io cycloalkyl-Ci-4 alkyl, G5-10 aryl, C6-io aryl-Ci-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)- C1
  • R 8 and R 9 are each independently selected from H and C1-4 alkyl
  • R 10 is Ci-6 alkyl optionally substituted by 1, 2 or 3 substituents independently selected from Ci-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 Ci-6 alkyl
  • R 13 is H or Ci4 alkyl
  • R 14 is H, Ci4 alkyl, C3 -7 cycloalkyl, C3-7 cycloalkyl-Ci4 alkyl, Gs-io aryl, C6-io aryl-Ci4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci 4 alkyl, 5-10 membered heteroaryl, or (5-10 membered heteroaryl)-Ci4 alkyl, C(0)R bl , C(0)OR al ,
  • R 13 and R 14 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7- membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents
  • R 15 is H, Ci4 alkyl, C3 -7 cycloalkyl, C3-7 cycloalkyl-Ci-4 alkyl, C6-io aryl, C6-io aryl-Ci-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci -4 alkyl, 5-10 membered heteroaryl, or (5-10 membered heteroaryl)-Ci-4 alkyl, wherein said Ci-4 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-Ci-4 alkyl, C6-io aryl, C6-io aryl-Ci-4 alkyl, 4-10 membered
  • heterocycloalkyl (4-10 membered heterocycloalkyl)-Ci-4 alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl)-Ci-4 alkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3 -7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, 5-6 membered heteroaryl, CN, OR al , SR al , C(0)R bl , C(0)NR cl R dl , C(0)OR al , OC(0)R bl ,
  • R 16 is Ci-4 alkyl or NR 18a R 18b wherein said C1-4 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, 5-6 membered heteroaryl, CN, OR al , SR al , C(0)R bl , C(0)NR cl R dl , C(0)OR al , OC(0)R bl , OC(0)NR cl R dl , NR cl R dl , NR cl C(0)R bl , NR cl C(0)NR cl R dl , NR cl C(0)OR al , S(0)R bl , S(0)NR cl R dl , S(0) 2 R bl , NR cl S(0) 2 R bl , NR cl S(0) 2 NR cl R d
  • R 17 is Ci-4 alkyl, NR 18a R 18b , or OR 18c , wherein said C1-4 alkyl is optionally substituted by 1 , 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, 5-6 membered heteroaryl, CN, OR al , SR al , C(0)R bl , C(0)NR cl R dl , C(0)OR al , OC(0)R bl , OC(0)NR cl R dl , NR cl R dl , NR cl C(0)R bl , NR cl C(0)NR cl R dl ,
  • R 18a and R 18b are each independently selected from H and C1-4 alkyl wherein said C1-4 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, 5-6 membered heteroaryl, CN, OR al , SR al , C(0)R bl , C(0)NR cl R dl , C(0)OR al , OC(0)R bl , OC(0)NR cl R dl , NR cl R dl , NR cl C(0)R bl , NR cl C(0)NR cl R dl , NR c4 C(0)OR al , S(0)R bl , S(0)NR cl R dl , S(0) 2 R bl , NR cl S(0) 2 R bl , NR cl S(0) 2 R bl
  • R 18a and R 18b together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, 5-6 membered heteroaryl, halo, CN, OR al , SR al , C(0)R bl , C(0)NR cl R dl , C(0)OR al , OC(0)R bl , OC(0)NR cl R dl , NR cl R dl , NR cl C(0)R bl , NR cl C(0)NR cl R dl , NR cl C(0)OR al , S(0)R bl , S(0)NR cl R dl , S(0) 2 R bl , NR cl S(0) 2 R
  • R 18c is H, Ci-6 alkyl, C3-10 cycloalkyl, C3-7 cycloalkyl-Ci-4 alkyl, G5-10 aryl, G5-10 aryl-Ci-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci alkyl, 5-10 membered heteroaryl, or (5-10 membered heteroaryl)-Ci-4 alkyl, wherein said Ci-6 alkyl, C3-7 cycloalkyl, C3-io cycloalkyl-Ci-4 alkyl, Gs-io aryl, C6-io aryl-Ci-4 alkyl, 4-10 membered
  • heterocycloalkyl (4-10 membered heterocycloalkyl)-Ci-4 alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl)-Ci -4 alkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, N0 2 , OR al , SR al , C(0)R bl , C(0)NR cl R dl , C(0)OR al , OC(0)R bl , OC(0)NR cl R dl , NR cl R dl , NR cl C(0)R bl , NR cl C(0)OR al , NR cl C(0)NR cl R dl , NR cl S(0)R bl , NR cl S(0) 2 R bl , NR cl S(0) 2 NR cl R dl , S(0)
  • R A is H, Cy 1 , halo, Ct-s alkyl, C 2 ⁇ alkenyl, CN, N0 2 , OR a2 , SR a2 , C(0)R b2 , C(0)NR c2 R d2 ,
  • Ci -6 alkyl and C 2-6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy 1 , halo, Ci-6 alkyl, C 2- 6 alkenyl, Ci- 6 haloalkyl, CN, N0 2 , OR a2 , SR a2 , C(0)R b2 , C(0)NR c2 R d2 , C(0)OR a2 , OC(0)R b2 , OC(0)NR c2 R d2 , NR ⁇ R ⁇ , NR
  • R B is H, Cy 2 , halo, Ci -6 alkyl, C 2 - 6 alkenyl, Ci -6 haloalkyl, CN, N0 2 , OR a3 , SR a3 , C(0)R b3 , C(0)NR c R d3 , C(0)OR a3 , OC(0)R b3 , OC(0)NR c R d3 , NR c R d3 , NR c C(0)R b3 , NR c C(0)OR a3 , NR c C(0)NR c R d3 , NR c S(0)R b3 , NR c S(0) 2 R b3 , NR c S(0) 2 R b3 , NR c S(0) 2 NR c R d3 , S(0)R b3 , S(0)NR c R d3 , S(0)R b3 , or S(0) 2 NR c R d3 ,
  • R c and R D are each independently selected from H, halo, Ci-6 alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, N0 2 , OR a4 , SR a4 , C(0)R b4 , C(0)NR c4 R d4 , C(0)OR a4 , OC(0)R b4 , OC(0)NR c4 R d4 , NR c4 R d4 , NR c4 C(0)R b4 , NR c4 C(0)OR a4 , NR c4 C(0)NR c4 R d4 , NR c4 S(0)R b4 , NR c4 S(0) 2 R b4 , NR c4 S(0) 2 NR c4 R d4 , S(0)R b4 , S(0)NR c4 R d4 , S(0)R b4 , S(0)NR c4 R d4 , S(0)R
  • heterocycloalkyl halo, Ct-s alkyl, C 2 ⁇ , alkenyl, Ci -6 haloalkyl, CN, N0 2 , OR a4 , SR a4 , C(0)R b4 , C(0)NR c4 R d4 , C(0)OR a4 , OC(0)R b4 , OC(0)NR c4 R d4 , NR c4 R d4 , NR c4 C(0)R b4 , NR c4 C(0)OR a4 , NR c4 C(0)NR c4 R d4 , NR c4 S(0)R b4 , NR c4 S(0) 2 R b4 , NR c4 S(0) 2 NR c4 R d4 , S(0)R b4 , S(0)NR c4 R d4 , S(0)R b4 , S(0)NR c4 R d4 , S(0)R b
  • Cy 1 and Cy2 are each independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy;
  • each R ⁇ is independently selected from halo, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, G5-10 aryl, C3 -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO2, OR a5 , SR a5 , C(0)R b5 , C(0)NR c5 R d5 , C(0)OR a5 , OC(0)R b5 , OC(0)NR c5 R d5 , NR c5 R d5 ,
  • NR c5 C(0)R b5 NR c5 C(0)OR a5 , NR c5 C(0)NR c5 R d5 , NR c5 S(0)R b5 , NR c5 S(0) 2 R b5 ,
  • Ci -6 alkyl, C2-6 alkenyl Gs-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, Ct-s alkyl, CN, N0 2 , OR a5 , SR a5 , C(0)R b5 , C(0)NR c5 R d5 , C(0)OR a5 , OC(0)R b5 , OC(0)NR c5 R d5 , NR C R , NR c5 C(0)R b5 , NR c5 C(0)OR a5 ,
  • each R a , R al , R a2 , R a3 , R a4 , and R a5 is independently selected from H, Ct-s alkyl, C haloalkyl, C2-6 alkenyl, C6-io aryl, C3 -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-io aryl-Ci4 alkyl, C3-io cycloalkyl-Ci4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, or (4-10 membered heterocycloalkyl)-C 14 alkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, Gs- 10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-io aryl- C1-4 alkyl, C3-10 cyclo
  • each R bl , R b2 , R b3 , R b4 , and R b5 is independently selected from H, Ct-s alkyl, CM haloalkyl, C2-6 alkenyl, C6-io aryl, C3 -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-io aryl-Ci -4 alkyl, C3-io cycloalkyl-Ci4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, or (4-10 membered heterocycloalkyl)-Ci4 alkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, Gs- 10 aryl, C3 -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6 -io aryl- C alkyl, C3-10 cycl
  • each R c , R d , R cl , R dl , R c2 , R d2 , R c3 , R d3 , R c4 , R d4 , R c5 , and R d5 is independently selected from H, Ci-6 alkyl, CM haloalkyl, C2-6 alkenyl, C6-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-io aryl-Ci4 alkyl, C3-10 cycloalkyl-Ci4 alkyl, (5- 10 membered heteroaryl)-Ci4 alkyl, or (4-10 membered heterocycloalkyl)-Ci4 alkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, C6-io aryl, C3-10 cycloalkyl, 5-10 membered heteroary
  • R c and R d together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, 5-6 membered heteroaryl, halo, CN, OR a6 , SR a6 , C(0)R b6 , C(0)NR c6 R d6 , C(0)OR a6 , OC(0)R b6 , OC(0)NR c6 R d6 , NR c6 R d6 , NR c6 C(0)R b6 , NR c6 C(0)NR c6 R d6 , NR c6 C(0)OR b6 , NR c6 C(0)NR c6 R d6 , NR c6 C(0)OR b6 ,
  • R cl and R dl together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, 5-6 membered heteroaryl, halo, CN, OR a6 , SR a6 , C(0)R b6 , C(0)NR c6 R d6 , C(0)OR a6 , OC(0)R b6 , OC(0)NR c6 R d6 , NR c6 R d6 , NR c6 C(0)R b6 , NR c6 C(0)NR c6 R d6 , NR c6 C(0)OR b6 , NR c6 C(0)NR c6 R d6 , NR c6 C(0)OR b6
  • R c3 and R d3 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C5-10 aryl, 5-6 membered heteroaryl, Ci-e haloalkyl, halo, CN, OR a6 , SR a6 , C(0)R b6 , C(0)NR c6 R d6 , C(0)OR a6 , OC(0)R b6 , OC(0)NR c6 R d6 , NR c6 R d6 , NR c6 C(0)R b6 , NR c6 C(0)NR c6 R d6 ,
  • Ci-6 alkyl, C3 -7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, OR a6 , SR a6 , C(0)R b6 , C(0)NR c6 R d6 , C(0)OR a6 , OC(0)R b6 , OC(0)NR c6 R d6 , NR c6 R d6 , NR c6 C(0)R b6 , NR c6 C(0)R b6 , NR c6 C(0)OR b6 , NR c6 C(0)R b6 , NR c6 C(0)OR b6 , NR c6 C(0)R b6 , NR c6 C(0)R b6 , NR c6 C(0)OR b6 , NR c6 C(0)
  • R c4 and R d4 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, 5-6 membered heteroaryl, Ci-e haloalkyl, halo, CN, OR a6 , SR a6 , C(0)R b6 , C(0)NR c6 R d6 , C(0)OR a6 , OC(0)R b6 , OC(0)NR c6 R d6 , NR c6 R d6 , NR c6 C(0)R b6 , NR c6 C(0)NR c6 R d6 ,
  • R c5 and R d5 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, 5-6 membered heteroaryl, Ct-s haloalkyl, halo, CN, OR a6 , SR a6 , C(0)R b6 , C(0)NR c6 R d6 , C(0)OR a6 , OC(0)R b6 , OC(0)NR c6 R d6 , NR c6 R d6 , NR c6 C(0)R b6 , NR c6 C(0)NR c6 R d6 ,
  • Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, and 5-6 membered heteroaryl are each optionally substituted by 1 , 2, or 3 substituents independently selected from halo, CN, OR a6 , SR a6 , C(0)R b6 , C(0)NR c6 R d6 , C(0)OR a6 ,
  • each R a6 , R b6 , R c6 , and R d6 is independently selected from H, C14 alkyl, C 2 4 alkenyl, C3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein said Ci-4 alkyl, C 2-4 alkenyl, C3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-4 alkyl, Ci -4 alkoxy, C 1-4 alky lthio, Ci alkylamino, and di(Ci -4 alkyl)amino;
  • n 1 or 2;
  • p is 1 , 2, or 3;
  • q 1 or 2;
  • any aforementioned 4-10 or 4-7 membered heterocycloalkyl group optionally comprises 1, 2, or 3 oxo substituents, wherein each oxo substituent that is present is substituted on a ring-forming carbon, nitrogen, or sulfur atom of the 4-10 or 4-7 membered heterocycloalkyl group.
  • L is O.
  • L is NR 4 .
  • W is CR 5 ; X is N; and Y is CR 7 .
  • W is N; X is N; and Y is CR 7 .
  • W is CR 5 ; X is CR 6 ; and Y is N.
  • W is CR 5 ;
  • X is CR 6 ; and
  • Y is CR 7 .
  • W is N; X is CR 6 ; and Y is CR 7 .
  • R 2 is H and R 3 is H.
  • R 2 is H and R 3 is C1-4 alkyl. In some embodiments, R 2 is H and R 3 is methyl.
  • R 2 is H and R 3 is C1-4 haloalkyl.
  • R 2 is H and R 3 is trifluoromethyl.
  • n 1
  • n is 2.
  • R 1 is H.
  • R 1 is Ci-io alkyl, C 3 -io cycloalkyl, phenyl, -(CR 8 R 9 ) p OC(0)R 10 , -(CR 8 R 9 )pNR n R 12 , or -(CR 8 R 9 ) p C(0)NR n R 12 , wherein said Ci-io alkyl, C3-10 cycloalkyl, and phenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from F, CI, Br, CN, C alkyl, and C14 haloalkyl.
  • R 1 is Ci-10 alkyl.
  • R 1 is ethyl
  • R 4 is H.
  • R 5 is H.
  • R 6 is H.
  • R 7 is other than H.
  • R 7 is C1-4 alkyl, NR 1 R 14 , or OR 15 .
  • R 7 is NR 1 R 14 .
  • R 7 is NH 2 .
  • R 7 is C 1-4 alkyl.
  • R 7 is OR 15 .
  • Ring A is C3-10 cycloalkyl.
  • Ring A is G5-10 aryl.
  • Ring A is phenyl
  • Ring A is 4 to 10-membered heterocycloalkyl.
  • Ring A is phenyl, adamantanyl, naphthyl, 1,2,3,4- tetrahydroquinoxalinyl, 3,4-dihydroqinazolinyl, 1,2,3,4-tetrahydroquinazolinyl, or pyridyl.
  • Ring A is 5 to 10-membered heteroaryl.
  • At least one of R A , R B , R c , and R D is other than hydrogen. In some embodiments, at least two of R A , R B , R c , and R D are other than hydrogen.
  • R A is Cy 1 . In some embodiments, R A is Gs-io aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R Cy .
  • R A is 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from K ⁇ .
  • R A is 5 to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from R Cy .
  • R A is pyrazolyl which is optionally substituted by 1 , 2, 3, 4, or 5 substituents independently selected from R Cy .
  • R A is 3-methyl-lH-pyrazol-l -yl.
  • R A is C6-io aryl optionally substituted by 1 , 2, or 3 substituents independently selected from R Cy .
  • R A is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from R Cy .
  • R B is H.
  • R B is Cy 2 , halo, Ci-6 alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, NO2,
  • R B is Cy 2 .
  • R B is Gs-io aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1 , 2, 3, 4, or 5 substituents independently selected from R Cy .
  • R B is halo, Ci-6 alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, N0 2 , OR a3 , SR a3 , C(0)R b3 , C(0)NR c R d3 , C(0)OR a3 , OC(0)R b3 , OC(0)NR c R d3 , NR c R d3 , NR c C(0)R b3 , NR c C(0)OR a3 , NR c C(0)NR c R d3 , NR c S(0)R b3 , NR c S(0) 2 R b3 , NR c S(0) 2 NR c R d3 , S(0)R b3 , S(0)NR c R d3 , S(0)R b3 , S(0)NR c R d3 , S(0)R b3 , and S(0) 2 NR c R d3 , wherein said G
  • R B is halo
  • R c is H.
  • R c is halo, Ci-6 alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, N0 2 , OR a4 , SR a4 , C(0)R b4 , C(0)NR c4 R d4 , C(0)OR a4 , OC(0)R b4 , OC(0)NR c4 R d4 , NR c4 R d4 , NR c4 C(0)R b4 , NR c4 C(0)OR a4 , NR c4 C(0)NR c4 R d4 , NR c4 S(0)R b4 , NR c4 S(0) 2 R b4 , NR c4 S(0) 2 NR c4 R d4 , S(0)R b4 , S(0)NR c4 R d4 , S(0)R b4 , S(0)NR c4 R d4 , S(0)R b4 , S(0)NR
  • R D is H.
  • R D is halo, Ci-6 alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, N0 2 , OR a4 , SR a4 , C(0)R b4 , C(0)NR c4 R d4 , C(0)OR a4 , OC(0)R b4 , OC(0)NR c4 R d4 , NR c4 R d4 , NR c4 C(0)R b4 , NR c4 C(0)OR a4 , NR c4 C(0)NR c4 R d4 , NR c4 S(0)R b4 , NR c4 S(0) 2 R b4 , NR c4 S(0) 2 NR c4 R d4 , S(0)R b4 , S(0)NR c4 R d4 , S(0)R b4 , S(0)NR c4 R d4 , S(0)R b4 , S(0)NR c
  • the compounds described herein have Formula Ila: lie.
  • the compounds described herein have Formula lid:
  • the compounds described herein have Formula He:
  • L is O.
  • L is NR4.
  • R 3 is H. In some embodiments, where the compounds described herein have Formula Ila, lib, lie, Ild, or He, R 2 is CF 3 and R 3 is H.
  • R 1 is H or Ci-io alkyl.
  • R A is Cy 1 .
  • R A is Gs-io aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R Cy .
  • R A is 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R Cy .
  • R A is 5 to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from R Cy .
  • R A is Gs-io aryl optionally substituted by 1, 2, or 3 substituents independently selected from R Cy .
  • R A is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from R Cy .
  • R B is Cy 2 .
  • R B is H, halo, Ci- 6 alkyl, C 2 -6 alkenyl, Ci- 6 haloalkyl, CN, OR a3 , C(0)NR c R d3 , or
  • Ci-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci -6 haloalkyl, CN, N0 2 , OR a3 , SR a3 , C(0)R b3 , C(0)NR c R d3 , C(0)OR a3 , OC(0)R b3 , OC(0)NR c R d3 , NR c R d3 , NR c C(0)R b3 , NR c C(0)OR a3 , NR c C(0)NR c R d3 , NR c S(0)R b3 , NR cl S(0) 2 R b3 , NR c S(0) 2 NR c R d3 , S(0)R b3 , S(0)NR c R d3 , S(0)R b3 , S(0)NR c R d3 , S(0)R b3 , S(0)NR
  • R D is H.
  • R 5 is H.
  • R 6 is H.
  • R 1 is H or Ci-io alkyl.
  • R A is Cy 1 .
  • R A is C6-io aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from K ⁇ .
  • R A is 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R Cy .
  • R A is 5 to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from K ⁇ .
  • R A is C 6 -io aryl optionally substituted by 1, 2, or 3 substituents independently selected from R Cy .
  • R A is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from K ⁇ .
  • R B is Cy 2 .
  • R B is H, halo, Ci -6 alkyl, C 2 - 6 alkenyl, Ci -6 haloalkyl, CN, OR a3 , C(0)NR c R d3 , or C(0)OR a3 , wherein said Ci-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci -6 haloalkyl, CN, NO2, OR a3 , SR a3 , C(0)R b3 , C(0)NR c R d3 , C(0)OR a3 , OC(0)R b3 , OC(0)NR c R d3 , NR c R d3 , NR c C(0)R b3 , NR c C(0)OR a3 , NR c C(0)NR c R d3 , NR c S(0)R b3 , NR cl S(0) 2 R b3 ,
  • R c is H.
  • R D is H
  • the compounds described herein have Formula IV:
  • R is H or Ci-io alkyl.
  • R A is
  • R A is C6-io aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R Cy .
  • R A is 5- 10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from K ⁇ .
  • R A is 5 to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from R Cy .
  • R A is C6-io aryl optionally substituted by 1, 2, or 3 substituents independently selected from R Cy .
  • R A is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from R Cy .
  • R B is
  • R is H, halo, Ci-6 alkyl, C 2 - 6 alkenyl, Ci -6 haloalkyl, CN, OR a3 , C(0)NR c R d3 , or C(0)OR a3 , wherein said Ci-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci -6 haloalkyl, CN, N0 2 , OR a3 , SR a3 , C(0)R b3 , C(0)NR c R d3 , C(0)OR a3 , OC(0)R b3 , OC(0)NR c R d3 , NR c R d3 , NR c C(0)R b3 , NR c C(0)OR a3 ,
  • R c is H
  • R D is H
  • the compounds described herein have Formula Va:
  • R 2 is
  • R is H or Ci-10 alkyl.
  • R A is
  • R A is Gs-io aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R Cy . In some embodiments, where the compounds described herein have Formula Va, R A is 5- 10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from K ⁇ .
  • R A is 5 to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected
  • R A is Gs-io aryl optionally substituted by 1, 2, or 3 substituents independently selected from R Cy .
  • R A is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from R Cy .
  • R B is
  • R B is H, halo, Ci-6 alkyl, C 2 - 6 alkenyl, Ci -6 haloalkyl, CN, OR a3 , C(0)NR c R d3 , or C(0)OR a3 , wherein said Ci-6 alkyl and C2-6 alkenyl are each optionally substituted with 1 , 2, or 3 substituents independently selected from halo, Ci -6 haloalkyl, CN, N0 2 , OR a3 , SR a3 , C(0)R b3 , C(0)NR c R d3 , C(0)OR a3 , OC(0)R b3 , OC(0)NR c R d3 , NR c R d3 , NR c C(0)R b3 , NR c C(0)OR a3 ,
  • the compounds described herein have Formula Vb:
  • R 2 is
  • R 1 is H or Ci-io alkyl.
  • R A is
  • R A is C6-io aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R Cy .
  • R A is 5-
  • R A is 5 to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from R Cy .
  • R A is C6-io aryl optionally substituted by 1, 2, or 3 substituents independently selected from R Cy .
  • R A is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from R Cy .
  • R B is
  • R B is H, halo, Ci-6 alkyl, C 2 - 6 alkenyl, Ct-s haloalkyl, CN, OR a3 , C(0)NR c R d3 , or C(0)OR a3 , wherein said Ci-6 alkyl and C2-6 alkenyl are each optionally substituted with 1 , 2, or 3 substituents independently selected from halo, Ci- 6 haloalkyl, CN, N0 2 , OR a3 , SR a3 , C(0)R b3 , C(0)NR c R d3 , C(0)OR a3 , OC(0)R b3 , OC(0)NR c R d3 , NR c R d3 , NR c C(0)R b3 , NR c C(0)OR a3 ,
  • the compounds described herein have Formula VI:
  • R 2 is CF 3 .
  • R 1 is H or Ci-io alkyl.
  • R B is
  • Cy 2 is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from R Cy .
  • R B is H, halo, Ci-6 alkyl, C 2 - 6 alkenyl, Ci -6 haloalkyl, CN, OR a3 , C(0)NR c R d3 , or C(0)OR a3 , wherein said Ci-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci -6 haloalkyl, CN, N0 2 , OR a3 , SR a3 , C(0)R b3 , C(0)NR c R d3 , C(0)OR a3 , OC(0)R b3 , OC(0)NR c R d3 , NR c R d3 , NR c C(0)R b3 , NR c C(0)OR a3 ,
  • R c is H. In some embodiments, where the compounds described herein have Formula VI, R D is H.
  • the compounds described herein have Formula VTA:
  • R 2 is
  • R 1 is
  • R B is
  • Cy 2 is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from R Cy .
  • R B is H, halo, Ci-6 alkyl, C 2 - 6 alkenyl, Ci -6 haloalkyl, CN, OR a3 , C(0)NR c R d3 , or C(0)OR a3 , wherein said Ci-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci -6 haloalkyl, CN, N0 2 , OR a3 , SR a3 , C(0)R b3 , C(0)NR c R d3 , C(0)OR a3 , OC(0)R b3 , OC(0)NR c R d3 , NR c R d3 , NR c C(0)R b3 , NR c C(0)OR a3 ,
  • the compounds described herein have Formula VII:
  • a is 0, 1, 2, or 3.
  • R 2 is CF 3 .
  • R 1 is H or Ci-io alkyl.
  • R B is
  • R B is
  • R B is H or halo.
  • R B is halo
  • R c is
  • R D is
  • R ⁇ is halo, Ci-6 alkyl, Ci -6 haloalkyl, 4-10 membered heterocycloalkyl, CN, N0 2 , OR a5 , SR a5 , C(0)R b5 , C(0)NR c5 R d5 , C(0)OR a5 , NR c5 R d5 , S(0) 2 R b5 , and S(0) 2 NR c5 R d5 , wherein said Ci -6 alkyl and 4- 10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci -6 alkyl, CN, N0 2 , OR a5 , SR a5 , C(0)R b5 , C(0)NR c5 R d5 , C(0)OR a5 , OC(0)R b5 , OC(0)NR c5 R d5
  • a is 0, 1, 2, or 3.
  • R 2 is
  • R 1 is H or Ci-io alkyl.
  • R B is Cy 2 .
  • R B is H, halo, Ci-6 alkyl, C 2-6 alkenyl, Ci -6 haloalkyl, CN, OR a3 , C(0)NR c R d3 , or C(0)OR a3 , wherein said Ci-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci -6 haloalkyl, CN, N0 2 , OR a3 , SR a3 , C(0)R b3 , C(0)NR c R d3 , C(0)OR a3 , OC(0)R b3 , OC(0)NR c R d3 , NR c R d3 , NR c C(0)R b3 , NR c C(0)OR a3 ,
  • R B is H or halo.
  • R B is halo
  • R c is
  • R D is
  • R Cy is halo, Ci-6 alkyl, Ci-6 haloalkyl, 4-10 membered heterocycloalkyl, CN, NO2, OR a5 , SR a5 , C(0)R b5 , C(0)NR c5 R d5 , C(0)OR a5 , NR c5 R d5 , S(0) 2 R b5 , and S(0) 2 NR c5 R d5 , wherein said Ci-6 alkyl and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci -6 alkyl, CN, N0 2 , OR a5 , SR a5 , C(0)R b5 , C(0)NR c5 R d5 , C(0)OR a5 , OC(0)R b5 , OC(0)NR c5 R d5 ,
  • the chiral carbon to which -C(0)OR 1 is attached has an S configuration.
  • the carbon to which -R 2 is attached is chiral and has an R configuration.
  • the compound used in the methods described herein is (S)-ethyl 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-carboxylate, or a pharmaceutically acceptable salt thereof.
  • the compound used in the methods described herein is (S)-8-(2- amino-6-((R)-l-(5-chloro-[l, -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 compound used in the methods described herein is (S)-ethyl 8- (2-amino-6-((R)-l-(3',4'-dimethyl-3-(3-methyl-lH-pyrazol-l-yl)-[l,r-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate, or a pharmaceutically acceptable salt thereof.
  • the compound used in the methods described herein is (S)-8-(2- amino-6-((R)- 1 -(3 ',4'-dimethy 1-3 -(3 -methyl- 1 H-pyrazol- 1 -yl)- [1,1 '-bipheny 1] -4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid, or a
  • the compound used in the methods described herein is (S)-ethyl 8- (2-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate, or a pharmaceutically acceptable salt thereof.
  • the compound used in the methods described herein is (S)-8-(2- amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-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).
  • the compound used in the methods described herein is (S)-ethyl 8-
  • the compound is (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(3'- fluoro-3-(3-methyl-lH-pyrazol-l-yl)-4'-propoxy-[l, -biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid, or a pharmaceutically acceptable salt thereof.
  • the substituents are independently selected, and substitution may be at any chemically accessible position. It is to be understood that substitution at a given atom is limited by valency.
  • the term "Ci-j" indicates a range which includes the endpoints, wherein i and j are integers and indicate the number of carbons. Examples include C1-4, Ci-6, and the like.
  • n- member ed where n is an integer typically describes the number of ring- forming atoms in a moiety where the number of ring-forming atoms is n.
  • piper idinyl 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
  • 1, 2, 3, 4- tetrahydro -naphthalene is an example of a 10-membered cycloalkyl group.
  • aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described. Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member as permitted by valency.
  • a pyridine ring or “pyridinyl” may refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring.
  • each variable can be a different moiety independently selected from the group defining the variable.
  • the two R groups can represent different moieties independently selected from the group defined for R.
  • Ci-j alkyl refers to a saturated hydrocarbon group that may be straight-chain or branched, having i to j carbon atoms.
  • the alkyl group contains from 1 to 10, 1 to 6, 1 to 4, or from 1 to 3 carbon atoms.
  • alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, ⁇ -propyl, isopropyl, n-butyl, s-butyl, and t-butyl.
  • Ci-j alkoxy refers to a group of formula -O-alkyl, wherein the alkyl group has i to j carbon atoms.
  • Example alkoxy groups include methoxy, ethoxy, and propoxy (e.g., n-propoxy and isopropoxy). In some embodiments, the alkyl group has 1 to 3 carbon atoms or 1 to 4 carbon atoms.
  • Ci-j alkenyl refers to an alkyl group having one or more double carbon- carbon bonds and having i to j carbon atoms. In some embodiments, the alkenyl moiety contains 2 to 6 or to 2 to 4 carbon atoms.
  • Example alkenyl groups include, but are not limited to, ethenyl, w-propenyl, isopropenyl, w-butenyl, seobutenyl, and the like.
  • Ci-j alkylamino refers to a group of formula -NH( alkyl), wherein the alkyl group has i to j carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • di-Ci-j-alkylamino refers to a group of formula -N(alkyl) 2 , wherein the two alkyl groups each has, independently, i to j carbon atoms.
  • each alkyl group independently has 1 to 6 or 1 to 4 carbon atoms.
  • thio refers to a group of formula -SH.
  • Ci-j alkylthio refers to a group of formula -S-alkyl, wherein the alkyl group has i to j carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • amino refers to a group of formula -NH 2 .
  • Ci-j aryl refers to a monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbon having i to j ring-forming carbon atoms, such as, but not limited to, phenyl, 1 -naphthyl, 2- naphthyl, anthracenyl, phenanthrenyl, and the like.
  • aryl is C 6 -io aryl.
  • the aryl group is a naphthalene ring or phenyl ring.
  • the aryl group is phenyl.
  • arylalkyl refers to a group of formula -Ci-j alkyl-(Ci-j aryl). In some embodiments, arylalkyl is Gs-io aryl-Ci-3 alkyl. In some embodiments, arylalkyl is Gs-io aryl-Ci-4 alkyl. In some embodiments, arylalkyl is benzyl.
  • Cycloalkyl refers to a non-aromatic cyclic hydrocarbon moiety having i to j ring-forming carbon atoms, which may optionally contain one or more alkenylene groups as part of the ring structure.
  • Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems.
  • cycloalkyl moieties that have one or more aromatic rings (aryl or heteroaryl) fused to the cycloalkyl ring, for example, benzo or pyrido derivatives of cyclopentane, cyclopentene, cyclohexane, and the like.
