WO2016109501A1 - Amide compounds as tryptophan hydroxylase inhibitors - Google Patents

Amide compounds as tryptophan hydroxylase inhibitors Download PDF

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WO2016109501A1
WO2016109501A1 PCT/US2015/067815 US2015067815W WO2016109501A1 WO 2016109501 A1 WO2016109501 A1 WO 2016109501A1 US 2015067815 W US2015067815 W US 2015067815W WO 2016109501 A1 WO2016109501 A1 WO 2016109501A1
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Prior art keywords
phenyl
carbamoyl
biphenyl
amino
ethyl
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PCT/US2015/067815
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French (fr)
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Stéphane De Lombaert
Daniel R. Goldberg
Joseph A. Moore Iii
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Karos Pharmaceuticals, Inc.
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Publication of WO2016109501A1 publication Critical patent/WO2016109501A1/en

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Definitions

  • the present invention is directed to amide compounds which are inhibitors of tryptophan hydroxylase (TPH), particularly isoform 1 (TPHl), that are useful in the treatment or prevention of diseases or disorders associated with peripheral serotonin including, for example,
  • 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. In the central nervous system (CNS), 5-HT regulates mood, appetite, and other behavioral functions. In the GI system, 5-HT plays a general prokinetic role and is an important mediator of sensation (e.g., nausea and satiety) between the GI tract and the brain.
  • idiopathic pulmonary fibrosis e.g. Eickelberg, O. et al. Increased expression of 5- hydroxytryptamine2A/B receptors in idiopathic pulmonary fibrosis: a rationale for therapeutic intervention 65, 949-955 (2010); Dygai, A.M. Effects of antiserotonin drug on the development of lung fibrosis and blood system reactions after intratracheal administration of bleomycin 4, 519-523 (2012); Distler, J. H. W. Platelet-derived serotonin links vascular disease and tissue fibrosis 208, 961-972 (2011)), or Raynaud's syndrome (e.g. Black, CM.
  • IPF idiopathic pulmonary fibrosis
  • the rate-limiting step in 5-HT biosynthesis is the hydroxylation of tryptophan by dioxygen, which is catalyzed by tryptophan hydroxylase (TPH; EC 1.14.16.4) in the presence of the cofactor (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4).
  • TPH tryptophan hydroxylase
  • 6R cofactor 6-R
  • AAAD aromatic amino acid decarboxylase
  • TPH belongs to the pterin-dependent aromatic amino acid hydroxylase family.
  • TPH1 and TPH2 Two vertebrate isoforms of TPH, namely TPH1 and TPH2, have been identified.
  • TPH1 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 TPH1 in the gut.
  • p- chlorophenylalanine a very weak and unselective irreversible inhibitor of TPH
  • pCPA p- chlorophenylalanine
  • pCPA is distimped centrally and, as a result, its administration has been linked to the onset of depression and other alterations of CNS functions in patients and animals.
  • p-Ethynyl phenylalanine is a more selective and more potent TPH inhibitor than pCPA (Stokes, A. H. et al.
  • p-Ethynylphenylalanine A Potent Inhibitor Of Tryptophan Hydroxylase. Journal of Neurochemistry 74, 2067-73 (2000), but also affects central 5-HT production and, like pCPA, is believed to irreversibly interfere with the synthesis of TPH (and possibly other proteins).
  • pCPA p-Chlorophenylalanine depletion of gastrointestinal 5-hydroxytryptamine
  • Biochem PharmacoJ 19, 2169-2172 (1970) and (Alpini, G. et al. "Serotonin metabolism is dysregulated in cholangiocarcinoma, which has implications for tumor growth," Cancer Res. 68, 9184-9193 (2008).
  • the present invention relates to a TPH-inhibiting compound of Formula I:
  • the present invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a TPH- inhibiting compound of the invention, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • the present invention further relates to a method of inhibiting TPH, such as TPH1, by contacting the TPH enzyme with a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the present invention further relates to a method of lowering peripheral serotonin in a patient comprising administering to the patient an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the present invention further relates to a method of treating or preventing a disease in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the present invention further relates to a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of disease in a patient.
  • the present invention further relates to use of a compound of Formula I, or a
  • the present invention relates to a TPH-inhibiting compound of Formula I:
  • Ring A is C 3-14 cycloalkyl, C 6 -io aryl, 4 to 14-membered heterocycloalkyl, or 5 to 10- membered heteroaryl;
  • Z is a bridging C 3-14 cycloalkyl group, a bridging C 6 -io aryl group, a bridging 4 to 14- membered heterocycloalkyl group, or a bridging 5 to 10-membered heteroaryl group, each optionally substituted by 1, 2, or 3 substituents independently selected from R z ;
  • R 1 is H, Ci-io alkyl, C3-10 cycloalkyl, phenyl, -(CR 9 R 10 ) p OC(O)R u , -(C R 9 R 10 ) P R U R 12 , or -(C R 9 R 10 )pC(O) R u R 12 , wherein said Ci-10 alkyl, C 3 -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 C1-4 haloalkyl;
  • R 2 is H, Ci-4 alkyl, C(0)R bl , C(0)NR cl R dl , or C(0)OR al ;
  • R 3 and R 4 are each independently selected from H, C1-4 alkyl, C1-4 haloalkyl, OH, and C1-4 alkoxy;
  • each R 5 is independently selected from halo, C1-4 alkyl, and C1-4 alkoxy;
  • R 6 is H or Ci-4 alkyl
  • R 6 and Z together with the N atom to which they are both attached, form a 4-7 membered heterocycloalkyl group optionally substituted by 1, 2, or 3 substituents independently selected from R z ;
  • each R 7 is independently selected from H, halo, and C1-4 alkyl
  • each R 8 is independently selected from H, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C6-io aryl, C 3 -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
  • heterocycloalkyl 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 ,
  • Ci-6 alkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, C6-io aryl, C 3 -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 R 8a , halo, Ci-6 alkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, 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 C(0)R b2 , NR c2 C(0)OR a2 , NR c2 C(0)NR c2 R d2 , NR c2
  • each R 8a is independently selected from C5-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C5-10 aryl-Ci-6 alkyl, C3-10 cycloalkyl-Ci-6 alkyl, 5- 10 membered hetero aryl- C 1-6 alkyl, and 4-10 membered heterocycloalkyl-Ci-6 alkyl, each of which is optionally substituted by 1 or 2 substituents independently selected from halo, Ci-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci -6 haloalkyl, CN, N0 2 , OR a2 , SR 32 , 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 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 a3 , and NR c R d3 ;
  • R 11 and R 12 are each independently selected from H and Ci-6 alkyl
  • R A is H, Cy 1 , halo, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, N0 2 , OR a4 , SR a4 , C(0)R M , 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 M , NR c4 S(0) 2 R M , NR c4 S(0) 2 NR c4 R d4 , S(0)R M , S(0)NR c4 R d4 , S(0) 2 R b4 , or S(0) 2 NR c4 R d4 , wherein said Ci -6 alkyl,
  • R B is H, Cy 2 , halo, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci -6 haloalkyl, 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 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 , NR c5 S(0) 2 R b5 , NR c5 S(0) 2 NR c5 R d5 , S(0)R b5 , S(0)NR c5 R d5 , S(0)
  • R c and R D are each independently selected from H, halo, Ci-6 alkyl, C 2- 6 alkenyl, C 2 - 6 alkynyl, Ci -6 haloalkyl, CN, N0 2 , 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)OR a6 , NR c6 C(0)NR c6 R d6 , NR c6 S(0)R b6 , NR c6 S(0) 2 R b6 , NR c6 S(0) 2 NR c6 R d6 , S(0)R b6 , S(0)NR c6 R d6 , S(0)R b6 , S(0)NR
  • Ci-6 alkyl, C 2 - 6 alkenyl, and C 2 - 6 alkynyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C 6 -io aryl, C3 -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, Ci-6 alkyl, C 2 - 6 alkenyl, Ci-6 haloalkyl, CN, N0 2 , 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)OR a6 , NR c6 C(0)NR c6 R d6 , NR c6 S(0)R b
  • each R z is halo, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 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 C(0)R b2 , NR c2 C(0)OR a2 , NR c2 C(0)NR c2 R d2 , NR c2 S(0)R b2 , NR c2 S(0) 2 R b2 , NR c2 S(0) 2 R b2 , NR c2 S(0) 2 R b2 , NR c2 S(0) 2 NR c2 R d2 , S(0)R b2 , S(0)NR
  • Cy 1 and Cy 2 are each independently selected from C6-io aryl, C 3 -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 is independently selected from halo, Ci-6 alkyl, Ci-6 haloalkyl, C 2- 6 alkenyl, C5-10 aryl, C 3 -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6 -io aryl-Ci- 4 alkyl, C 3- io cycloalkyl-Ci-4 alkyl, (5-10 membered heteroaryl)-C 1 -4 alkyl, (4-10 membered heterocycloalkyl)-Ci- 4 alkyl, CN, N0 2 , OR a7 , SR a7 , C(0)R b7 , C(0)NR c7 R d7 , C(0)OR a7 ,
  • each R al , R bl , R cl , and R dl is independently selected from H, Ci -6 alkyl, CM haloalkyl, C 6 - 10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl;
  • 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
  • Ci-6 alkyl independently selected from halo, Ci-6 alkyl, and Ci-6 haloalkyl;
  • each R a2 , R a3 , R a4 , R a5 , R a6 , R a7 , R b2 , R b4 , R b5 , R b6 , R b7 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 , R d2 , R d3 , R d4 , R d5 , R d6 , and R d7 is independently selected from H, Ci -6 alkyl, CM haloalkyl, C 2-6 alkenyl, C6-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
  • heterocycloalkyl C 6 -io aryl-Ci-4 alkyl, C3-10 cycloalkyl-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, and (4-10 membered heterocycloalkyl)-Ci- 4 alkyl, wherein said Ci-6 alkyl, C 2- 6 alkenyl, C6-io aryl, C3 -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6 -io aryl-Ci-4 alkyl, C3-10 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 CM alkyl, halo, CN, OR a8 , C(0)R b8
  • each R a8 , R b8 , R c8 , and R d8 is independently selected from H, CM alkyl, C 2-4 alkenyl, C3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein said CM 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, CM alkyl, Ci-4 alkoxy, C 1-4 alky lthio, CM alkylamino, and di(Ci-4 alkyl) amino; n is 0, 1, 2, 3, or