  • the cycloalkyl group includes a fused aromatic ring
  • the cycloalkyl group can be attached at either an atom in the aromatic or non-aromatic portion.
  • One or more ring-forming carbon atoms of a cycloalkyl group can be oxidized to form carbonyl linkages.
  • cycloalkyl is C3-10 or C3-7 cycloalkyl, which can be monocyclic or polycyclic.
  • exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantanyl and the like.
  • the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • cycloalkylalkyl refers to a group of formula— Ci-j alkyl-(Ci-j cycloalkyl).
  • cycloalkylalkyl is C3-7 cycloalkyl- C 1-3 alkyl, wherein the cycloalkyl portion is monocyclic.
  • cycloalkylalkyl is C3-7 cycloalkyl-Ci4 alkyl.
  • Ci-j haloalkoxy refers to a group of formula -O-haloalkyl having i to j carbon atoms.
  • An example haloalkoxy group is OCF3.
  • An additional example haloalkoxy group is OCHF2.
  • the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • halo refers to a halogen atom selected from F, CI, I or Br. In some embodiments, “halo” refers to a halogen atom selected from F, CI, or Br. In some embodiments, the halo group is F.
  • Ci-j haloalkyl refers to an alkyl group having from one halogen atom to 2s+l halogen atoms which may be the same or different, where "s" is the number of carbon atoms in the alkyl group, wherein the alkyl group has i to j carbon atoms.
  • the haloalkyl group is fluoromethyl, difluoromethyl, or trifluoromethyl. In some embodiments, the haloalkyl group is trifluoromethyl. In some embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • heteroaryl refers to a monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic moiety, having one or more heteroatom ring members selected from nitrogen, sulfur and oxygen.
  • the heteroaryl group is a 5- to 10-membered heteroaryl ring, which is monocyclic or bicyclic and which has 1 , 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • the heteroaryl group is a 5- to 6-membered heteroaryl ring, which is monocyclic and which has 1 , 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • heteroaryl group When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different.
  • the nitrogen atoms in the ring(s) of the heteroaryl group can be oxidized to form N-oxides.
  • Example heteroaryl groups include, but are not limited to, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, azolyl, oxazole, thiazole, imidazole, furan, thiophene, quinoline, isoquinoline, indole, benzothiophene, benzofuran, benzisoxazole, imidazo[l,2-6]thiazole, purine, and the like.
  • a 5-membered heteroaryl is a heteroaryl group having five ring-forming atoms comprising carbon and one or more (e.g., 1 , 2, or 3) ring atoms independently selected from N, O, and S.
  • Example five-membered heteroaryls 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.
  • a six-membered heteroaryl is a heteroaryl group having six ring-forming atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S.
  • Example six-membered heteroaryls include pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.
  • heteroarylalkyl refers to a group of formula— Ci-j alkyl- (heteroaryl).
  • the heteroarylalkyl is 5-6 membered heteteroaryl-Ci-3 alkyl or 5-6 membered heteteroaryl-C 1 -4 alky 1, wherein the heteroaryl portion is monocyclic and has 1 , 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • heterocycloalkyl refers to a non-aromatic ring or ring system, which optionally contains one or more alkenylene groups as part of the ring structure, and which has at least one heteroatom ring member independently selected from nitrogen, sulfur and oxygen.
  • heteroatom ring member independently selected from nitrogen, sulfur and oxygen.
  • Heterocycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems, including spiro systems. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings (aryl or heteroaryl) fused to the non-aromatic ring, for example, 1,2,3,4-tetrahydro-quinoline, dihydrobenzofuran and the like. Where the
  • heterocycloalkyl group includes a fused aromatic ring, the heterocycloalkyl group can be attached at either an atom in the aromatic or non-aromatic portion.
  • the carbon atoms or heteroatoms in the ring(s) of the heterocycloalkyl group can be oxidized (e.g. have one or two oxo substituents) to form a carbonyl, or sulfonyl group (or other oxidized linkage) or a nitrogen atom can be quaternized.
  • the heterocycloalkyl group is 5- to 10- membered, which can be monocyclic or bicyclic and which has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • the heterocycloalkyl group is 5- to 6-membered or 5- to 7-membered.
  • heterocycloalkyl groups include 1, 2, 3, 4-tetrahydroquinoline, dihydrobenzofuran, azetidine, azepane, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, and pyran.
  • heterocycloalkyl groups include 2-oxotetrahydrofuranyl, 2-oxopyrrolidinyl, 2-oxoimidazolidinyl, l-oxo-l,2,3,4-tetrahydroisoquinolin-6-yl, and 2-oxo-l,3-dioxolan-4-yl.
  • heterocycloalkylalkyl refers to a group of formula Ci-j alkyl-
  • heterocycloalkyl In some embodiments, heterocycloalkylalkyl is 5-10 membered
  • the heterocycloalkyl portion is monocyclic or bicyclic and has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • heterocycloalkylalkyl is 5-6 membered heterocycloalkyl-Ci-4 alkyl wherein the heterocycloalkyl portion is monocyclic and has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • the compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereoisomers, are intended unless otherwise indicated.
  • An example method includes fractional recrystallization using a chiral resolving acid which is an optically active, salt-forming organic acid.
  • Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and
  • L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as ⁇ -camphorsulfonic acid.
  • resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of a-methylbenzylamine (e.g., S and R forms, or diastereoisomerically pure forms),
  • Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine).
  • an optically active resolving agent e.g., dinitrobenzoylphenylglycine
  • Suitable elution solvent composition can be determined by one skilled in the art.
  • Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton.
  • Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H- imidazole, 1H-, 2H- and 4 ⁇ -
  • Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • compound is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted.
  • Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.
  • Compounds herein identified by name or structure without specifying the particular configuration of a stereocenter are meant to encompass all the possible configurations at the stereocenter. For example, if a particular stereocenter in a compound of the invention could be R or S, but the name or structure of the compound does not designate which it is, than the stereocenter can be either R or S.
  • All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., hydrates and solvates) or can be isolated.
  • the compounds of the invention, or salts thereof are substantially isolated.
  • substantially isolated is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected.
  • Partial separation can include, for example, a composition enriched in the compounds of the invention.
  • Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds of the invention, or salt thereof. Methods for isolating compounds and their salts are routine in the art.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • ambient temperature and “room temperature,” as used herein, are understood in the art, and refer generally to a temperature, e.g., a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a
  • the present invention also includes pharmaceutically acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an 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 or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, EtOAc, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (CH3CN) are preferred.
  • non-aqueous media like ether, EtOAc, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (CH3CN) are preferred.
  • suitable salts are found in Remington's Pharmaceutical Sciences, 17 th Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, (5(5(1), 1-19, and in Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection
  • the term "individual” or “patient,” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the phrase "therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • treating refers to 1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology), or 2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology).
  • preventing refers to inhibiting onset or worsening of the disease; for example, in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.
  • the therapeutic methods of the invention can further include administering at least one additional therapeutic agent together with the TPHl -inhibiting compound or prodrug thereof.
  • the additional therapeutic agent can be combined with the TPHl -inhibiting agent or prodrug thereof in a single dosage form, or the agents can be administered simultaneously or sequentially in separate dosage forms.
  • Additional therapeutic agents for combination therapy include, for example, ASK1 inhibitors such as GS-4997, monoclonal antibodies against LOXL2 such as seuzumab, non-steroidal anti- inflammatory drugs (NSAID), and anti-hyperlipidemic agents (e.g., a fibrate, a statin, a tocotrienol, a niacin, a bile acid sequestrants (resin), a cholesterol absorption inhibitor, a pancreatic lipase inhibitor, and a sympathomimetic amine).
  • fibrates includes bezafibrate, ciprofibrate, clofibrate, gemfibrozil, and fenofibrate.
  • cholesterol absorption inhibitors examples include ezetimibe, a phytosterol, a sterol, and a stanol.
  • Other agents include pioglitazone, vitamin E, and metformin.
  • Additional treatment methods can include reducing weight (if the patient is obese or overweight), having a balanced and healthy diet, increasing physical activity, and avoiding alcohol.
  • the methods described herein include administering a TPH1 -inhibiting agent or prodrug thereof described herein to patients (e.g., animals and humans) in need of such treatment in appropriate dosages that will provide prophylactic and/or therapeutic efficacy.
  • the dose and dosing regimen required for use in the treatment or prevention of any particular disease or disorder will typically vary from patient to patient depending on, for example, particular compound or composition selected, the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medication or special diets then being followed by the patient, and other factors.
  • the appropriate dosage and dosing regimen can be determined by the treating physician.
  • a compound described herein can be administered orally, subcutaneously, topically, parenterally, or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • Parenteral administration can involve subcutaneous injections, intravenous or intramuscular injections or infusion techniques.
  • the compound(s) can be delivered in the form of an aerosol spray from pressurized packs or a nebulizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoro methane,
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • Treatment duration can be as long as deemed necessary by a treating physician.
  • the compounds and compositions can be administered one to four or more times per day. In some cases, depending on the properties of the compound and depending on the formulation, administration can be less than once per day, for example, once every other day or once per week.
  • a treatment period can terminate when a desired result, for example a particular therapeutic effect, is achieved. Or a treatment period can be continued indefinitely.
  • the methods described herein include administering to patients a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutical excipients or carriers.
  • compositions can be prepared as solid dosage forms for oral administration (e.g., capsules, tablets, pills, dragees, powders, granules and the like).
  • a tablet can be prepared by compression or molding.
  • Compressed tablets can include one or more binders, lubricants, glidants, inert diluents, preservatives, disintegrants, 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 a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches. Other suitable
  • pharmaceutical formulation and dosage forms include inhalants.
  • compositions of this invention suitable for parenteral administration include a compound of the invention together with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions.
  • the composition can be in the form of a sterile powder which can be reconstituted into a sterile injectable solutions or dispersion just prior to use.
  • TPHl inhibitors, and prodrugs thereof, described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art.
  • the compounds described in the Examples can be prepared according to the procedures provided in U.S. Pub. No. 2015/0080393, which is incorporated herein by reference in its entirety.
  • the procedures of Example lu below can be generally used to prepare TPHl -inhibiting compounds.
  • Step 1 To a solution of (R)-l-(4-bromo-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethanol (160 mg, 0.2 mmol, Intermediate 1, see US Pub. No. 2015/0080393 paragraph [0409]) in dioxane (2 mL) was added 2-amino-4,6-dichloropyrimidine (100 mg, 0.16 mmol) and CS2CO3 (48 ,g, 0.16 mmol). The reaction was heated to 80 °C for 16 h, cooled to RT, and filtered.
  • Step 2 To a solution of 4-[(lR)-l-[4-bromo-2-(3-methylpyrazol-l-yl)phenyl]-2,2,2-trifluoro- ethoxy]-6-chloro-pyrimidin-2-amine (125 mg, 0.3 mmol, Step 1) in dioxane (3 mL) was added (S)-2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (95 mg, 0.3 mmol, US Pub. No. 2015/0080393 paragraph [0469]) and Na 2 C0 3 (182 mg, 0.35 mmol).
  • Step 3 To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-l-(4-bromo-2-(3-methyl-lH- pyrazol-l-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3- dicarboxylate (300 mg, 0.4 mmol, Step 2) in ethanol (2 mL) and water (0.5 mL) was added phenylboronic acid (143 mg, 0.8 mmol), PdCl 2 (PPh 3 )2 (41 mg, 0.058 mmol), and Cs 2 C0 3 (390 mg, 1.2 mmol). The reaction was heated to 60 °C for 16 h, then cooled to RT, filtered through celite and concentrated in vacuo. Purification by normal phase silica gel column
  • Step 4 A solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-l-(3-(3-methyl-lH- pyrazol-l-yl)-[l,l'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3- dicarboxylate (240 mg, 0.4 mmol, Step 3) in EtO Ac (5 mL) was hyrogenated using an H-Cube apparatus and a 10% (w/w) Pd/C cartridge with a flow rate of 1.0 mL/min at RT.
  • Step 5 To a solution of (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-l-(3-(3-methyl-lH-pyrazol- l-yl)-[l,l'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (50 mg, 0.08 mmol) from Step 4 in THF (2.0 mL) and water (0.2 mL), was added lithium hydroxide monohydrate (58 mg, 0.05 mmol).
  • Example lm (S)-8-(2-amino-6-((R)-l-(3',4'-dimethyl-3-(3-methyl-lH-pyrazol-l-yl)-[l,l'- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
  • Example 3a (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(2-(3-methyl-lH-pyrazol-l-yl)-4-(l- (methylsulfonyl)piperidin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
  • Example 5a (S)-8-(2-amino-6-((R)-l-(3'-(ethoxycarbonyl)-3-(3-methyl-lH-pyrazol-l-yl)- [1,1 '-biphenyl] -4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
  • Example 5b (S)-8-(2-amino-6-((R)- l-(4'-(ethoxycarbonyl)-3- (3-methyl- IH-pyrazol- 1-yl)- [l,l'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
  • Example 12a (S)-8-(2-amino-6-((R)-l-(4-ethyl-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin- -yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
  • Example 13 (3S)-8-(2-amino-6-((lR)-l-(4-(l,2-dihydroxyethyl)-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
  • Example 17 (S)-8-(2-amino-6-((R)-l-(4-(ethoxycarbonyl)-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
  • Example 18a (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4-(((l,l,l,3,3,3-hexafluoro-2- methylpropan-2-yl)oxy)carbonyl)-2-(3-methyl-lH-pyrazol-l-yl)phenyl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
  • Example 19a (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(2-(3-methyl-lH-pyrazol-l-yl)-5- vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
  • Example 22a (S)-8-(2-amino-6-((R)-l-(5-ethyl-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
  • Example 28 (S)-8-(6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)-2-methyl pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic
  • Example 30a 8-(6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)-2-phenoxypyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
  • Example 34c (S)-8-(2-amino-6-((R)-l-(5-chloro-[l,l'-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4- l)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
  • Step 1 To a solution of (R)-l-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethanol (Intermediate 43, see U.S. Pub. No. 2015/0080393 paragraph [0463]) (400 mg, 1.4 mmol) in dioxane (25 mL) was added 4,6-dichloropyrimidin-2-amine (1.1 g, 7 mmol) and CS2CO3 (1.3 g, 4 mmol). The mixture was heated for 24 h at 80 °C. The reaction was then cooled to RT and filtered. The solvent was removed in vacuo, then CH2CI2 and heptane was added. The solvent volume was reduced until a solid precipitated out.
  • Step 2 To a solution of (R)-4-(l-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)-6- chloropyrimidin-2-amine (100 mg, 0.24 mmol, Step 1) in dioxane (5 mL) was added (S)-2- benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (100 mg, 0.29 mmol, U.S. Pub. No. 2015/0080393 paragraph [0469]), and NaHC0 3 (300 mg, 3.5 mmol).
  • Step 3 To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-l-(2-bromo-4-chlorophenyl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (100 mg, 0.13 mmol) in 10: 1 dioxane:water (5 mL) was phenyl boronic acid (33 mg, 0.27 mmol), KHCO3 (27 mg, 0.3 mmol), and PdC ⁇ dppfj-CEbCb. (6 mg, 0.007 mmol).
  • Step 4 N-CBZ Deprotection was accomplished via method B to provide (S)-ethyl 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-carboxylate an off-white solid.
  • Step 5 Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-[l,r-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the LiOH general method provided the title compound as an off-white solid as the zwitterionic form.
  • Example 36b (S)-8-(6-((R)-l-(2-(lH-benzo[d]imidazol-l-yl)-4-chlorophenyl)-2,2,2- trifluoroethoxy)-2-aminop rimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
  • Example 36c (S)-8-(2-amino-6-((R)-l-(4-chloro-2-(lH-indazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
  • Example 36d (S)-8-(2-amino-6-((R)-l-(4-bromo-2-(piperazin-l-yl)phenyl)-2,2,2 trifluoroethoxy)pyrimidin- -yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
  • Example 36e (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4'-isopropoxy-3-(piperazin-l-yl)- [l,l'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
  • Example 36f (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4'-isopropoxy-3-morpholino-[l,l'- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
  • Example 39a 8-(4-Amino-6-((naphthalen-2-ylmethyl)amino)-l,3,5-triazin-2-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
  • Example 40 8-(4-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)-l,3,5-triazin-2- l)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
  • Example 42a (S)-8-(2-amino-6-((R)-l-(3'-chloro-[l,l'-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4- l)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
  • Example 42b (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(3'-fluoro-[l,l , -biphenyl]-2- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
  • Example 50 (S)-8-(2-Amino-6-((R)-2,2,2-trifluoro-l-(3'-(methylsulfonyl)-4-((E)-prop-l-en- l-yl)-[l,l'-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
  • Example 51a (S)-8-(6-((R)-l-([l,l , :4',l M -terphenyl]-2 , -yl)-2,2,2-trifluoroethoxy)-2- aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
  • Example 51b (S)-8-(6-((R)-l-([l,l , :3 , ,l M -terphenyl]-2'-yl)-2,2,2-trifluoroethoxy)-2- aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
  • Example 52a (S)-8-(2-Amino-6-((R)-l-(3,4-dimethyl-3"-(methylsulfonyl)-[l,l':3 , ,l M - terphenyl]-4'-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
  • Example 54a (S)-8-(2-Amino-6-((R)-2,2,2-trifluoro-l-(3'-(methylsulfonyl)-5-propyl-[l,l'- biphenyl]-2-yl)ethoxy)pyrimidin-4- l)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
  • Example 54b (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4-isopropoxy-[l,l':3',l"-terphenyl]- 4'-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
  • Example 54c (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4-propoxy-[l,l':3',l"-terphenyl]-4'- yl)ethoxy)pyrimidin-4- l)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
  • Example 54d (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(5-(methylsulfonyl)-[l,l'-biphenyl]-2- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
  • Example 54e (S)-8-(2-amino-6-((R)-2,2,2-trifluoro- l-(3-fluoro-4-p ropoxy- [1 , 1 ' :3' , 1 "- terphenyl]-4'-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
  • Example 54f (S)-8-(2-amino-6-((R)-l-(3,4-dimethyl-[l,l':3',l M -terphenyl]-4 , -yl)-2,2,2- trifluoroethoxy)pyrimidin-4- l)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
  • Example 54i (R)-8-(2-amino-6-((S)-l-(5-chloro-[l,l'-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4- l)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
  • Example 54j (S)-8-(2-amino-6-((S)-l-(5-chloro-[l,l'-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4- l)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
  • Example 54k (S)-8-(2-amino-6-((S)-l-(3',4 , -dimethyl-3-(3-methyl-lH-pyrazol-l-yl)-[l,l'- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
  • Example 541 (R)-8-(2-amino-6-((S)-l-(3',4 , -dimethyl-3-(3-methyl-lH-pyrazol-l-yl)-[l,l'- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
  • Example 54m ( ⁇ -S-i -amino-e-ii ⁇ -l-iS' ⁇ '-dimethyl-S-iS-methyl-lH-pyrazol-l-yl)-!,!'- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
  • Example 55an (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(3'-methoxy-[l,l , -biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
  • diazaspiro[4.5]decane-3-carboxylic acid be (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4-(isoquinolin-7- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
  • Example 59a (S)-8-(2-amino-6-((R)-l-(4-bromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decan -3-carboxylic acid
  • Example 59b (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(naphthalen-2-yl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decan -3-carboxylic acid
  • Example 60 9-(2-Amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4- l)-3,9-diazaspiro[5.5]undecane-2-carboxylic acid
  • reaction mixture was then warmed to RT for an additional 30-40 min, then cooled to 0-5 °C, and 2 M HCl in diethyl ether (0.5 mL) was added. The reaction mixture was then allowed to warm RT and then concentrated in vacuo. Normal phase silica gel chromatography provide the title compound as an off-white solid.
  • Example 64a (S)-Octyl 8-(2-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate
  • Example 65a (S)-Tert-butyl 8-(2-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate
  • Example 66a (S)-2-(Dimethylamino)ethyl 8-(2-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH- pyrazol-l-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
  • Example 67a (S)-isopropyl 8-(2-amino-6-((R)-l-(3',4'-dimethyl-3-(3-methyl-lH-pyrazol-l- yl)-[l,l'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
  • Example 68a (S)-isopropyl 8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4'-isopropoxy-3-(3-methyl- lH-pyrazol-l-yl)-[l,l'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
  • Example 69a (S)-isopropyl 8-(2-amino-6-((R)-l-(5-chloro-[l,l'-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate
  • Example 70 (S)-methyl 8-(2-amino-6-((R)-l-(5-chloro-3'-(methylsulfonyl)-[l,l'-biphenyl]- 2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate
  • TPH1 -inhibiting compounds, their prodrugs, and dosage forms, useful according to the present invention include telotristat and salts thereof, including telotristat etiprate (LX1032). See, for example, U.S. Pat. Pub. Nos. 2008/0153852, 2009/0029993, 2009/0088447, 2010/0240906, 2012/0316171, 2013/0137635, 2013/0172376, 2013/0303763 and PCT Pub. No. WO 2010/065333 and WO 2014/082034.
  • Example A Murine Model of NASH C57bl6 Mice on a Methionine-Choline Deficient (MCD) Diet

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

TRYPTOPHAN HYDROXYLASE INHIBITORS FOR USE IN THE TREATMENT
OF LIVER DISEASES
FIELD OF THE INVENTION
The present invention 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), or prodrugs thereof.
BACKGROUND OF THE INVENTION
Liver diseases such as non-alcoholic fatty liver disease (NAFLD) is characterized by the presence of hepatic steatosis, with or without inflammation and fibrosis, in the absence of alcohol history. NAFLD includes non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH). NASH affects about 2 to 5 percent of Americans according to the National Heath Instistute. NASH can occur in people who drink little or no alcohol and is usually a silient disease with few or no symptoms. NASH can be characterized by having fat in the liver, which is not normal, as well as having inflammation and damage. Although some people with NASH may feel normal, NASH can become severe and lead to fibrosis and cirrhosis, where the liver is permanently damaged and scarred. Diseased or damaged liver tissue caused, for example, from NASH-related cirrhosis can eventually lead to hepatocellular carcinoma.
Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that modulates central and peripheral functions by acting on neurons, smooth muscle, and other cell types. 5-HT is involved in the control and modulation of multiple physiological and psychological processes. Dysregulation of the peripheral 5-HT signaling system has been reported to be involved in the etiology of several conditions such as inflammatory (e.g. Margolis, K. G. 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 Activates Dendritic Cell Function In The Context Of Gut
Inflammation. The American Journal of Pathology 178, 662-71 (2011)), and liver diseases or disorders (e.g. Ebrahimkhani, M. R. 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, Oct 2010, 151(10): 4776-4786; and Crane, J.D. et al. Nature Medicine 21(2), 166-172 (2015).
Two vertebrate isoforms of tryptophan hydrolase (TPH), namely TPHl and TPH2, have been identified. TPHl is primarily expressed in the pineal gland and non-neuronal tissues, such as enterochromaffin (EC) cells located in the gastrointestinal (GI) tract. TPH2 (the dominant form in the brain) is expressed exclusively in neuronal cells, such as dorsal raphe or myenteric plexus cells. The peripheral and central systems involved in 5-HT biosynthesis are isolated, with 5-HT being unable to cross the blood-brain barrier. Therefore, the pharmacological effects of 5- HT can be modulated by agents affecting TPH in the periphery, mainly TPHl in the gut.
Increased 5-HT has been proposed to impact the pathophysiology of the liver through multiple mechanisms. For example, accumulation of lipids can sensitize the liver to
pathophysiology associated with NASH; hepatic oxidation of 5-HT can generate lipid peroxide and ROS leading to mitochondrial dysfunction; and pro-fibrotic and mitogenic activity mediated through 5-HT receptor binding and TGFP signaling leads to fibrosis.
There is a need for new therapies to treat liver diseases such as NAFLD, NASH, and hepatocellular carcinoma. The methods described herein employing TPHl inhibiors are intended to address this need.
SUMMARY OF THE I VENTION
The present disclosure relates to methods of treating or preventing liver diseases such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma in a patient, comprising administering to the patient a therapeutically effective amount of a TPHl inhibitor, or prodrug thereof.
The present disclosure also relates to methods of decreasing alanine aminotransferase (ALT), aspartate aminotransferase (AST), cholesterols, triglycerides, or glucose in a patient comprising administering to the patient a therapeutically effective amount of a TPHl inhibitor, or prodrug thereof. The present disclosure also relates to methods of reducing lipid deposits in the liver of a patient comprising administering to the patient a therapeutically effective amount of a TPH1 inhibitor, or prodrug thereof.
The present disclosure further relates to a TPH1 inhibitor, or prodrug thereof, for use in the treatment or prevention of liver diseases such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma in a patient.
The present disclosure further relates to use of a TPH1 inhibitor, or prodrug thereof, in the treatment or prevention of liver diseases such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma in a patient.
The present disclosure further relates to use of a TPH1 inhibitor, or prodrug thereof, for the preparation of a medicament for the treatment or prevention of liver diseases such as nonalcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma in a patient.
DETAILED DESCRIPTION
The present disclosure relates to methods of treating or preventing liver diseases, such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma in a patient, comprising administering to said patient a therapeutically effective amount of a TPH inhibitor, such as a TPH1 inhibitor, or a prodrug thereof. In some embodiments, the diasease is NAFLD. In some embodiments, the disease is NASH. In some embodiments, the disease is hepatocellular carcinoma.
The present disclosure also includes methods of treating or preventing one or more diseases or symptoms that can be associated with NAFLD, NASH, or hepatocellular carcinoma in a patient comprising administering to the patient a therapeutically effective amount of a TPH inhibitor, such as a TPH1 inhibitor, or a prodrug thereof. These diseases or symptoms include, for example, inflammation, fibrosis, cirrhosis, fatigue, weight loss, weakness, fluid retention, muscle wasting, bleeding from the intestines, liver failure, weight gain, obese, diabetes (e.g., type 2 diabetes or type 1 diabetes), prediabetes, lipid disorders, elevated serum lipids, elevated liver enzymers in serum, elevated cholesterol, and elevated triglycerides.
Also provided herein are methods of decreasing alanine aminotransferase (ALT), aspartate aminotransferase (AST), cholesterols, triglycerides, or glucose in a patient (e.g., in a patient's serum concentrations and/or liver) 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 methods provided herein also include reducing lipid deposits in the liver of a patient 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 decreasing the concentration of ALT in a patients serum or liver. In some embodiments, the method is a method of decreasing the concentration of AST in a patients serum or liver.
Examples of TPHl inhibitors, and their corresponding prodrugs, that can be used according to the methods of the present invention are described, for example, in U.S. Patent Publication Nos. 2016/0272655, 2016/0096836, 2015/0366865, 2015/00080393, 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, 2009/0005381, and
2008/0108077, as well as in PCT Pub. No.WO 2016/109501 and WO 2016/109501, each of which is incorporated herein by reference in its entirety. An example prodrug that can be used according the methods of the present invention is the ester compound (S)-ethyl 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-carboxylate which can be metabolized internally by a patient to form the corresponding acid compound (S)-8-(2-amino-6-((R)-l-(5-chloro-[l,l'-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid, which is a TPHl inhibitor.
In some embodiments, the compound that can be used according to the methods of the invention is a compound of Formula I:
Figure imgf000005_0001
I
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is C3-10 cycloalkyl, C6-io 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;
wherein only one of X and Y is N;
R1 is H, Ci-10 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, -(CR8R9)pOC(0)R10, -(CR8R9)PNRUR12 , or -(CR8R9)pC(0)NRnR12, wherein said Ci-10 alkyl, C3 -10 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and phenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from F, CI, Br, CN, C1-4 alkyl, and Ci-4 haloalkyl;
R2 and R3 are each independently selected from H, C1-4 alkyl, and C1-4 haloalkyl;
R4 is H or Ci-4 alkyl;
R5 and R6 are each independently selected from H, halo, and C1-4 alkyl;
R7 is H, Ci-4 alkyl, C2-6 alkenyl, C3 -10 cycloalkyl, C3-io cycloalkyl-Ci4 alkyl, C6-io aryl, Gs- 10 aryl-Ci-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci -4 alkyl, 5-10 membered heteroaryl, (5-10 membered heteroaryl)-Ci-4 alkyl, NR1 R14, OR15, C(0)R16,
S(0)qR17, wherein said C1-4 alkyl, C2-6 alkenyl, C3 -10 cycloalkyl, C3-io cycloalkyl-Ci-4 alkyl, G5-10 aryl, C6-io aryl-Ci alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalky 1)- C1-4 alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl)-Ci4 alkyl are each optionally substituted by 1, 2, or 3 substituents selected from halo, C1-4 alkyl, C2-6 alkenyl, amino, Ci-4 alkylamino, C2-8 dialkylamino, hydroxy, and Ci-4 alkoxy;
R8 and R9 are each independently selected from H and C1-4 alkyl;
R10 is Ci-6 alkyl optionally substituted by 1, 2 or 3 substituents independently selected from Ci-6 haloalkyl, C3 -10 cycloalkyl, ORa, and NRcRd;
R11 and R12 are each independently selected from H and Ci-6 alkyl;
R13 is H or C1-4 alkyl; R is H, Ci-4 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-Ci alkyl, C6-io aryl, C6-io aryl-Ci-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, 5-10 membered heteroaryl, or (5-10 membered heteroaryl)-Ci-4 alkyl, C(0)Rbl, C(0)ORal,
C(0)NRclRdl, S(0)Rbl, S(0)2RM, or S(0)2NRclRdl, wherein said CM alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-Ci-4 alkyl, C6-io aryl, C6-io aryl-Ci-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci -4 alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl)-Ci-4 alkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CM alkyl, CM haloalkyl, CN, N02, OR'1, SRal, C(0)Rbl, C(0)NRclRdl, C(0)ORal, OC(0)Rbl, OC(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)ORal,
NRclC(0)NRclRdl, NRclS(0)Rbl, NRclS(0)2Rbl, NRclS(0)2NRclRdl, S(0)Rbl, S(0)NRclRdl, S(0)2Rbl, and S(0)2NRclRdl;
or R13 and R14 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7- membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents
independently selected from Ci-6 alkyl, C3 -7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, 5-6 membered heteroaryl, halo, CN, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)ORal, OC(0)Rbl, OC(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)ORal, S(0)Rbl, S(0)NRclRdl, S(0)2Rbl, NRclS(0)2Rbl, NRclS(0)2NRclRdl, and S(0)2NRclRdl, wherein said Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Gs-io aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)ORal, OC(0)Rbl,
OC(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)ORal, S(0)Rbl,
S(0)NRclRdl, S(0)2Rbl, NRclS(0)2Rbl, NRclS(0)2NRclRdl, and S(0)2NRclRdl;
R15 is H, Ci-4 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-Ci-4 alkyl, Gs-io aryl, C6-io aryl-Ci-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci4 alkyl, 5-10 membered heteroaryl, or (5-10 membered heteroaryl)-Ci-4 alkyl, wherein said CM alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-Ci-4 alkyl, Gs-io aryl, G5-10 aryl-Ci4 alkyl, 4-10 membered
heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl)-Ci4 alkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Gs-io aryl, 5-6 membered heteroaryl, CN, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)ORal, OC(0)Rbl, OC(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)ORal, S(0)Rbl,
S(0)NRclRdl, S(0)2RM, NRclS(0)2RM, NRclS(0)2NRclRdl, and S(0)2NRclRdl;
R16 is Ci4 alkyl or NR18aR18b wherein said C1-4 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, 5-6 membered heteroaryl, CN, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)ORal, OC(0)Rbl, OC(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)ORal, S(0)Rbl, S(0)NRclRdl, S(0)2Rbl, NRclS(0)2Rbl, NRclS(0)2NRclRdl, and S(0)2NRclRdl;
R17 is Ci-4 alkyl, NR18aR18b, or OR18c, wherein said C1-4 alkyl is optionally substituted by 1 , 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, 5-6 membered heteroaryl, CN, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)ORal, OC(0)Rbl, OC(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl,
NRclC(0)ORal, S(0)Rbl, S(0)NRclRdl, S(0)2Rbl, NRclS(0)2Rbl, NRclS(0)2NRclRdl, and S(0)2NRclRdl;
R18a and R18b are each independently selected from H and C1-4 alkyl wherein said C1-4 alkyl is optionally substituted by 1 , 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, 5-6 membered heteroaryl, CN, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)ORal, OC(0)Rbl, OC(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRc4C(0)ORal, S(0)Rbl, S(0)NRclRdl, S(0)2Rbl, NRclS(0)2Rbl,
NRclS(0)2NRclRdl, and S(0)2NRclRdl;
or R18a and R18b together with the N atom to which they are attached form a 4-, 5-, 6-, or
7-membered heterocycloalkyl group optionally substituted with 1 , 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, 5-6 membered heteroaryl, halo, CN, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)ORal, OC(0)Rbl, OC(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)ORal, S(0)Rbl, S(0)NRclRdl, S(0)2Rbl, NRclS(0)2Rbl, NRclS(0)2NRclRdl, and S(0)2NRclRdl, wherein said Ci-6 alkyl, C3 -7 cycloalkyl, 4-7 membered heterocycloalkyl, Gs-io aryl, and 5-6 membered heteroaryl are each optionally substituted by 1 , 2, or 3 substituents independently selected from halo, CN, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)ORal, OC(0)Rbl,
OC(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)ORal, S(0)Rbl,
S(0)NRclRdl, S(0)2Rbl, NRclS(0)2Rbl, NRclS(0)2NRclRdl, and S(0)2NRclRdl; R c is H, Ci-6 alkyl, C3-io cycloalkyl, C3-7 cycloalkyl-Ci-4 alkyl, Gs-io aryl, C6-io aryl-Ci-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, 5-10 membered heteroaryl, or (5-10 membered heteroaryl)-Ci-4 alkyl, wherein said Ci-6 alkyl, C3-7 cycloalkyl, C3-io cycloalkyl-Ci alkyl, Gs-io aryl, C6-io aryl-Ci alkyl, 4-10 membered
heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci4 alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl)-Ci-4 alkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CM alkyl, CM haloalkyl, CN, N02, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)ORal, OC(0)Rbl, OC(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)ORal, NRclC(0)NRclRdl, NRclS(0)Rbl, NRclS(0)2Rbl, NRclS(0)2NRclRdl, S(0)Rbl, S(0)NRclRdl, S(0)2Rbl, and S(0)2NRclRdl;
RA is H, Cy1, halo, Ci-6 alkyl, C2-6 alkenyl, CN, N02, ORa2, SRa2, C(0)Rb2, C(0)NRc2Rd2, C(0)ORa2, OC(0)Rb2, OC(0)NRc2Rd2, NR^R^, NRc2C(0)Rb2, NRc2C(0)ORa2,
NRc2C(0)NRc2Rd2, NRc2S(0)Rb2, NRc2S(0)2Rb2, NRc2S(0)2NRc2Rd2, S(0)Rb2, S(0)NRc2Rd2, S(0)2Rb2, or S(0)2NRc2Rd2, wherein said Ci-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy1, halo, Ci-6 alkyl, C2- 6 alkenyl, Ci-6 haloalkyl, CN, N02, ORa2, SRa2, C(0)Rb2, C(0)NRc2Rd2, C(0)ORa2, OC(0)Rb2, OC(0)NRc2Rd2, NRc2Rd2, NRc2C(0)Rb2, NRc2C(0)ORa2, NRc2C(0)NRc2Rd2, NRc2S(0)Rb2, NRc2S(0)2Rb2, NRc2S(0)2NRc2Rd2, S(0)Rb2, S(0)NRc2Rd2, S(0)2Rb2, and S(0)2NRc2Rd2;
RB is H, Cy2, halo, Ci-6 alkyl, C2-6 alkenyl, Ct-s haloalkyl, CN, N02, ORa3, SRa3, C(0)Rb3, C(0)NRc Rd3, C(0)ORa3, OC(0)Rb3, OC(0)NRc Rd3, NRc Rd3, NRc C(0)Rb3, NRc C(0)ORa3, NRc C(0)NRc Rd3, NRc S(0)Rb3, NRc S(0)2Rb3, NRc S(0)2NRc Rd3, S(0)Rb3, S(0)NRc Rd3, S(0)2Rb3, or S(0)2NRc Rd3, wherein said Ci-e alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy2, halo, Ci-6 alkyl, C2- 6 alkenyl, Ci-6 haloalkyl, CN, N02, ORa3, SRa3, C(0)Rb3, C(0)NRc Rd3, C(0)ORa3, OC(0)Rb3, OC(0)NRc Rd3, NRc Rd3, NRc C(0)Rb3, NRc C(0)ORa3, NRc C(0)NRc Rd3, NRc S(0)Rb3, NRclS(0)2Rb3, NRc S(0)2NRc Rd3, S(0)Rb3, S(0)NRc Rd3, S(0)2Rb3, and S(0)2NRc Rd3;
Rc and RD are each independently selected from H, halo, Ci-6 alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, N02, ORa4, SRa4, C(0)Rb4, C(0)NRc4Rd4, C(0)ORa4, OC(0)Rb4, OC(0)NRc4Rd4, NRc4Rd4, NRc4C(0)Rb4, NRc4C(0)ORa4, NRc4C(0)NRc4Rd4, NRc4S(0)Rb4, NRc4S(0)2Rb4, NRc4S(0)2NRc4Rd4, S(0)Rb4, S(0)NRc4Rd4, S(0)2Rb4, and S(0)2NRc4Rd4; wherein said G-s alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C6-io aryl, C3-io cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, Ci-6 alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, N02, ORa4, SRa4, C(0)Rb4, C(0)NRc4Rd4, C(0)ORa4, OC(0)Rb4, OC(0)NRc4Rd4, NRc4Rd4, NRc4C(0)Rb4, NRc4C(0)ORa4, NRc4C(0)NRc4Rd4, NRc4S(0)Rb4, NRc4S(0)2Rb4, NRc4S(0)2NRc4Rd4, S(0)Rb4, S(0)NRc4Rd4, S(0)2Rb4, and S(0)2NRc4Rd4;
Cy1 and Cy2 are each independently selected from C6-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted by 1 , 2, 3, 4, or 5 substituents independently selected from RCy;
each R^ is independently selected from halo, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, G5-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO2, ORa5, SRa5, C(0)Rb5, C(0)NRc5Rd5, C(0)ORa5, OC(0)Rb5, OC(0)NRc5Rd5, NRc5Rd5,
NRc5C(0)Rb5, NRc5C(0)ORa5, NRc5C(0)NRc5Rd5, NRc5S(0)Rb5, NRc5S(0)2Rb5,
NRc5S(0)2NRc5Rd5, S(0)Rb5, S(0)NRc5Rd5, S(0)2Rb5, and S(0)2NRc5Rd5, wherein said Cw alkyl, C2-6 alkenyl C6-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, CN, N02, ORa5, SRa5, C(0)Rb5, C(0)NRc5Rd5, C(0)ORa5, OC(0)Rb5, OC(0)NRc5Rd5, NRc5Rd5, NRc5C(0)Rb5, NRc5C(0)ORa5, NRc5C(0)NRc5Rd5, NRc5S(0)Rb5, NRc5S(0)2Rb5, NRc5S(0)2NRc5Rd5, S(0)Rb5, S(0)NRc5Rd5, S(0)2Rb5, and
S(0)2NRc5Rd5;
each Ra, Ral, Ra2, Ra3, Ra4, and Ra5 is independently selected from H, Ci-6 alkyl, Ci-4 haloalkyl, C2-6 alkenyl, Gs-io aryl, C3 -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-io aryl-Ci-4 alkyl, C3-io cycloalkyl-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, or (4-10 membered heterocycloalkyl)-Ci-4 alkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, Gs- lo aryl, C3 -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Gs-io aryl- Ci4 alkyl, C3-10 cycloalkyl-Ci alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, and (4-10 membered heterocycloalkyl)-Ci-4 alkyl are each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, halo, CN, ORa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6,
NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6; each Rbl, Rb2, Rb3, Rb4, and Rb5 is independently selected from H, Ci-6 alkyl, Ci-4 haloalkyl, C2-6 alkenyl, C6-io aryl, C3 -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-io aryl-Ci-4 alkyl, C3-10 cycloalkyl-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, or (4-10 membered heterocycloalkyl)-Ci-4 alkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, Gs- 10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-io aryl- C1-4 alkyl, C3-io cycloalkyl-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, and (4-10 membered heterocycloalkyl)-Ci-4 alkyl are each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from Ci-4 alkyl, halo, CN, ORa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6,
NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
each Rc , Rd, Rcl, Rdl, Rc2, R^, Rc3, Rd3, Rc4, Rd4, Rc5, and Rd5 is independently selected from H, Ci-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C6-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-io aryl-Ci-4 alkyl, C3-io cycloalkyl-Ci-4 alkyl, (5- 10 membered heteroaryl)-Ci-4 alkyl, or (4- 10 membered heterocycloalkyl)-Ci-4 alkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, C6-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-io aryl-Ci-4 alkyl, C3-io cycloalkyl-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, and (4-10 membered heterocycloalkyl)-Ci-4 alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6,
NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6,
NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
or any Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, 5-6 membered heteroaryl, halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6,
S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6, wherein said Ci-6 alkyl, C3 -7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, and 5-6 membered heteroaryl are optionally substituted by 1 , 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRC Rd , NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
or any Rcl and Rdl together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, 5-6 membered heteroaryl, halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6, wherein said Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Gs-io aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6,
OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6,
S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
or any Rc2 and K02 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1 , 2, or 3 substituents independently selected from Ci-6 alkyl, C3 -7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, and 5-6 membered heteroaryl, Ci-e haloalkyl, halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6,
NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6, wherein said Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6,
OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
or any Rc3 and Rd3 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, 5-6 membered heteroaryl, Ci-e haloalkyl, halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6,
NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and
S(0)2NRc6Rd6, wherein said Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, and 5-6 membered heteroaryl are each optionally substituted by 1 , 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6,
OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
or any Rc4 and Rd4 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1 , 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, 5-6 membered heteroaryl, Ct-s haloalkyl, halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6,
NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and
S(0)2NRc6Rd6, wherein said Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, and 5-6 membered heteroaryl are each optionally substituted by 1 , 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6,
OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
or any Rc5 and Rd5 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, 5-6 membered heteroaryl, Ci-6 haloalkyl, halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6,
NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6, wherein said Ci-6 alkyl, C3 -7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6,
OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
each Ra6, Rb6, Rc6, and Rd6 is independently selected from H, C1-4 alkyl, C2-4 alkenyl, C3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein said Ci-4 alkyl, C2-4 alkenyl, C3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, Ci alkyl, Ci alkoxy, Ci-4 alkylthio, Ci-4 alkylamino, and di(Ci4 alkyl)amino;
n is 1 or 2;
p is 1, 2, or 3; and
q is 1 or 2;
wherein any aforementioned 4-10 or 4-7 membered heterocycloalkyl group optionally comprises 1, 2, or 3 oxo substituents, wherein each oxo substituent that is present is substituted on a ring- forming carbon, nitrogen, or sulfur atom of the 4-10 or 4-7 membered heterocycloalkyl group.
In some embodiments, the TPH-inhibiting compound described herein is a compound of Formula I:
Figure imgf000014_0001
I
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is C3-10 cycloalkyl, C6-io 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;
wherein only one of X and Y is N;
R1 is H, Ci-10 alkyl, C3 -10 cycloalkyl, phenyl, -(CR8R9)pOC(0)R10, -(CR8R9)pNRnR12 , or -(CR8R9)pC(0)NRnR12, wherein said Ci-10 alkyl, C3-10 cycloalkyl, and phenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from F, CI, Br, CN, C14 alkyl, and Ci4 haloalkyl; R2 and R3 are each independently selected from H, C1-4 alkyl, and C1-4 haloalkyl;
R4 is H or CM alkyl;
R5 and R6 are each independently selected from H, halo, and C1-4 alkyl;
R7 is H, Ci-4 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C3-io cycloalkyl-Ci4 alkyl, C6-io aryl, C6- 10 aryl-Ci-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, 5-10 membered heteroaryl, (5-10 membered heteroaryl)-Ci-4 alkyl, NR1 R14, OR15, C(0)R16, S(0)qR17, wherein said C1-4 alkyl, C2-6 alkenyl, C3 -10 cycloalkyl, C3-io cycloalkyl-Ci-4 alkyl, G5-10 aryl, C6-io aryl-Ci-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)- C1-4 alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl)-Ci4 alkyl are each optionally substituted by 1, 2, or 3 substituents selected from halo, C1-4 alkyl, C2-6 alkenyl, amino, C 1-4 alky lamino, C2-8 dialkylamino, hydroxy, and Ci alkoxy;
R8 and R9 are each independently selected from H and C1-4 alkyl;
R10 is Ci-6 alkyl optionally substituted by 1, 2 or 3 substituents independently selected from Ci-6 haloalkyl, C3 -10 cycloalkyl, ORa, and NRcRd;
R11 and R12 are each independently selected from H and Ci-6 alkyl;
R13 is H or Ci4 alkyl;
R14 is H, Ci4 alkyl, C3 -7 cycloalkyl, C3-7 cycloalkyl-Ci4 alkyl, Gs-io aryl, C6-io aryl-Ci4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci 4 alkyl, 5-10 membered heteroaryl, or (5-10 membered heteroaryl)-Ci4 alkyl, C(0)Rbl, C(0)ORal,
C(0)NRclRdl, S(0)Rbl, S(0)2RM, or S(0)2NRclRdl, wherein said Ci-4 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-Ci4 alkyl, Gs-io aryl, C6-io aryl-Ci4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci 4 alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl)-Ci4 alkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, CN, NO2, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)ORal, OC(0)Rbl, OC(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)ORal,
NRclC(0)NRclRdl, NRclS(0)Rbl, NRclS(0)2Rbl, NRclS(0)2NRclRdl, S(0)Rbl, S(0)NRclRdl, S(0)2Rbl, and S(0)2NRclRdl;
or R13 and R14 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7- membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents
independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C5-10 aryl, 5-6 membered heteroaryl, halo, CN, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)ORal, OC(0)Rbl, OC(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)ORal, S(0)Rbl, S(0)NRclRdl, S(0)2Rbl, NRclS(0)2Rbl, NRclS(0)2NRclRdl, and S(0)2NRclRdl, wherein said Ci-6 alkyl, C3 -7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)ORal, OC(0)Rbl,
OC(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)ORal, S(0)Rbl,
S(0)NRclRdl, S(0)2Rbl, NRclS(0)2Rbl, NRclS(0)2NRclRdl, and S(0)2NRclRdl ;
R15 is H, Ci4 alkyl, C3 -7 cycloalkyl, C3-7 cycloalkyl-Ci-4 alkyl, C6-io aryl, C6-io aryl-Ci-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci -4 alkyl, 5-10 membered heteroaryl, or (5-10 membered heteroaryl)-Ci-4 alkyl, wherein said Ci-4 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-Ci-4 alkyl, C6-io aryl, C6-io aryl-Ci-4 alkyl, 4-10 membered
heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl)-Ci-4 alkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3 -7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, 5-6 membered heteroaryl, CN, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)ORal, OC(0)Rbl,
OC(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)ORal, S(0)Rbl,
S(0)NRclRdl, S(0)2Rbl, NRclS(0)2Rbl, NRclS(0)2NRclRdl, and S(0)2NRclRdl ;
R16 is Ci-4 alkyl or NR18aR18b wherein said C1-4 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, 5-6 membered heteroaryl, CN, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)ORal, OC(0)Rbl, OC(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)ORal, S(0)Rbl, S(0)NRclRdl, S(0)2Rbl, NRclS(0)2Rbl, NRclS(0)2NRclRdl, and S(0)2NRclRdl;
R17 is Ci-4 alkyl, NR18aR18b, or OR18c, wherein said C1-4 alkyl is optionally substituted by 1 , 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, 5-6 membered heteroaryl, CN, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)ORal, OC(0)Rbl, OC(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl,
NRclC(0)ORal, S(0)Rbl, S(0)NRclRdl, S(0)2Rbl, NRclS(0)2Rbl, NRclS(0)2NRclRdl, and S(0)2NRclRdl;
R18a and R18b are each independently selected from H and C1-4 alkyl wherein said C1-4 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, 5-6 membered heteroaryl, CN, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)ORal, OC(0)Rbl, OC(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRc4C(0)ORal, S(0)Rbl, S(0)NRclRdl, S(0)2Rbl, NRclS(0)2Rbl,
NRclS(0)2NRclRdl, and S(0)2NRclRdl;
or R18a and R18b together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, 5-6 membered heteroaryl, halo, CN, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)ORal, OC(0)Rbl, OC(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)ORal, S(0)Rbl, S(0)NRclRdl, S(0)2Rbl, NRclS(0)2Rbl, NRclS(0)2NRclRdl, and S(0)2NRclRdl, wherein said Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)ORal, OC(0)Rbl,
OC(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)ORal, S(0)Rbl,
S(0)NRclRdl, S(0)2Rbl, NRclS(0)2Rbl, NRclS(0)2NRclRdl, and S(0)2NRclRdl;
R18c is H, Ci-6 alkyl, C3-10 cycloalkyl, C3-7 cycloalkyl-Ci-4 alkyl, G5-10 aryl, G5-10 aryl-Ci-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci alkyl, 5-10 membered heteroaryl, or (5-10 membered heteroaryl)-Ci-4 alkyl, wherein said Ci-6 alkyl, C3-7 cycloalkyl, C3-io cycloalkyl-Ci-4 alkyl, Gs-io aryl, C6-io aryl-Ci-4 alkyl, 4-10 membered
heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl)-Ci -4 alkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, N02, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)ORal, OC(0)Rbl, OC(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)ORal, NRclC(0)NRclRdl, NRclS(0)Rbl, NRclS(0)2Rbl, NRclS(0)2NRclRdl, S(0)Rbl, S(0)NRclRdl, S(0)2Rbl, and S(0)2NRclRdl;
RA is H, Cy1, halo, Ct-s alkyl, C2^ alkenyl, CN, N02, ORa2, SRa2, C(0)Rb2, C(0)NRc2Rd2,
C(0)ORa2, OC(0)Rb2, OC(0)NRc2Rd2, NRc2Rd2, NRc2C(0)Rb2, NRc2C(0)ORa2,
NRc2C(0)NRc2Rd2, NRc2S(0)Rb2, NRc2S(0)2Rb2, NRc2S(0)2NRc2Rd2, S(0)Rb2, S(0)NRc2Rd2, S(0)2Rb2, or S(0)2NRc2Rd2, wherein said Ci-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy1, halo, Ci-6 alkyl, C2- 6 alkenyl, Ci-6 haloalkyl, CN, N02, ORa2, SRa2, C(0)Rb2, C(0)NRc2Rd2, C(0)ORa2, OC(0)Rb2, OC(0)NRc2Rd2, NR^R^, NRc2C(0)Rb2, NRc2C(0)ORa2, NRc2C(0)NRc2Rd2, NRc2S(0)Rb2, NRc2S(0)2Rb2, NRc2S(0)2NRc2Rd2, S(0)Rb2, S(0)NRc2Rd2, S(0)2Rb2, and S(0)2NRc2Rd2;
RB is H, Cy2, halo, Ci-6 alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, N02, ORa3, SRa3, C(0)Rb3, C(0)NRc Rd3, C(0)ORa3, OC(0)Rb3, OC(0)NRc Rd3, NRc Rd3, NRc C(0)Rb3, NRc C(0)ORa3, NRc C(0)NRc Rd3, NRc S(0)Rb3, NRc S(0)2Rb3, NRc S(0)2NRc Rd3, S(0)Rb3, S(0)NRc Rd3, S(0)2Rb3, or S(0)2NRc Rd3, wherein said Ci-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy2, halo, Ci-6 alkyl, C2- 6 alkenyl, Ci-6 haloalkyl, CN, N02, ORa3, SRa3, C(0)Rb3, C(0)NRc Rd3, C(0)ORa3, OC(0)Rb3, OC(0)NRc Rd3, NRc Rd3, NRc C(0)Rb3, NRc C(0)ORa3, NRc C(0)NRc Rd3, NRc S(0)Rb3, NRclS(0)2Rb3, NRc S(0)2NRc Rd3, S(0)Rb3, S(0)NRc Rd3, S(0)2Rb3, and S(0)2NRc Rd3;
Rc and RD are each independently selected from H, halo, Ci-6 alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, N02, ORa4, SRa4, C(0)Rb4, C(0)NRc4Rd4, C(0)ORa4, OC(0)Rb4, OC(0)NRc4Rd4, NRc4Rd4, NRc4C(0)Rb4, NRc4C(0)ORa4, NRc4C(0)NRc4Rd4, NRc4S(0)Rb4, NRc4S(0)2Rb4, NRc4S(0)2NRc4Rd4, S(0)Rb4, S(0)NRc4Rd4, S(0)2Rb4, and S(0)2NRc4Rd4; wherein said Ci-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Gs-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, halo, Ct-s alkyl, C2^, alkenyl, Ci-6 haloalkyl, CN, N02, ORa4, SRa4, C(0)Rb4, C(0)NRc4Rd4, C(0)ORa4, OC(0)Rb4, OC(0)NRc4Rd4, NRc4Rd4, NRc4C(0)Rb4, NRc4C(0)ORa4, NRc4C(0)NRc4Rd4, NRc4S(0)Rb4, NRc4S(0)2Rb4, NRc4S(0)2NRc4Rd4, S(0)Rb4, S(0)NRc4Rd4, S(0)2Rb4, and S(0)2NRc4Rd4;
Cy1 and Cy2 are each independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy;
each R^ is independently selected from halo, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, G5-10 aryl, C3 -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO2, ORa5, SRa5, C(0)Rb5, C(0)NRc5Rd5, C(0)ORa5, OC(0)Rb5, OC(0)NRc5Rd5, NRc5Rd5,
NRc5C(0)Rb5, NRc5C(0)ORa5, NRc5C(0)NRc5Rd5, NRc5S(0)Rb5, NRc5S(0)2Rb5,
NRc5S(0)2NRc5Rd5, S(0)Rb5, S(0)NRc5Rd5, S(0)2Rb5, and S(0)2NRc5Rd5, wherein said Ci-6 alkyl, C2-6 alkenyl Gs-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, Ct-s alkyl, CN, N02, ORa5, SRa5, C(0)Rb5, C(0)NRc5Rd5, C(0)ORa5, OC(0)Rb5, OC(0)NRc5Rd5, NRC R , NRc5C(0)Rb5, NRc5C(0)ORa5, NRc5C(0)NRc5Rd5,
NRc5S(0)Rb5, NRc5S(0)2Rb5, NRc5S(0)2NRc5Rd5, S(0)Rb5, S(0)NRc5Rd5, S(0)2Rb5, and
S(0)2NRc5Rd5;
each Ra, Ral, Ra2, Ra3, Ra4, and Ra5 is independently selected from H, Ct-s alkyl, C haloalkyl, C2-6 alkenyl, C6-io aryl, C3 -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-io aryl-Ci4 alkyl, C3-io cycloalkyl-Ci4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, or (4-10 membered heterocycloalkyl)-C 14 alkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, Gs- 10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-io aryl- C1-4 alkyl, C3-10 cycloalkyl-Ci4 alkyl, (5-10 membered heteroaryl)-Ci4 alkyl, and (4-10 membered heterocycloalkyl)-Ci4 alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Ci-4 alkyl, halo, CN, ORa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6,
NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
each Rbl, Rb2, Rb3, Rb4, and Rb5 is independently selected from H, Ct-s alkyl, CM haloalkyl, C2-6 alkenyl, C6-io aryl, C3 -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-io aryl-Ci-4 alkyl, C3-io cycloalkyl-Ci4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, or (4-10 membered heterocycloalkyl)-Ci4 alkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, Gs- 10 aryl, C3 -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-io aryl- C alkyl, C3-10 cycloalkyl-Ci-4 alkyl, (5-10 membered heteroaryl)-C 1-4 alkyl, and (4-10 membered heterocycloalkyl)-Ci4 alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from CM alkyl, halo, CN, ORa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6,
NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
each Rc , Rd, Rcl, Rdl, Rc2, Rd2, Rc3, Rd3, Rc4, Rd4, Rc5, and Rd5 is independently selected from H, Ci-6 alkyl, CM haloalkyl, C2-6 alkenyl, C6-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-io aryl-Ci4 alkyl, C3-10 cycloalkyl-Ci4 alkyl, (5- 10 membered heteroaryl)-Ci4 alkyl, or (4-10 membered heterocycloalkyl)-Ci4 alkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, C6-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-io aryl-Ci4 alkyl, C3-10 cycloalkyl-Ci4 alkyl, (5-10 membered heteroaryl)-Ci alkyl, and (4-10 membered heterocycloalkyl)-Ci4 alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Ci-4 alkyl, halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6,
NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6,
NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
or any Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, 5-6 membered heteroaryl, halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6, wherein said Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Gs-io aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
or any Rcl and Rdl together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, 5-6 membered heteroaryl, halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6, wherein said Ci-6 alkyl, C3 -7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, and 5-6 membered heteroaryl are each optionally substituted by 1 , 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6,
OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6,
S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
or any Rc2 and together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C5-10 aryl, and 5-6 membered heteroaryl, Q-s haloalkyl, halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRC Rd , NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6, wherein said Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
or any Rc3 and Rd3 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C5-10 aryl, 5-6 membered heteroaryl, Ci-e haloalkyl, halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6,
NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6, wherein said Ci-6 alkyl, C3 -7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
or any Rc4 and Rd4 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, 5-6 membered heteroaryl, Ci-e haloalkyl, halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6,
NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6, wherein said G-s alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
or any Rc5 and Rd5 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, 5-6 membered heteroaryl, Ct-s haloalkyl, halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6,
NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6, wherein said Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, and 5-6 membered heteroaryl are each optionally substituted by 1 , 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6,
OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
each Ra6, Rb6, Rc6, and Rd6 is independently selected from H, C14 alkyl, C24 alkenyl, C3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein said Ci-4 alkyl, C2-4 alkenyl, C3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-4 alkyl, Ci-4 alkoxy, C 1-4 alky lthio, Ci alkylamino, and di(Ci-4 alkyl)amino;
n is 1 or 2;
p is 1 , 2, or 3; and
q is 1 or 2;
wherein any aforementioned 4-10 or 4-7 membered heterocycloalkyl group optionally comprises 1, 2, or 3 oxo substituents, wherein each oxo substituent that is present is substituted on a ring-forming carbon, nitrogen, or sulfur atom of the 4-10 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 is H and R3 is H.
In some embodiments, R2 is H and R3 is C1-4 alkyl. In some embodiments, R2 is H and R3 is methyl.
In some embodiments, R2 is H and R3 is C1-4 haloalkyl.
In some embodiments, R2 is H and R3 is trifluoromethyl.
In some embodiments, n is 1.
In some embodiments, n is 2.
In some embodiments, R1 is H.
In some embodiments, R1 is Ci-io alkyl, C3-io cycloalkyl, phenyl, -(CR8R9)pOC(0)R10, -(CR8R9)pNRnR12 , or -(CR8R9)pC(0)NRnR12, wherein said Ci-io alkyl, C3-10 cycloalkyl, and phenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from F, CI, Br, CN, C alkyl, and C14 haloalkyl.
In some embodiments, R1 is Ci-10 alkyl.
In some embodiments, R1 is ethyl.
In some embodiments, R4 is H.
In some embodiments, R5 is H.
In some embodiments, R6 is H.
In some embodiments, R7 is other than H.
In some embodiments, R7 is C1-4 alkyl, NR1 R14, or OR15.
In some embodiments, R7 is NR1 R14.
In some embodiments, R7 is NH2.
In some embodiments, R7 is C 1-4 alkyl.
In some embodiments, R7 is OR15.
In some embodiments, Ring A is C3-10 cycloalkyl.
In some embodiments, Ring A is G5-10 aryl.
In some embodiments, Ring A is phenyl.
In some embodiments, Ring A is 4 to 10-membered heterocycloalkyl.
In some embodiments, Ring A is phenyl, adamantanyl, naphthyl, 1,2,3,4- tetrahydroquinoxalinyl, 3,4-dihydroqinazolinyl, 1,2,3,4-tetrahydroquinazolinyl, or pyridyl.
In some embodiments, Ring A is 5 to 10-membered heteroaryl.
In some embodiments, at least one of RA, RB, Rc, and RD is other than hydrogen. In some embodiments, at least two of RA, RB, Rc, and RD are other than hydrogen.
In some embodiments, RA is Cy1. In some embodiments, RA is Gs-io aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy.
In some embodiments, RA is 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from K^.
In some embodiments, RA is 5 to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.
In some embodiments, RA is pyrazolyl which is optionally substituted by 1 , 2, 3, 4, or 5 substituents independently selected from RCy.
In some embodiments, RA is 3-methyl-lH-pyrazol-l -yl.
In some embodiments, RA is C6-io aryl optionally substituted by 1 , 2, or 3 substituents independently selected from RCy.
In some embodiments, RA is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.
In some embodiments, RB is H.
In some embodiments, RB is Cy2, halo, Ci-6 alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, NO2,
OR33, SRa3, C(0)Rb3, C(0)NRc Rd3, C(0)ORa3, OC(0)Rb3, OC(0)NRc Rd3, NRc Rd3,
NRc C(0)Rb3, NRc C(0)ORa3, NRc C(0)NRc Rd3, NRc S(0)Rb3, NRc S(0)2Rb3,
NRc S(0)2NRc Rd3, S(0)Rb3, S(0)NRc Rd3, S(0)2Rb3, and S(0)2NRc Rd3, wherein said Cw alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy2, halo, Ci-6 alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, N02, ORa3, SRa3, C(0)Rb3, C(0)NRc Rd3, C(0)ORa3, OC(0)Rb3, OC(0)NRc Rd3, NRc Rd3, NRc C(0)Rb3, NRc C(0)ORa3, NRc C(0)NRc Rd3, NRc S(0)Rb3, NRclS(0)2Rb3, NRc S(0)2NRc Rd3, S(0)Rb3, S(0)NRc Rd3, S(0)2Rb3, and S(0)2NRc Rd3.
In some embodiments, RB is Cy2.
In some embodiments, RB is Gs-io aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1 , 2, 3, 4, or 5 substituents independently selected from RCy.
In some embodiments, RB is halo, Ci-6 alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, N02, ORa3, SRa3, C(0)Rb3, C(0)NRc Rd3, C(0)ORa3, OC(0)Rb3, OC(0)NRc Rd3, NRc Rd3, NRc C(0)Rb3, NRc C(0)ORa3, NRc C(0)NRc Rd3, NRc S(0)Rb3, NRc S(0)2Rb3, NRc S(0)2NRc Rd3, S(0)Rb3, S(0)NRc Rd3, S(0)2Rb3, and S(0)2NRc Rd3, wherein said G-s alkyl and C2^> alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy2, halo, Ci- 6 alkyl, C2-6 alkenyl, Ct-s haloalkyl, CN, N02, ORa3, SRa3, C(0)Rb3, C(0)NRc Rd3, C(0)ORa3, OC(0)Rb3, OC(0)NRc Rd3, NRc Rd3, NRc C(0)Rb3, NRc C(0)ORa3, NRc C(0)NRc Rd3, NRc S(0)Rb3, NRclS(0)2Rb3, NRc S(0)2NRc Rd3, S(0)Rb3, S(0)NRc Rd3, S(0)2Rb3, and
S(0)2NRc Rd3.
In some embodiments, RB is halo.
In some embodiments, Rc is H.