  • n 1, 2, 3, or 4;
  • p 1, 2, 3, or 4;
  • R 2 is C(0)OR al , R al is Ci -6 alkyl, m is 2, n is 0, R 3 is H, R 4 is H, R 6 is H, R 7 is H, R s is H, R A is H, R B is H, R c is H, and R D is H; then ring A is other than indolyl and naphthyl;
  • R 2 is C(0)OR al , R al is Ci -6 alkyl, m is 2, n is 0, R 3 is H, R 4 is H, R 6 is H, R 7 is H, R 8 is H, R A is cyclohexyl or phenyl, R B is H, R c is H, and R D is H; then ring A is other than phenyl;
  • the present invention relates to a TPH-inhibiting compound of
  • Ring A is C 3-14 cycloalkyl, C 6 -io aryl, 4 to 14-membered heterocycloalkyl, or 5 to 10- membered heteroaryl;
  • Z is a bridging C 3 -14 cycloalkyl group, a bridging C 6 -io aryl group, a bridging 4 to 14- membered heterocycloalkyl group, or a bridging 5 to 10-membered heteroaryl group, each optionally substituted by 1, 2, or 3 substituents independently selected from R z ;
  • R 1 is H, Ci-io alkyl, C3-10 cycloalkyl, phenyl, -(CR 9 R 10 ) p OC(O)R u , -(C R 9 R 10 ) P R U R 12 , or -(C R 9 R 10 )pC(O) R u R 12 , wherein said Ci-10 alkyl, C 3 -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 C1-4 haloalkyl;
  • R 2 is H, Ci-4 alkyl, C(0)R bl , C(0)NR cl R dl , or C(0)OR al ;
  • R 3 and R 4 are each independently selected from H, C1-4 alkyl, C1-4 haloalkyl, OH, and C1-4 alkoxy;
  • each R 5 is independently selected from halo, C1-4 alkyl, and C1-4 alkoxy;
  • R 6 is H or Ci-4 alkyl
  • R 6 and Z together with the N atom to which they are both attached, form a 4-7 membered heterocycloalkyl group optionally substituted by 1, 2, or 3 substituents independently selected from R z ;
  • each R 7 is independently selected from H, halo, and C1-4 alkyl; each R is independently selected from H, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C6-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
  • heterocycloalkyl CN, N0 2 , OR a2 , SR a2 , C(0)R b2 , C(0) R c2 R d2 , C(0)OR a2 , OC(0)R b2 ,
  • Ci-6 alkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, 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, C 2- 6 alkenyl, C 2- 6 alkynyl, 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 C(0)R b2 , NR c2 C(0)OR a2 , NR c2 C(0)NR c2 R d2 , NR c2 S(0)R a
  • R 7 and R 8 when taken together with the single carbon atom to which they are both attached, form a C3-7 cycloalkyl group optionally substituted by 1, 2, or 3 substituents independently selected from halo, Ci-6 alkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, 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 C(0)R b2 NR c2 C(0)OR a2 , NR c2 C(0)NR c2 R d2 , NR c2 S(0)R b2 , NR c2 S(0) 2 R b2 ,
  • 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, C3-10 cycloalkyl, OR a3 , and NR c R d3 ;
  • R 11 and R 12 are each independently selected from H and Ci-6 alkyl
  • R A is H, Cy 1 , halo, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, N0 2 , OR a4 , SR a4 , C(0)R M , C(0)NR c4 R d4 , C(0)OR a4 , OC(0)R M , OC(0)NR c4 R d4 , NR c4 R d4 , NR c4 C(0)R M , NR c4 C(0)OR a4 , NR c4 C(0)NR c4 R d4 , NR c4 S(0)R M , NR c4 S(0) 2 R M , NR c4 S(0) 2 NR c4 R d4 , S(0)R M , S(0)NR c4 R d4 , S(0) 2 R M , or S(0) 2 NR c4 R d4 , wherein said Ci -6 alkyl, C 2-6 alkeny
  • R B is H, Cy 2 , halo, Ci -6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, Ci -6 haloalkyl, 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 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 , NR c5 S(0) 2 R b5 , NR c5 S(0) 2 R b5 , NR c5 S(0) 2 R b5 , NR c5 S(0) 2 R
  • R c and R D are each independently selected from H, halo, Ci-6 alkyl, C 2- 6 alkenyl, C 2 - 6 alkynyl, Ci -6 haloalkyl, CN, N0 2 , 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)OR a6 , NR c6 C(0)NR c6 R d6 , NR c6 S(0)R b6 , NR c6 S(0) 2 R b6 , NR c6 S(0) 2 NR c6 R d6 , S(0)R b6 , S(0)NR c6 R d6 , S(0)R b6 , S(0)NR
  • Ci-6 alkyl, C 2 - 6 alkenyl, and C 2 - 6 alkynyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C 6 -io aryl, C3 -10 cycloalkyl, 5-10 membered heteroaiyl, 4-10 membered heterocycloalkyl, halo, Ci-6 alkyl, C 2 - 6 alkenyl, Ci-6 haloalkyl, CN, N0 2 , 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)OR a6 , NR c6 C(0)NR c6 R d6 , NR c6 S(0)R a
  • each R z is halo, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci -6 haloalkyl, CN, N0 2 , OR a2 ,
  • Ci -6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with a substituent selected from halo, CN, N0 2 , OR
  • Cy 1 and Cy 2 are each independently selected from C6-io aryl, C 3 -10 cycloalkyl, 5-10 membered heteroaiyl, 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 is independently selected from halo, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C 6 -io aryl, C3 -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6 -io aryl-Ci- 4 alkyl, C3-10 cycloalkyl-Ci-4 alkyl, (5-10 membered heteroaryl)-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-Ci- 4 alkyl, CN, N0 2 , OR a7 , SR a7 , C(0)R b7
  • each R al , R bl , R cl , and R dl is independently selected from H, Ci -6 alkyl, CM haloalkyl, C 6 - 10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl;
  • 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
  • Ci-6 alkyl independently selected from halo, Ci-6 alkyl, and Ci-6 haloalkyl;
  • each R a2 , R a3 , R a4 , R a5 , R a6 , R a7 , R b2 , R b4 , R b5 , R b6 , R b7 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 , R d2 , R d3 , R d4 , R d5 , R d6 , and R d7 is independently selected from H, Ci -6 alkyl, CM haloalkyl, C 2-6 alkenyl, C6-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
  • heterocycloalkyl C 6 -io aryl-Ci-4 alkyl, C3-10 cycloalkyl-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, and (4-10 membered heterocycloalkyl)-Ci-4 alkyl, wherein said Ci-6 alkyl, C 2- 6 alkenyl, C6-io aryl, C3 -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6 -io aryl-Ci-4 alkyl, C3-10 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 CM alkyl, halo, CN, OR a8 , C(0)R b8 ,
  • each R A8 , R B8 , R C8 , and R D8 is independently selected from H, C alkyl, C 2 -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, C 1-4 alkyl,
  • n 0, 1, 2, 3, or 4;
  • n 1, 2, 3, or 4;
  • p 1, 2, 3, or 4;
  • R 2 is C(0)OR al , R al is Ci -6 alkyl, m is 2, n is 0, R 3 is H, R 4 is H, R 6 is H, R 7 is H, R s is H, R A is H, R B is H, R c is H, and R D is H; then ring A is other than indolyl and naphthyl;
  • R 2 is C(0)OR al , R al is Ci -6 alkyl, m is 2, n is 0, R 3 is H, R 4 is H, R 6 is H, R 7 is H, R 8 is H, R A is cyclohexyl or phenyl, R B is H, R c is H, and R D is H; then ring A is other than phenyl;
  • Ring A is C 6 -io aryl or 5 to 10-membered heteroaryl.
  • Ring A is phenyl, naphthyl, pyridyl, indazolyl, or imidazolyl. In some embodiments, Ring A is phenyl.
  • Z is a bridging C 3-14 cycloalkyl group, a bridging C 6 -io aryl group, a bridging 4 to 14-membered heterocycloalkyl group, or a bridging 5 to 10-membered heteroaryl group, each optionally substituted by 1, 2, or 3 substituents independently selected from R z .
  • Z is a bridging C3-7 cycloalkyl group.
  • Z is a bridging cyclobutyl group or bridging cyclohexyl group. In some embodiments, Z is:
  • R 6 and Z together with the N atom to which they are both attached, form a 4-7 membered heterocycloalkyl group optionally substituted by 1, 2, or 3 substituents independently selected from R z .
  • R 1 is H, Ci-10 alkyl, or C3-10 cycloalkyl.
  • R 1 is H or Ci-10 alkyl.
  • R 1 is H or C1-4 alkyl.
  • R 1 is H or ethyl.
  • R 1 is H.
  • R 1 is ethyl
  • R 1 is Ci-10 alkyl or C3-10 cycloalkyl.
  • R 1 is ethyl, propyl, butyl, pentyl, or cyclopentyl.
  • R 2 is H, C alkyl, C(0)R bl , or C(0) R cl R dl .
  • R 2 is H.
  • R 3 and R 4 are each independently selected from H and C1-4 In some embodiments, R 3 and R 4 are both H.
  • R 6 is H or methyl.
  • R 6 is H.
  • each R 7 is independently selected from H and C1-4 alkyl.
  • each R 7 is independently selected from H and methyl.
  • R 7 is H.
  • each R is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C6-io aryl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, and OR a2 ; wherein said Ci-6 alkyl, C6-io aryl, C3 -10 cycloalkyl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 8a , halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci -6 haloalkyl, CN, N0 2 , OR a2 , SR a2 , C(0)R b2 , C(0) R c2 R d2 , C(0)OR a2 , OC(0)R b2 , OC(0) R c2 R d2 , NR c2 R
  • each R 8 is independently selected from H, Ci-6 alkyl, C3-10 cycloalkyl, and 4-10 membered heterocycloalkyl; wherein said Ci-6 alkyl, C3-10 cycloalkyl, and 4- 10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 8a , halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, CN, N0 2 , OR a2 , SR 32 , 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 C(0)R b2 , NR c2 C(0)OR a2 , NR c2 C(0)NR c2 R d2
  • each R 8 is independently selected from H, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C6-io aryl, C3 -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, N0 2 , OR a2 , SR 32 , C(0)R b2 , C(0)NR c2 R d2 , C(0)OR a2 ,
  • Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 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, C2-6 alkenyl, C2-6 alkynyl, Ci -6 haloalkyl, CN, N0 2 , OR 32 , 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 C(0)R b2 , NR c2 C(0)OR a2 , NR c2 C(0)NR c2 R
  • each R 8 is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C6-io aryl, C3 -10 cycloalkyl, 4-10 membered heterocycloalkyl, and OR a2 , wherein said Ci-6 alkyl, C6-io aryl, C3 -10 cycloalkyl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 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 c2 C(0)R b2 ,
  • each R 8 is independently selected from H, Ci-6 alkyl, or C3-10 cycloalkyl, wherein said Ci-6 alkyl and C3-10 cycloalkyl, are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci-6 alkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, Ci-6 haloalkyl, CN, N0 2 , OR a2 , SR a2 , C(0)R b2 , C(0) R c2 R d2 , C(0)OR a2 , OC(0)R b2 , OC(0) R c2 R d2 , R c2 R d2 , R c2 C(0)R b2 , R c2 C(0)OR a2 , R c2 C(0) R c2 R d2 , R c2 S(0)R b2 , R c2 S(0) 2 R b2 , R c2 S(0)
  • each R 8 is independently selected from H, Ci-6 alkyl, or C3-7 cycloalkyl, wherein said Ci-6 alkyl is optionally substituted by hydroxyl and said C3-7 cycloalkyl is optionally substituted by 1 or 2 methyl groups.
  • each R 8 is independently selected from H and 4-7 membered heterocycloalkyl optionally substituted with 1 or 2 substituents independently selected Ci-6 alkyl and benzyl.
  • each R 8 is independently selected from H, piperidinyl, and piperazinyl, each optionally substituted with 1 or 2 substituents independently selected Ci-6 alkyl and benzyl.
  • each R 8 is independently selected from H and Ci-6 alkyl.
  • each R 8 is independently selected from H and C3-7 cycloalkyl.
  • each R 8 is independently selected from H and 2-propyl.
  • R 7 and R 8 when taken together with the single carbon atom to which they are both attached, form a C3-7 cycloalkyl group optionally substituted by 1, 2, or 3 substituents independently selected from halo, Ci-6 alkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, 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 C(0)R b2 , NR c2 C(0)OR a2 , NR c2 C(0)NR c2 R d2 , NR c2 S(0)R b2 , NR c2 S(0) 2 R b2 , NR c2 S(0) 2 NR c2 NR c
  • R 7 and R 8 when taken together with the single carbon atom to which they are both attached, form a C3-7 cycloalkyl group.
  • R 7 and R 8 when taken together with the single carbon atom to which they are both attached, form a cyclopropyl group or a cyclobutyl group.
  • n is 0 or 1.
  • n 0.
  • m is 1.
  • n is 2.
  • m is 3.
  • m is 4.
  • R A is H, Cy 1 , halo, C2-6 alkynyl, or OR a4 , wherein said C2-6 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 1 , halo, Ci-6 alkyl, C2-6 alkenyl, Ci -6 haloalkyl, CN, N0 2 , OR a4 , SR a4 , C(0)R M , C(0)NR c4 R d4 , C(0)OR a4 , OC(0)R M , OC(0)NR c4 R d4 , NR c4 R d4 , NR c4 C(0)R M , NR c4 C(0)OR a4 ,
  • R A is Cy 1 , halo, C2-6 alkynyl, or OR a4 , wherein said C2-6 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 1 , halo, Ci-6 alkyl, C2-6 alkenyl, Ci -6 haloalkyl, CN, N0 2 , OR a4 , SR a4 , C(0)R M , C(0)NR c4 R d4 , C(0)OR a4 , OC(0)R M , 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 M , NR c4 S(0) 2 R M , NR c4 S(0) 2 NR c4 R d4 , S
  • R A is Cy 1 .
  • Cy 1 is selected from phenyl, pyrazolyl, pyrimidinyl, pyridyl, cyclohexyl, cyclohexenyl, indazolyl, quinolyl, isoquinolyl, piperidinyl, thiazolyl, imidazolyl, benzimidazolyl, and benzo[d][l,3]dioxolyl, each of which is optionally substituted by 1, 2, or 3 substituents independently selected from R Cy .
  • Cy 1 is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from R Cy .
  • Ci-6 alkyl is independently selected from halo, Ci-6 alkyl, Ci-6 haloalkyl, C 6 -io aryl, C3 -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, OR a7 , C(0)NR c7 R d7 , C(0)OR a7 , and NR c7 R d7 , wherein said Ci -6 alkyl is optionally substituted with 1 or 2 substituents independently selected from OR a7 and NR c7 R d7 .
  • dimethylaminocarbonyl methoxymethyl, hydroxymethyl, hydroxyethyl, isopropyloxymethyl, aminomethyl, carboxyl, carboxy ethyl ester, oxetanyl, dimethylaminoethyloxy, t-butoxy, cyclopropyloxy,
  • R B is H, halo, or OR a5 .
  • R B is H.
  • R c is H.
  • R D is H.
  • the compound has Formula II:
  • the compound has Formula IV: In some embodiments, the compound has Formula VII:
  • 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
  • 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.
  • 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 Ci-4, Ci-6, and the like.
  • n-membered 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.
  • piperidinyl is an example of a 6-membered heterocycloalkyl ring
  • pyrazolyl is an example of a 5- membered heteroaryl ring
  • pyridyl is an example of a 6-membered heteroaryl ring
  • 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 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).
  • 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, «-propenyl, isopropenyl, «-butenyl, sec-butenyl, and the like.
  • Ci-j alkynyl employed alone or in combination with other terms, refers to an alkyl group having one or more carbon-carbon triple bonds. In some embodiments, the alkynyl moiety contains 2 to 6 or 2 to 4 carbon atoms.
  • Example alkynyl groups include, but are not limited to, ethynyl, propyn-l-yl, propyn-2-yl, and the like.
  • Ci-j alkylamino refers to a group of formula - H(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 - H 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 C 6 -io aryl-Ci-3 alkyl. In some embodiments, arylalkyl is C 6 -io aryl-Ci-4 alkyl. In some embodiments, arylalkyl is benzyl.
  • Cycloalkyl 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.
  • 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-Ci-3 alkyl, wherein the cycloalkyl portion is monocyclic.
  • cycloalkylalkyl is C3-7 cycloalkyl-Ci-4 alkyl.
  • 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 trifluoro methyl.
  • the haloalkyl group is trifluoromethyl.
  • 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-£]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).
  • 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.
  • the heteroarylalkyl is 5-6 membered heteteroaryl-Ci-3 alkyl or 5-6 membered heteteroaryl-Ci-4 alkyl, 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-C 1 -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.
  • bridging when used to describe a cyclic group (as in a ring), is meant to refer to a ring that connects at least two portions of a molecule.
  • Z when Z is a bridging aryl group, the aryl group is linked to both Ring A (lefthand side of molecule) and the nitrogen atom of the NR 6 moeity (righthand side of molecule) in compounds of Formula I.
  • the two portions of the molecule which are linked via the bridging ring can be connected to the bridging ring at, for example, a single ring-forming atom of the bridging ring, adjacent ring- forming atoms of the bridging ring, or non-adjacent ring-forming atoms of the bridging ring.
  • 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), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine,
  • 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 4H- 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.
  • 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.
  • 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 (CH CN) are preferred.
  • non-aqueous media like ether, EtOAc, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (CH CN) 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, 66(1), 1-19, and in Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection,
  • reaction progress may be monitored by thin layer chromatography (TLC) or HPLC-MS if desired.
  • Intermediates and products may be purified by chromatography on silica gel, recrystallization, HPLC and/or reverse phase HPLC.
  • reactive functional groups such as hydroxy, amino, thio, or carboxy groups
  • the incorporation of such groups, and the methods required to introduce and remove them are known to those skilled in the art (for example, see Greene, Wuts, Protective Groups in Organic Synthesis. 2nd Ed. (1999)).
  • One or more deprotection steps in the synthetic schemes may be required to ultimately afford
  • Step 1 an amine (see, e.g., Intermediate B) is treated in DMF with Intermediate A in the presence of a coupling agent (e.g., HATU, Et 3 ) to provide amide C.
  • Step 2 ethyl ester hydrolysis (e.g. with LiOH in aqueous THF) provides acid D.
  • Various esters can be made by converting D to an acid chloride (e.g with SOCh) followed by the addition of another alcohol to provide E.
  • Removal of the the N-Boc protecting group can be accomplished with a strong acid (e.g. TFA) to provide F.
  • a strong acid e.g. TFA
  • the amino acid G can be prepared directly from D in Step 4a via removal of the the N-Boc protecting group directly with strong acid (e.g. TFA).
  • the acid intermediate A used in Scheme 1 can be prepared according to Scheme 2. Briefly, in Step 1, (S)-ethyl 2-amino-3-(4-hydroxyphenyl)propanoate (H) is reacted with (Boc) 2 0 in the presence of a base (e.g., NaHC0 ) in a solvent (e.g., THF/MeOH) to provide J. In Step 2, the hydroxyl group is converted to a triflate (e.g., with Tf 2 0) in the presence of a base (e.g., pyridine) at low to ambient temperature to provide K.
  • a base e.g., NaHC0
  • a solvent e.g., THF/MeOH
  • Step 3 palladium-catalyzed hydroxy carbonylation is accomplished with a catalytic amount of palladium catalyst (e.g., Pd(OAc) 2 ) in the presence of CO (e.g., 1 atm) and a base (e.g., iPr 2 Et), and then mixture is heated for a period of time (e.g. 12-24 h) to provide A.
  • a catalytic amount of palladium catalyst e.g., Pd(OAc) 2
  • CO e.g., 1 atm
  • a base e.g., iPr 2 Et
  • Amine N can be prepared as described in Scheme 3. Briefly, in Step 1, nitrile L is reacted with a base (e.g. LDA) at low temperature (e.g. -78 °C) in THF followed by the addition of an electrophilic reagent (e.g. R 8 -X) to provide M. Step 2, nitrile M is then reduced (e.g. with BH -THF) in THF at low temperature (e.g. 0 °C) to provide N.
  • a base e.g. LDA
  • an electrophilic reagent e.g. R 8 -X
  • Amine T can be prepared as described in Scheme 4. Briefly, in Step 1, ethyl 2-(4- bromophenyl)acetate (O) is reacted with a base (e.g. NaH) at low temperature (e.g. -10 °C) in THF followed by addition of an electrophilic reagent (e.g. 2-bromopropane) to provide P. Step 2, the ethyl ester is hydrolyzed to the acid Q with base (e.g. KOH). In Step 3, diastereomeric salt formation and recrystallization (e.g. with R-(+)-phenylethylamine) provides R. Step 4, amide formation occurs via treating the acid with a coupling reagent (e.g. oxalyl chloride) and then treatment with H4OH to provide S. Step 5, amide S is reduced (e.g. with BH3-THF) in THF at low temperature (e.g. 0 °C) to provide T.