In some embodiments, Rc is halo, Ci-6 alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, N02, ORa4, SRa4, C(0)Rb4, C(0)NRc4Rd4, C(0)ORa4, OC(0)Rb4, OC(0)NRc4Rd4, NRc4Rd4, NRc4C(0)Rb4, NRc4C(0)ORa4, NRc4C(0)NRc4Rd4, NRc4S(0)Rb4, NRc4S(0)2Rb4, NRc4S(0)2NRc4Rd4, S(0)Rb4, S(0)NRc4Rd4, S(0)2Rb4, and S(0)2NRc4Rd4; wherein said Ci-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C6-io aryl, C3- 10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, Ci-6 alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, N02, ORa4, SRa4, C(0)Rb4, C(0)NRc4Rd4, C(0)ORa4, OC(0)Rb4, OC(0)NRc4Rd4, NRc4Rd4, NRc4C(0)Rb4, NRc4C(0)ORa4, NRc4C(0)NRc4Rd4, NRc4S(0)Rb4, NRc4S(0)2Rb4, NRc4S(0)2NRc4Rd4, S(0)Rb4, S(0)NRc4Rd4, S(0)2Rb4, and S(0)2NRc4Rd4.
In some embodiments, RD is H.
In some embodiments, RD is halo, Ci-6 alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, N02, ORa4, SRa4, C(0)Rb4, C(0)NRc4Rd4, C(0)ORa4, OC(0)Rb4, OC(0)NRc4Rd4, NRc4Rd4, NRc4C(0)Rb4, NRc4C(0)ORa4, NRc4C(0)NRc4Rd4, NRc4S(0)Rb4, NRc4S(0)2Rb4, NRc4S(0)2NRc4Rd4, S(0)Rb4, S(0)NRc4Rd4, S(0)2Rb4, and S(0)2NRc4Rd4; wherein said Ct-s alkyl and C2^, alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Gs-io aryl, C3- 10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, Ci-6 alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, N02, ORa4, SRa4, C(0)Rb4, C(0)NRc4Rd4, C(0)ORa4, OC(0)Rb4, OC(0)NRc4Rd4, NRc4Rd4, NRc4C(0)Rb4, NRc4C(0)ORa4, NRc4C(0)NRc4Rd4, NRc4S(0)Rb4, NRc4S(0)2Rb4, NRc4S(0)2NRc4Rd4, S(0)Rb4, S(0)NRc4Rd4, S(0)2Rb4, and S(0)2NRc4Rd4.
In some embodiments, the compounds described herein have Formula Ila:
Figure imgf000026_0001
lie.
In some embodiments, the compounds described herein have Formula lid:
Figure imgf000027_0001
In some embodiments, the compounds described herein have Formula He:
Figure imgf000027_0002
In some embodiments, where the compounds described herein have Formula Ila, lib, lie, lid, or He, L is O.
In some embodiments, where the compounds described herein have Formula Ila, lib, lie, lid, or He, L is NR4.
In some embodiments, where the compounds described herein have Formula Ila, lib, lie, lid, or He, R3 is H. In some embodiments, where the compounds described herein have Formula Ila, lib, lie, Ild, or He, R2 is CF3 and R3 is H.
In some embodiments, where the compounds described herein have Formula Ila, lib, lie, Ild, or He, R1 is H or Ci-io alkyl.
In some embodiments, where the compounds described herein have Formula Ila, lib, lie,
Ild, or He, RA is Cy1.
In some embodiments, where the compounds described herein have Formula Ila, lib, lie, Ild, or He, RA is Gs-io aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy.
In some embodiments, where the compounds described herein have Formula Ila, lib, lie,
Ild, or He, RA is 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy.
In some embodiments, where the compounds described herein have Formula Ila, lib, lie, Ild, or He, RA is 5 to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.
In some embodiments, where the compounds described herein have Formula Ila, lib, lie, Ild, or He, RA is Gs-io aryl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.
In some embodiments, where the compounds described herein have Formula Ila, lib, lie, Ild, or He, RA is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.
In some embodiments, where the compounds described herein have Formula Ila, lib, lie, Ild, or He, RB is Cy2.
In some embodiments, where the compounds described herein have Formula Ila, lib, lie, Ild, or He, RB is H, halo, Ci-6 alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, ORa3, C(0)NRc Rd3, or
C(0)ORa3, wherein said Ci-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci-6 haloalkyl, CN, N02, ORa3, SRa3, C(0)Rb3, C(0)NRc Rd3, C(0)ORa3, OC(0)Rb3, OC(0)NRc Rd3, NRc Rd3, NRc C(0)Rb3, NRc C(0)ORa3, NRc C(0)NRc Rd3, NRc S(0)Rb3, NRclS(0)2Rb3, NRc S(0)2NRc Rd3, S(0)Rb3, S(0)NRc Rd3, S(0)2Rb3, and S(0)2NRc Rd3. In some embodiments, where the compounds described herein have Formula Ila, lib, lie, lid, or He, Rc is H.
In some embodiments, where the compounds described herein have Formula Ila, lib, lie, lid, or He, RD is H.
In some embodiments, where the compounds described herein have Formula Ila, lib, lie, lid, or He, R5 is H.
In some embodiments, where the compounds described herein have Formula Ila, lib, lie, lid, or He, R6 is H.
In some e Ilia or nib:
Figure imgf000029_0001
Ilia
Figure imgf000029_0002
In some embodiments, where the compounds described herein have Formula Ilia or inb, R1 is H or Ci-io alkyl.
In some embodiments, where the compounds described herein have Formula Ilia or inb, RA is Cy1.
In some embodiments, where the compounds described herein have Formula Ilia or inb,
RA is C6-io aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from K^.
In some embodiments, where the compounds described herein have Formula Ilia or inb, RA is 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy .
In some embodiments, where the compounds described herein have Formula Ilia or inb, RA is 5 to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from K^.
In some embodiments, where the compounds described herein have Formula Ilia or inb, RA is C6-io aryl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.
In some embodiments, where the compounds described herein have Formula Ilia or inb, RA is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from K^.
In some embodiments, where the compounds described herein have Formula Ilia or inb, RB is Cy2.
In some embodiments, where the compounds described herein have Formula Ilia or inb,
RB is H, halo, Ci-6 alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, ORa3, C(0)NRc Rd3, or C(0)ORa3, wherein said Ci-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci-6 haloalkyl, CN, NO2, ORa3, SRa3, C(0)Rb3, C(0)NRc Rd3, C(0)ORa3, OC(0)Rb3, OC(0)NRc Rd3, NRc Rd3, NRc C(0)Rb3, NRc C(0)ORa3, NRc C(0)NRc Rd3, NRc S(0)Rb3, NRclS(0)2Rb3, NRc S(0)2NRc Rd3, S(0)Rb3, S(0)NRc Rd3, S(0)2Rb3, and S(0)2NRc Rd3.
In some embodiments, where the compounds described herein have Formula Ilia or inb, Rc is H.
In some embodiments, where the compounds described herein have Formula Ilia or inb, RD is H.
In some embodiments, the compounds described herein have Formula IV:
Figure imgf000031_0001
IV.
In some embodiments, where the compounds described herein have Formula IV, R2 i i:s
CF3.
In some embodiments, where the compounds described herein have Formula IV, R is H or Ci-io alkyl.
In some embodiments, where the compounds described herein have Formula IV, RA is
Cy1.
In some embodiments, where the compounds described herein have Formula IV, RA is C6-io aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy.
In some embodiments, where the compounds described herein have Formula IV, RA is 5- 10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from K^.
In some embodiments, where the compounds described herein have Formula IV, RA is 5 to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.
In some embodiments, where the compounds described herein have Formula IV, RA is C6-io aryl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.
In some embodiments, where the compounds described herein have Formula IV, RA is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.
In some embodiments, where the compounds described herein have Formula IV, RB is
Cy2. In some embodiments, where the compounds described herein have Formula IV, R is H, halo, Ci-6 alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, ORa3, C(0)NRc Rd3, or C(0)ORa3, wherein said Ci-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci-6 haloalkyl, CN, N02, ORa3, SRa3, C(0)Rb3, C(0)NRc Rd3, C(0)ORa3, OC(0)Rb3, OC(0)NRc Rd3, NRc Rd3, NRc C(0)Rb3, NRc C(0)ORa3,
NRc C(0)NRc Rd3, NRc S(0)Rb3, NRclS(0)2Rb3, NRc S(0)2NRc Rd3, S(0)Rb3, S(0)NRc Rd3, S(0)2Rb3, and S(0)2NRc Rd3.
In some embodiments, where the compounds described herein have Formula IV, Rc is H.
In some embodiments, where the compounds described herein have Formula IV, RD is H.
In some embodiments, the compounds described herein have Formula Va:
Figure imgf000032_0001
Va.
In some embodiments, where the compounds described herein have Formula Va, R2 is
CF3
In some embodiments, where the compounds described herein have Formula Va, R is H or Ci-10 alkyl.
In some embodiments, where the compounds described herein have Formula Va, RA is
Cy1.
In some embodiments, where the compounds described herein have Formula Va, RA is Gs-io aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy. In some embodiments, where the compounds described herein have Formula Va, RA is 5- 10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from K^.
In some embodiments, where the compounds described herein have Formula Va, RA is 5 to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected
In some embodiments, where the compounds described herein have Formula Va, RA is Gs-io aryl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.
In some embodiments, where the compounds described herein have Formula Va, RA is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.
In some embodiments, where the compounds described herein have Formula Va, RB is
Cy2.
In some embodiments, where the compounds described herein have Formula Va, RB is H, halo, Ci-6 alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, ORa3, C(0)NRc Rd3, or C(0)ORa3, wherein said Ci-6 alkyl and C2-6 alkenyl are each optionally substituted with 1 , 2, or 3 substituents independently selected from halo, Ci-6 haloalkyl, CN, N02, ORa3, SRa3, C(0)Rb3, C(0)NRc Rd3, C(0)ORa3, OC(0)Rb3, OC(0)NRc Rd3, NRc Rd3, NRc C(0)Rb3, NRc C(0)ORa3,
NRc C(0)NRc Rd3, NRc S(0)Rb3, NRclS(0)2Rb3, NRc S(0)2NRc Rd3, S(0)Rb3, S(0)NRc Rd3, S(0)2Rb3, and S(0)2NRc Rd3.
In some embodiments, the compounds described herein have Formula Vb:
Figure imgf000033_0001
In some embodiments, where the compounds described herein have Formula Vb, R2 is
CF3.
In some embodiments, where the compounds described herein have Formula Vb, R1 is H or Ci-io alkyl.
In some embodiments, where the compounds described herein have Formula Vb, RA is
Cy1.
In some embodiments, where the compounds described herein have Formula Vb, RA is C6-io aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy.
In some embodiments, where the compounds described herein have Formula Vb, RA is 5-
10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from K^.
In some embodiments, where the compounds described herein have Formula Vb, RA is 5 to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.
In some embodiments, where the compounds described herein have Formula Vb, RA is C6-io aryl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.
In some embodiments, where the compounds described herein have Formula Vb, RA is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.
In some embodiments, where the compounds described herein have Formula Vb, RB is
Cy2.
In some embodiments, where the compounds described herein have Formula Vb, RB is H, halo, Ci-6 alkyl, C2-6 alkenyl, Ct-s haloalkyl, CN, ORa3, C(0)NRc Rd3, or C(0)ORa3, wherein said Ci-6 alkyl and C2-6 alkenyl are each optionally substituted with 1 , 2, or 3 substituents independently selected from halo, Ci-6 haloalkyl, CN, N02, ORa3, SRa3, C(0)Rb3, C(0)NRc Rd3, C(0)ORa3, OC(0)Rb3, OC(0)NRc Rd3, NRc Rd3, NRc C(0)Rb3, NRc C(0)ORa3,
NRc C(0)NRc Rd3, NRc S(0)Rb3, NRclS(0)2Rb3, NRc S(0)2NRc Rd3, S(0)Rb3, S(0)NRc Rd3, S(0)2Rb3, and S(0)2NRc Rd3.
In some embodiments, the compounds described herein have Formula VI:
Figure imgf000035_0001
In some embodiments, where the compounds described herein have Formula VI, R2 is CF3.
In some embodiments, where the compounds described herein have Formula VI, R1 is H or Ci-io alkyl.
In some embodiments, where the compounds described herein have Formula VI, RB is
Cy2.
In some embodiments, where the compounds described herein have Formula VI, Cy2 is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.
In some embodiments, where the compounds described herein have Formula VI, RB is H, halo, Ci-6 alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, ORa3, C(0)NRc Rd3, or C(0)ORa3, wherein said Ci-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci-6 haloalkyl, CN, N02, ORa3, SRa3, C(0)Rb3, C(0)NRc Rd3, C(0)ORa3, OC(0)Rb3, OC(0)NRc Rd3, NRc Rd3, NRc C(0)Rb3, NRc C(0)ORa3,
NRc C(0)NRc Rd3, NRc S(0)Rb3, NRclS(0)2Rb3, NRc S(0)2NRc Rd3, S(0)Rb3, S(0)NRc Rd3, S(0)2Rb3, and S(0)2NRc Rd3.
In some embodiments, where the compounds described herein have Formula VI, Rc is H. In some embodiments, where the compounds described herein have Formula VI, RD is H.
In some embodiments, the compounds described herein have Formula VTA:
Figure imgf000036_0001
VIA.
In some embodiments, where the compounds described herein have Formula VIA, R2 is
CF3.
In some embodiments, where the compounds described herein have Formula VIA, R1 is
H or Ci-io alkyl.
In some embodiments, where the compounds described herein have Formula VIA, RB is
Cy2.
In some embodiments, where the compounds described herein have Formula VIA, Cy2 is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.
In some embodiments, where the compounds described herein have Formula VIA, RB is H, halo, Ci-6 alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, ORa3, C(0)NRc Rd3, or C(0)ORa3, wherein said Ci-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci-6 haloalkyl, CN, N02, ORa3, SRa3, C(0)Rb3, C(0)NRc Rd3, C(0)ORa3, OC(0)Rb3, OC(0)NRc Rd3, NRc Rd3, NRc C(0)Rb3, NRc C(0)ORa3,
NRc C(0)NRc Rd3, NRc S(0)Rb3, NRclS(0)2Rb3, NRc S(0)2NRc Rd3, S(0)Rb3, S(0)NRc Rd3, S(0)2Rb3, and S(0)2NRc Rd3.
In some embodiments, the compounds described herein have Formula VII:
Figure imgf000037_0001
wherein a is 0, 1, 2, or 3.
In some embodiments, where the compounds described herein have Formula VII, R2 is CF3.
In some embodiments, where the compounds described herein have Formula VII, R1 is H or Ci-io alkyl.
In some embodiments, where the compounds described herein have Formula VII, RB is
Cy2.
In some embodiments, where the compounds described herein have Formula VII, RB is
H, halo, Ci-6 alkyl, C2^, alkenyl, Ci-6 haloalkyl, CN, ORa3, C(0)NRc Rd3, or C(0)ORa3, wherein said Ci-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci-6 haloalkyl, CN, N02, ORa3, SRa3, C(0)Rb3, C(0)NRc Rd3, C(0)ORa3, OC(0)Rb3, OC(0)NRc Rd3, NRc Rd3, NRc C(0)Rb3, NRc C(0)ORa3,
NRc C(0)NRc Rd3, NRc S(0)Rb3, NRclS(0)2Rb3, NRc S(0)2NRc Rd3, S(0)Rb3, S(0)NRc Rd3, S(0)2Rb3, and S(0)2NRc Rd3.
In some embodiments, where the compounds described herein have Formula VII, RB is H or halo.
In some embodiments, where the compounds described herein have Formula VII, RB is halo.
In some embodiments, where the compounds described herein have Formula VII, Rc is
H. In some embodiments, where the compounds described herein have Formula VII, RD is
H.
In some embodiments, where the compounds described herein have Formula VII, R^ is halo, Ci-6 alkyl, Ci-6 haloalkyl, 4-10 membered heterocycloalkyl, CN, N02, ORa5, SRa5, C(0)Rb5, C(0)NRc5Rd5, C(0)ORa5, NRc5Rd5, S(0)2Rb5, and S(0)2NRc5Rd5, wherein said Ci-6 alkyl and 4- 10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, CN, N02, ORa5, SRa5, C(0)Rb5, C(0)NRc5Rd5, C(0)ORa5, OC(0)Rb5, OC(0)NRc5Rd5, NRc5Rd5, NRc5C(0)Rb5, NRc5C(0)ORa5,
NRc5C(0)NRc5Rd5, NRc5S(0)Rb5, NRc5S(0)2Rb5, NRc5S(0)2NRc5Rd5, S(0)Rb5, S(0)NRc5Rd5, S(0)2Rb5, and S(0)2NRc5Rd5.
In some embodiments the compounds described herein have Formula VIII:
Figure imgf000038_0001
wherein a is 0, 1, 2, or 3.
In some embodiments, where the compounds described herein have Formula VIII, R2 is
CF3.
In some embodiments, where the compounds described herein have Formula VIII, R1 is H or Ci-io alkyl.
In some embodiments, where the compounds described herein have Formula VIII, RB is Cy2.
In some embodiments, where the compounds described herein have Formula VIII, RB is H, halo, Ci-6 alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, ORa3, C(0)NRc Rd3, or C(0)ORa3, wherein said Ci-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci-6 haloalkyl, CN, N02, ORa3, SRa3, C(0)Rb3, C(0)NRc Rd3, C(0)ORa3, OC(0)Rb3, OC(0)NRc Rd3, NRc Rd3, NRc C(0)Rb3, NRc C(0)ORa3,
NRc C(0)NRc Rd3, NRc S(0)Rb3, NRclS(0)2Rb3, NRc S(0)2NRc Rd3, S(0)Rb3, S(0)NRc Rd3, S(0)2Rb3, and S(0)2NRc Rd3.
In some embodiments, where the compounds described herein have Formula VIII, RB is H or halo.
In some embodiments, where the compounds described herein have Formula VIII, RB is halo.
In some embodiments, where the compounds described herein have Formula VIII, Rc is
H.
In some embodiments, where the compounds described herein have Formula VIII, RD is
H.
In some embodiments, where the compounds described herein some embodiments have Formula VIII, RCy is halo, Ci-6 alkyl, Ci-6 haloalkyl, 4-10 membered heterocycloalkyl, CN, NO2, ORa5, SRa5, C(0)Rb5, C(0)NRc5Rd5, C(0)ORa5, NRc5Rd5, S(0)2Rb5, and S(0)2NRc5Rd5, wherein said Ci-6 alkyl and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, CN, N02, ORa5, SRa5, C(0)Rb5, C(0)NRc5Rd5, C(0)ORa5, OC(0)Rb5, OC(0)NRc5Rd5, NRc5Rd5, NRc5C(0)Rb5, NRc5C(0)ORa5, NRc5C(0)NRc5Rd5, NRc5S(0)Rb5, NRc5S(0)2Rb5, NRc5S(0)2NRc5Rd5, S(0)Rb5, S(0)NRc5Rd5, S(0)2Rb5, and S(0)2NRc5Rd5.
In some embodiments, where the compounds described herein have Formula VIII, a is 0.
In some embodiments, the chiral carbon to which -C(0)OR1 is attached has an S configuration.
In some embodiments, the carbon to which -R2 is attached is chiral and has an R configuration.
In some embodiments, the compound used in the methods described herein is (S)-ethyl 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-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)-l-(5-chloro-[l, -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.
In some embodiments, the compound used in the methods described herein is (S)-ethyl 8- (2-amino-6-((R)-l-(3',4'-dimethyl-3-(3-methyl-lH-pyrazol-l-yl)-[l,r-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-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'-dimethy 1-3 -(3 -methyl- 1 H-pyrazol- 1 -yl)- [1,1 '-bipheny 1] -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)-ethyl 8- (2-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-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)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-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)-ethyl 8-
(2-amino-6-((R)-2,2,2-trifluoro-l-(3'-fluoro-3-(3-methyl-lH-pyrazol-l-yl)-4'-propoxy-[l, - biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate, or a
pharmaceutically acceptable salt thereof (see Example 63 i).
In some embodiments, the compound is (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(3'- fluoro-3-(3-methyl-lH-pyrazol-l-yl)-4'-propoxy-[l, -biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid, or a pharmaceutically acceptable salt thereof.
It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. The term "substituted" means that an atom or group of atoms formally replaces hydrogen as a "substituent" attached to another group. The hydrogen atom is formally removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms. The term "optionally substituted" means unsubstituted or substituted. The substituents are independently selected, and substitution may be at any chemically accessible position. It is to be understood that substitution at a given atom is limited by valency. Throughout the definitions, the term "Ci-j" indicates a range which includes the endpoints, wherein i and j are integers and indicate the number of carbons. Examples include C1-4, Ci-6, and the like.
The term "n- member ed" where n is an integer typically describes the number of ring- forming atoms in a moiety where the number of ring-forming atoms is n. For example, piper idinyl 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.
At various places in the present specification various aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described. Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member as permitted by valency. For example, the term "a pyridine ring" or "pyridinyl" may refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring.
For compounds of the invention in which a variable appears more than once, each variable can be a different moiety independently selected from the group defining the variable. For example, where a structure is described having two R groups that are simultaneously present on the same compound, the two R groups can represent different moieties independently selected from the group defined for R.
As used herein, the term "Ci-j alkyl," employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched, having i to j carbon atoms. In some embodiments, the alkyl group contains from 1 to 10, 1 to 6, 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, ^-propyl, isopropyl, n-butyl, s-butyl, and t-butyl.
As used herein, the term "Ci-j alkoxy," employed alone or in combination with other terms, refers to a group of formula -O-alkyl, wherein the alkyl group has i to j carbon atoms. Example alkoxy groups include methoxy, ethoxy, and propoxy (e.g., n-propoxy and isopropoxy). In some embodiments, the alkyl group has 1 to 3 carbon atoms or 1 to 4 carbon atoms. As used herein, "Ci-j alkenyl" refers to an alkyl group having one or more double carbon- carbon bonds and having i to j carbon atoms. In some embodiments, the alkenyl moiety contains 2 to 6 or to 2 to 4 carbon atoms. Example alkenyl groups include, but are not limited to, ethenyl, w-propenyl, isopropenyl, w-butenyl, seobutenyl, and the like.
As used herein, the term "Ci-j alkylamino" refers to a group of formula -NH( alkyl), wherein the alkyl group has i to j carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
As used herein, the term "di-Ci-j-alkylamino" refers to a group of formula -N(alkyl)2, wherein the two alkyl groups each has, independently, i to j carbon atoms. In some
embodiments, each alkyl group independently has 1 to 6 or 1 to 4 carbon atoms.
As used herein, the term "thio" refers to a group of formula -SH.
As used herein, the term "Ci-j alkylthio" refers to a group of formula -S-alkyl, wherein the alkyl group has i to j carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
As used herein, the term "amino" refers to a group of formula -NH2.
As used herein, the term " Ci-j aryl," employed alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbon having i to j ring-forming carbon atoms, such as, but not limited to, phenyl, 1 -naphthyl, 2- naphthyl, anthracenyl, phenanthrenyl, and the like. In some embodiments, aryl is C6-io aryl. In some embodiments, the aryl group is a naphthalene ring or phenyl ring. In some embodiments, the aryl group is phenyl.
As used herein, the term "arylalkyl" refers to a group of formula -Ci-j alkyl-(Ci-j aryl). In some embodiments, arylalkyl is Gs-io aryl-Ci-3 alkyl. In some embodiments, arylalkyl is Gs-io aryl-Ci-4 alkyl. In some embodiments, arylalkyl is benzyl.
As used herein, the term "carbonyl," employed alone or in combination with other terms, refers to a -C(=0)- group.
As used herein, the term "carboxy" refers to a group of formula -C(=0)OH.
As used herein, the term "Ci-j cycloalkyl," employed alone or in combination with other terms, refers to a non-aromatic cyclic hydrocarbon moiety having i to j ring-forming carbon atoms, which may optionally contain one or more alkenylene groups as part of the ring structure. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings (aryl or heteroaryl) fused to the cycloalkyl ring, for example, benzo or pyrido derivatives of cyclopentane, cyclopentene, cyclohexane, and the like. Where the cycloalkyl group includes a fused aromatic ring, the cycloalkyl group can be attached at either an atom in the aromatic or non-aromatic portion. One or more ring-forming carbon atoms of a cycloalkyl group can be oxidized to form carbonyl linkages. In some embodiments, cycloalkyl is C3-10 or C3-7 cycloalkyl, which can be monocyclic or polycyclic. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantanyl and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
As used herein, the term "cycloalkylalkyl" refers to a group of formula— Ci-j alkyl-(Ci-j cycloalkyl). In some embodiments, cycloalkylalkyl is C3-7 cycloalkyl- C 1-3 alkyl, wherein the cycloalkyl portion is monocyclic. In some embodiments, cycloalkylalkyl is C3-7 cycloalkyl-Ci4 alkyl.
As used herein, "Ci-j haloalkoxy" refers to a group of formula -O-haloalkyl having i to j carbon atoms. An example haloalkoxy group is OCF3. An additional example haloalkoxy group is OCHF2. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
As used herein, the term "halo" refers to a halogen atom selected from F, CI, I or Br. In some embodiments, "halo" refers to a halogen atom selected from F, CI, or Br. In some embodiments, the halo group is F.
As used herein, the term "Ci-j haloalkyl," employed alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2s+l halogen atoms which may be the same or different, where "s" is the number of carbon atoms in the alkyl group, wherein the alkyl group has i to j carbon atoms. In some embodiments, the haloalkyl group is fluoromethyl, difluoromethyl, or trifluoromethyl. In some embodiments, the haloalkyl group is trifluoromethyl. In some embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms.
As used herein, the term "heteroaryl," employed alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic moiety, having one or more heteroatom ring members selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl group is a 5- to 10-membered heteroaryl ring, which is monocyclic or bicyclic and which has 1 , 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl group is a 5- to 6-membered heteroaryl ring, which is monocyclic and which has 1 , 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. The nitrogen atoms in the ring(s) of the heteroaryl group can be oxidized to form N-oxides. Example heteroaryl groups include, but are not limited to, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, azolyl, oxazole, thiazole, imidazole, furan, thiophene, quinoline, isoquinoline, indole, benzothiophene, benzofuran, benzisoxazole, imidazo[l,2-6]thiazole, purine, and the like.
A 5-membered heteroaryl is a heteroaryl group having five ring-forming atoms comprising carbon and one or more (e.g., 1 , 2, or 3) ring atoms independently selected from N, O, and S. Example five-membered heteroaryls 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.
A six-membered heteroaryl is a heteroaryl group having six ring-forming atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Example six-membered heteroaryls include pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.
As used herein, the term "heteroarylalkyl" refers to a group of formula— Ci-j alkyl- (heteroaryl). In some embodiments, heteroarylalkyl 5-10 membered heteteroaryl-Ci-4 alkyl, wherein the heteroaryl portion is monocyclic or bicyclic and has 1 , 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroarylalkyl is 5-6 membered heteteroaryl-Ci-3 alkyl or 5-6 membered heteteroaryl-C 1 -4 alky 1, wherein the heteroaryl portion is monocyclic and has 1 , 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
As used herein, the term "heterocycloalkyl," employed alone or in combination with other terms, refers to a non-aromatic ring or ring system, which optionally contains one or more alkenylene groups as part of the ring structure, and which has at least one heteroatom ring member independently selected from nitrogen, sulfur and oxygen. When the heterocycloalkyl groups contains more than one heteroatom, the heteroatoms may be the same or different.
Heterocycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems, including spiro systems. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings (aryl or heteroaryl) fused to the non-aromatic ring, for example, 1,2,3,4-tetrahydro-quinoline, dihydrobenzofuran and the like. Where the
heterocycloalkyl group includes a fused aromatic ring, the heterocycloalkyl group can be attached at either an atom in the aromatic or non-aromatic portion. The carbon atoms or heteroatoms in the ring(s) of the heterocycloalkyl group can be oxidized (e.g. have one or two oxo substituents) to form a carbonyl, or sulfonyl group (or other oxidized linkage) or a nitrogen atom can be quaternized. In some embodiments, the heterocycloalkyl group is 5- to 10- membered, which can be monocyclic or bicyclic and which has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heterocycloalkyl group is 5- to 6-membered or 5- to 7-membered. Examples of heterocycloalkyl groups include 1, 2, 3, 4-tetrahydroquinoline, dihydrobenzofuran, azetidine, azepane, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, and pyran. Further examples of heterocycloalkyl groups include 2-oxotetrahydrofuranyl, 2-oxopyrrolidinyl, 2-oxoimidazolidinyl, l-oxo-l,2,3,4-tetrahydroisoquinolin-6-yl, and 2-oxo-l,3-dioxolan-4-yl.
As used herein, the term "heterocycloalkylalkyl" refers to a group of formula Ci-j alkyl-
(heterocycloalkyl). In some embodiments, heterocycloalkylalkyl is 5-10 membered
heterocycloalkyl-Ci-3 alkyl or 5-10 membered heterocycloalkyl-Ci-4 alkyl, wherein the heterocycloalkyl portion is monocyclic or bicyclic and has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments,
heterocycloalkylalkyl is 5-6 membered heterocycloalkyl-Ci-4 alkyl wherein the heterocycloalkyl portion is monocyclic and has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereoisomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention may be isolated as a mixture of isomers or as separated isomeric forms.
Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. An example method includes fractional recrystallization using a chiral resolving acid which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and
L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as β-camphorsulfonic acid.
Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of a-methylbenzylamine (e.g., S and R forms, or diastereoisomerically pure forms),
2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine,
1,2-diaminocyclohexane, and the like.
Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art.
Compounds of the invention can also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H- imidazole, 1H-, 2H- and 4Η-
1, 2, 4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole.
Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.
The term "compound," as used herein, is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified. Compounds herein identified by name or structure without specifying the particular configuration of a stereocenter are meant to encompass all the possible configurations at the stereocenter. For example, if a particular stereocenter in a compound of the invention could be R or S, but the name or structure of the compound does not designate which it is, than the stereocenter can be either R or S.
All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., hydrates and solvates) or can be isolated.
In some embodiments, the compounds of the invention, or salts thereof, are substantially isolated. By "substantially isolated" is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compounds of the invention. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds of the invention, or salt thereof. Methods for isolating compounds and their salts are routine in the art.
The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The expressions, "ambient temperature" and "room temperature," as used herein, are understood in the art, and refer generally to a temperature, e.g., a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a
temperature from about 20 °C to about 30 °C.
The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an 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 or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, EtOAc, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (CH3CN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, (5(5(1), 1-19, and in Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002).
As used herein, the term "individual" or "patient," used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
As used herein, the phrase "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
As used herein the term "treating" or "treatment" refers to 1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology), or 2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology).
As used herein the term "preventing" or "prevention" refers to inhibiting onset or worsening of the disease; for example, in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.
Combination Therapy
The therapeutic methods of the invention can further include administering at least one additional therapeutic agent together with the TPHl -inhibiting compound or prodrug thereof. The additional therapeutic agent can be combined with the TPHl -inhibiting agent or prodrug thereof in a single dosage form, or the agents can be administered simultaneously or sequentially in separate dosage forms. Additional therapeutic agents for combination therapy include, for example, ASK1 inhibitors such as GS-4997, monoclonal antibodies against LOXL2 such as simtuzumab, non-steroidal anti- inflammatory drugs (NSAID), and anti-hyperlipidemic agents (e.g., a fibrate, a statin, a tocotrienol, a niacin, a bile acid sequestrants (resin), a cholesterol absorption inhibitor, a pancreatic lipase inhibitor, and a sympathomimetic amine). Examples of fibrates includes bezafibrate, ciprofibrate, clofibrate, gemfibrozil, and fenofibrate. Examples of cholesterol absorption inhibitors includes ezetimibe, a phytosterol, a sterol, and a stanol. Other agents include pioglitazone, vitamin E, and metformin. Additional treatment methods can include reducing weight (if the patient is obese or overweight), having a balanced and healthy diet, increasing physical activity, and avoiding alcohol.