  • Biaryl compounds (V) can be prepared as described in Scheme 5 (Ar is an aromatic moiety like, for example, substituted or unsubstituted phenyl).
  • amine T is treated with Intermediate A in the presence of a coupling agent (e.g., HATU, Et 3 ) to provide amide S.
  • Aryl coupling e.g. Suzuki
  • a boronic acid e.g. ArB(OH)2
  • a transition metal coupling agent e.g. Pd(dppf)Cl2
  • biaryl compounds can be prepared as described in Scheme 6.
  • bromide U is treated with bis(pinacolato)diboron in the presence of a transition metal coupling agent (e.g., Pd(dppf)2) to provide amide W.
  • aryl coupling e.g. Suzuki
  • W an aryl bromide
  • a transition metal coupling agent e.g. Pd(dppf)Cl2
  • Step 1 epoxide W is treated with a Grignard reagent in the presence of a transition metal (e.g., Cul) to provide amine X.
  • Step 2 under Mitsunobu conditions with X in the presence of phthalimide, triphenyl phosphine and diisopropyl azodicarboxylate provides Y.
  • Step 3 aminolysis catalyzed by a lipase (e.g. lipase B from Candida antarctica) provides amino compound Z which can be used to prepare compounds of the invention by the methods described, for example, in Scheme 1.
  • a lipase e.g. lipase B from Candida antarctica
  • Step 1 Suzuki coupling with pyridine boronic acid A' provide B'.
  • Step 2 reduction of the pyridine B' with lithium triethylborohydride in a solvent (e.g. THF) provides piperidine C
  • Step 3 chiral HPLC allows for the seperation of both enatiomers, as exmplified by D' which can be used to prepare compounds of the invention by the methods described, for example, in Scheme 1.
  • the compounds of the invention can be used to inhibit the activity of the TPHl enzyme in a cell by contacting the cell with an inhibiting amount of a compound of the invention.
  • the cell can be part of the tissue of a living organism, or can be in culture, or isolated from a living organism. Additionally, the compounds of the invention can be used to inhibit the activity of the TPHl enzyme in an animal, individual, or patient, by administering an inhibiting amount of a compound of the invention to the cell, animal, individual, or patient.
  • Compounds of the invention can also lower peripheral serotonin levels in an animal, individual, or patient, by administering an effective amount of a compound of the invention to the animal, individual, or patient.
  • the compounds of the invention can lower levels of peripheral serotonin (e.g., 5-HT in the GI tract) selectively over non-peripheral serotonin (e.g., 5-HT in the CNS).
  • the compounds of the invention are useful in the treatment and prevention of various diseases associated with abnormal expression or activity of the TPHl enzyme, or diseases associated with elevated or abnormal peripheral serotonin levels.
  • the treatment or prevention includes administering to a patient in need thereof a therapeutically effective amount of a TPHl inhibitor of the invention.
  • the disease or disorder treatable by administration of one or more of the compounds provided herein is characterized by an altered rate of the tryptophan-serotonin metabolism wherein the rate limiting step of tryptophan- serotonin metabolism is the hydroxylation of L-Tryp catalyzed by TPH (e.g., TPHl).
  • Biological assays can be used to determine the inhibitory effect of compounds against TPH (such as TPHl) in vitro and/or in vivo.
  • TPH such as TPHl
  • In vitro biochemical assays for human, mouse, and rat TPHl and human TPH2, PheOH, and TH may be used to measure inhibition of enzyme activity and the selectivity among TPHl, TPH2, PheOH, and TH.
  • the efficacy of these compounds can be determined, for example, by measuring their effect on intestinal 5-HT levels in rodents after oral administration.
  • a TPHl inhibitor of the invention include bone disease such as, for example, osteoporosis, osteoporosis pseudoglioma syndrome (OPPG), osteopenia, osteomalacia, renal osteodystrophy, Paget's disease, fractures, and bone metastasis.
  • the disease is osteoporosis, such as primary type 1 (e.g., postmenopausal osteoporosis), primary type 2 (e.g., senile osteoporosis), and secondary (e.g., steroid- or glucocorticoid-induced osteoporosis).
  • primary type 1 e.g., postmenopausal osteoporosis
  • primary type 2 e.g., senile osteoporosis
  • secondary e.g., steroid- or glucocorticoid-induced osteoporosis
  • the present invention further includes methods of treating or preventing bone fracture such as, for example, osteoporotic or traumatic fracture, or surgical fractures associated with an orthopedic procedure (e.g., limb lengthening, bunion removal, an increase in bone formation associated with a prosthesis, bone metastasis, or spinal fusion).
  • bone fracture such as, for example, osteoporotic or traumatic fracture, or surgical fractures associated with an orthopedic procedure (e.g., limb lengthening, bunion removal, an increase in bone formation associated with a prosthesis, bone metastasis, or spinal fusion).
  • cardiovascular diseases such as aortic and coronary artery diseases, atherosclerosis,
  • the PH disease is pulmonary arterial hypertension (PAH).
  • PAH pulmonary arterial hypertension
  • PAH treatable or preventable include (1) idiopathic (IP AH), (2) familial (FPAH), and (3) associated (APAH) which is the most common type of PAH.
  • IP AH idiopathic
  • FPAH familial
  • APAH associated
  • PAH PAH which is associated with other medical conditions including, for example, (1) collagen vascular disease (or connective tissue disease) which include autoimmune diseases such as scleroderma or lupus; (2) congenital heart and lung disease; (3) portal hypertension (e.g., resulting from liver disease); (4) HIV infection; (5) drugs (e.g., appetite suppressants, cocaine, and amphetamines; (6) other conditions including thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia,
  • APAH can also be PAH associated with abnormal narrowing in the pulmonary veins and/or capillaries such as in pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis.
  • PVOD pulmonary veno-occlusive disease
  • pulmonary capillary hemangiomatosis Another type of PAH is associatead with persistent pulmonary hypertension of the newborn (PPHN).
  • PPHN pulmonary veno-occlusive disease
  • APAH can aslo be PAH associated with radiation pneumonitis.
  • fibrotic diseases such as: pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), interstitial lung disease, etc.), skin fibrosis (e.g., scleroderma), fibrosis of various other organ tissues such as heart fibrosis (e.g. fibrosis of the heart valves), kidney fibrosis, liver fibrosis, etc.
  • pulmonary fibrosis e.g., idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), interstitial lung disease, etc.
  • skin fibrosis e.g., scleroderma
  • fibrosis of various other organ tissues such as heart fibrosis (e.g. fibrosis of the heart valves), kidney fibrosis, liver fibrosis, etc.
  • any of which may be caused by chronic diseases such as fatty liver disease (e.g., in the case of liver fibrosis) and diabetic nephropathy (e.g., in the case of kidney fibrosis).
  • fatty liver disease e.g., in the case of liver fibrosis
  • diabetic nephropathy e.g., in the case of kidney fibrosis.
  • fatty liver disease e.g., in the case of liver fibrosis
  • diabetic nephropathy e.g., in the case of kidney fibrosis
  • Best Pr act Res Clin Rheumatol e.g., "Lung fibrosis by serotonin receptor antagonists in mice.” Eur Respir J. 2008, 32(2):426-36; Konigshoff, M. et al. "5-Hydroxytryptamine 2A/B receptors in idiopathic pulmonary fibrosis.” Thorax. 2010, 65(11):949—
  • the compounds of the invention can be used in the treatment or prevention of liver disease including, for example, hepatitis.
  • the hepatitis is associated with or induced by an autoimmune process (e.g., autoimmune hepatitis or primary biliary cirrhosis).
  • the hepatitis is associated with or induced by alcoholic or toxic liver destruction.
  • the hepatitis is associated with or induced by a viral infection, such as an infection by HAV, HBV, HCV, HDV, HEV, or HGV.
  • Further diseases treatable or preventable by the methods of the invention include metabolic diseases such as diabetes and hyperlipidemia; pulmonary diseases such as pulmonary embolism, adult respiratory distress syndrome (ARDS); gastrointestinal diseases such as inflammatory bowel diseases (IBD), irritable bowel syndrome (e.g., post-infectious), colitis (e.g., ulcerative colitis), chemotherapy-induced emesis, diarrhea, carcinoid syndrome, celiac disease, Crohn's disease, celiac disease, abdominal pain, dyspepsia, constipation (e.g., idiopathic constipation), lactose intolerance, necrotizing entercolitis, Ogilvie's syndrome, pancreatic cholera syndrome, pancreatic insufficiency, Zollinger-Ellison Syndrome, or other gastrointestinal inflammatory conditions; cancers such as liver cancer, breast cancer, cholangiocarcinoma, colon cancer, colorectal cancer, neuroendocrine tumors, pancreatic cancer, prostate cancer, and bone cancer
  • myeoloproliferative syndrome myelodysplastic syndrome, Hodgkin's lymphoma, non- Hodgkin's lymphoma, myeloma, and anemia such as aplastic anemia and anemia assocated with kidney disease; and blood cancers (e.g., leukemias such as acute lymphocytic leukemia (ALL), chronic lymphocytic leukemica (CLL), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML)).
  • ALL acute lymphocytic leukemia
  • CLL chronic lymphocytic leukemica
  • AML acute myeloid leukemia
  • CML chronic myeloid leukemia
  • the compounds of the invention are also useful in the treatment or prevention of myxomatous mitral valve disease. Lacerda, C. M. et al. "Local serotonin mediates cyclic strain- induced phenotype transformation, matrix degradation, and glycosaminoglycan synthesis in cultured sheep mitral valves.” Am J Physiol Heart Circ Physiol. 302(10): H1983-1990 (2012).
  • the present invention includes methods of lowering plasma cholesterol, lowering plasma triglycerides, lowering plasma glycerol, lowering plasma free fatty acids in a patient by administering to said patient a therapeutically effective amount of a compound of the invention.
  • the present invention includes methods of treating or preventing thrombosis, sleep disorders, pain, diabetes (type 1 or type 2), complications associated with liver transplantation or regeneration, serotonin syndrome, Raynaud's syndrome, subarachnoid hemorrhage, abdominal migraine, CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, telangiectasia), Gilbert's syndrome, nausea, multiple endocrine neoplasia (MEN) types I and II, pheochromacytoma, somatization disorder, functional anorectal disorders, functional bloating, immune tolerance and inflammatory diseases including, e.g. multiple sclerosis and systemic sclerosis.
  • MEN endocrine neoplasia
  • somatization disorder e.g. multiple sclerosis and systemic sclerosis.