Administration, Pharmaceutical Formulations, Dosage Forms
The methods described herein include administering a TPH1 -inhibiting agent or prodrug thereof described herein to patients (e.g., animals and humans) in need of such treatment in appropriate dosages that will provide prophylactic and/or therapeutic efficacy. The dose and dosing regimen required for use in the treatment or prevention of any particular disease or disorder will typically vary from patient to patient depending on, for example, particular compound or composition selected, the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medication or special diets then being followed by the patient, and other factors. The appropriate dosage and dosing regimen can be determined by the treating physician.
A compound described herein can be administered orally, subcutaneously, topically, parenterally, or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Parenteral administration can involve subcutaneous injections, intravenous or intramuscular injections or infusion techniques.
For nasal administration or administration by inhalation or insufflation, the compound(s) can be delivered in the form of an aerosol spray from pressurized packs or a nebulizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoro methane,
dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges for use in an inhaler or insufflator (for example capsules and cartridges comprised of gelatin) may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
Treatment duration can be as long as deemed necessary by a treating physician. For example, the compounds and compositions can be administered one to four or more times per day. In some cases, depending on the properties of the compound and depending on the formulation, administration can be less than once per day, for example, once every other day or once per week. A treatment period can terminate when a desired result, for example a particular therapeutic effect, is achieved. Or a treatment period can be continued indefinitely.
In some embodiments, the methods described herein include administering to patients 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 as solid dosage forms for oral administration (e.g., capsules, tablets, pills, dragees, powders, granules and the like). A tablet can be prepared by compression or molding. Compressed tablets can include one or more binders, lubricants, glidants, inert diluents, preservatives, disintegrants, 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 a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches. Other suitable
pharmaceutical formulation and dosage forms include inhalants.
Pharmaceutical compositions of this invention suitable for parenteral administration include a compound of the invention together with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions.
Alternatively, the composition can be in the form of a sterile powder which can be reconstituted into a sterile injectable solutions or dispersion just prior to use.
The invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of non-critical parameters which can be changed or modified to yield essentially the same results. The compounds of the Examples were found to be inhibitors of TPH1. EXAMPLES
The TPHl inhibitors, and prodrugs thereof, described herein can be prepared in a number 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 U.S. Pub. No. 2015/0080393, which is incorporated herein by reference in its entirety. The procedures of Example lu below can be generally used to prepare TPHl -inhibiting compounds.
Example lu: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(3-(3-methyl-lH-pyrazol-l-yl)-[l,l'- biphenyl]-4-yl)ethoxy)pyrimidin-4- l)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000051_0001
Step 1: To a solution of (R)-l-(4-bromo-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethanol (160 mg, 0.2 mmol, Intermediate 1, see US Pub. No. 2015/0080393 paragraph [0409]) in dioxane (2 mL) was added 2-amino-4,6-dichloropyrimidine (100 mg, 0.16 mmol) and CS2CO3 (48 ,g, 0.16 mmol). The reaction was heated to 80 °C for 16 h, cooled to RT, and filtered. The solvent was removed in vacuo and the residue was dissolved in a mixture of CH2CI2 and heptane, concentrated to half the volume, filtered, and concentrated again in vacuo. Purification via normal phase silica gel chromatography (QLCk/Heptane) provided 4-[(lR)-l- [4-bromo-2-(3-methylpyrazol-l-yl)phenyl]-2,2,2-trifluoro-ethoxy]-6-chloro-pyrimidin-2-amine as an off-white solid.
Step 2: To a solution of 4-[(lR)-l-[4-bromo-2-(3-methylpyrazol-l-yl)phenyl]-2,2,2-trifluoro- ethoxy]-6-chloro-pyrimidin-2-amine (125 mg, 0.3 mmol, Step 1) in dioxane (3 mL) was added (S)-2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (95 mg, 0.3 mmol, US Pub. No. 2015/0080393 paragraph [0469]) and Na2C03 (182 mg, 0.35 mmol). The reaction was heated to 90 °C for 130 h, then cooled to RT, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtO Ac/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6- ((R)-l-(4-bromo-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Step 3: To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-l-(4-bromo-2-(3-methyl-lH- pyrazol-l-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3- dicarboxylate (300 mg, 0.4 mmol, Step 2) in ethanol (2 mL) and water (0.5 mL) was added phenylboronic acid (143 mg, 0.8 mmol), PdCl2(PPh3)2 (41 mg, 0.058 mmol), and Cs2C03 (390 mg, 1.2 mmol). The reaction was heated to 60 °C for 16 h, then cooled to RT, filtered through celite and concentrated in vacuo. Purification by normal phase silica gel column
(EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-l-(3-(3- methyl-1 H-pyrazol-1 -yl)-[ 1 , 1 '-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2, 8-diazaspiro[4.5]decane- 2,3 -dicarboxy late as a white solid.
Step 4: A solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-l-(3-(3-methyl-lH- pyrazol-l-yl)-[l,l'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3- dicarboxylate (240 mg, 0.4 mmol, Step 3) in EtO Ac (5 mL) was hyrogenated using an H-Cube apparatus and a 10% (w/w) Pd/C cartridge with a flow rate of 1.0 mL/min at RT. Purification on normal phase silica gel (EtO Ac/heptane) provided (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-l- (3 -(3 -methyl- 1 H-pyrazol-1 -yl)-[ 1 , 1 '-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate.
Step 5: To a solution of (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-l-(3-(3-methyl-lH-pyrazol- l-yl)-[l,l'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (50 mg, 0.08 mmol) from Step 4 in THF (2.0 mL) and water (0.2 mL), was added lithium hydroxide monohydrate (58 mg, 0.05 mmol). The reaction mixture was stirred at RT for 2 h, then the solution was neutralized with 1 N HC1, and concentrated in vacuo. Purification by normal phase silica gel column (EtO Ac/heptane) provided the title compound as an off-white solid as the zwitterionic form. Example lm: (S)-8-(2-amino-6-((R)-l-(3',4'-dimethyl-3-(3-methyl-lH-pyrazol-l-yl)-[l,l'- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
Figure imgf000053_0001
Example Icq: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(3'-(hydroxymethyl)-4'-methyl-3-(3- methyl- IH-pyrazol- 1-yl)- [ 1, 1 '-biphenyl] -4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- rboxylic acid
Figure imgf000053_0002
Example lcr: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4'-(hydroxymethyl)-3'-methyl-3-(3- methyl- IH-pyrazol- 1-yl)- [ 1, 1 '-biphenyl] -4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carbox lic acid
Figure imgf000053_0003
Table la.
Figure imgf000054_0001
Ex. Cy CAS Name
No.
(3S)-8-(2-amino-6-((lR)-2,2,2-tnfluoro-l-(3-(3-methyl-lH- pyrazol- 1 -yl)-4'-(methylsulfinyl)-[ 1 , 1 '-bipheny l]-4- la
yl)ethoxy)pyrimidin-4-yl)-2, 8-diazaspiro [4.5] decane-3 -
1
carboxylic acid
(S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(3-(3-methyl-lH- pyrazol- 1 -yl)-4'-(methylthio)-[ 1 , 1 '-biphenyl]-4-yl) lb
ethoxy)pyrimidin-4-yl)-2,8-diazaspiro [4.5]decane-3- carboxylic acid
(S)-8-(2-amino-6-((R)-l-(3'-carboxy-3-(3-methyl-lH- pyrazol- 1 -yl)- [1,1 '-bipheny l]-4-yl)-2,2,2- lc
trifluoroethoxy)pyrimidin-4-yl)-2, 8-diazaspiro [4.5] decane-3 -
OH
carboxylic acid
HO (S)-8-(2-amino-6-((R)-l-(3'-carboxy-3-(3-methyl-lH- pyrazol- 1 -yl)- [1,1 '-bipheny l]-4-yl)-2,2,2-
Id trifluoroethoxy)pyrimidin-4-yl)-2, 8-diazaspiro [4.5] decane-3 - carboxylic acid
(S)-8-(2-amino-6-((R)-l-(4'-carboxy-3 -(3 -methyl- 1H- pyrazol- 1 -yl)- [1,1 '-bipheny l]-4-yl)-2,2,2- le
trifluoroethoxy)pyrimidin-4-yl)-2, 8-diazaspiro [4.5] decane-3 -
OH
carboxylic acid
H N^i (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(2-(3-methyl-lH- pyrazol-l-yl)-4-(l,2,3,6-tetrahydropyridin-4-
If
yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3 -carboxylic acid
(S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(2-(3-methyl-lH- lg y pyrazol-l-yl)-4-(pyridin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
\ (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(2-(3-methyl-lH- pyrazo 1-1 -yl)-4-(l -methyl- lH-pyrazol-4- lh "Oy yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3 -carboxylic acid
(S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(4-(isoxazol-4-yl)-2- li (3 -methyl- 1 H-pyrazol- 1 -yl)phenyl)ethoxy)pyr imidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid (S)-8-(2-amino-6-((R)-l-(4-(3,6-dihydro-2H-pyran-4-yl)-2- (3 -methyl- 1 H-pyrazol- 1 -yl)phenyl)-2, 2,2- ij trifluoroethoxy)pyrimidin-4-yl)-2, 8-diazaspiro [4.5] decane-3 - carboxylic acid
(S)-8-(6-((R)-l-(4-(l-acetyl-l,2,3,6-tetrahydropyndin-4-yl)- 2-(3-methyl- 1 H-pyrazol- 1 -yl)phenyl)-2,2,2-trifluoroethoxy)- lk
2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4'-isopropoxy-3-(3-
11 methyl-1 H-pyrazol- 1 -yl)-[ 1 , 1 '-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
(S)-8-(2-amino-6-((R)-l-(3',4'-dimethyl-3-(3-methyl-lH- lm pyrazol- 1 -yl)- [1,1 '-bipheny l]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2, 8-diazaspiro [4.5] decane-3 - carboxylic acid
(S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(4-(2- methoxypyridin-4-yl)-2-(3 -methyl- lH-pyrazol- 1 -
In
1 yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3 -carboxylic acid
H (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(4-(3-methyl-lH-
N-N
indazol-6-yl)-2-(3 -methyl- 1 H-pyrazol- 1 - lo yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3 -carboxylic acid
(S)-8-(2-amino-6-((R)-l-(4'-(tert-butyl)-3-(3-methyl-lH- pyrazol- 1 -yl)- [1,1 '-bipheny l]-4-yl)-2,2,2- lp trifluoroethoxy)pyrimidin-4-yl)-2, 8-diazaspiro [4.5] decane-3 - carboxylic acid
(S)-8-(2-amino-6-((R)-l-(4'-ethoxy-3-(3-methyl-lH-pyrazol- lq 1 -yl)-[ 1 , 1 '-bipheny l]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
(S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(4-(2- methoxypyrimidin-5-yl)-2-(3-methyl-lH-pyrazol-l- lr
yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3 -carboxylic acid
(S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(4-(6- methoxypyridin-3 -yl)-2-(3 -methyl- lH-pyrazol- 1 -
Is
yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3 -carboxylic acid
(S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(3-(3-methyl-lH- lu pyrazol- 1 -yl)- [1,1 '-bipheny l]-4-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
(S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(3-(3-methyl-lH- pyrazol-l-yl)-2',3',4',5'-tetrahydro-[l,l'-biphenyl]-4- lv
yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid (S)-8-(2-amino-6-((R)-l-(3'-cyano-3-(3-methyl-lH-pyrazol- 1 -yl)-[ 1 , 1 '-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- lw yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000056_0001
(S)-8-(6-((R)-l-(4'-(acetamidomethyl)-3 -(3 -methyl- 1H- pyrazol- 1 -yl)- [1,1 '-bipheny l]-4-yl)-2,2,2-trifluoroethoxy)-2- lx
aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
V (S)-8-(6-((R)-l-(4'-(2-acetamidoethyl)-3 -(3 -methyl- 1H-
HN. pyrazol- 1 -yl)- [1,1 '-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)-2- iy aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
(S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(2-(3-methyl-lH- lz pyrazol-l-yl)-4-(quinolin-7-yl)phenyl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
(S)-8-(6-((R)-l-(4-(lH-indol-6-yl)-2-(3-methyl-lH-pyrazol- l-yl)phenyl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)- laa 2,8-diazaspiro[4.5]decane-3-carboxylic acid
(S)-8-(2-amino-6-((R)-l-(4'-(aminomethyl)-3 -(3 -methyl- 1H- pyrazol- 1 -yl)- [1,1 '-bipheny l]-4-yl)-2,2,2- lab
trifluoroethoxy)pyrimidin-4-yl)-2, 8-diazaspiro [4.5] decane-3 - carboxylic acid
(S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(3'-fluoro-3-(3- methyl-1 H-pyrazol- 1 -yl)-[ 1 , 1 ' -bipheny 1] -4- lac
yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
(S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(2-(3-methyl-lH- pyrazol-l-yl)-4-(quinolin-6-yl)phenyl)ethoxy)pyrimidin-4- lad
yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
(S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(4'-methyl-3-(3- methyl-1 H-pyrazol- 1 -yl)-[ 1 , 1 ' -bipheny 1] -4- lae
yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
(S)-8-(2-amino-6-((R)-l-(3',4'-dichloro-3-(3-methyl-lH- pyrazol- 1 -yl)- [1,1 '-bipheny l]-4-yl)-2,2,2- laf
trifluoroethoxy)pyrimidin-4-yl)-2, 8-diazaspiro [4.5] decane-3 - carboxylic acid
(S)-8-(2-amino-6-((R)-l-(3',4'-difluoro-3-(3-methyl-lH- pyrazol- 1 -yl)- [1,1 '-bipheny l]-4-yl)-2,2,2- lag
trifluoroethoxy)pyrimidin-4-yl)-2, 8-diazaspiro [4.5] decane-3 - carboxylic acid (S)-8-(2-amino-6-((R)-l-(4'-chloro-3-(3-methyl-lH-pyrazol- lah 1 -yl)-[ 1 , 1 '-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
(S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(2-(3-methyl-lH- lai pyrazol-l-yl)-4-(pyrimidin-5-yl)phenyl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
F (S)-8-(2-amino-6-((R)-l-(3'-chloro-3-(3-methyl-lH-pyrazol- 1 -yl)-5 '-(trifluoromethy l)-[ 1 , 1 '-biphenyl] -4-yl)-2,2,2- lak trifluoroethoxy)pyrimidin-4-yl)-2, 8-diazaspiro [4.5] decane-3 - carboxylic acid
(S)-8-(2-amino-6-((R)-l-(3'-chloro-4'-ethoxy-3-(3-methyl- lH-pyrazol- 1 -yl)-[ 1 , 1 '-biphenyl]-4-yl)-2,2,2- lal
trifluoroethoxy)pyrimidin-4-yl)-2, 8-diazaspiro [4.5] decane-3 - carboxylic acid
(S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(3-(3-methyl-lH- pyrazol-1 -yl)-3'-(trifluoromethyl)-[ 1 , 1 ' -biphenyl] -4- lam
yl)ethoxy)pyrimidin-4-yl)-2, 8-diazaspiro [4.5] decane-3 - carboxylic acid
(S)-8-(2-amino-6-((R)-l-(3'-chloro-5'-methyl-3-(3-methyl- lH-pyrazol- 1 -yl)-[ 1 , 1 '-biphenyl]-4-yl)-2,2,2- lan
trifluoroethoxy)pyrimidin-4-yl)-2, 8-diazaspiro [4.5] decane-3 - carboxylic acid
(S)-8-(2-amino-6-((R)-l-(4'-chloro-3'-fluoro-3-(3-methyl-lH- pyrazol- 1 -yl)- [1,1 '-bipheny l]-4-yl)-2,2,2- lao Χ trifluoroethoxy)pyrimidin-4-yl)-2, 8-diazaspiro [4.5] decane-3 - carboxylic acid
(S)-8-(2-amino-6-((R)-l-(3'-ethoxy-3-(3-methyl-lH-pyrazol- lap 1 -yl)-[ 1 , 1 '-bipheny l]-4-yl)-2, 2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(3'-fluoro-4'-methyl- 3-(3-methyl- 1 H-pyrazol- 1 -yl)-[ 1 , 1 '-biphenyl]-4- laq X yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
CI (S)-8-(2-amino-6-((R)-l-(3'-chloro-4'-fluoro-3-(3-methyl-lH- pyrazol- 1 -yl)- [1,1 '-bipheny l]-4-yl)-2,2,2- lar
trifluoroethoxy)pyrimidin-4-yl)-2, 8-diazaspiro [4.5] decane-3 - carboxylic acid
(S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(3-(3-methyl-lH- pyrazol- 1 -yl)-3'-(trifluoromethoxy)-[ 1 , 1 '-biphenyl] -4- las
yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
(S)-8-(2-amino-6-((R)-l-(3',5'-dimethyl-3-(3-methyl-lH- pyrazol- 1 -yl)- [1,1 '-bipheny l]-4-yl)-2,2,2- lat
trifluoroethoxy)pyrimidin-4-yl)-2, 8-diazaspiro [4.5] decane-3 - carboxylic acid (S)-8-(2-amino-6-((R)-l-(3',4'-difluoro-3-(3-methyl-lH- p 1 -yl)- [1,1 '-bipheny l]-4-yl)-2,2,2- lau X yrazol- trifluoroethoxy)pyrimidin-4-yl)-2, 8-diazaspiro [4.5] decane-3 - carboxylic acid
(S)-8-(2-amino-6-((R)-l-(3',5'-difluoro-3-(3-methyl-lH- pyrazol- 1 -yl)- [1,1 '-bipheny l]-4-yl)-2,2,2- lav
trifluoroethoxy)pyrimidin-4-yl)-2, 8-diazaspiro [4.5] decane-3 - carboxylic acid
(S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(4'-fluoro-3-(3- methyl-1 H-pyrazol- 1 -yl)-3 '-(trifluoro methyl)- [ 1 , 1 '-biphenyl]- law
4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
(S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(3'-fluoro-4'- isopropoxy-3 -(3 -methyl- 1 H-pyrazol- 1 -yl)- [ 1 , 1 '-biphenyl] -4- lax
yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
(S)-8-(2-amino-6-((R)-l-(3'-ethoxy-5'-fluoro-3-(3-methyl- lH-pyrazol- 1 -yl)-[ 1 , 1 '-biphenyl]-4-yl)-2,2,2- lay * trifluoroethoxy)pyrimidin-4-yl)-2, 8-diazaspiro [4.5] decane-3 - carboxylic acid
(S)-8-(2-amino-6-((R)-l-(3'-(tert-butyl)-3-(3-methyl-lH- pyrazol- 1 -yl)- [1,1 '-bipheny l]-4-yl)-2,2,2- laz
trifluoroethoxy)pyrimidin-4-yl)-2, 8-diazaspiro [4.5] decane-3 - carboxylic acid
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4'-fluoro-3'-methyl- 3-(3-methyl- 1 H-pyrazol- 1 -yl)-[ 1 , 1 '-biphenyl]-4- lba
Figure imgf000058_0001
yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
(S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(3'-isopropyl-3-(3- methyl-1 H-pyrazol- 1 -yl)-[ 1 , 1 ' -biphenyl] -4- lbb
yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
oro-l-(3'-isopropoxy-3-(3- methyl-1 H-pyrazol- 1 -yl)-[ 1 , 1 ' -biphenyl] -4- lbc AA (S)-8-(2-amino-6-((R)-2,2,2-triflu yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
(S)-8-(2-amino-6-((R)-l-(4'-chloro-3'-methyl-3-(3-methyl- lH-pyrazol- 1 -yl)-[ 1 , 1 '-biphenyl]-4-yl)-2,2,2- lbd
trifluoroethoxy)pyrimidin-4-yl)-2, 8-diazaspiro [4.5] decane-3 - carboxylic acid
(S)-8-(2-amino-6-((R)-l-(3'-carbamoyl-3-(3-methyl-lH- pyrazol- 1 -yl)- [1,1 '-bipheny l]-4-yl)-2,2,2- lbe
o trifluoroethoxy)pyrimidin-4-yl)-2, 8-diazaspiro [4.5] decane-3 - carboxylic acid
Figure imgf000059_0001
(S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(3'-methyl-3-(3- methyl- 1 H-pyrazol- 1 -yl)-4'-(trifluoromethoxy)-[ 1 , 1 '- lbq
biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
F (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(3'-fluoro-5'- isopropoxy-3 -(3 -methyl- 1 H-pyrazol- 1 -yl)- [ 1 , 1 '-biphenyl] -4- lbr
yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
(S)-8-(2-amino-6-((R)-l-(3'-chloro-5'-fluoro-3-(3-methyl-lH- pyrazol- 1 -yl)- [1,1 '-biphenyl]-4-yl)-2,2,2- lbs
trifluoroethoxy)pyrimidin-4-yl)-2, 8-diazaspiro [4.5] decane-3 - carboxylic acid
(S)-8-(2-amino-6-((R)-l-(4'-chloro-3-(3-methyl-lH-pyrazol- 1 -yl)-3 '-(tnfluoromethyl)-[ 1 , 1 '-biphenyl] -4-yl)-2,2,2- lbt
trifluoroethoxy)pyrimidin-4-yl)-2, 8-diazaspiro [4.5] decane-3 - carboxylic acid
(S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(3'-fluoro-3-(3- methyl- 1 H-pyrazol- 1 -yl)-5 '-(trifluoro methyl)- [ 1 , 1 '-biphenyl]- lbu 4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
(S)-8-(2-amino-6-((R)-l-(3'-chloro-4'-isopropoxy-3-(3- methyl- 1 H-pyrazol- 1 -yl)-[ 1 , 1 '-biphenyl]-4-yl)-2,2,2- lbv
trifluoroethoxy)pyrimidin-4-yl)-2, 8-diazaspiro [4.5] decane-3 - carboxylic acid
(S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(2-(3-methyl-lH- lbw pyrazol- 1 -yl)-4-(naphthalen-2-yl)phenyl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
(S)-8-(2-amino-6-((R)-l-(4'-(benzyloxy)-3'-fluoro-3-(3- methyl- 1 H-pyrazol- 1 -yl)-[ 1 , 1 '-biphenyl]-4-yl)-2,2,2- lbx
trifluoroethoxy)pyrimidin-4-yl)-2, 8-diazaspiro [4.5] decane-3 - carboxylic acid
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4'-isopropoxy-3'- methy 1-3 -(3 -methyl- 1 H-pyrazol- 1 -yl)- [1,1 '-biphenyl] -4- lby
yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
(S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(3'-fluoro-3-(3- methy 1- 1 H-pyrazol- 1 -yl)-4'-propoxy- [1,1 -biphenyl] -4- lbz
yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
(S)-8-(2-amino-6-((R)-l-(4'-butoxy-3'-fluoro-3-(3-methyl- lH-pyrazol- 1 -yl)-[ 1 , 1 '-biphenyl]-4-yl)-2,2,2- lea
trifluoroethoxy)pyrimidin-4-yl)-2, 8-diazaspiro [4.5] decane-3 - carboxylic acid
Figure imgf000061_0001
Figure imgf000062_0001
carboxylic acid
Example lcp: (S)-8-(2-amino-6-((R)-l-(3',4'-dimethyl-3-(3-(trifluoromethyl)-lH-pyrazol-l- yl)-[l,l'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
Figure imgf000063_0001
Example 2: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(2-(3-methyl-lH-pyrazol-l-yl)-4- (piperidin-4-yl)phenyl)ethox rimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000063_0002
Example 3a: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(2-(3-methyl-lH-pyrazol-l-yl)-4-(l- (methylsulfonyl)piperidin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
Figure imgf000063_0003
Table 2a.
Figure imgf000064_0001
Example 4: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(3'-methoxy-4'-(methoxycarbonyl)-3-(3- methyl- IH-pyrazol- 1-yl)- [ 1, 1 '-biphenyl] -4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carbox lic acid
Figure imgf000064_0002
Example 5a: (S)-8-(2-amino-6-((R)-l-(3'-(ethoxycarbonyl)-3-(3-methyl-lH-pyrazol-l-yl)- [1,1 '-biphenyl] -4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
Figure imgf000065_0001
Example 5b : (S)-8-(2-amino-6-((R)- l-(4'-(ethoxycarbonyl)-3- (3-methyl- IH-pyrazol- 1-yl)- [l,l'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
Figure imgf000065_0002
Example 6: (S)-8-(2-amino-6-((R)-l-(4-(3-carboxypropyl)-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000065_0003
Example 7: (S)-8-(2-amino-6-((R)-l-(4-(2-carboxyethyl)-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000066_0001
Example 9: (S)-8-(2-amino-6-((R)-l-(4-(3-ethoxy-3-oxopropyl)-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000066_0002
Example lOd: (S)-8-(2-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4- l)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000066_0003
Table 3a.
Figure imgf000067_0001
* Stereochemistry defined in name in table below
Figure imgf000067_0002
10k CI H H 8-(2-amino-6-((R)-l-(5-chloro-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
101 H H (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4-methoxy-2-(3- methyl- 1 H-pyrazol- 1 -yl)phenyl)ethoxy)pyrimidin-4-yl)-2, 8- diazaspiro[4.5]decane-3-carboxylic acid
10m H Br H (S)-8-(2-amino-6-((R)-l-(4-bromo-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
10η Br H H (S)-8-(2-amino-6-((R)-l-(5-bromo-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
Example 10ο: (S)-8-(2-amino-6-((R)-l-(4-bromo-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin- -yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000068_0001
Example lOp: (S)-8-(2-amino-6-((R)-l-(4-chloro-2-(3-(trifluoromethyl)-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000068_0002
Example lOpa: (S)-8-(2-amino-6-((R)-l-(2-(3-(tert-butyl)-lH-pyrazol-l-yl)-4-chlorophenyl)- 2,2,2-trifluoroethoxy)pyrimi in-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000069_0001
Example lOq: (S)-8-(2-amino-6-((R)-l-(4-chloro-2-(3-isopropyl-lH-pyrazol-l-yl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidin-4- l)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000069_0002
Example lOr: (S)-8-(2-amino-6-((R)-l-(4-chloro-2-(3-cyclopropyl-lH-pyrazol-l-yl)phenyl)- 2,2,2-trifluoroethoxy)pyrimi in-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000069_0003
Example 11: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(6-methyl-2-(3-methyl-lH-pyrazol-l- yl)pyridin-3-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000070_0001
Example 12a: (S)-8-(2-amino-6-((R)-l-(4-ethyl-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin- -yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000070_0002
Figure imgf000070_0003
12c (S)-8-(2-amino-6-((R)-l-(4-butyl-2-(3-methyl-lH- 588
pyrazol-l-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Example 13: (3S)-8-(2-amino-6-((lR)-l-(4-(l,2-dihydroxyethyl)-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000071_0001
Example 14: (S)-8-(2-amino-6-((R)-l-(4-cyano-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000071_0002
Example 15: (S)-8-(2-amino-6-((R)-l-(4-carbamoyl-2-(3-methyl-lH-pyrazol-l-yl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000072_0001
Example 16: (S)-8-(2-amino-6-((R)-l-(4-carboxy-2-(3-methyl-lH-pyrazol-l-yl)phenyl)- 2,2,2-trifluoroethoxy) pyrimidin-4- l)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000072_0002
Example 17: (S)-8-(2-amino-6-((R)-l-(4-(ethoxycarbonyl)-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000072_0003
Example 18a: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4-(((l,l,l,3,3,3-hexafluoro-2- methylpropan-2-yl)oxy)carbonyl)-2-(3-methyl-lH-pyrazol-l-yl)phenyl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000073_0001
Figure imgf000073_0002
18f (S)-8-(2-amino-6-((R)-l-(4-((cyclopentyloxy)carbonyl)-2-(3-methyl- lH-pyrazol-l-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
Example 19a: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(2-(3-methyl-lH-pyrazol-l-yl)-5- vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000074_0001
Table 6a.
Figure imgf000074_0002
Figure imgf000074_0003
19d (S)-8-(2-amino-6-((R)-l-(5-((E)-2-carboxyvinyl)-2-(3- 602.6 methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
Table 7a.
Figure imgf000075_0001
Figure imgf000075_0002
j OH (S)-8-(2-amino-6-((R)-l-(3'-(2-carboxyethyl)-4-(3-methyl-lH-pyrazol-l- yl)-[ 1 , 1 '-biphenyl] -3 -yl)-2, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2, 8- diazaspiro[4.5]decane-3-carboxylic acid k (S)-8-(2-amino-6-((R)-l-(4'-(2-carboxyethyl)-4-(3-methyl-lH-pyrazol-l- yl)-[ 1 , 1 '-biphenyl] -3 -yl)-2, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2, 8- diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000076_0001
1 (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4'-(hydroxymethyl)-3'-methyl-4- (3 -methyl- lH-pyrazol- 1 -yl)-[ 1 , 1 '-biphenyl]-3-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid m (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(3'-(hydroxymethyl)-4'-methyl-4- (3 -methyl- lH-pyrazol- 1 -yl)-[ 1 , 1 '-biphenyl]-3-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid n (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(4-(3-methyl-lH-pyrazol-l-yl)- [1,1 '-biphenyl] -3 -yl)ethoxy)pyrimidin-4-yl)-2, 8-diazaspiro [4.5] decane-3 - carboxylic acid
o (S)-8-(2-amino-6-((R)-l-(3',4'-difluoro-4-(3-methyl-lH-pyrazol-l-yl)- [l, -biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid p CI (S)-8-(2-amino-6-((R)-l-(3',4'-dichloro-4-(3-methyl-lH-pyrazol-l-yl)- [l, -biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid q CI (S)-8-(2-amino-6-((R)-l-(4'-chloro-4-(3-methyl-lH-pyrazol-l-yl)-[l,r- biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid r (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4'-(hydroxymethyl)-4-(3-methyl- lH-pyrazol- 1 -yl)-[ 1 , 1 '-biphenyl]-3-yl)ethoxy)pyrimidin-4-yl)-2, 8- diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000076_0002
Example 20: (S)-8-(2-amino-6-((R)-l-(2'-(ethoxycarbonyl)-4-(3-methyl-lH-pyrazol-l-yl)- [l,l'-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
Figure imgf000077_0001
Example 21: (S)-8-(2-amino-6-((R)-l-(4'-(ethoxycarbonyl)-4-(3-methyl-lH-pyrazol-l-yl)- [l,l'-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
Figure imgf000077_0002
Example 22a: (S)-8-(2-amino-6-((R)-l-(5-ethyl-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000078_0001
Figure imgf000078_0002
diazaspiro[4.5]decane-3-carboxylic acid
Example 23: (S)-8-(2-Amino-6-((R)-l-(5-(ethoxycarbonyl)-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000079_0001
Example 24: (S)-8-(2-Amino-6-((R)-l-(5-carboxy-2-(3-methyl-lH-pyrazol-l-yl)phenyl)- 2,2,2-trifluoroethoxy) pyrimidin-4- l)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000079_0002
Example 25: (S)-8-(2-Amino-6-((R)-2,2,2-trifluoro-l-(4-(hydroxymethyl)-2-(3-methyl-lH- pyrazol-l-yl)phenyl)ethox rimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000079_0003
Example 26: (S)-8-(2-amino-6-((R)-l-(4-((dimethylamino)methyl)-2-(3-methyl-lH-pyrazol- l-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000080_0001
Example 27: (S)-8-(6-((R)-l-(4-Bromo-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)-2-methyl rimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000080_0002
Example 28: (S)-8-(6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)-2-methyl pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic
Figure imgf000080_0003
Ex. No. I Cy CAS Name a (S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-l-(4-(2-methoxypyridin-4- yl)-2-(3-methyl-lH-pyrazol-l-yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
b (S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-l-(3-(3-methyl-lH-pyrazol- 1 -yl)-4'-(methylsulfonyl)-[ 1 , 1 '-biphenyl]-4-yl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
c (S)-8-(6-((R)- 1-(3 ',4'-difluoro-3-(3 -methyl- IH-pyrazol- 1 -yl)- [ 1 , Γ- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
d (S)-8-(6-((R)-l-(3',4'-dimethyl-3-(3-methyl-lH-pyrazol-l-yl)- [l,l'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
e (S)-8-(6-((R)-l-(3'-(ethoxycarbonyl)-3-(3-methyl-lH-pyrazol-l- y 1) - [ 1 , 1 '-biphenyl] -4-yl)-2, 2,2-trifluoroethoxy)-2- methylpyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid f (S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-l-(4-(6-methoxypyridin-3- yl)-2-(3-methyl-lH-pyrazol-l-yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
g (S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-l-(4-(2-methoxypyrimidin- 5-yl)-2-(3-methyl-lH-pyrazol-l-yl)phenyl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
h (S)-8-(6-((R)-l-(2',4'-dimethoxy-3-(3-methyl-lH-pyrazol-l-yl)- [l,l'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
i (S)-8-(6-((R)-l-(4'-(ethoxycarbonyl)-3-(3-methyl-lH-pyrazol-l- y 1) - [ 1 , 1 '-biphenyl] -4-yl)-2, 2,2-trifluoroethoxy)-2- methylpyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
j (S)-8-(6-((R)-l-(4'-(dimethylcarbamoyl)-3-(3-methyl-lH-pyrazol- 1 -yl)-[ 1 , 1 '-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)-2- methylpyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
k (S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-l-(4-(2-methoxypyridin-3- yl)-2-(3-methyl-lH-pyrazol-l-yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
1 (S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-l-(3'-fluoro-4'-methoxy-3- (3-methyl-lH-pyrazol-l-yl)-[l,l'-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (S)-8-(6-((R)-l-(3'-(dimethylcarbamoyl)-3-(3-methyl-lH-pyrazol- 1 -yl)-[ 1 , 1 '-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)-2- methylpyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Table 10.
Figure imgf000082_0001
Figure imgf000082_0002
Figure imgf000083_0001
Example 30a: 8-(6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)-2-phenoxypyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000083_0002
Table 11a.
Figure imgf000084_0001
Ex. R CAS Name
No.
30a 8-(6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)-2-phenoxypyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
30b 8-(6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)-2-(cyclohexyloxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
Example 31: 8-(6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)-2-(cyclohexylamino)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
Figure imgf000084_0002
Example 32: (S)-8-(6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)-2-(cyclobutanecarboxamido)pyrimidin-4-yl)-2,8-diazaspiro[4.5] decane-3- carboxylic acid
Figure imgf000085_0001
Example 33: (S)-8-(2-amino-6-((R)-l-(4-chloro-2-(2-oxopyrrolidin-l-yl)phenyl)-2,2,2- trifluoroethoxy) pyrimidin-4- l)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000085_0002
Example 34c: (S)-8-(2-amino-6-((R)-l-(5-chloro-[l,l'-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4- l)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000085_0003
Step 1: To a solution of (R)-l-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethanol (Intermediate 43, see U.S. Pub. No. 2015/0080393 paragraph [0463]) (400 mg, 1.4 mmol) in dioxane (25 mL) was added 4,6-dichloropyrimidin-2-amine (1.1 g, 7 mmol) and CS2CO3 (1.3 g, 4 mmol). The mixture was heated for 24 h at 80 °C. The reaction was then cooled to RT and filtered. The solvent was removed in vacuo, then CH2CI2 and heptane was added. The solvent volume was reduced until a solid precipitated out. The solid was filtered and the procedure repeated several times to provide (R)-4-(l-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)-6-chloropyrimidin-2-amine as a white solid.
Step 2: To a solution of (R)-4-(l-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)-6- chloropyrimidin-2-amine (100 mg, 0.24 mmol, Step 1) in dioxane (5 mL) was added (S)-2- benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (100 mg, 0.29 mmol, U.S. Pub. No. 2015/0080393 paragraph [0469]), and NaHC03 (300 mg, 3.5 mmol). After 5 h, an additional amount of NaHCCb (300 mg, 3.5 mmol) was added and the reaction mixture was heated to 90 °C for 36 h. The reaction was then cooled to RT and filtered. Purification by normal phase silica gel column (EtO Ac/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-l-(2-bromo-4- chlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Step 3: To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-l-(2-bromo-4-chlorophenyl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (100 mg, 0.13 mmol) in 10: 1 dioxane:water (5 mL) was phenyl boronic acid (33 mg, 0.27 mmol), KHCO3 (27 mg, 0.3 mmol), and PdC^dppfj-CEbCb. (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 EtO Ac. The combined organic layers were dried over Na2S04, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtO Ac/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-l-(5-chloro-[l,r-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid. Step 4: N-CBZ Deprotection was accomplished via method B to provide (S)-ethyl 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-carboxylate an off-white solid.
Step 5: Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-[l,r-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the LiOH general method provided the title compound as an off-white solid as the zwitterionic form. Example 34u: (S)-8-(2-amino-6-((R)-l-(5-chloro-3'-sulfamoyl-[l,l'-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidi -4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000087_0001
Table 12a.
Figure imgf000087_0002
* Stereochemistry defined in name in table below
Figure imgf000087_0003
e 8-(2-amino-6-((R)- 1 -(5-chloro-3 '-mtro-[ 1 , 1 '-biphenyl] -2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2, 8-diazaspiro [4.5] decane-3 - carboxylic acid
ό
f 8-(2-amino-6-((R)-l-(3'-amino-5-chloro-[l, -biphenyl]-2-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
g 8-(2-amino-6-((R)- 1 -(5-chloro-4'-nitro-[ 1 , 1 '-biphenyl] -2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2, 8-diazaspiro [4.5] decane-3 - carboxylic acid h 8-(2-amino-6-((R)-l-(4'-amino-5-chloro-[l,r-biphenyl]-2-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
Ν Η2
i (S)-8-(2-amino-6-((R)-l-(4-chloro-2-(6-methylpyridin-2- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
j (S)-8-(2-amino-6-((R)-l-(5-chloro-3'-(ethylsulfonyl)-[l,r- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid k (S)-8-(2-amino-6-((R)- 1 -(5-chloro-3'-(propylsulfonyl)- [ 1 , Γ- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid 1 (S)-8-(2-amino-6-((R)-l-(3'-(butylsulfonyl)-5-chloro-[l,r- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
o
m (S)-8-(2-amino-6-((R)-l-(5-chloro-3'-(hydroxymethyl)-[l,r- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
HO
n (S)-8-(2-amino-6-((R)- 1 -(5-chloro-3 '-(methylsulfonamido)-[ 1 , 1 '- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
o=s=o
1
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Example 35: (S)-8-(2-amino-6-((R)-l-(5-chloro-3'-(ethoxycarbonyl)-[l,l'-biphenyl]-2-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000098_0001
Example 36: (S)-8-(2-amino-6-((R)-l-(4-chloro-2-(2-methoxyethoxy)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000098_0002
Example 36b: (S)-8-(6-((R)-l-(2-(lH-benzo[d]imidazol-l-yl)-4-chlorophenyl)-2,2,2- trifluoroethoxy)-2-aminop rimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000098_0003
Example 36c: (S)-8-(2-amino-6-((R)-l-(4-chloro-2-(lH-indazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000099_0001
Example 36d: (S)-8-(2-amino-6-((R)-l-(4-bromo-2-(piperazin-l-yl)phenyl)-2,2,2 trifluoroethoxy)pyrimidin- -yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000099_0002
Example 36e: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4'-isopropoxy-3-(piperazin-l-yl)- [l,l'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000099_0003
Example 36f: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4'-isopropoxy-3-morpholino-[l,l'- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000100_0001
Example 36g: (S)-8-(6-((R)-l-([l,l'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)-2- pyrimidin-4-yl)-2,8-diazaspiro 4.5]decane-3-carboxylic acid
Figure imgf000100_0002
Example 37: (3S)-8-(6-(l-((lr,3r,5S,7S)-adamantan-2-yl)ethoxy)-2-aminopyrimidin-4-yl)- 2,8-diazaspiro[4.5] decane-3-carbox lic acid
Figure imgf000100_0003
Example 38: (S)-8-(6-((lr,3r,5S,7S)-adamantan-2-ylmethoxy)-2-aminopyrimidin diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000101_0001
Example 39a: 8-(4-Amino-6-((naphthalen-2-ylmethyl)amino)-l,3,5-triazin-2-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000101_0002
Figure imgf000101_0003
39c 8-(4-amino-6-((2-(piperidin-l-yl)benzyl)amino)-l,3,5-triazin-2-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
39d 8-(4-(([l,l'-biphenyl]-3-ylmethyl)amino)-6-amino-l,3,5-triazin-2- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
39e 8-(4-amino-6-(((R)-l-(naphthalen-2-yl)ethyl)amino)-l,3,5-triazin- 2-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Example 40: 8-(4-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)-l,3,5-triazin-2- l)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000102_0001
Example 41a: (S)-8-(2-Amino-6-((2-(piperidin-l-yl)benzyl)amino)pyrimidin
diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000102_0002
Table 14a.
Figure imgf000103_0001
Figure imgf000103_0003
Example 42a: (S)-8-(2-amino-6-((R)-l-(3'-chloro-[l,l'-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4- l)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000103_0002
Example 42b: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(3'-fluoro-[l,l,-biphenyl]-2- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000104_0001
Example 43: (S)-8-(5-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyridazin- -yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000104_0002
Example 44: (S)-8-(4-((R)-2,2,2-trifluoro-l-(2-(3-methyl-lH-pyrazol-l- yl)phenyl)ethoxy)pyridin-2-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
and
Example 45: (S)-8-(4-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2 trifluoroethoxy)pyridin-2- l)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000104_0003
Example 44: X = H
Example 46: 8-(4-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)-6-phenoxypyrimidin-2-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000105_0001
Example 47: (3S)-8-(2-Amino-6-(l-(2,6-dibromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4 yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000105_0002
Example 48: (S)-8-(2-Amino-6-((R)-l-(2,5-dibromophenyl)-2,2,2- trifluoroethoxy)pyrimidin-4- l)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000105_0003
Example 49: (S)-8-(2-Amino-6-((R)-2,2,2-trifluoro-l-(3'-(methylsulfonyl)-4-propyl-[l,l'- biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000106_0001
Example 50: (S)-8-(2-Amino-6-((R)-2,2,2-trifluoro-l-(3'-(methylsulfonyl)-4-((E)-prop-l-en- l-yl)-[l,l'-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000106_0002
Example 51a: (S)-8-(6-((R)-l-([l,l,:4',lM-terphenyl]-2,-yl)-2,2,2-trifluoroethoxy)-2- aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000106_0003
Example 51b: (S)-8-(6-((R)-l-([l,l,:3,,lM-terphenyl]-2'-yl)-2,2,2-trifluoroethoxy)-2- aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000107_0001
Example 52a: (S)-8-(2-Amino-6-((R)-l-(3,4-dimethyl-3"-(methylsulfonyl)-[l,l':3,,lM- terphenyl]-4'-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
Figure imgf000107_0002
Table 16a.
Figure imgf000107_0003
Figure imgf000107_0004
Figure imgf000108_0001
Example 53: (S)-8-(2-Amino-6-((R)-2,2,2-trifluoro-l-(3'-(methylsulfonyl)-5-((E)-prop-l-en- l-yl)-[l,l'-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000108_0002
Example 54a: (S)-8-(2-Amino-6-((R)-2,2,2-trifluoro-l-(3'-(methylsulfonyl)-5-propyl-[l,l'- biphenyl]-2-yl)ethoxy)pyrimidin-4- l)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000108_0003
Example 54b: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4-isopropoxy-[l,l':3',l"-terphenyl]- 4'-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000109_0001
Example 54c: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4-propoxy-[l,l':3',l"-terphenyl]-4'- yl)ethoxy)pyrimidin-4- l)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000109_0002
Example 54d: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(5-(methylsulfonyl)-[l,l'-biphenyl]-2- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000109_0003
Example 54e: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro- l-(3-fluoro-4-p ropoxy- [1 , 1 ' :3' , 1 "- terphenyl]-4'-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000110_0001
Example 54f: (S)-8-(2-amino-6-((R)-l-(3,4-dimethyl-[l,l':3',lM-terphenyl]-4,-yl)-2,2,2- trifluoroethoxy)pyrimidin-4- l)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000110_0002
Example 54g: (S)-8-(6-((R)-l-([l,l,:3',lM-terphenyl]-4,-yl)-2,2,2-trifluoroethoxy)-2- minopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000110_0003
Example 54i: (R)-8-(2-amino-6-((S)-l-(5-chloro-[l,l'-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4- l)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000111_0001
Example 54j: (S)-8-(2-amino-6-((S)-l-(5-chloro-[l,l'-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4- l)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000111_0002
Example 54k: (S)-8-(2-amino-6-((S)-l-(3',4,-dimethyl-3-(3-methyl-lH-pyrazol-l-yl)-[l,l'- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
Figure imgf000111_0003
Example 541: (R)-8-(2-amino-6-((S)-l-(3',4,-dimethyl-3-(3-methyl-lH-pyrazol-l-yl)-[l,l'- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
Figure imgf000112_0001
Example 54m: (^-S-i -amino-e-ii^-l-iS'^'-dimethyl-S-iS-methyl-lH-pyrazol-l-yl)-!!,!'- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
Figure imgf000112_0002
Example 55an: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(3'-methoxy-[l,l,-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000112_0003
Table 17a.
I l l
Figure imgf000113_0001
Figure imgf000113_0002
k (S)-8-(2-amino-6-((R)-l-(4-(benzo[d]thiazol-6-yl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
1 (S)-8-(6-((R)-l-(4-([l,2,4]tnazolo[l,5-a]pyridin-6- yl)phenyl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000114_0001
m (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(4-(naphthalen-2- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
n (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(3'-methoxy-4'- methyl-[l, -biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
o (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(3'-methoxy-5'- methyl-[l, -biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
p (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(5'-methoxy-2'- methyl-[l, -biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid q (S)- 8-(2-amino-6-((R)- 1 -(3 ',4'-dimethoxy- [1,1 '-biphenyl] -4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
r o o (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(3'-methoxy-4'- (pyrrolidine-1 -carbonyl)-[l , 1 '-biphenyl] -4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
s (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(4-(l-oxo-l,3- dihydroisobenzofuran-5-yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
t (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(4-(2-oxo-l,2- dihydroquinolin-6-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid u (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(4-(l-methyl-2- oxo- 1 ,2-dihydroquinolin-6-yl)phenyl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid v (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(4-(2-oxo-l,2,3,4- tetrahydroquinolin-6-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000115_0001
diazaspiro[4.5]decane-3-carboxylic acid ah (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(4-(2- methoxyquinolin-6-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid ai (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(4-(2- (methylthio)quinolin-6-yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid aj (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(4-(l-methyl-2- oxo- 1 ,2,3,4-tetrahydroquinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
ak (3 S)-8-(2-amino-6-(2,2,2-tnfluoro- 1 -(3'-fluoro-[ 1 , 1 '- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
al (3 S)-8-(2-amino-6-(2,2,2-trifluoro- 1 -(3'-methoxy-[ 1 , 1 '-
(X biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
am (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(3'-fluoro-[l,r-
<X biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid an (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(3'-methoxy-[l,r- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid ao (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(3'-fluoro-5'- methoxy-[l, l'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
ap (S)- 8-(2-amino-6-((R)- 1 -(3 5'-difluoro- [ 1 , 1 '-biphenyl] -4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
aq (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(4'-methoxy-[l,r- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
ar (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(2'-methoxy-[l,r- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000117_0001
diazaspiro[4.5]decane-3-carboxylic acid be (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4-(isoquinolin-7- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
bf (S)-8-(2-amino-6-((R)- 1 -(4'-((dimethylamino)methyl)-[ 1 , 1 '- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
bg (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(4-(quinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
bh CO, (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(4-(quinolin-7- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
bi (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4-(quinoxalin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
bj (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro- 1 -(4-(2-methyl- 1 - oxo- 1 ,2,3,4-tetrahydroisoquinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
bk (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4-(quinazolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid bl (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(4'-fluoro-2'- methoxy-[l, l'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
bm (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(2'-fluoro-3'- methoxy-[l, l'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- F diazaspiro[4.5]decane-3-carboxylic acid
bn (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(2'-fluoro-5'- methoxy-[l, l'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
F
bo (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(4-(6- methylpyridin-3-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
bp (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(4'-(pyrrolidine-l- carbonyl)-[ 1 , 1 '-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000119_0001
cd (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(4'- (trifluoromethyl)-[ 1 , 1 '-biphenyl]-4-yl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acidce a, (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(2'- (trifluoromethyl)-[ 1 , 1 '-biphenyl]-4-yl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
F
cf (S)-8-(2-amino-6-((R)-l-(2',6'-difluoro-[l,r-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000120_0001
cg (S)-8-(2-amino-6-((R)-l-(2',6'-dimethyl-[l,r-biphenyl]-4-
9; yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
ch (S)-8-(2-amino-6-((R)-l-(3',4'-dimethyl-[l,r-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
ci (S)-8-(2-amino-6-((R)- 1 -(4'-(tert-butyl)-[ 1 , 1 '-biphenyl] -4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
cj (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(4'-isopropyl-[l,r- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
ck (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(3'-isopropyl-[l,r- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
cl (S)-8-(2-amino-6-((R)-l-(3',4'-dichloro-[l,r-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
cm (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(4'- (trifluoromethoxy)-[ 1 , 1 '-biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acidcn (S)-8-(2-amino-6-((R)-l-(2',3'-dimethyl-[l,r-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
co (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(3',4',5'-tnfluoro- [l,l'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
cp (S)-8-(2-amino-6-((R)-l-(4'-chloro-2'-methyl-[l,r- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000121_0001
diazaspiro[4.5]decane-3-carboxylic acid dc F (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(4-(3- fluoroquinolin-6-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid dd (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro- 1 -(4'-propoxy-[ 1 , 1 '- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid de (S)-8-(2-amino-6-((R)-l-(4'-(diethylcarbamoyl)-[l,r- biphenyl]-4-yl)-2,2,2-trifluoroethoxy) pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
df H2N (S)-8-(2-amino-6-((R)-l-(4'-carbamoyl-[l,r-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
dg (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(4'- (methylcarbamoyl)- [1,1 '-biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic aciddh s (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(4'-((2- morpholinoethyl)carbamoyl)-[ 1 , 1 '-biphenyl]-4- ¾ yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
di o (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(4'- (methylsulfonyl)-[ 1 , 1 '-biphenyl]-4-yl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic aciddj (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro- 1 -(4'-sulfamoyl-[ 1 , 1 '- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid dk (S)-8-(2-amino-6-((R)-l -(4'-(dimethylcarbamoyl)-[ 1 , Γ- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid dl H (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4'-(piperazine-l- carbonyl)-[ 1 , 1 '-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000123_0001
Example 56: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4-(l,2,3,4-tetrahydroquinoxalin-6-yl) phenyl)ethoxy)pyrimidin-4- l)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000123_0002
Example 57: (S)-8-(2-amino-6-((R)- l-(3,4-dihydroquinazolin-6-yl)-2,2,2- trifluoroethoxy)pyrimidin-4- l)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000123_0003
Example 58: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(l,2,3,4-tetrahydroquinazolin-6- yl)ethoxy) pyrimidin-4-yl)- -diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000124_0001
Example 59a: (S)-8-(2-amino-6-((R)-l-(4-bromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decan -3-carboxylic acid
Figure imgf000124_0002
Example 59b: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(naphthalen-2-yl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decan -3-carboxylic acid
Figure imgf000124_0003
Example 59c: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4-(3-fluoroquinolin-6-yl)-2- methylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000125_0001
Example 59d: (S)-8-(2-amino-6-((R)-l-(2-ethyl-4-(3-fluoroquinolin-6-yl)phen;
trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000125_0002
Example 60: 9-(2-Amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4- l)-3,9-diazaspiro[5.5]undecane-2-carboxylic acid
Figure imgf000125_0003
Example 61: (S)-8-(2-Amino-6-((4-(3-methyl-lH-indazol-6-yl)phenoxy)methyl)pyrimidin yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000125_0004
Example 62: (S)-8-(2-amino-6-((5-chloro-3'-(methylsulfonyl)-[l,l'-biphenyl]-2- yl)methoxy)pyrimidin-4-yl -2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000126_0001
Example 63bd: (S)-ethyl 8-(2-amino-6-((R)-l-(3',4'-dimethyl-3-(3-methyl-lH-pyrazol-l-yl)-
[l,l'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
Figure imgf000126_0002
Example 63kp: (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-l-(3'-(hydroxymethyl)-4'- methyl-3-(3-methyl-lH-pyrazol-l-yl)-[l,l'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decan -3-carboxylate
Figure imgf000126_0003
Example 63i: (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-[l,l'-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidi -4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate
Figure imgf000127_0001
A solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-l-(5-chloro-[l,l'-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (from Step 3, Example 34c, 315 mg, 0.43 mmol) in acetonitrile (300 mL) was added TMSI (0.13 mL, 0.9 mmol). The reaction mixture was then warmed to RT for an additional 30-40 min, then cooled to 0-5 °C, and 2 M HCl in diethyl ether (0.5 mL) was added. The reaction mixture was then allowed to warm RT and then concentrated in vacuo. Normal phase silica gel chromatography provide the title compound as an off-white solid.
Table 18a.
Figure imgf000127_0002
Figure imgf000127_0003
Figure imgf000128_0001
ι (S)-ethyl 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 -carboxy late j (S)-ethyl 8-(2-amino-6-((R)- 1 -(3 '-amino-5-chloro-[ 1,1'- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2, 8-diazaspiro [4.5] decane-3 -carboxy late k (S)-ethyl 8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(3'- (methylsulfonyl)-5-propyl-[l, -biphenyl]-2- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 1 (S)-ethyl 8-(2-amino-6-((R)- 1 -(4-(l ,3 -dimethyl- 1H- indol-5-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylate m (S)-ethyl 8-(6-((R)- 1 -(3 '-acrylamido-5-chloro-[ 1 , 1 '- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)-2- aminopyrimidin-4-yl)-2, 8-diazaspiro [4.5] decane-3 - carboxy late n (S)-ethyl 8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(3'- fluoro-4'-methoxy- [1,1 -biphenyl] -4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
o (S)-ethyl 8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(4-(l- methyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro [4.5] decane-3 -carboxy late
p (S)-ethyl 8-(2-amino-6-((R)-2,2,2-tnfluoro-l -(4-(2- oxo- 1 ,2,3,4-tetrahydroquinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro [4.5] decane-3 -carboxy late q (S)-ethyl 8-(2-amino-6-((R)-2,2,2-tnfluoro-l -(4-(2- oxo- 1 ,2-dihydroquinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro [4.5] decane-3 -carboxy late
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
diazaspiro [4.5] decane-3 -carboxy late am (S)-ethyl 8-(2-amino-6-((R)-l-(3'-(ethoxycarbonyl)-3- (3-methyl-lH-pyrazol-l-yl)-[l,r-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate
an (S)-ethyl 8-(2-amino-6-((R)-l-(4'-(ethoxycarbonyl)-3- (3-methyl-lH-pyrazol-l-yl)-[l,r-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate ao r B°r (S)-ethyl 8-(2-amino-6-((R)-l-(2,6-dibromophenyl)-
2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate ap (S)-ethyl 8-(2-amino-6-((R)- 1 -(3 5-dichloro-[ 1 , 1 '- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2, 8-diazaspiro [4.5] decane-3 -carboxy late aq (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-3'-methyl-
[l,l'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylate ar (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-3'- (trifluoromethyl)-[ 1 , 1 '-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro [4.5] decane-3 -carboxy late as (S)-ethyl 8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(3-(3- methyl- 1 H-pyrazol- 1 -yl)-4'-(methylthio)- [1,1'-
S N
biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro [4.5] decane-3 -carboxy late at (S)-ethyl 8-(2-amino-6-((R)- 1 -(4-chloro-[ 1 , 1 '- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2, 8-diazaspiro [4.5] decane-3 -carboxy late au (S)-ethyl 8-(2-amino-6-((R)-2,2,2-tnfluoro-l -(4'- methy 1-3 -(3 -methyl- 1 H-pyrazol- 1 -yl)- [ 1 , 1 '-biphenyl] - 4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylate av (S)-ethyl 8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(3'- methy 1-3 -(3 -methyl- 1 H-pyrazol- 1 -yl)- [ 1 , 1 '-biphenyl] - 4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylate
aw (S)-ethyl 8-(2-amino-6-((R)-l-(3',4'-dichloro-3-(3- methyl- 1 H-pyrazol- 1 -yl)-[ 1 , 1 '-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate ax (S)-ethyl 8-(2-amino-6-((R)- 1 -(4-chloro-2-(2- oxopyrrolidin-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate
ay ethyl 8-(2-amino-6-((R)- 1 -(4-chloro-2-(3 -methyl- 1 H- pyrazol- 1 -yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate az (S)-ethyl 8-(2-amino-6-((R)-l-(4-chloro-2-(3-methyl- lH-pyrazol-1 -yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate ba (S)-ethyl 8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(3'- methoxy-[l, 1 '-biphenyl] -4-yl)ethoxy)pyrimidin-4-yl)- 2, 8-diazaspiro [4.5] decane-3 -carboxy late
bb (S)-ethyl 8-(2-amino-6-((R)-2,2,2-tnfluoro-l -(4- methoxy-2-(3-methyl-lH-pyrazol-l- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro [4.5] decane-3 -carboxy late bc (S)-ethyl 8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(3'- fluoro-[ 1 , 1 '-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2, 8- diazaspiro[4.5]decane-3-carboxylate bd (S)-ethyl 8-(2-amino-6-((R)-l-(3',4'-dimethyl-3-(3- methyl- 1 H-pyrazol- 1 -yl)-[ 1 , 1 '-bipheny l]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate be (S)-ethyl 8-(2-amino-6-((R)-l-(4-ethyl-2-(3-methyl- lH-pyrazol-1 -yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate bf (S)-ethyl 8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(2-(3- methyl- 1 H-pyrazol- 1 -yl)-4-
N propylphenyl)ethoxy)pyrimidin-4-yl)-2,8- ? diazaspiro[4.5]decane-3-carboxylate bg (S)-ethyl 8-(2-amino-6-((R)-l-(4-butyl-2-(3-methyl- lH-pyrazol-1 -yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate bh (S)-ethyl 8-(2-amino-6-((R)- 1 -(5-(ethoxycarbonyl)-2- (3 -methyl- 1 H-pyrazol- 1 -yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate
o
bi (S)-ethyl 8-(2-amino-6-((R)- 1 -(4-(ethoxycarbonyl)-2- (3 -methyl- 1 H-pyrazol- 1 -yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate o
bj o (S)-ethyl 8-(2-amino-6-((R)-l-(5-((E)-3-ethoxy-3- oxoprop- 1 -en- 1 -yl)-2-(3 -methyl- 1 H-pyrazol- 1 - yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate bk (S)-ethyl 8-(2-amino-6-((R)-l-(5-(3-ethoxy-3- oxopropyl)-2-(3 -methyl- 1 H-pyrazo 1- 1 -yl)pheny 1)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate
bl (S)-ethyl 8-(2-amino-6-((R)-2,2,2-tnfluoro-l -(6- methyl-2-(3 -methyl- 1 H-pyrazol- 1 -yl)pyridin-3 - yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate b (S)-ethyl 8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(2-(3- methy 1- 1 H-pyrazol- 1 -yl)-5 -((E)-prop- 1 -en- 1 - yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate bn (S)-ethyl 8-(2-amino-6-((R)-l-(3',4'-dimethyl-4-(3- methyl- 1 H-pyrazol- 1 -yl)-[ 1 , 1 '-bipheny l]-3-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate bo (S)-ethyl 8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(2-(3- methyl- 1 H-pyrazol- 1 -yl)-5- propylphenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate bp (S)-ethyl 8-(2-amino-6-((R)-l-(5-ethyl-2-(3-methyl- lH-pyrazol-1 -yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate bq (S)-ethyl 8-(2-amino-6-((R)-l-(5-butyl-2-(3-methyl- lH-pyrazol-1 -yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-
0* diazaspiro[4.5]decane-3-carboxylate
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
cp (S)-ethyl 8-(6-((R)-l-(4'-(acetamidomethyl)-3-(3- methyl- 1 H-pyrazol- 1 -yl)-[ 1 , 1 '-bipheny l]-4-yl)-2,2,2-
N trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate
o
cq (S)-ethyl 8-(6-((R)-l-(4'-(2-acetamidoethyl)-3-(3- methyl- 1 H-pyrazol- 1 -yl)-[ 1 , 1 '-bipheny l]-4-yl)-2,2,2- trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate
H
cr (S)-ethyl 8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(2-(3- methyl- 1 H-pyrazol- 1 -yl)-4-(quinolin-7- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate
cs (S)-ethyl 8-(2-amino-6-((R)-2,2,2-tnfluoro-l -(4-(2- methoxypyr idin-4-yl)-2-(3 -methyl- 1 H-pyrazo 1- 1 - yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate
ct (S)-ethyl 8-(6-((R)-l-(4-(lH-indol-6-yl)-2-(3-methyl- lH-pyrazol-l-yl)phenyl)-2,2,2-trifluoroethoxy)-2- aminopyrimidin-4-yl)-2, 8-diazaspiro [4.5] decane-3 - carboxylate
cu o (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-3'- (ethoxycarbonyl)-[ 1 , 1 '-biphenyl] -2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro [4.5] decane-3 -carboxylate cv 0 2'-((R)-l-((2-amino-6-((S)-3-(ethoxycarbonyl)-2,8- diazaspiro[4.5]decan-8-yl)pyrimidin-4-yl)oxy)-2,2,2- trifluoroethyl)-5 '-chloro- [ 1 , 1 '-biphenyl] -3 - carboxylic acid
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
dy (S)-ethyl 8-(2-amino-6-((R)-l-(3',4'-difluoro-3-(3- methyl- 1 H-pyrazol- 1 -yl)-[ 1 , 1 '-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate
F
dz (S)-ethyl 8-(2-amino-6-((R)-l-(4'-chloro-3-(3-methyl- lH-pyrazol-l-yl)-[l,l'-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate
ea (S)-ethyl 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 -carboxy late
Figure imgf000145_0001
eb (S)-ethyl 8-(2-amino-6-((R)-l-(4'-chloro-4-(3-methyl-
-CXX lH-pyrazol-l-yl)-[l,l'-biphenyl]-3-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro [4.5] decane-3 -carboxy late ec (S)-ethyl 8-(2-amino-6-((R)-l-(3',4'-difluoro-4-(3- methyl- 1 H-pyrazol- 1 -yl)-[ 1 , 1 '-biphenyl]-3-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro [4.5] decane-3 -carboxy late
F
ed (S)-ethyl 8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(4-(3- methyl-1 H-pyrazol-1 -yl)-[ 1 , 1 '-biphenyl]-3- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
ee (S)-ethyl 8-(2-amino-6-((R)-l-(3',4'-dichloro-4-(3- methyl- 1 H-pyrazol- 1 -yl)-[ 1 , 1 '-biphenyl]-3-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro [4.5] decane-3 -carboxy late ef F (S)-ethyl 8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(3'- fluoro-[ 1 , 1 '-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2, 8- diazaspiro [4.5] decane-3 -carboxy late eg (S)-ethyl 8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(2-(3- methy 1- 1 H-pyrazo 1- 1 - yl) - 5 - (pyr imidin- 5 - yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate eh (S)-ethyl 8-(2-amino-6-((R)-l-(4',5-dichloro-3'-fluoro-
[l,l'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylate
^^^^
ei (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-3'-ethoxy-
[l,l'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylate ej (S)-ethyl 8-(2-amino-6-((R)-l-(3',5-dichloro-4'-ethoxy-
[l,l'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylate
ek (S)-ethyl 8-(2-amino-6-((R)-l-(3',5-dichloro-5'-fluoro-
[l,l'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylate el (S)-ethyl 8-(2-amino-6-((R)-l-(3'-(tert-butyl)-5-chloro-
[l,l'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylate
em (S)-ethyl 8-(2-amino-6-((R)-l-(3',5-dichloro-5'- (trifluoromethyl)-[ 1 , 1 '-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate en (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-3'-fluoro-5'- (trifluoromethyl)-[ 1 , 1 '-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate eo (S)-ethyl 8-(2-amino-6-((R)- 1 -(3 '-chloro-[ 1 , 1 '- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2, 8-diazaspiro [4.5] decane-3 -carboxy late ep (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-3'-methoxy-
[l,l'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylate eq (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-3'-isopropoxy- [l,l'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylate
er (S)-ethyl 8-(2-amino-6-((R)-l-(3',5-dichloro-4'-methyl- [l,l'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylate
es (S)-ethyl 8-(2-amino-6-((R)-l-(3',5-dichloro-4'- isopropoxy- [1,1 '-biphenyl] -2-yl)-2, 2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro [4.5] decane-3 -carboxy late et (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-3'-fluoro-4'- isopropoxy- [1,1 '-biphenyl] -2-yl)-2, 2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro [4.5 ]decane-3 -carboxy late eu (S)-ethyl 8-(2-amino-6-((R)-l-(4',5-dichloro-3'- (trifluoromethyl)-[ 1 , 1 '-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro [4.5 ]decane-3 -carboxy late
ev (S)-ethyl 8-(2-amino-6-((R)- 1 -(5-chloro-3'-fluoro-[ 1,1'- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2, 8-diazaspiro [4.5] decane-3 -carboxy late ew (S)-ethyl 8-(2-amino-6-((R)-l-(4',5-dichloro-3'-methyl- [l, -biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylate ex (S)-ethyl 8-(2-amino-6-((R)-l-(3',5-dichloro-4'- (trifluoromethyl)-[ 1 , 1 '-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate ey (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-3',5'-difluoro-
[l, -biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylate
Figure imgf000148_0001
ez CI (S)-ethyl 8-(2-amino-6-((R)-l-(3',5-dichloro-4'-fluoro-
[l, -biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylate
CI
fa F (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-3',4'-difluoro-
[l, -biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylate
CI
fb (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-3',4'-dimethyl- [l, -biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylate
^^^^^^c^
fc (S)-ethyl 8-(2-amino-6-((R)-l-(4',5-dichloro-3',5'- dimethyl-[l, l'-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate
^c^^^^^
fd F (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-4'-ethoxy-3'- fluoro-[ 1 , 1 '-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate
CI fe (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-3',5'-dimethyl- [l,l'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylate ff (S)-ethyl 8-(2-amino-6-((R)-l-(3',5-dichloro-5'-methyl- [l,l'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylate fg (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-4'-fluoro-3'- methyl-[l, l'-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate fh (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-3'-methyl-4'- (trifluoromethoxy)-[ 1 , 1 '-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate fi (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-3'- (trifluoromethoxy)-[ 1 , 1 '-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate fj (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-3'-isopropyl-
[l,l'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylate £k (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-3',5'- bis(trifluoro methyl)- [ 1 , 1 '-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate
fl (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-3'-fluoro-4'- methyl-[l, l'-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate fm (S)-ethyl 8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(3',5,5'- trichloro- [ 1 , 1 '-bipheny 1] -2-yl)ethoxy)pyrimidin-4-yl)- 2, 8-diazaspiro [4.5] decane-3 -carboxy late
fn (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-4'-fluoro-3'- (trifluoromethyl)-[ 1 , 1 '-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro [4.5] decane-3 -carboxy late
Figure imgf000150_0001
fo (S)-ethyl 8-(2-amino-6-((R)-l-(4-chloro-2-(pyndin-3- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro [4.5] decane-3 -carboxy late
CI
fp F (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-3'-fluoro-5'- isopropoxy- [1,1 '-biphenyl] -2-yl)-2, 2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro [4.5 ]decane-3 -carboxy late
CI
fq F (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-3'-ethoxy-5'- fluoro-[ 1 , 1 '-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro [4.5 ]decane-3 -carboxy late
CI
fr (S)-ethyl 8-(2-amino-6-((R)-l-(3'-(tert-butyl)-5-chloro- 5'-methyl-[l,l'-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro [4.5 ]decane-3 -carboxy late fs (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-3'-cyano-[l,r- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2, 8-diazaspiro [4.5] decane-3 -carboxy late
CI
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
ho (S)-ethyl 8-(6-((R)-l-(2-(lH-benzo[d]imidazol-l-yl)-4- chlorophenyl)-2,2,2-trifluoroethoxy)-2- aminopyrimidin-4-yl)-2, 8-diazaspiro [4.5] decane-3 - cP carboxylate hp (S)-ethyl 8-(2-amino-6-((R)-l-(4-chloro-2-(lH-indazol- l-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro [4.5] decane-3 -carboxylate hq (S)-ethyl 8-(2-amino-6-((R)- 1 -(4-chloro-2-(2- isopropylpyridin-4-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro [4.5] decane-3 -carboxylate hr (S)-ethyl 8-(2-amino-6-((R)- 1 -(5-chloro-4'-fluoro-[ 1,1'- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2, 8-diazaspiro [4.5] decane-3 -carboxylate
F
hs (S)-ethyl 8-(2-amino-6-((R)- 1 -(4', 5-dichloro-[ 1 , 1 '- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2, 8-diazaspiro [4.5] decane-3 -carboxylate ht (S)-ethyl 8-(2-amino-6-((R)- 1 -(5-chloro-4'-methyl-
[l, -biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylate hu (S)-ethyl 8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(2-(3- methyl- 1 H-pyrazol- 1 -yl)-4-(naphthalen-2- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro [4.5] decane-3 -carboxylate hv (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-2',3',4',5'- tetrahydro-[l,l'-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro [4.5] decane-3 -carboxylate
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
ir (S)-ethyl 8-(2-amino-6-((R)-2,2,2-tnfluoro-l -(4- propoxy-[l , 1 ': 3', 1 "-terphenyl]-4'-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate
is (S)-ethyl 8-(2-amino-6-((R)-l-(4-chloro-2-(5- chlorothiophen-2-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate
CI
it o (S)-ethyl 8-(2-amino-6-((R)-2,2,2-tnfluoro-l -(4'- (methylsulfonyl)-[ 1 , 1 '-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
iu o (S)-ethyl 8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(3-(3- methyl- 1 H-pyrazol- 1 -yl)-4'-(methylsulfonyl)-[ 1 , Γ- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate
lv (S)-ethyl 8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(3-(3- methyl- 1 H-pyrazol- 1 -yl)-4'-propoxy- [1,1 '-bipheny 1] -4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate ft
ix o (S)-ethyl 8-(2-amino-6-((R)- 1 -(4'-(diethylcarbamoyl)- 3-(3 -methyl- lH-pyrazol- 1 -yl)-[ 1 , 1 -biphenyl]-4-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate
ly o (S)-ethyl 8-(2-amino-6-((R)-2,2,2-tnfluoro-l -(4'- (methylcarbamoyl)- [1,1 '-bipheny 1] -4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
(S)-ethyl 8-(2-amino-6-((S)-l-(3',4'- bis(hydroxymethyl)-3 -(3-methyl- 1 H-pyrazol- 1 -yl)- [l, -biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylate
Example 64a: (S)-Octyl 8-(2-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate
Figure imgf000170_0001
Table 19a.