  • the compounds of the invention are also useful in the treatment or prevention of inflammatory disease, such as allergic airway inflammation (e.g., asthma). See, e.g., Durk, T. et al. "Production of serotonin by tryptophan hydroxylase 1 and release via platelets contribute to allergic airway inflammation.” Am J Respir Crit Care Med. 187(5): 476-485 (2013).
  • an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal.
  • an in vitro cell can be a cell in a cell culture.
  • an in vivo cell is a cell living in an organism such as a mammal.
  • the term "contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • "contacting" the enzyme with a compound of the invention includes the administration of a compound of the present invention to an individual or patient, such as a human, having the TPH1 enzyme, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the TPH1 enzyme.
  • 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.
  • Combination Therapy 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.
  • One or more additional pharmaceutical agents or treatment methods can be used in combination with the compounds of the present invention for treatment or prevention of various diseases, disorders or conditions disclosed herein.
  • the agents can be combined with the present compounds in a single dosage form, or the agents can be administered simultaneously or sequentially in separate dosage forms.
  • Example pharmaceutical agents that may be useful in a combination therapy for blood disorders like blood cancers include parathyroid hormone, anti-sclerostin antibodies, kathepsin K inhibitors, and anti-Dickopff 1.
  • Example pharmaceutical agents that may be useful in a combination therapy for cancer include leuprolide, goserelin, buserelin, flutamide, nilutamide, ketoconazole, aminoglutethimide, mitoxantrone, estramustine, doxorubicin, etoposide, vinblastine, paclitaxel, carboplatin, and vinorelbine.
  • Therapies that can be combined with TPH inhibition include radiation therapy, high- intensity focused ultrasound, or surgery (e.g., removal of diseased tissues).
  • drugs for use in treating cancer include testolactone, anastrozole, letrozole, exemestane, vorozole, formestane, fadrozole, GnRH-analogues, temozolomide, bavituximab, cyclophosphamide, fluorouracil, fulvestrant, gefitinib, trastuzumab, IGF-1 antibodies, lapatinib, methotrexate, olaparib, BSI-201, pazopanib, rapamycin, ribavirin, sorafenib, sunitinib, tamoxifen, docetaxel, vatalinib, bevacizumab, and octreotide.
  • Example pharmaceutical agents that may be useful in combination therapy for cardiovascular or pulmonary diseases include endothelin receptor antagonists such as
  • ambrisentan BMS-193884, bosentan, darusentan, SB-234551, sitaxsentan, tezosentan and macitentan.
  • Anticoagulants such as warfarin, acenocoumarol, phenprocoumon, phenindione, heparin, fondaparinux, argatroban, bivalirudin, lepirudin, and ximelagatran may also be useful in combination therapy.
  • Pharmaceutical agents for combination therapy further include calcium channel blockers like amlodipine, felodipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, lacidipine, lercanidipine, phenylalkylamines, verapamil, gallopamil, diltiazem, and menthol.
  • Prostacyclins like epoprostenol, iloprost and treprostinil may also be combined with the TPH inhibitors of the invention.
  • PDE5 inhibitors like sildenafil, tadalafil, and vardenafil
  • diuretics like furosemide, ethacrynic acid, torasemide, bumetanide,
  • hydrochlorothiazide spironolactone, mannitol, nitric oxide or nitric oxide releasers, and soluble guanylate cyclase stimulators, such as riociguat.
  • soluble guanylate cyclase stimulators such as riociguat.
  • APJ receptor agonists WO 2013/111110
  • IP receptor agonists WO 2013/105057; WO 2013/105066; WO 2013/105061; WO 2013/105063; WO 2013/105065; WO 2013/105058
  • PDGF receptor inhibitors WO 2013/030802
  • Example pharmaceutical agents that may be useful in combination therapy for metabolic disorders include HSL inhibitors such as those disclosed in International Patent Publications WO2006/074957; WO2005/073199; WO2004/11 1031; WO2004/111004; WO2004/035550; WO2003/051841 ; WO2003/051842; and WO2001/066531.
  • Example pharmaceutical agents that may be useful in combination therapy for bone disorders and diseases include bisphosphantes such as etidronate, clodronate, tiludronate, pamidronate, neridronate, olpadronate, alendronate, ibandronate, risedronate, cimadronate, zoledronate, and the like.
  • Serotonin receptor modulators such as 5-HTIB , 5-HT 2 A, and 5-HT 2 B agonists or antagonists, may also be useful in combination therapy for bone disease.
  • SSRI selective serotonin reuptake inhibitors
  • beta blockers such as IPS339, ICI1 18,551, butaxamine, metipranolol, nadol, oxprenolol, penbutolol, pindolol, propranolol, timolol, and sotalol.
  • Further useful agents for combination therapy for the treatment of bone disorders, such as osteoporosis include teriparatide, strontium ranelate, raloxifene, and denosumab.
  • the compounds of the invention can be administered to patients (animals and humans) in need of such treatment in appropriate dosages that will provide prophylactic and/or therapeutic efficacy.
  • the dose 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 can be determined by the treating physician.
  • a compound of this invention can be administered orally, subcutaneously, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • administration can involve subcutaneous injections, intravenous or intramuscular injections or infusion techniques.
  • Treatment duration can be as long as deemed necessary by a treating physician.
  • the compositions can be administered one to four or more times per day.
  • 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 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.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders.
  • Liquid dosage forms for oral administration can include, for example, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • Suspensions can include one or more suspending agents
  • Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • compositions and compounds of the present invention can be administered by aerosol which can be administered, for example, by a sonic nebulizer.
  • 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.
  • the compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art.
  • synthetic procedures known in the art.
  • all proposed reaction conditions including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated.
  • the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed.
  • Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated.
  • the starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials.
  • Method A Waters BEH C18, 3.0 x 30 mm, 1.7 ⁇ , was used at a temperature of 50 °C and at a flow rate of 1.5 mL/min, 2 ⁇ ⁇ injection, mobile phase: (A) water with 0.1% formic acid and 1% acetonitrile, mobile phase (B) MeOH with 0.1% formic acid; retention time given in minutes.
  • Method B An Agilent Zorbax Bonus RP, 2.1 x 50 mm, 3.5 ⁇ , was used at a temperature of 50 °C and at a flow rate of 0.8 mL/min, 2 ⁇ ⁇ injection, mobile phase: (A) water with 0.1%) formic acid and 1%> acetonitrile, mobile phase (B) MeOH with 0.1%> formic acid; retention time given in minutes.
  • Method C An API 150EX mass spectrometer linked to a Shimadzu LC-10AT LC system with a diode array detector was used.
  • the spectrometer had an electrospray source operating in positive and negative ion mode.
  • LC was carried out using an Agilent ZORBAX XDB 50 x 2.1 mm C18 column and a 0.5 mL/minute flow rate.
  • Solvent A 95% water, 5% acetonitrile containing 0.01% formic acid;
  • Solvent B acetonitrile. The gradient was shown as below.
  • Microwave experiments were carried out using a Biotage InitiatorTM, which uses a single- mode resonator and dynamic field tuning. Temperatures from 40-250 °C were achieved, and pressures of up to 20 bars were reached.
  • Preparative HPLC purification was carried out using either a C18-reverse-phase column from Genesis (C18) or a C6-phenyl column from Phenomenex (C6 Ph) (100 x 22.5 mm i.d. with 7 micron particle size, UV detection at 230 or 254 nm, flow 5-15mL/min), eluting with gradients from 100-0 to 0-100 % water/acetonitrile or water/MeOH containing 0.1% formic acid. Fractions containing the required product (identified by LCMS analysis) were pooled, the organic fraction removed by evaporation, and the remaining aqueous fraction lyophilised, to give the product.
  • Step 1 To a solution of 2-([l,l * -biphenyl]-4-yl)acetonitrate (CAS# 31603-77-7, 500 mg, 2.6 mmol) in toluene (5 mL) was added sodium amide (222 mg, 10 mmol) at RT. The mixture was heated to 35 °C for 15 min. Then 1,3-diiodopropane (490 mg, 2.6 mmol) was added dropwwise and the reaction was stirred at 35 °C for 16 h. After this time, an additional equivalent of sodium amide was added and the reaction was heated to 50 °C for 4.5 h.
  • Step 2 A solution of l-([l,l'-biphenyl]-4-yl)cyclobutanecarbonitrile (119 mg, 0.5 mmol) in ether (5 mL) was cooled to 0 °C followed by the dropwise addition of LAH (1 mL of a 1M ether solution). The reaction was warmed to RT and stirred for 2 h. After this time, the reaction was cooled to 0 °C and quenched sequentially with water, 15% NaOH, and water, and then extracted with ethyl acetate. The organic layer was washed with brine, dried over Na 2 S04, filtered and concentrated in vacuo. Purification via normal phase column chromatography
  • Step 1 A solution of diisopropyl amine (576 mg, 5.7 mmol) in THF (2.5 mL) was cooled to -78 °C and n-butyl lithium (2.5 M in hexanes, 1 mL) was added. The reaction was stirred for 30 min at -78 °C. After this time, 2-([l, l'-biphenyl]-4-yl)acetonitrile (CAS# 31603-77-7, 500 mg, 2.6 mmol) was added and the reaction was stirred for 5 min, then cyclopentyl bromide (CAS# 137-43-9, 467 mg, 3.1 mmol) was added.
  • Step 2 To a solution of 2-([l,l'-biphenyl]-4-yl)-2-cyclopentylacetonitrile (173 mg, 0.7 mmol) in THF (5 mL) was added borane in THF (1 M, 9.9 mL). The reaction mixture was heated to 65 °C for 2 h. After this time, the reaction was cooled to RT and quenched with HCl (1 N, 5 mL), and then the pH was adjusted to -8.5 with NaOH (IN) and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na 2 S04, filtered and concentrated in vacuo. Purification via normal phase column chromatography (CH 2 Cl2:MeOH:NH40H/ 90: 10: 1) provided the title compound as a colorless oil. LCMS (MH + ): 266.
  • Step 1 To a solution of 2-([l,l'-biphenyl]-4-yl)acetonitrile (CAS# 31603-77-7, 250 mg, 1.3 mmol) in toluene (5 mL) was added sodium amide (0.1 mL, 1.3 mmol). After 20 min, 1- trifluoromethyl-l,2-benziodoxol-3-(lH)-one (CAS#: 887144-94-7, 440 mg, 1.4 mmol) was added dropwise and the reaction was stirred at RT for 16 h. After this time, the reaction was quenched with water and extracted with ethyl acetate.
  • Step 2 The tile compound was prepared as described for 2-([l,l'-biphenyl]-4-yl)-2- cyclopentylethanamine (step 2) as a colorless oil.
  • Step 1 A solution of diisopropyl amine (576 mg, 5.7 mmol) in THF (2.5 mL) was cooled to -78 °C and n-butyl lithium (2.3 M in hexanes, 1 mL) was added. The reaction was stirred for 30 min at -78 °C. After this time, 2-([l, l'-biphenyl]-4-yl)acetonitrile (1.0 g, 5.6 mmol) was added and the reaction was stirred for 15 min at -78 C. Then acetone (1.9 mL, 26 mmol) was added and the reaction was warmed to RT for 16 h. The reaction was then quenched with HCl (IN) and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na 2 S04, filtered and concentrated in vacuo. Purification via normal phase column
  • Step 2 To a solution of 2-([l,l'-biphenyl]-4-yl)-3,3-dimethyl-5-oxohexanenitrile (700 mg, 2.4 mmol) in THF (5 mL) was added borane in THF (1 M, 24 mL) and the reaction mixture was heated to 65 °C for 2 h. After this time, the reaction was cooled to RT and quenched with HCl (1 N, 5 mL), and then the pH was adjusted to -8.5 with NaOH (IN) and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na 2 S04, filtered and concentrated in vacuo.
  • Step 1 A solution of l-bromo-2-chloro-4-methylbenzene (1.0 g, 4.90 mmol), BS (0.87 g, 4.90 mmol) and AIBN (1%) in CC1 4 (10 mL) was heated to reflux for 12 h. After cooling to RT, the reaction mixture was filtered and the filtrate was evaporated to provide l-bromo-4- (bromomethyl)-2-chlorobenzene as a yellow oil.
  • Step 2 A solution of l-bromo-4-(bromomethyl)-2-chlorobenzene (1.38 g, 4.90 mmol), TMSCN (0.58 g, 5.9 mmol) and K 2 C0 3 (0.81 g, 5.9 mmol) in CH CN (10 mL) was heated to 50 °C for 6 h. After this time, the reaction mixture was cooled to RT and concentrated in vacuo. The residue was extracted with ethyl acetate and the organic layer was washed with brine, dried over Na 2 SC " 4, filtered and concentrated in vacuo to provide 2-(4-bromo-3-chlorophenyl) acetonitrile as a colorless oil.
  • Step 3 To a solution of 2-(4-bromo-3-chlorophenyl) acetonitrile (800 mg, 3.47 mmol) and phenylboronic acid (508 mg, 4.16 mmol) in 1,4-dioxane (10 mL) was added aqueous Na 2 C0 3 (2M, 4mL) and PdCl 2 (PPh 3 ) 2 (3%), and the reaction was heated to 95 °for 12 h. After this time, the reaction mixture was cooled to RT and quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na 2 SC"4, filtered and concentrated in vacuo to provide. Purification via normal phase column chromatography (hexane/ethyl acetate: 40/1) provided 2-(2-chlorobiphenyl-4-yl)acetonitrile as a yellow oil.
  • Step 4 A solution of 2-(2-chlorobiphenyl-4-yl)acetonitrile (376 mg, 1.65 mmol) and Raney-Ni (190 mg) in a solution of H in CH OH (6 mL) was stirred at RT for 12 h under 1 atm of H 2 . After this time, the reaction mixture was filtered and the filtrate was concentrated in vacuo to provide the title compound as a yellow liquid.
  • Step 2 A solution of biphenyl-4-carbaldehyde (500 mg, 2.74 mmol), ethane- 1,2-diol (2 mL) and 4-methylbenzenesulfonic acid (47 mg, 0.274 mmol) in toluene (6 mL) was heated at 140 °C for 4 d. After this time, the reaction was cooled to RT and the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na 2 SC"4, filtered and concentrated in vacuo. Purification via normal phase column chromatography (hexane/ethyl acetate: 10/1) provided 2-(Biphenyl-4-yl)-l,3-dioxolane as a white solid.
  • Step 3 A solution of 2-(biphenyl-4-yl)-l,3-dioxolane (460 mg, 2.03 mmol), TMSCN (242 mg, 2.44 mmol) and Znl 2 (1.3 g, 4.06 mmol) in CH 2 C1 2 (10 mL) was stirred at RT for 3.5 h. After this time, the reaction mixture was quenched with saturated Na 2 C0 3 and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na 2 SC"4, filtered and concentrated in vacuo. Purification via normal phase column chromatography (hexane/ethyl acetate: 3/1) provided 2-(biphenyl-4-yl)-2-(2-hydroxyethoxy)acetonitrile as colorless gel.
  • Step 4 A solution of 2-(biphenyl-4-yl)-2-(2-hydroxyethoxy)acetonitrile (76 mg, 0.30 mmol) and Raney-Ni (50 mg) in a solution of H 3 (7 N in CH 3 OH) (6 mL) was stirred at RT for 12 h under 1 atm of H 2 . After this time, the reaction was filtered and the filtrate was
  • Stepl A solution of N-(3-bromopropyl)phthalimide (CAS#: 5460-29-7 , 13.4 g, 5 mmol) and triphenyl phosphine (13.2 g, 5 mmol) in m-xylene (75 mL) was heated to 145 °C for 40 h. After this time, the reaction was cooled to RT, filtered, washed with ether and dried in vacuo to provide (3-(l,3-dioxoisoindolin-2-yl)propyl)triphenylphosphonium bromide as a white solid.
  • Step 2 A solution of (3-(l,3-dioxoisoindolin-2-yl)propyl)triphenylphosphonium bromide (2.7 g, 5 mmol) in THF (30 mL) was cooled to 0 °C and potassium t-butoxide (0.56 g, 5 mmol) was added solution was stirred at 0 °C for 15 min and then [l, l'-biphenyl]-2-carbaldehyde (CAS#: 1203-68-5, 0.91 g, 5 mmol) was added. The reaction was warmed to RT and stirred for 12 h.
  • Step 3 A solution of (Z)-2-(4-([l, l'-biphenyl]-2-yl)but-3-en-l-yl)isoindoline-l,3-dione (550 mg, 1.56 mmol) in hydrazine (5 mL) and ethanol (10 mL) was heated to 75 °C for 2 h. After this time, the reaction was cooled to RT, concentrated in vacuo and purified directly via normal phase column chromatography (MeOH:CH 2 Cl 2 : Lt OH/98: 1 : 1) to provide the title compound as a clear oil.
  • Step 1 To a solution of 4-fluoro-3-formyl-benzonitrile (CAS#: 146137-79-3, 6 g, 40.2 mmol) in DMF (30 mL) was added phenylhydrazine hydrochloride (6.12 g, 42.3 mmol). The reaction mixture was stirred for 2 h at 80 °C. Then K 2 C0 (11.11 g, 80.5 mmol) was added and the reaction mixture was heated to 140 °C for an additional 12 h. After this time, the reaction was cooled to RT, and then poured into ice-water and extracted with ethyl acetate.
  • Step 2 A solution of l-phenyl-lH-indazole-5-carbonitrile (2.1 g, 9.5 mmol) in EtOH (20 mL) and NaOH (40% in water, 20 mL) was heated to reflux for 12 h. After this time, the reaction was cooled to RT, and the reaction mixture was concentrated in vacuo. The pH of the residue was adjusted to ⁇ 3 by the addition of HC1 (6.0 N) to provide an off-white solid that filtered to provide 1 -phenyl- lH-indazole-5-carboxylic acid.
  • Step 3 To a solution of l-phenyl-lH-indazole-5-carboxylic acid (2.0 g, 8.4 mmol) was added BH3-THF (1.0 M, 20 mL) and the reaction mixture was heated to reflux for 12 h. After this time, the reaction was cooled to RT and the reaction mixture was quenched with
  • Step 4 To the 1 : 1 mixture of 5 -(chloromethyl)-l -phenyl- lH-indazole and (1-phenyl-lH- indazol-5-yl) (1.0 g, 4.4 mmol) in DMF (10 mL) was added NaCN (428 mg, 8.7 mmol) and the reaction was heated to 50 °C for 48 h. After this time, the reaction mixture was cooled to RT and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na 2 S04, filtered and concentrated in vacuo. Purification via normal phase column chromatography (hexane/ethyl acetate: 2/1) provided 2-(l-phenyl-lH-indazol-5-yl)acetonitrile as an off-white solid.
  • Step 5 To a solution of 2-(l-phenyl-lH-indazol-5-yl)acetonitrile(730 mg, 3.13 mmol) in THF (10 mL) was added BH 3 -THF (1.0 M, 15 mL) and the reaction was heated to reflux for 12 h. After this time, the reaction was cooled to RT and HC1 (3.0 N, 10 mL) was added and the reaction mixture was then heated to reflux for 3 h. The reaction mixture was then cooled to RT and NaHC0 3 (aq) was added to adjust the pH ⁇ 7. The reaction mixture was then extracted with ethyl acetate.
  • Step 1 To a solution of 3-((tert-butoxycarbonyl)amino)propanoic acid (CAS#: 26250- 90-8, 2 g, 10.58 mmol) in DMF (20 mL) was added Cs 2 C0 3 (1.72 g, 5.28 mmol) and the reaction mixture was stirred at RT for 1 h. After this time, 2-bromo-l-phenylethanone (CAS#: 70-11-1, 2.1 g, 0.256 mmol) was added and the reaction mixture was stirred for an additional 12 h at RT. The solvent was then removed in vacuo and ethyl acetate was added (50 mL) and the resultant white solid was filtered away from the reaction mixture. The filtrate was concentrated in vacuo to provide 2-oxo-2-phenylethyl 3-((tert-butoxycarbonyl)amino)propanoate as a light yellow solid that was used without further purification.
  • Step 2 To a solution of 2-oxo-2-phenylethyl 3-((tert-butoxycarbonyl)amino)propanoate (3 g, 9.8 mmol) in xylene (25 mL) was added ammonium acetate (7.84 g, 102 mmol ). The reaction mixture was heated to 140 °C for 2 h. After this time, the reaction mixture was cooled to RT and then poured into saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na 2 SC"4, filtered and concentrated in vacuo.
  • Step 3 To a solution of tert-butyl (2-(4-phenyl-lH-imidazol-2-yl)ethyl)carbamate (200 mg, 0.7 mmol) in MeOH (2 mL) was added HC1 (3.6 M in MeOH, 10 mL) and stirred at RT for 3 h. After this time, the reaction mixture was concentrated in vacuo to provide the title compound as a yellow oil that was used without further purification. LCMS (MH + ): 224.1.