Figure imgf000170_0002
Figure imgf000170_0003
trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylate
64c (S)-pentyl 8-(2-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH- 637 pyrazol- 1 -yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2, 8- diazaspiro [4.5] decane-3 -carboxylate
64d (S)-cyclohexyl 8-(2-amino-6-((R)-l-(4-chloro-2-(3- 648 methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3 -carboxylate
64e (S)-propyl 8-(2-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH- 608 pyrazol-l-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2, 8- diazaspiro [4.5] decane-3 -carboxylate
64f (S)-neopentyl 8-(2-amino-6-((R)-l-(4-chloro-2-(3-methyl- 636 lH-pyrazol- 1 -yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate
64g (S)-butyl 8-(2-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH- 622 pyrazol-l-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2, 8- diazaspiro [4.5] decane-3 -carboxylate
64h (S)-isopropyl 8-(2-amino-6-((R)- 1 -(4-chloro-2-(3-methyl- 622 lH-pyrazol- 1 -yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate
Example 65a: (S)-Tert-butyl 8-(2-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate
Figure imgf000171_0001
Table 20a.
Figure imgf000172_0001
Figure imgf000172_0002
Example 66a: (S)-2-(Dimethylamino)ethyl 8-(2-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH- pyrazol-l-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
Figure imgf000173_0001
Figure imgf000173_0002
Example 67a: (S)-isopropyl 8-(2-amino-6-((R)-l-(3',4'-dimethyl-3-(3-methyl-lH-pyrazol-l- yl)-[l,l'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
Figure imgf000174_0001
Table 22a.
Figure imgf000174_0002
Example 68a: (S)-isopropyl 8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4'-isopropoxy-3-(3-methyl- lH-pyrazol-l-yl)-[l,l'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
Figure imgf000175_0001
Figure imgf000175_0002
Table 23a.
Figure imgf000175_0003
Example 69a: (S)-isopropyl 8-(2-amino-6-((R)-l-(5-chloro-[l,l'-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate
Figure imgf000176_0001
Figure imgf000176_0002
Table 24a.
Figure imgf000176_0003
Example 70: (S)-methyl 8-(2-amino-6-((R)-l-(5-chloro-3'-(methylsulfonyl)-[l,l'-biphenyl]- 2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate
Figure imgf000177_0001
Example 71: (S)-methyl 8-(2-amino-6-((R)-l-(5-chloro-3'-sulfamoyl-[l,l'-biphenyl]-2-yl)- 2,2,2-trifluoroethoxy)pyri -carboxylate
Figure imgf000177_0002
Additional TPH1 -inhibiting compounds, their prodrugs, and dosage forms, useful according to the present invention include telotristat and salts thereof, including telotristat etiprate (LX1032). See, for example, U.S. Pat. Pub. Nos. 2008/0153852, 2009/0029993, 2009/0088447, 2010/0240906, 2012/0316171, 2013/0137635, 2013/0172376, 2013/0303763 and PCT Pub. No. WO 2010/065333 and WO 2014/082034.
Example A. Murine Model of NASH C57bl6 Mice on a Methionine-Choline Deficient (MCD) Diet
This study is designed to study the effect of the compounds of the present disclosure on a murine model of NASH C57bl6 mice on a MCD diet. An oral dose of the Compound 63 i (also known as the compound of Example 63 i) at 200 mg/kg elicited a positive effect on plasma and liver lipids as well as liver function enzymes in a murine model of NASH. The NASH model was induced by placing C57bL6 mice on a MCD diet which impairs VLDL assembly resulting in disruption of hepatic triglyceride secretion and subsequent fat accumulation within the liver (Rizki G, et al., J Lipid Res. 2006;2280-2290). MCD-fed mice were orally administered 200 mg/kg Compound 63 i once daily for 4 weeks. Treatment with Compound 63 i significantly reversed the effects of MCD feeding on serum lipids and liver triglycerides, bringing
concentrations back toward those observed in untreated, chow-fed control mice. Compound 63 i also significantly decreased alanine aminotransferase (ALT) and aspartate aminotransferase
(AST) serum concentrations, suggesting that TPHl inhibition improved liver function compared to MCD-fed vehicle controls.
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 aminotransferase (ALT) assay (Cayman Chemical - Cat #700260), aspartate
aminotransferase (AST) assay (Sigma - Cat #MAK055), phosphate buffered saline (Sigma - Cat#P3813), sucrose (Sigma - Cat #S7903), gum Arabic (Sigma - Cat #G9752), oil red O in 0.5% propylene glycol (Polyscientific - Cat #sl 848), and OCT Compound (Tissue Tek - Cat #4583).
The control diet was an irradiated rodent diet 18% protein (Envigo #2918). The challenge diet was a MCD diet (Envigo #TD90262).
Oral doses of 200 mg/kg Compound 63 i (as a free base) were prepared in a 0.5% methyl cellulose vehicle prepared in water. Vehicle was added to the compound on the day of dosing and the mixture was briefly sonnicated then mixed for -20 minutes until a homogenous suspension was achieved. Doses were administered by oral gavage at 10 mL/kg of body weight.
The animals used for the study are described below.
Figure imgf000178_0001
Male mice (n=10 per group) arrived at the facility at 28-30 g and were housed 5 per cage on corncob bedding. The animals were acclimated to handling for 7-10 days prior to the start of the study. Mice were administered a single oral dose of vehicle (0.5% methyl cellulose in water) or 200 mg/kg Compound 63 i once daily for 4 weeks prior to the start of the dark cycle. During the dosing period, vehicle and Compound 63i-treated mice were fed either a normal chow diet or a MCD diet. On week 4, blood samples were collected from fed mice for measurement of cholesterol, triglycerides, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in isolated serum. Following whole body perfusion in situ with 10 rriL of PBS, the central lobe of the liver was removed and fixed in 4% paraformaldehyde for histological measurements. An additional liver sample (100 mg) was snap frozen in liquid nitrogen for measurement of liver triglycerides. Blood Collection
On week 4, mice were anesthetized with isofluorane administered 2% in oxygen continuous via inhalation. Whole blood samples (800 μΐ.) were obtained via cardiac puncture and allowed to clot at room temperature for 30 minutes. Serum was isolated by centrifugation at 7000 rpm for 20 minutes and stored at -80 °C for measurement of cholesterol, triglycerides, alanine aminotransferase and aspartate aminotransferase.
Serum Cholesterol
Cholesterol concentrations were measured in serum using a colorimetric assay (Wako Diagnostics) according to kit instructions. Briefly, 3 μΐ. of each standard or sample was added to the wells of a 96-well clear bottom plate. Standards were prepared by diluting a 200 mg/dL stock solution in water. The reaction was accomplished by adding 300 μΐ. of the assay reagent and incubating at 37 °C for 5 minutes. The absorbance was read on a spectrophotometer at 600 nm. Serum Triglycerides
Triglyceride concentrations were measured in serum using a colorimetric assay (Wako Diagnostics) according to kit instructions. Briefly, 4 μΐ. of each standard or sample was added to the wells of a 96-well clear bottom plate. Standards were prepared by diluting a 98 mg/dL stock solution in water. The reaction was accomplished by adding 180 μL of the first assay reagent and incubating at 37 °C for 5 minutes. The reaction continued by adding 60 μL of the second assay reagent and incubating at 37 °C for an additional 5 minutes. The absorbance was read on a spectrophotometer at 600 nm.
Serum Alanine Aminotransferase
Serum was isolated as described in above and liver function was assessed by measuring alanine aminotransferase (ALT) concentrations in serum using a colorimetric assay according to kit instructions. Briefly, 20 μL of serum samples or standards were added to a clear bottom 96- well plate with 150 μL of substrate and 20 μL co-factor. After the samples were incubated at 37 °C for 15 minutes, the reaction was initiated by adding 20 μL of an ALT initiator. The absorbance was immediately read on a spectrophotometer at 340 nm every minute for 5 minutes. Change in absorbance (ΔΑ340/ min) was determined by calculating the change in absorbance at 2 points over the linear portion of the curve (a), and ALT activity (U/mL) was calculated using the equation in (b):
(a) (A340 Time 1 - A340 Time 2) b) (ΔΑ340/ min x 0.21 mL)
Time 2 (min) - Time 1 (min) (4.11mM"1 * 0.02mL)
Serum Aspartate Aminotransferase
Serum was isolated as described in above and liver function was assessed by measuring aspartate aminotransferase (AST) concentrations in serum using a colorimetric assay according to kit instructions. Briefly, 5 μL of serum samples or standards were added to a clear bottom 96- well plate with 45μL of AST assay buffer. Standards were prepared by diluting a 1 mM glutamate stock in AST assay buffer. The reaction was accomplished by adding 100 μL of a reaction mix containing 80 μL of buffer + 2μL enzyme + 8μL developer + 10μL substrate and incubating at 37 °C for 3 minutes. The initial absorbance [AST]initiai was read on a
spectrophotometer at 450 nm. Sample incubation continued at 37 °C and absorbance was read every 5 minutes at 450nm. The reaction was complete [AST]firai when the most active sample had a value greater than the highest standard. For each sample, the concentration of glutamate generated (nmoL), or A[AST], was determined as:
[AST]final - [AST]initial
AST activity (nmoL/min/mL), or the concentration of enzyme that will generate 1 μηκΛ of glutamate per minute at 37 °C was calculated as: A[AST] x Sample Dilution Factor
(Reaction Time) x V
where,
Reaction Time (min) = Tfmai - 1 initial
V (rriL) = Volume added to well
Liver Collection
Following blood collection, mice were euthanized by exsanguination under anesthesia according to regulations in the Guide for the Care and Use of Laboratory Animals and whole body perfusion was accomplished with 10 mL of PBS. A liver sample was snap frozen in liquid N2 and stored at -80 °C until processed for triglyceride measurements. The central lobe of the liver was removed and fixed in 4% paraformaldehyde for 24 hours prior to processing for histological measurements. Liver Triglycerides
Frozen liver samples (50 mg) were transferred to tubes containing 1 mm high impact zirconium beads (Benchmark Scientific) and 500 μL of 5% Triton X-100 in phosphate buffered saline. The samples were homogenized for 2 minutes on a Bead Bug microtube homogenator (Benchmark Scientific) until completely solubilized and centrifuged at 13,000 rpm for 5 minutes at 4 °C. Prior to assay, the samples were further diluted 1 :4 in 5% Triton X-100. Liver triglyceride concentrations were measured using a colorimetric assay (Wako Diagnostics) according to kit instructions. Briefly, 4 μL of sample or standards were added to the wells 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 accomplished by adding 180 μL of the first assay reagent and incubating at 37 °C for 5 minutes. The reaction continued by adding 60 μL of the second assay reagent and incubating at 37 °C for an additional 5 minutes. The absorbance was read on a spectrophotometer at 600 nm.
Hepatic Lipid Deposition
A randomly chosen subset of formalin fixed liver tissue samples was infiltrated with a
30% sucrose + 1% gum arabic solution at 4 °C for 24-48 hours prior to being embedded in OCT compound within a cryostat chamber at -18 °C. Liver samples were cryo-sectioned at 10 μΜ and stained with Oil red O in 0.5% propylene glycol for evaluation of lipid deposition. Statistical Analysis
Analysis of variance (ANOVA) was used to test for significant differences between groups. Post-hoc Bonferroni multiple comparison test analysis was used to determine significant differences among means. All statistical analysis was accomplished using Graph Pad Prism 5 software.
The results are summarized in below. Table Al. Effect of Compound 63i on Serum Cholesterol and Triglycerides in Male C57bL6 Mice Fed a MCD Diet for 4 weeks
Figure imgf000182_0001
Serum was isolated from blood samples collected from MCD diet fed C57bL6 mice following oral administration of 200 mg/kg Compound 63 i for 4 weeks. Cholesterol and triglyceride concentrations were measured by colorimetric assays. A significant improvement in serum cholesterol and in serum triglycerides toward normal was observed in Compound 63 i treated mice. *P<0.05 and ****P<0.0001 significance relative to MCD fed vehicle controls.
Table A2. Effect of Compound 63i on Liver Triglycerides in Male C57bL6 Mice Fed a MCD Diet for 4 weeks
Figure imgf000182_0002
200mpk
Compound
StDev 0.226 0.451 0.424 0.436 218 4.8 4.5
63i
MCD Diet
Untreated Mean 0.586 1.172 0.963 0.755 377 49.8 7 g** Chow Diet StDev 0.343 0.685 0.469 0.317 159 5.1 3.8
Liver tissue samples were collected from MCD diet fed C57bL6 mice following oral administration of 200mg/kg Compound 63 i for 4 weeks. Triglyceride concentrations were measured by a colorimetric assay. A non- significant improvement in liver triglycerides toward normal was observed in Compound 63 i treated mice. **P<0.01 significance relative to MCD fed vehicle controls.
Table A3. Effect of Compound 63 i on Serum Alanine Aminotransferase (ALT) in Male
C57bL6 Mice Fed a MCD Diet for 4 weeks
Figure imgf000183_0001
Serum was isolated from blood samples collected from MCD diet fed C57bL6 mice following oral administration of 200mg/kg Compound 63 i for 4 weeks. Alanine aminotransferase (ALT) concentrations were measured by a colorimetric assay. 1 AA34o/min = (A340 Time 1 - A340 Time 2)1 5 minutes. 2 ALT Activity = (ΔΑ340/ min x 0.21mL) / (4.1 lmM"1 * 0.02mL). A significant improvement in serum ALT toward normal was observed in Compound 63 i treated mice. ***P<0.001 significance relative to MCD fed vehicle controls. Table A4. Effect of Compound 63i on Serum Aspartate Aminotransferase (AST) in Male C57bL6 Mice Fed a MCD Diet for 4 weeks
Figure imgf000184_0001
Serum was isolated from blood samples collected from MCD diet fed C57bL6 mice following oral administration of 200mg/kg Compound 63 i for 4 weeks. AST concentrations were measured by a colorimetric assay. AST Activity = A[AST] / Reaction Time x Sample Volume. A significant improvement in serum AST toward normal was observed in Compound 63i treated mice. ***P<0.001 and ****P<0.0001 significance relative to MCD fed vehicle controls.
A significant decrease in lipid deposition was observed in liver tissue collected from MCD fed C57bL6 mice following oral administration of 200mg/kg Comopund 63 i for 4 weeks (results not shown).
Example B. Murine Model of NASH ApoE Knockout Mice on a High Fat Diet
This study is designed to study the effect of the compounds of the present disclosure on a murine model of NASH ApoE knockout mice on a high fat diet. An oral dose of Compound 63 i (also referred to as the compound of Example 63 i) at 200 mg/kg elicited a positive effect on liver pathophysiology in a murine model of NASH. The NASH model was induced by placing ApoE knockout mice on a high fat diet. High fat fed mice were orally administered 200 mg/kg Compound 63 i once daily for 8 weeks. Treatment with Compound 63 i significantly reversed the effects of high fat feeding on hepatic lipid deposits and liver architecture compared to high fat fed vehicle controls. A significant decrease in serum serotonin with no effect on serum cholesterol, triglycerides or glucose was observed in mice treated with Compound 63 i.
The materials used in this study are described in the table below.
Chemical Supplier and catalogue number Alanine aminotransferase (ALT) assay Cayman Chemical - Cat #700260
Analine Blue Polysciences - Cat #02570
Ascorbic Acid Sigma - Cat #A0278
Aspartate aminotransferase (AST) assay Sigma - Cat #MAK055
Cholesterol assay kit Wako Diagnostics - Cat #439-17501
Chromotrophe 2R Sigma - Cat #C3143
Ethylene diamine tetraacetic acid, 0.250M VWPv - Cat #BDH3590-2
Formalin EKI - Cat #4499
Glucose Oxidase assay kit Cayman - #10009582
Gum Arabic Sigma - Cat #G9752
Hematoxylin, Gill III
Butler Schein - Cat #NDC11695-6776-
Isofluorane
2
Methyl cellulose Sigma - Cat #M7140
OCT Compound Tissue Tek - Cat #4583
Oil red 0 in 0.5% propylene glycol Polyscientific - Cat #sl848
Phosphate buffered saline Sigma - Cat #P3813
Phosphomolybdic Acid Polyscientific - Cat #s2176
Pierce BCA Protein, Fisher - Cat
Protein colorimetric assay kit
#23225
American Bioanalytical - Cat
Sodium Acetate
#ABO1909
Sodium Bisulfate Sigma - Cat #307823
Sodium dodecyl sulfate Sigma - Cat #436143
Sodium hydroxide Sigma - Cat #221465
Sucrose Sigma - Cat #S7903
Trichloracetic acid Sigma - Cat #T0699
Wako Diagnostics - Cat #461-08992
Triglyceride assay kit
Wako Diagnostics - Cat #461-09092
Triglyceride standard Wako Diagnostics - Cat #464-01601
Weigert's Iron Hematoxylin Polysciences - Cat #25373
The control diet was an irradiated rodent diet 18% protein (Envigo #2918). The challenge diet was a high fat diet with 1.25% cholesterol and 21% fat from coconut oil (Research Diets #D15100301).
The test compound was the compound of Example 63 i (also referred to as Compound
63 i). It is used as a free base. Oral doses of 200 mg/kg Compound 63i were prepared in a 0.5% methyl cellulose vehicle prepared in water. Vehicle was added to the compound on the day of dosing and the mixture was briefly sonnicated then mixed for -20 minutes until a homogenous suspension was achieved. Doses were administered by oral gavage at 10 mL/kg of body weight. The animals used in the study are described in the table below.
Figure imgf000186_0001
Male mice (n=10 per group) arrived at the facility at 28-3 Og and were housed 4 per cage on corncob bedding. The animals were acclimated to handling for 7-10 days prior to the start of the study. Mice were administered a single oral dose of vehicle (0.5% methyl cellulose in water) or 200 mg/kg Compound 63 i once daily for 8 weeks prior to the start of the dark cycle. During the dosing period, vehicle and Compound 63 i treated mice were fed either a normal chow diet or a high fat diet containing 1.25% cholesterol and 21% fat from coconut oil. On week 8, blood samples were collected from fed mice for measurement of serotonin, cholesterol, triglycerides and glucose in isolated serum. Following whole body perfusion in situ with 10 mL of PBS, the central lobe of the liver was removed and fixed in 4% paraformaldehyde for histological measurements.
Blood Collection
On week 8, mice were anesthetized with isofluorane administered 2% in oxygen continuous via inhalation. Whole blood samples (800 μΐ.) were obtained via cardiac puncture and allowed to clot at room temperature for 30 minutes. Serum was isolated by centrifugation at 7000 rpm for 20 minutes and stored at -80 °C for measurement of serotonin, cholesterol, triglycerides and glucose.
Serum Serotonin Measurement
Serum samples were extracted in a trichloroacetic acid (TCA) homogenization buffer. Briefly, 100 μΙ_, of TCA buffer was added to 50 μΙ_, of serum in a 1.5 mL micro fuge tube. The sample was vortexed in the buffer and centrifuged at 13,000 rpm for 30 minutes at 4 °C. The supernate was carefully removed and transferred to a glass tube for measurement of serotonin with fluorometric detection using the conditions described above.
High Performance Liquid Chromatography (HPLC) Conditions
HPLC homogenization buffer was prepared as follows:
Figure imgf000187_0001
HPLC measurements were made using a Perkin Elmer Flexar HPLC system equipped with a fluorescent detector and a Brownlee validated aqueous CI 8 column (3 μιτι, 50 x 2.1 mm; Perkin Elmer). Mobile phase used was 100 mM sodium acetate, pH 3.5. Detection was achieved at an excitation wavelength of 280 nm and an emission wavelength of 330 nm.
Serum Cholesterol
Cholesterol concentrations were measured in serum using a colorimetric assay (Wako Diagnostics) according to kit instructions. Briefly, 3 μΕ of each standard or sample was added to the wells of a 96-well clear bottom plate. Standards were prepared by diluting a 200 mg/dL stock solution in water. The reaction was accomplished by adding 300 μΕ of the assay reagent and incubating at 37 °C for 5 minutes. The absorbance was read on a spectrophotometer at 600 nm.
Serum Triglycerides
Triglyceride concentrations were measured in serum using a colorimetric assay (Wako Diagnostics) according to kit instructions. Briefly, 4 μΕ of each standard or sample was added to the wells of a 96-well clear bottom plate. Standards were prepared by diluting a 98 mg/dL stock solution in water. The reaction was accomplished by adding 180 μΕ of the first assay reagent and incubating at 37 °C for 5 minutes. The reaction continued by adding 60 μΕ of the second assay reagent and incubating at 37 °C for an additional 5 minutes. The absorbance was read on a spectrophotometer at 600 nm. Serum Glucose
Glucose oxidase concentrations were measured in serum using a colorimetric assay (Cayman) according to kit instructions. Briefly, 15 μΐ. of each standard or sample was added to the wells of a 96- well clear bottom plate each containing 85 μΐ. of an assay buffer provided by the vendor. Standards were prepared by diluting a 100 mg/dL stock solution in assay buffer. The reaction was accomplished by adding 100 μΐ. of enzyme reagent and incubating at 37 °C for 10 minutes. The absorbance was read on a spectrophotometer at 500-520 nm. Liver Collection
Following blood collection, mice were euthanized by exsanguination under anesthesia according to regulations in the Guide for the Care and Use of Laboratory Animals and whole body perfusion was accomplished with 10 mL of PBS. The central lobe of the liver was removed and fixed in 4% paraformaldehyde for 24 hours prior to processing for histological measurements.
Histological Analysis
A randomly chosen subset of formalin fixed liver tissue samples was infiltrated with a 30% sucrose + 1% gum arabic solution at 4 °C for 24-48 hours prior to being embedded in OCT compound within a cryostat chamber at -18 °C. Liver samples were cryo-sectioned at 10 μηι and stained with Oil red O in 0.5% propylene glycol for evaluation of lipid deposition.
A portion of the liver was processed, embedded in paraffin and sectioned at 5 μηι for staining of Mallory Bodies and structural changes with chromotrophe-analine blue. Statistical Analysis
Analysis of variance (ANOVA) was used to test for significant differences between groups. Post-hoc Bonferroni multiple comparison test analysis was used to determine significant differences among means. All statistical analysis was accomplished using Graph Pad Prism 5 software.
The results are summarized below. Table Bl. Effect of Compound 63i on Serum Serotonin in Male ApoE Knockout Mice Fed Either a High Fat or Chow Diet for 8 Weeks
Figure imgf000189_0001
Serum was isolated from blood samples collected from ApoE Knockout mice following weeks of oral dosing with 200 mg/kg Compound 63 i while fed either a high fat or chow diet. Serotonin (5-HT) was measured by high performance liquid chromatography. A significant decrease in serum 5-HT was observed in Compound 63i treated mice on both the chow and fat diet. ****p<0.0001 and††††p<0.0001 significance relative to high fat or chow fed vehicle controls, respectively. Table B2. Effect of Compound 63 i on Serum Cholesterol, Triglycerides and Glucose in Male ApoE Knockout Mice Fed Either a High Fat or Chow Diet for 8 Weeks
Figure imgf000189_0002
Serum was isolated from blood samples collected from ApoE knockout mice following 8 weeks of oral dosing with 200 mg/kg Compound 63 i while fed either a high fat or chow diet. Cholesterol, triglyceride and glucose concentrations were measured by a colorimetric assay. No significant changes in cholesterol, triglycerides, or glucose were observed regardless of diet.
Lipid deposition was evaluated in liver tissue collected from high fat fed ApoE Knockout mice following oral administration of 200 mg/kg Compound 63 i for 8 weeks. Lipid deposits were indicated by dark red Oil red O staining which demonstrates a qualitative decrease in lipid deposition in fat fed mice treated with Compound 63 i as compared to vehicle treated mice.
Improvement in liver architecture was observed in liver tissue collected from high fat fed ApoE Knockout mice following oral administration of 200 mg/kg Compound 63i for 8 weeks. An increase in appearance of vacuoles around major vessels and a breakdown of structural integrity was demonstrated by chromatrophe 2B-analine blue staining in mice treated with vehicle compared to those treated with 200 mg/kg Compound 63 i.
Example C. Murine Model of NASH LDLr Knockout Mice on a Methionine Choline Deficient (MCD) or High Fat Diet
This study is designed to study the effect of the compounds of the present disclosure on a murine model of NASH LDLr knockout mice on a MCD or high fat diet. An oral dose of Compound 63 i (also referred to as the compound of Example 63 i) at 200 mg/kg elicited a positive effect on liver pathophysiology in two murine models of NASH. In the first, the NASH model was induced by placing LDLr knockout mice on a MCD diet which impairs VLDL assembly resulting in disruption of hepatic triglyceride secretion and subsequent fat
accumulation within the liver (Rizki G., et al., J Lipid Res. 2006;2280-2290). In the second, the NASH model was induced by placing LDLr knockout mice on a high fat diet containing 1.25% cholesterol and 21% fat from coconut oil. MCD or fat fed mice were orally administered 200 mg/kg Compound 63 i once daily for 3 and 8 weeks, respectively. Treatment with Compound 63 i significantly reversed the effects of high fat feeding on hepatic lipid deposits and liver architecture compared to high fat fed vehicle controls. A significant decrease in serum serotonin with no effect on serum cholesterol, triglycerides or glucose was observed in mice treated with Compound 63 i.
The chemicals used in this study are described below:
Chemical Supplier and catalogue number Ascorbic Acid Sigma - Cat #A0278
Ethylene diamine tetraacetic acid,
VWR - Cat #BDH3590-2
0.250M
Formalin EKI - Cat #4499
Gum Arabic Sigma - Cat #G9752
Hematoxylin, Gill III
Isofluorane Butler Schein - Cat #NDC11695-6776-2
Methyl cellulose Sigma - Cat #M7140
OCT Compound Tissue Tek - Cat #4583
Oil red 0 in 0.5% propylene glycol Polyscientific - Cat #sl848
Phosphate buffered saline Sigma - Cat #P3813
Protein colorimetric assay kit Pierce BCA Protein, Fisher - Cat #23225
Sodium Acetate American Bioanalytical - Cat #ABO1909
Sodium Bisulfate Sigma - Cat #307823
Sodium dodecyl sulfate Sigma - Cat #436143
Sodium hydroxide Sigma - Cat #221465
Sucrose Sigma - Cat #S7903
Trichloracetic acid Sigma - Cat #T0699
The control diet was an irradiated rodent diet 18% protein (Envigo #2918). The challenge diets were a MCD diet (Envigo #TD90262) and high fat diet with 1.25% cholesterol and 21% fat from coconut oil (Research Diets #D15100301).
Oral doses of 200 mg/kg Compound 63 i (free base) were prepared in a 0.5% methyl cellulose vehicle prepared in water. Vehicle was added to the compound on the day of dosing and the mixture was briefly sonnicated then mixed for -20 minutes until a homogenous suspension was achieved. Doses were administered by oral gavage at 10 mL/kg of body weight.
The animals used in the study are described in the table below.
Figure imgf000191_0001
Figure imgf000192_0001
Male mice (n=10 per group) arrived at the facility at 28-30 g and were housed 4 per cage on corncob bedding. The animals were acclimated to handling for 7-10 days prior to the start of the study. Mice were fed either a MCD diet or a high fat diet containing 1.25% cholesterol and 21% fat from coconut oil for 3 and 8 weeks, respectively. While on diet, mice were administered a single oral dose of vehicle (0.5% methyl cellulose in water) or 200 mg/kg Compound 63 i once daily prior to the start of the dark cycle. At the end of the dosing period, blood samples were collected from fed mice for in-house measurement of serum serotonin and measurement of serum cholesterol, triglycerides, glucose, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) by an outside contractor. Following whole body perfusion in situ with 10 rriL of PBS, the central lobe of the liver was removed and fixed in 4% paraformaldehyde for histological measurements. Gut 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 isofluorane administered 2% in oxygen continuous via inhalation. Whole blood samples (1 mL) were obtained via cardiac puncture and allowed to clot at room temperature for 30 minutes. Serum was isolated by centrifugation at 6000 rpm for 20 minutes and a 50 μΐ. sample was stored at -80° C for measurement of serotonin. The remaining serum was shipped to Charles River (Shrewsbury,
Mass) for measurements of serum cholesterol, triglycerides, glucose, and liver function enzymes (ALT and AST).
Serum Serotonin Measurement
Serum samples were extracted in a trichloroacetic acid (TCA) homogenization buffer.
Briefly, 100 μL of TCA buffer was added to 50 μL of serum in a 1.5 mL micro fuge tube. The sample was vortexed in the buffer and centrifuged at 13,000 rpm for 30 minutes at 4 °C. The supernate was carefully removed and transferred to a glass tube for measurement of serotonin with fluorometric detection using the conditions described above. High Performance Liquid Chromatography (HPLC) Conditions
HPLC homogenization buffer were prepared according to the table below.
Figure imgf000193_0001
HPLC measurements were made using a Perkin Elmer Flexar HPLC system equipped with a fluorescent detector and a Brownlee validated aqueous CI 8 column (3 μπι, 50 x 2.1 mm; Perkin Elmer). Mobile phase used was 100 mM sodium acetate, pH 3.5. Detection was achieved at an excitation wavelength of 280 nm and an emission wavelength of 330 nm. Gut Mucosa Collection
Following blood collection, mice were euthanized by exsanguination under anesthesia according to regulations in the Guide for the Care and Use of Laboratory Animals and whole body perfusion was accomplished with 10 mL PBS. The stomach was located and
approximately 6-8 cm of intestine beginning at the pyloric sphincter (duodenum) and the adjacent 6-8cm (jejunum) were removed. The duodenum was discarded and the intestinal contents of the jejunum were flushed out using a dosing needle attached to a 10 cc syringe filled with PBS. A longitudinal cut was then made along one side of the segment which was opened flat on a glass microscope slide. The gut mucosa was scraped away from the luminal surface using a second microscope slide and collected in 2mL flat bottom microfuge tubes.
Approximately 50mg of each sample was transferred to a second 2mL flat bottom microfuge tube for extraction and serotonin measurement.
Gut Mucosal Serotonin Measurement
Gut mucosa samples were extracted in a trichloroacetic acid (TCA) homogenization buffer. Briefly, 300 μΕ of TCA buffer was added to 50-75 mg of tissue in a 2 mL flat bottom microfuge tube. The tissue was homogenized in the buffer and centrifuged at 13,000 rpm for 30 minutes at 4 °C. The supernate was carefully removed and transferred to a glass tube for measurement of serotonin with fluorometric detection using the conditions described above. After completely removing any residual supernate from the tissue pellets, 1200 μΐ. of 5% sodium dodecyl sulfate buffer (SDS) prepared in 0.1 N sodium hydroxide (NaOH) was added to each microfuge tube and the samples were solubilized in a 37 °C oven overnight prior to protein measurement.
Gut Mucosal Protein
Gut mucosal protein concentration was measured in digested mucosa tissue pellets using a colorimetric assay (Pierce BCA Protein, Fisher) according to kit instructions. Briefly, 5 μΐ. of sample was diluted in a clear bottom 96-well plate with 20 μΐ. of 5% SDS buffer prepared in 0. IN NaOH. Standards were prepared by diluting a 2 mg/mL stock albumen solution in 5% SDS buffer. The reaction was accomplished by adding 200 μΐ. of the BCA protein reagent and incubating at 37 °C for 30 minutes. The absorbance was read on a spectrophotometer at 562 nm.
Liver Collection
Following blood collection, mice were euthanized by exsanguination under anesthesia according to regulations in the Guide for the Care and Use of Laboratory Animals and whole body perfusion was accomplished with 10 mL of PBS. The central lobe of the liver was removed and fixed in 4% paraformaldehyde for 24 hours prior to processing for histological measurements.
Histological Analysis
A randomly chosen subset of formalin fixed liver tissue samples was infiltrated with a
30% sucrose + 1% gum arabic solution at 4 °C for 24-48 hours prior to being embedded in OCT compound within a cryostat chamber at -18 °C. Liver samples were cryo-sectioned at 10 μηι and stained with Oil red O in 0.5% propylene glycol for evaluation of lipid deposition. Statistical Analysis
Analysis of variance (ANOVA) was used to test for significant differences between groups. Post-hoc Bonferroni multiple comparison test analysis was used to determine significant differences among means. All statistical analysis was accomplished using Graph Pad Prism 5 software.
The results are summarized below.
Table CI. Effect of Compound 63i on Serum Serotonin in Male LDLr Knockout Mice Fed Either a MCD Diet or a High Fat Diet
Figure imgf000195_0001
Serum was isolated from blood samples from LDLr knockout mice following oral dosing with 200 mg/kg Compound 63 i while fed a MCD diet or a 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 Compound 63 i treated mice on both regardless of diet. ****p<0.0001 and††††p<0.0001 significance relative to high fat or MCD fed vehicle controls, respectively.
Table B2. Effect of Compound 63 i on Mucosa Serotonin in Male LDLr Knockout Mice Fed Either a MCD Diet or a High Fat Diet
Figure imgf000195_0002
200mpk
Compound
63i
Fat Diet Stdev 0.20 61.25 626 0.01
Vehicle Mean 10.05 3014.24 5679 0.53
MCD Diet Stdev 0.90 270.09 573 0.04
200mpk
Compound Mean 0.23 69.14 5172 0.01††††
63i
MCD Diet Stdev 0.09 28.10 564 0.01
Normal Mean 5.58 1673.80 5054 0.33
Chow Stdev 0.83 248.56 432 0.05
Serotonin (5-HT) was measured in gut mucosa from LDLr knockout mice following oral dosing with 200 mg/kg Compound 63 i while fed a MCD diet or a high fat diet for 3 and 8 weeks, respectively. 5-HT was measured by high performance liquid chromatography. A significant decrease in gut mucosal 5-HT was observed in Compound 63 i treated mice regardless of diet. ****p<0.0001 and††††p<0.0001 significance relative to high fat or MCD fed vehicle controls, respectively.
Table C3. Effect of Compound 63 i on Serum Cholesterol, Triglycerides and Glucose in Male LDLr Knockout Mice Fed Either a MCD Diet or a High Fat Diet
Figure imgf000196_0001
Serum was isolated from blood samples from LDLr knockout mice following oral dosing with 200 mg/kg Compound 63 i while fed a MCD diet or a high fat diet for 3 and 8 weeks, respectively. Samples were shipped overnight to Charles River Labs (Shrewsbury, Mass) for measurement of cholesterol, triglyceride and glucose concentrations. **p<0.01 and†p<0.05 significance relative to high fat or MCD fed vehicle controls, respectively.
Table C4. Effect of Compound 63 i on Liver Function Enzymes Alanine Aminotransferase (ALT) and Aspartine Aminotransferase (AST) in Male LDLr Knockout Mice Fed Either a MCD Diet or a High Fat Diet
Figure imgf000197_0001
Serum was isolated from blood samples from LDLr knockout mice following oral dosing with 200 mg/kg Compound 63 i while fed an MCD diet or a high fat diet for 3 and 8 weeks, respectively. Samples were shipped overnight to Charles River Labs (Shrewsbury, Mass) for measurement of the liver function enzymes ALT and AST.
Lipid deposition was evaluated in liver tissue collected from an MCD diet fed LDLr knockout mice following oral administration of 200 mg/kg Compound 63i for 3 weeks. Lipid deposits are indicated by dark red Oil red O staining which demonstrates a qualitative decrease in lipid deposition in MCD diet fed mice treated with Compound 63 i as compared to vehicle treated mice.
Lipid deposition was evaluated in liver tissue collected from high fat fed LDLr Knockout mice following oral administration of 200 mg/kg Compound 63 i for 8 weeks. Lipid deposits are indicated by dark red Oil red O staining which demonstrates a qualitative decrease in lipid deposition in fat fed mice treated with Compound 63 i as 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 from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patent, patent applications, and publications, cited in the present application is incorporated herein by reference in its entirety.

Claims

What is claimed is:
1. A method of treating or preventing a disease in a patient wherein the disease is nonalcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or hepatocellular carcinoma, comprising administering to said patient a therapeutically effective amount of a TPHl inhibitor, or a prodrug thereof.
2. The method of claim 1 wherein the disease is NAFLD.
3. The method of claim 1 wherin the disease is NASH.
4. The method of claim 1 wherien the disease is hepatocellular carcinoma.
5. A method of decreasing serum or liver concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), cholesterols, triglycerides, or glucose in a patient comprising administering to said patient a therapeutically effective amount of a TPHl inhibitor, or a prodrug thereof.
6. A method of reducing lipid deposits in the liver of a patient comprising administering to said patient a therapeutically effective amount of a TPHl inhibitor, or a prodrug thereof.
7. A method of treating or preventing one or more diseases or symptoms in a patient associated with non-alcoholic fatty liver disease (NAFLD), NASH, or hepatocellular carcinoma selected from inflammation, fibrosis, cirrhosis, fatigue, weight loss, weakness, fluid retention, muscle wasting, bleeding from the intestines, liver failure, weight gain, obese, diabetes, prediabetes, lipid disorders, elevated serum lipids, elevated cholesterol, and elevated
triglycerides, comprising administering to said patient a therapeutically effective amount of a TPHl inhibitor, or a prodrug thereof.
8. The method of any one of claims 1-7, wherein the TPHl inhibitor, or prodrug thereof, is a compound of Formula I:
Figure imgf000200_0001
I
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is C3-10 cycloalkyl, C6-io 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;
wherein only one of X and Y is N;
R1 is H, Ci-10 alkyl, C3 -10 cycloalkyl, phenyl, -(CR8R9)POC(0)R10, -(CR8R9)PNRnR12 , or -(CR8R9)pC(0)NRnR12, wherein said Ci-io alkyl, C3-10 cycloalkyl, and phenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from F, CI, Br, CN, Ci-4 alkyl, and Ci-4 haloalkyl;
R2 and R3 are each independently selected from H, C1-4 alkyl, and C1-4 haloalkyl;
R4 is H or Ci-4 alkyl;
R5 and R6 are each independently selected from H, halo, and C1-4 alkyl;
R7 is H, Ci-4 alkyl, C2-6 alkenyl, C3 -10 cycloalkyl, C3-io cycloalkyl-Ci4 alkyl, C6-io aryl, Gs- 10 aryl-Ci-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci -4 alkyl, 5-10 membered heteroaryl, (5-10 membered heteroaryl)-Ci-4 alkyl, NR1 R14, OR15, C(0)R16, S(0)qR17, wherein said C1-4 alkyl, C2-6 alkenyl, C3 -10 cycloalkyl, C3-io cycloalkyl-Ci-4 alkyl, G5-10 aryl, C6-io aryl-Ci alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalky 1)- C1-4 alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl)-Ci4 alkyl are each optionally substituted by 1 , 2, or 3 substituents selected from halo, Ci-4 alkyl, C2-6 alkenyl, amino, Ci-4 alkylamino, C2-8 dialkylamino, hydroxy, and Ci alkoxy;
R8 and R9 are each independently selected from H and C1-4 alkyl;
R10 is Ci-6 alkyl optionally substituted by 1, 2 or 3 substituents independently selected from Ci-6 haloalkyl, C3-io cycloalkyl, ORa, and NR¾d;
R11 and R12 are each independently selected from H and Ci-6 alkyl;
R13 is H or Ci4 alkyl;
R14 is H, Ci-4 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-Ci-4 alkyl, C6-io aryl, C6-io aryl-Ci-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, 5-10 membered heteroaryl, or (5-10 membered heteroaryl)-Ci-4 alkyl, C(0)Rbl, C(0)ORal,
C(0)NRclRdl, S(0)Rbl, S(0)2RM, or S(0)2NRclRdl, wherein said C1-4 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-Ci-4 alkyl, C6-io aryl, C6-io aryl-Ci-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci -4 alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl)-Ci-4 alkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, CN, N02, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)ORal, OC(0)Rbl, OC(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)ORal,
NRclC(0)NRclRdl, NRclS(0)Rbl, NRclS(0)2Rbl, NRclS(0)2NRclRdl, S(0)Rbl, S(0)NRclRdl, S(0)2Rbl, and S(0)2NRclRdl;
or R13 and R14 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7- membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents
independently selected from Ci-6 alkyl, C3 -7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, 5-6 membered heteroaryl, halo, CN, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)ORal, OC(0)Rbl, OC(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)ORal, S(0)Rbl, S(0)NRclRdl, S(0)2Rbl, NRclS(0)2Rbl, NRclS(0)2NRclRdl, and S(0)2NRclRdl, wherein said Ci-6 alkyl, C3 -1 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)ORal, OC(0)Rbl,
OC(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)ORal, S(0)Rbl,
S(0)NRclRdl, S(0)2Rbl, NRclS(0)2Rbl, NRclS(0)2NRclRdl, and S(0)2NRclRdl;
R15 is H, Ci-4 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-Ci-4 alkyl, C6-io aryl, C6-io aryl-Ci-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci 4 alkyl, 5-10 membered heteroaryl, or (5-10 membered heteroaryl)-Ci-4 alkyl, wherein said C1-4 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-Ci-4 alkyl, C6-io aryl, C6-io aryl-Ci-4 alkyl, 4-10 membered
heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci4 alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl)-Ci-4 alkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, 5-6 membered heteroaryl, CN, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)ORal, OC(0)Rbl,
OC(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)ORal, S(0)Rbl,
S(0)NRclRdl, S(0)2Rbl, NRclS(0)2Rbl, NRclS(0)2NRclRdl, and S(0)2NRclRdl ;
R16 is Ci-4 alkyl or NR18aR18b wherein said C1-4 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, 5-6 membered heteroaryl, CN, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)ORal, OC(0)Rbl, OC(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)ORal, S(0)Rbl, S(0)NRclRdl, S(0)2Rbl, NRclS(0)2Rbl, NRclS(0)2NRclRdl, and S(0)2NRclRdl;
R17 is Ci-4 alkyl, NR18aR18b, or OR18c, wherein said Ci-4 alkyl is optionally substituted by 1 , 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, 5-6 membered heteroaryl, CN, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)ORal, OC(0)Rbl, OC(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl,
NRclC(0)ORal, S(0)Rbl, S(0)NRclRdl, S(0)2Rbl, NRclS(0)2Rbl, NRclS(0)2NRclRdl, and S(0)2NRclRdl;
R18a and R18b are each independently selected from H and C1-4 alkyl wherein said C1-4 alkyl is optionally substituted by 1 , 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Gs-io aryl, 5-6 membered heteroaryl, CN, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)ORal, OC(0)Rbl, OC(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRc4C(0)ORal, S(0)Rbl, S(0)NRclRdl, S(0)2Rbl, NRclS(0)2Rbl,
NRclS(0)2NRclRdl, and S(0)2NRclRdl;
or R18a and R18b together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1 , 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, 5-6 membered heteroaryl, halo, CN, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)ORal, OC(0)Rbl, OC(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)ORal, S(0)Rbl, S(0)NRclRdl, S(0)2Rbl, NRclS(0)2Rbl, NRclS(0)2NRclRdl, and S(0)2NRclRdl, wherein said Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)ORal, OC(0)Rbl,
OC(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)ORal, S(0)Rbl,
S(0)NRclRdl, S(0)2Rbl, NRclS(0)2Rbl, NRclS(0)2NRclRdl, and S(0)2NRclRdl;
R18c is H, Ci-6 alkyl, C3-10 cycloalkyl, C3-7 cycloalkyl-Ci-4 alkyl, Gs-io aryl, C6-io aryl-Ci-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci -4 alkyl, 5-10 membered heteroaryl, or (5-10 membered heteroaryl)-Ci-4 alkyl, wherein said Ci-6 alkyl, C3-7 cycloalkyl, C3-io cycloalkyl-Ci-4 alkyl, Gs-io aryl, C6-io aryl-Ci-4 alkyl, 4-10 membered
heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci4 alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl)-Ci-4 alkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C alkyl, C1-4 haloalkyl, CN, N02, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)ORal, OC(0)Rbl, OC(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)ORal, NRclC(0)NRclRdl, NRclS(0)Rbl, NRclS(0)2Rbl, NRclS(0)2NRclRdl, S(0)Rbl, S(0)NRclRdl, S(0)2Rbl, and S(0)2NRclRdl;
RA is H, Cy1, halo, Ci-6 alkyl, C2.6 alkenyl, CN, N02, ORa2, SRa2, C(0)Rb2, C(0)NRc2Rd2, C(0)ORa2, OC(0)Rb2, OC(0)NRc2Rd2, NR^R^, NRc2C(0)Rb2, NRc2C(0)ORa2,
NRc2C(0)NRc2Rd2, NRc2S(0)Rb2, NRc2S(0)2Rb2, NRc2S(0)2NRc2Rd2, S(0)Rb2, S(0)NRc2Rd2, S(0)2Rb2, or S(0)2NRc2Rd2, wherein said Ci-e alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy1, halo, Ci-6 alkyl, C2- 6 alkenyl, Ci-6 haloalkyl, CN, N02, ORa2, SRa2, C(0)Rb2, C(0)NRc2Rd2, C(0)ORa2, OC(0)Rb2, OC(0)NRc2Rd2, NRc2Rd2, NRc2C(0)Rb2, NRc2C(0)ORa2, NRc2C(0)NRc2Rd2, NRc2S(0)Rb2, NRc2S(0)2Rb2, NRc2S(0)2NRc2Rd2, S(0)Rb2, S(0)NRc2Rd2, S(0)2Rb2, and S(0)2NRc2Rd2;
RB is H, Cy2, halo, Ci-6 alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, N02, ORa3, SRa3, C(0)Rb3, C(0)NRc Rd3, C(0)ORa3, OC(0)Rb3, OC(0)NRc Rd3, NRc Rd3, NRc C(0)Rb3, NRc C(0)ORa3, NRc C(0)NRc Rd3, NRc S(0)Rb3, NRc S(0)2Rb3, NRc S(0)2NRc Rd3, S(0)Rb3, S(0)NRc Rd3, S(0)2Rb3, or S(0)2NRc Rd3, wherein said Ci-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy2, halo, Ci-6 alkyl, C2- 6 alkenyl, Ci-6 haloalkyl, CN, N02, ORa3, SRa3, C(0)Rb3, C(0)NRc Rd3, C(0)ORa3, OC(0)Rb3, OC(0)NRc Rd3, NRc Rd3, NRc C(0)Rb3, NRc C(0)ORa3, NRc C(0)NRc Rd3, NRc S(0)Rb3, NRclS(0)2Rb3, NRc S(0)2NRc Rd3, S(0)Rb3, S(0)NRc Rd3, S(0)2Rb3, and S(0)2NRc Rd3; Rc and RD are independently selected from H, halo, Ci-6 alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, N02, ORa4, SRa4, C(0)Rb4, C(0)NRc4Rd4, C(0)ORa4, OC(0)Rb4, OC(0)NRc4Rd4, NRc4Rd4, NRc4C(0)Rb4, NRc4C(0)ORa4, NRc4C(0)NRc4Rd4, NRc4S(0)Rb4, NRc4S(0)2Rb4, NRc4S(0)2NRc4Rd4, S(0)Rb4, S(0)NRc4Rd4, S(0)2Rb4, and S(0)2NRc4Rd4; wherein said Ci-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Gs-io aryl, C3 -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, halo, Ci-6 alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, N02, ORa4, SRa4, C(0)Rb4, C(0)NRc4Rd4, C(0)ORa4, OC(0)Rb4, OC(0)NRc4Rd4, NRc4Rd4, NRc4C(0)Rb4, NRc4C(0)ORa4, NRc4C(0)NRc4Rd4, NRc4S(0)Rb4, NRc4S(0)2Rb4, NRc4S(0)2NRc4Rd4, S(0)Rb4, S(0)NRc4Rd4, S(0)2Rb4, and S(0)2NRc4Rd4;
Cy1 and Cy2 are each independently selected from Gs-io aryl, C3 -10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy;
each RCy is independently selected from halo, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, G5-10 aryl, C3 -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO2, ORa5, SRa5, C(0)Rb5, C(0)NRc5Rd5, C(0)ORa5, OC(0)Rb5, OC(0)NRc5Rd5, NRc5Rd5,
NRc5C(0)Rb5, NRc5C(0)ORa5, NRc5C(0)NRc5Rd5, NRc5S(0)Rb5, NRc5S(0)2Rb5,
NRc5S(0)2NRc5Rd5, S(0)Rb5, S(0)NRc5Rd5, S(0)2Rb5, and S(0)2NRc5Rd5, wherein said Cw alkyl, C2-6 alkenyl C6-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, CN, N02, ORa5, SRa5, C(0)Rb5, C(0)NRc5Rd5, C(0)ORa5, OC(0)Rb5, OC(0)NRc5Rd5, NRc5Rd5, NRc5C(0)Rb5, NRc5C(0)ORa5, NRc5C(0)NRc5Rd5, NRc5S(0)Rb5, NRc5S(0)2Rb5, NRc5S(0)2NRc5Rd5, S(0)Rb5, S(0)NRc5Rd5, S(0)2Rb5, and
S(0)2NRc5Rd5;
each Ra, Ral, Ra2, Ra3, Ra4, and Ra5 is independently selected from H, Ci-6 alkyl, Ci-4 haloalkyl, C2-6 alkenyl, C6-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-io aryl-Ci-4 alkyl, C3-io cycloalkyl-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, or (4-10 membered heterocycloalkyl)-Ci-4 alkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, Gs- io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Gs-io aryl- Ci4 alkyl, C3-io cycloalkyl-Ci4 alkyl, (5-10 membered heteroaryl)-C 14 alkyl, and (4-10 membered heterocycloalkyl)-Ci-4 alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C alkyl, halo, CN, ORa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6,
NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
each Rbl, Rb2, Rb3, Rb4, and Rb5 is independently selected from H, Ci-6 alkyl, Ci-4 haloalkyl, C2-6 alkenyl, Gs-io aryl, C3 -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-io aryl-Ci4 alkyl, C3-io cycloalkyl-Ci4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, or (4-10 membered heterocycloalkyl)-Ci4 alkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, Gs- 10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-io aryl- Ci-4 alkyl, C3-10 cycloalkyl-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, and (4-10 membered heterocycloalkyl)-Ci alkyl are each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from Ci-4 alkyl, halo, CN, ORa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6,
NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
each Rc , Rd, Rcl, Rdl, Rc2, Rd2, Rc3, Rd3, Rc4, Rd4, Rc5, and Rd5 is independently selected from H, Ci-6 alkyl, C14 haloalkyl, C2-6 alkenyl, C6-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-io aryl-Ci-4 alkyl, C3-10 eye loalkyl-C 14 alkyl, (5- 10 membered heteroaryl)-Ci-4 alkyl, or (4-10 membered heterocycloalkyl)-Ci-4 alkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, C6-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-io aryl-Ci-4 alkyl, C3-io cycloalkyl-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, and (4-10 membered heterocycloalkyl)-Ci-4 alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C14 alkyl, halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6,
NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6,
NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
or any Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1 , 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, 5-6 membered heteroaryl, halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6, wherein said Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
or any Rcl and Rdl together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1 , 2, or 3 substituents independently selected from Ci-6 alkyl, C3 -7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, 5-6 membered heteroaryl, halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6, wherein said Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Gs-io aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6,
OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6,
S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
or any Rc2 and together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C5-10 aryl, and 5-6 membered heteroaryl, Ci-e haloalkyl, halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6,
NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6, wherein said Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6,
OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
or any Rc3 and Rd3 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, 5-6 membered heteroaryl, Ct-s haloalkyl, halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6,
NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6, wherein said Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
or any Rc4 and Rd4 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3 -7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, 5-6 membered heteroaryl, Ci-6 haloalkyl, halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6,
NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6, wherein said Ci-6 alkyl, C3 -7 cycloalkyl, 4-7 membered heterocycloalkyl, C5-10 aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
or any Rc5 and Rd5 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, 5-6 membered heteroaryl, Ci-6 haloalkyl, halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6,
NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6, wherein said Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, G5-10 aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6; each Ra6, Rb6, Rc6, and R* is independently selected from H, CM alkyl, C2-4 alkenyl, C3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein said Ci-4 alkyl, C2-4 alkenyl, C3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-4 alkyl, Ci alkoxy, C 1-4 alky lthio, Ci-4 alkylamino, and di(Ci4 alkyl)amino;
n is 1 or 2;
p is 1, 2, or 3; and
q is 1 or 2;
wherein any aforementioned 4-10 or 4-7 membered heterocycloalkyl group optionally comprises 1, 2, or 3 oxo substituents, wherein each oxo substituent that is present is substituted on a ring- forming carbon, nitrogen, or sulfur atom of the 4-10 or 4-7 membered heterocycloalkyl group.
9. The method of claim 8, wherein the compound is a compound of Formula Ila:
Figure imgf000208_0001
Ila.
10. The method of claim 8 or 9, wherein L is O.
11. The method of any one of claims 8-10, wherein R3 is H.
12. The method of any one of claims 8-11, wherein R2 is CF3 and R3 is H.
13. The method of any one of claims 8-12, wherein R1 is H or Ci-10 alkyl.
14. The method of any one of claims 8-13, wherein RA is C6-io aryl optionally substituted by
1, 2, 3, 4, or 5 substituents independently selected from RCy.
15. The method of any one of claims 8-14, wherein RA is phenyl optionally substituted by 1,
2, or 3 substituents independently selected from K^.
16. The method of any one of claims 8-15, wherein Rc is H.
17. The method of any one of claims 8-16, wherein RD is H.
18. The method of any one of claims 8-17, wherein R5 is H.
19. The method of any one of claims 8 and 12-17, wherein the compound is a compound of Formula IV:
Figure imgf000209_0001
IV.
20. The method of any one of claims 8 and 12-17, wherein the compound is a compound of Formula Va:
Figure imgf000210_0001
Va.
21. The method of any one of claims 8 and 12-17, wherein the compound is a compound of Formula VII:
Figure imgf000210_0002
VII
wherein a is 0, 1, 2, or 3.
22. The method of any one of claims 8-21, wherein the chiral carbon to which -QC^OR1 is attached has an S configuration.
23. The method of any one of claims 8-22, wherein the carbon to which -R2 is attached has an R configuration.
24. The method of any one of claims 1-7, wherein the TPH1 inhibitor, or a prodrug thereof, is (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-[l, -biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate, or a pharmaceutically acceptable salt thereof.
25. The method of any one of claims 1-7, wherein the TPH1 inhibitor, or a prodrug thereof, is (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-[l, -biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate.
26. The method of any one of claims 1-7, wherein the TPH1 inhibitor, or a prodrug thereof, is (S)-8-(2-amino-6-((R)-l-(5-chloro-[l, -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.
27. The method of any one of claims 1-7, wherein the TPH1 inhibitor, or a prodrug thereof, is (S)-8-(2-amino-6-((R)-l-(5-chloro-[l, -biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid.
28. A method of treating non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or hepatocellular carcinoma in a patient, comprising administering to said patient a therapeutically effective amount of a compound that is metabolized to form (S)-8- (2-amino-6-((R)-l-(5-chloro-[l, -biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid.
29. A method of decreasing serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), cholesterols, triglycerides, or glucose in a patient comprising administering to said patient a therapeutically effective amount of a compound that is metabolized to form (S)-8-(2-amino-6-((R)-l-(5-chloro-[l,l'-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid.
30. A method of reducing lipid deposits in the liver of a patient comprising administering to said patient a therapeutically effective amount of a compound that is metabolized to form (S)-8- (2-amino-6-((R)-l-(5-chloro-[l,l'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8 diazaspiro[4.5]decane-3-carboxylic acid.
31. A method of treating or preventing one or more diseases or symptoms in a patient associated with non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or hepatocellular carcinoma, selected from inflammation, fibrosis, cirrhosis, fatigue, weight loss, weakness, fluid retention, muscle wasting, bleeding from the intestines, liver failure, weight gain, obese, diabetes, prediabetes, lipid disorders, elevated serum lipids, elevated cholesterol, and elevated triglycerides, comprising administering to said patient a therapeutically effective amount of a compound that is metabolized to form (S)-8-(2-amino-6-((R)-l-(5-chloro- [1,1 '-biphenyl] -2-yl)-2, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2, 8-diazaspiro [4.5] decane-3 - carboxylic acid.
32. The method of any one of claims 28-31 wherein the compound that is metabolized to form (S)-8-(2-amino-6-((R)-l-(5-chloro-[l, -biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid is (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-[l,l'- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate, or a pharmaceutically acceptable salt thereof.
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