  • Step 1 A solution of ethyl 2-(4-bromophenyl)acetate (CAS#: 14062-25-0, 40 g, 164.5 mmol) in DMF (200 mL) was cooled to -10 °C followed by the slow addition of NaH (60% in oil, 4.34g, 181 mmol) in several portions. The reaction mixture was stirred for 15 min and 2- bromopropane (22.2 g, 181 mmol) was added dropwise over 10 min. The reaction mixture was allowed to warm to RT and stirred for 12 h. After this time, the reaction mixture was concentrated in vacuo and then extracted with ethyl acetate.
  • Step 2 To a solution of ethyl 2-(4-bromophenyl)-3-methylbutanoate (26 g, 91.2 mmol) in EtOH (50 mL) was added aq. KOH (5 N,50 mL) and the reaction was heated to reflux for 12 h. The reaction mixture was then cooled to RT, and concentrated in vacuo.
  • Step 3 To a solution of 2-(4-bromophenyl)-3-methylbutanoic acid (12.7 g, 49.4 mmol) in C3 ⁇ 4CN (75 mL) was added R-(+)-l-phenylethylamine (3.0 g, 24.7 mmol) in C3 ⁇ 4CN (50 mL). After 1 h, the crystalline precipitate was filtered off, washed with cold C3 ⁇ 4CN and dried in vacuo. To obtain high enantioselectivity, the crystalline diastereomeric salt was recrystallized an additional 3 times from MeOH and DMF (1 : 1) (filtering drying and then subjecting to the process each time).
  • Step 4 To a 0 °C solution of (R)-2-(4-bromophenyl)-3-methylbutanoic acid (6 g, 23.6 mmol) in CH 2 C1 2 (20 ml) was added oxalyl chloride (6 g, 47.2 mmol) dropwise over a 10 min period. After the complete addition of oxalyl chloride, DMF (2 drops) was added to and the reaction was warmed to RT for 2 h.
  • Step 5 To a solution of (R)-2-(4-bromophenyl)-3-methylbutanamide (5.5 g, 21.7 mmol) was added BH3-THF (50 mL) and then heated to reflux for 12 h. After this time, the reaction mixture was cooled to RT and a second addition of BH3-THF (50 mL) was added and the reaction mixture was heated to reflux for an additional 12 h. After this time, the reaction mixture was cooled to RT, and quenched with 3 N HCl, and then heated to reflux for 3 h. The reaction was then cooled to RT and 1 N NaOH was added dropwise to adjust the pH to ⁇ 7 and then the entire mixture was extracted with ethyl acetate.
  • Step 1 To a solution of (R)-2-(4-bromophenyl)-3-methylbutan-l -amine (Intermediate 44 radical 1 g, 4.1 mmol) in CH 2 C1 2 (10 mL) was added (Boc) 2 0 (1 g, 4.5 mmol) and TEA (1.2 mL, 8.2 mmol) The reaction mixture was stirred at RT for 3 h and then diluted with water and extracted with CH 2 C1 2 . The organic layer was washed with brine, dried over Na 2 SC"4, filtered and concentrated in vacuo. Purification via normal phase column chromatography
  • Step 2 To a 0 °C solution of (R)-tert-butyl (2-(4-bromophenyl)-3-methylbutyl)carbamate (300 mg, 0.87 mmol) in DMF (5 mL) was added NaH (39 mg, 0.964 mmol) and the reaction was stirred for 15 min. After this time, methyl iodide (254.33 mg, 1.75 mmol) was added, and the reaction was warmed to RT and stirred for 2 h. Then, the reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na 2 SC"4, filtered and concentrated in vacuo.
  • Step 3 To a 0 °C solution of (R)-tert-butyl (2-(4-bromophenyl)-3-methylbutyl) (methyl) carbamate in CH 2 C1 2 (6 mL) was added TFA (1.5 mL) and the reaction mixture was stirred for 1 h at 0 °C. After this time, the reaction mixture was concentrated, and saturated aqueous
  • Step 1 t-Butyl magnesium chloride in ether (2M, 61 ml) was added to a solution of 4- bromo benzaldehyde (15g) in THF (200 ml) at 0 °C. The mixture was allowed to warm RT and stirred for 5 h. Saturated H4CI solution was added and extracted with ethyl acetate. The organic layer was dried and concentrated. The crude was purified by flash chromatography (3% to 10% ethyl acetate in hexane) to provide (4-bromophenyl)(t-butyl)methanonol as a colorless oil. (7.9 g).
  • Step 2 To a solution of l-(4-bromophenyl)-2,2-dimethylpropan-l-ol (3.8 g, 15.7 mmol) in CH 2 C1 2 (20 ml) was added a homogeneous mixture of PCC (12 g) and silica gel (12 g). The mixture was stirred at room temperature for 4 h. Filtration of the reaction mixture through a short silica pad with excess CH2CI2 provided (4-bromophenyl)(t-butyl)methanone (3.4 g).
  • Step 3 To a solution of methyl triphenylphosphonium bromide (8.8 g) in THF (100 mL) at -78 °C was added n-BuLi (2.5 M in hexane, 10.4 mL) slowly. The mixture was stirred at 0 °C for 30 min. To the reaction mixture was added a solution of (4-bromophenyl)(t-butyl)methanone (21) (5.3 g) in THF (10 mL). The mixture was allowed to warm to room temperature, stirred 24 h, and partitioned between TBME and saturated NH4CI solution. The combined organics were dried, filtered and concentrated in vacuo. The residue was purified by flash chromatography with 50: 1 hexane/EA to provide 3, 3 -dimethyl -2-(4-bromophenyl)-l-butene (3.7 g).
  • Step 4 To a solution of 3,3-dimethyl2-(4-bromophenyl)-l-butene(22) (2.5g) in THF at 0
  • Step 5 To a mixture 3,3-dimethyl-2-(4-bromophenyl)butanol (1.81g) in DMF (20 mL) at room temperature was added PDC (8.2 g) in portions. The mixture was stirred at room temperature overnight, and then diluted with EA (100 mL), filtered through a celite pad. The filtrate was washed with water, brine and dried, filtered and concentrated to give the crude product which was purified by flash chromatography with 4: 1 hexane/EA to provide 3,3- dimethyl-2-(4-bromophenyl)butanoic acid as a white solid (0.7 g).
  • Step 6 A solution of 3,3-dimthyl-2-(4-bromophenyl)butanoic acid (0.7 g) in 4 mL of thionyl chloride was stirred at RT for 12 h. Thionyl chloride was removed under vacuum and chased twice with CH2CI2. After drying under vacuum, 2-(4-bromophenyl)-3,3-dimethylbutanoyl chloride was obtained as an oil (0.6 g).
  • Step 7 To a solution of (R)-4-benzyl-2-oxazolidinone (0.5 g) in THF (20 mL) was cooled to -78 °C and n-BuLi (2.5 M in hexane, 1.5 mL) was added drop-wise. The mixture was stirred 30 min then a solution of 2-(4-bromophenyl)-3,3-dimethylbutanoyl chloride (0.6 g) in THF (3 mL) was added at -78°C. The mixture was stirred for 1 h and the saturated H4CI solution (20 mL) was added. The organic layer was separated and the aqueous layer was extracted twice with TBME (10 mL).
  • Step 8 To a solution of (4R)-4-benzyl-3-[(2R)-2-tert-butyl-2-(4-bromophenyl)acetyl]- 1.3-oxazolidin-2-one (2 g, 4.65 mmol) in THF/water (60/20 mL) was added 30% H 2 0 2 (3.8 mL) at 0 °C and stirred for 10 min. Then LiOH.H 2 0 (400 mg, 9.3 mmol ) was added. The reaction mixture was stirred at RT overnight. After cooling to 0 °C, Na 2 S0 (4.8 g, 37.2 mmol) was added and the mixture was stirred for 30 min, and then extracted with EA.
  • Step 9 To a solution of (R)-2-(4-bromophenyl)-3,3-dimethylbutanoic acid (900 mg, 3.32 mmol) in CH 2 C1 2 (10 mL) was added (COCl) 2 (1 mL) at 0 °C, then DMF (1 drop) was added and stirred for 2 h. After this time, the reaction mixture was concentrated, and the resulting residue was poured into H .H 2 0 and filtered. The solid was collected to afford (R)-2-(4- bromophenyl)-3,3-dimethylbutanamide (600 mg) that was used in the next step without further purification.
  • Step 10 A solution of (R)-2-(4-bromophenyl)-3,3-dimethylbutanamide (600 mg, 2.22 mmol) in THF was cooled to 0 °C to which BH .THF (50 mL) was added slowly, then the mixture was refluxed for 12 h. After this time, the reaction was cooled to RT and 3 N HCl (10 mL) was added. The mixture was refluxed for 2 h, then cooled to RT.
  • Step 1 To a 0 °C solution of spiro[3.5]nonan-7-ol (CAS#: 1393450-96-8, 1 g, 140 mmol) in CH2CI2 was added triphenylphosphine (0.08 g, 0.28 mmol), imidazole (0.03 g, 0.43 mmol), and iodine (0.05 g, 0.03 mmol). The mixture was heated at 100 °C for 1 h then cooled to RT. The mixture was poured into a saturated solution of NaHC0 . Excess triphenylphosphine was destroyed by the addition of iodine until the iodine coloration persisted in the organic layer.
  • Step 2 The title compound was made as described for Intermediate 44 ((R)-2-(4 bromophenyl)-3-methylbutan-l -amine) using 7-iodospiro[3.5]nonane in place of 2- bromopropane.
  • Step 1 To a 0 °C solution of (S)-ethyl 2-((tert-butoxycarbonyl)amino)-3-(4- hydroxyphenyl)propanoate (CAS#: 72594-77-5, 7 g, 22.7 mmol) in CH 2 C1 2 (70 mL), was added pyridine (8.95 g, 113.2 mmol) followed by the dropwise addition of trifluoromethanesulfonic anhydride (6.7 g, 23.7 mmol) over a 30 min period. After this time, the reaction was stirred at 0 °C for 5 h, then extracted with CH 2 C1 2 .
  • Step 2 To a solution of (S)-ethyl 2-((tert-butoxycarbonyl)amino)-3-(4-(((trifluoromethyl) sulfonyl)oxy)phenyl)propanoate (10 g, 22.6 mmol) in DMF/H 2 0 (45 mL/15 mL) was added iPr 2 NEt(5.8 g, 45.2 mmol), l,3-bis(diphenylphosphino)propane (560 mg, 1.4 mmol), and
  • Step 1 To a solution of (S)-4-(2-((tert-butoxycarbonyl)amino)-3-ethoxy-3- oxopropyl)benzoic acid (Intermediate A, 200 mg, 0.82 mmol) in DMF (10 mL) was added (R)-2- (4-bromophenyl)-3-methylbutan-l -amine (Intermediate 44, 278 mg, 1.24 mmol), HATU (623 mg, 1.64 mmol), and TEA (166 mg, 1.64 mmol), and the reaction was stirred for 48 h at RT. After this time, the reaction was diluted with water and extracted with ethyl acetate.
  • Step 2 To a solution of (S)-ethyl 3-(4-(((R)-2-(4-bromophenyl)-3-methylbutyl) carbamoyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (200 mg, 0.36 mmol) in dioxane (5.0 mL)/Na 2 C03 (2.5 mL, 2.0 M, aq.) was added phenyl boronic acid (66 mg, 0.54 mmol) followed by Pd(dppf)Cl 2 (26 mg, 0.036 mmol). The reaction was purged with N 2 and then heated to 90 °C for 3 h.
  • Step 3 To a 0 °C solution of (S)-ethyl 3-(4-(((R)-2-([l, l * -biphenyl]-4-yl)-3-methylbutyl) carbamoyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (150 mg, 0.27 mmol) in CH 2 C1 2 (6 mL), was added dropwise TFA (1.5 mL). The reaction was warmed to RT for 3 h, then concentrate in vacuo. To the resulting residue was added saturated aqueous solution of NaHC0 3 to adjust the pH to -7.5 and then extracted with CH 2 C1 2 .
  • Step 4 To a 0 °C solution of (S)-ethyl 3-(4-(((R)-2-([l, l'-biphenyl]-4-yl)-3-methylbutyl) carbamoyl)phenyl)-2-aminopropanoate (75 mg, 0.16 mmol) in MeOH (6 mL), was added dropwise 5 N NaOH (2 mL) and then the reaction mixture was warmed to RT for 3 h. After this time, the reaction mixture was acidified with 3N HC1 to adjust the pH to 6-7, the MeOH was removed in vacuo and the resultant solid was filtered, washed with H 2 0, and dried in vacuo to provide the title compound as a white solid.
  • Step 1 To a solution of (S)-ethyl 3-(4-(((R)-2-(4-bromophenyl)-3-methylbutyl) carbamoyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (Example la, Step 2, (200 mg, 0.36 mmol) in DMF (10 mL) was add Pd(PPh 3 ) 2 Cl2 (38 mg, 0.054 mmol), Cul (14 mg, 0.072 mmol) and PPh 3 (19 mg, 0.072 mmol).
  • the title compound was produced by following Steps 3-4 as described for Example la to provide a white solid.
  • Step 1 A solution of Intermediate B: (S)-ethyl 2-((tert-butoxycarbonyl)amino)-3-(4- (((R)-3-methyl-2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)butyl)carbamoyl)phenyl) propanoate (200 mg, 0.33 mmol), 2-bromopyridine ( 80 mg, 0.493 mmol), Pd(dppf)C12 (24 mg, 0.0329 mmol) and 2M Na 2 C0 3 (1 mL) in dioxane (3 mL) was purged with N 2 and then heated at 80 °C for 3 h.
  • Steps 2 & 3 The title compound was produced by following Steps 3-4 as described for Example la to provide a white solid.
  • LCMS (MH + ): 432.53.
  • Step 1 To a solution of (S)-4-(2-((tert-butoxycarbonyl)amino)-3-ethoxy-3- oxopropyl)benzoic acid (Intermediate A, 200 mg, 0.82 mmol) in DMF (10 mL) was added 2-(4- bromophenyl)ethanamine (200 mg, 1.0 mmol), HATU (623 mg, 1.64 mmol), and TEA (166 mg, 1.64 mmol), and the reaction was stirred for 48 h at RT. After this time, the reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na 2 SC"4, filtered and concentrated in vacuo. Purification via normal phase column
  • Step 2 To a solution of (S)-ethyl 3-(4-((4-bromophenethyl)carbamoyl)phenyl)-2-((tert- butoxycarbonyl)amino)propanoate (200 mg, 0.38 mmol) in dioxane (5.0 mL)/Na 2 C03 (2.5 mL, 2.0 M, aq.) was added 4-methoxy phenyl boronic acid (70 mg, 0.55 mmol) followed by
  • Step 3 To a 0 °C solution of (S)-ethyl 2-((tert-butoxycarbonyl)amino)-3-(4-((2-(4'- methoxy-[l, l'-biphenyl]-4-yl)ethyl)carbamoyl)phenyl)propanoate (125 mg, 0.23 mmol) in CH2CI2 (6 mL), was added dropwise TFA (1.5 mL). The reaction was warmed to RT for 3 h, then concentrate in vacuo. To the resulting residue was added saturated aqueous solution of NaHCC to adjust the pH to -7.5 and then extracted with CH2CI2.
  • Step 4 To a 0 °C solution of (S)-ethyl 2-amino-3-(4-((2-(4'-methoxy-[l, l'-biphenyl]-4- yl)ethyl)carbamoyl)phenyl)propanoate (75 mg, 0.16 mmol) in MeOH (6 mL), was added dropwise 5 N NaOH (2 mL) and then the reaction mixture was warmed to RT for 3 h.
  • reaction mixture was acidified with 3N HC1 to adjust the pH to 6-7, the MeOH was removed in vacuo and the resultant solid was filtered, washed with H2O, and dried in vacuo to provide the title compound as a white solid.
  • Step 1 To a solution of (S)-4-(2-((tert-butoxycarbonyl)amino)-3-ethoxy-3- oxopropyl)benzoic acid (Intermediate A, 200 mg, 0.82 mmol) in DMF (10 mL) was added (2- ([l, l'-biphenyl]-4-yl)ethanamine (Intermediate 5, 236 mg, 1.2 mmol), HATU (623 mg, 1.64 mmol) and TEA (166 mg, 1.64 mmol) and the mixture was stirred for 48 h at RT. After this time, the reaction was diluted with water and extracted with ethyl acetate.
  • Step 2 To a 0 °C solution of (S)-ethyl 3-(4-((2-([l,l'-biphenyl]-4-yl)ethyl)carbamoyl) phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (150 mg, 0.29 mmol) in CH2CI2 (6 mL), was added dropwise TFA (1.5 mL). The reaction was warmed to RT for 3 h, then concentrated in vacuo. To the resulting residue was added saturated aqueous solution of NaHC0 to adjust the pH to -7.5 and then extracted with CH2CI2.
  • Step 3 To a 0 °C solution of (S)-ethyl 3-(4-((2-([l,l * -biphenyl]-4-yl)ethyl)carbamoyl) phenyl)-2-aminopropanoate 75 mg, 0.18 mmol) in MeOH (6 mL), was added dropwise NaOH (5N, 2 mL) and the reaction mixture was warmed to RT for 3 h. After this time, the reaction mixture was acidified with HC1 (3N) to adjust the pH to 6-7, then the MeOH was removed in vacuo and the resultant solid was filtered, washed with H2O, and dried in vacuo to provide the title compound as a white solid.
  • Step 1 A solution of (S)-2-amino-3-(4-((3-(2-bromophenyl)propyl) carbamoyl) phenyl)propanoic acid (Example 145, 140 mg, 0.27 mmol), CsOAc (99 mg, 0.51 mmol), Pd(dppf)Cl2 (38 mg, 0.051 mmol) and isoquinolin-7-ylboronic acid (88 mg, 0.51 mmol) in THF (3 mL) was purged with N 2 and then heated to 90 °C for 3 h. After this time, the reaction was cooled to RT and extracted with ethyl acetate.
  • Step 2 To a 0 °C solution of (S)-ethyl 2-((tert-butoxycarbonyl)amino)-3-(4-((3-(2- (isoquinolin-7-yl)phenyl)propyl)carbamoyl)phenyl)propanoate (100 mg, 0.17 mmol) in CH2CI2 (5 mL), was added dropwise TFA (1.2 mL). The reaction was warmed to RT for 3 h, then concentrate in vacuo. To the resulting residue was added saturated aqueous solution of NaHC0 to adjust the pH to -7.5 and then extracted with CH2CI2.
  • Step 3 To a 0 °C solution of (S)-ethyl 2-amino-3-(4-((3-(2-(isoquinolin-7- yl)phenyl)propyl)carbamoyl)phenyl)propanoate (75 mg, 0.16 mmol) in MeOH (6 mL), was added dropwise 5 N NaOH (2 mL) and then the reaction mixture was warmed to RT for 3 h. After this time, the reaction mixture was acidified with 3N HC1 to adjust the pH to 6-7, the MeOH was removed in vacuo and the resultant solid was filtered, washed with H2O, and dried in vacuo to provide the title compound as a white solid.
  • Step 1 To a solution of ethyl 2-(4-bromophenyl)acetate (CAS#: 77143-76-1, 38 g, 0.16 mol) in DMF (380 mL), NaH ( 6.9 g,0.173 mol, 60% in oil ) was added at -20 °CEbver 1 h and then the mixture was stirred at the same temperature for 2 h. After this time, tert-butyl 4- iodopiperidine-l-carboxylate (CAS#: 301673-14-3, 53.5 g,0.17 mol) was added dropwise at -10 °C.
  • Step 2 To a solution of tert-butyl 4-(l-(4-bromophenyl)-2-ethoxy-2-oxoethyl)piperidine-
  • Step 3 To a solution of 2-(4-bromophenyl)-2-(l-(tert-butoxycarbonyl)piperidin-4- yl)acetic acid (10 g, 0.025 mol) in DMF (100 mL) was added (R)-l-phenylethanamine (1.52 g, 0.013 mol) and the mixture was stirred at RT for lh. The solid was filtered, washed with water and dried under vacuum to provide (R)-l-phenylethanamine (R)-2-(4-bromophenyl)-2-(l-(tert- butoxycarbonyl)piperidin-4-yl)acetate.
  • Step 4 To a solution of (R)-2-(4-bromophenyl)-2-(l-(tert-butoxycarbonyl)piperidin-4- yl)acetic acid (4.5 g, 11.2 mmol) in THF (400 mL) was added a solution of (Boc) 2 0 (3.20 g, 14.7 mmol) in THF (50 mL) at OSC over 30 min and then pyridine (581 mg,7.3 mmol) and H4CO3 ( 1.16 g, 14.6 mmol) was added at O°C0 The mixture was warmed to RT and stirred for 12 h, then poured into water and extracted with ethyl acetate.
  • Step 5 To a solution of (R)-tert-butyl 4-(2-amino-l-(4-bromophenyl)-2- oxoethyl)piperidine-l-carboxylate (2 g, 5.1 mmol) in CH2CI2 (20 mL) was added TFA (5 mL) dropwise at 0SC. The mixture was warmed to RT and then stirred for 2h, and then concentrated and dissolved in acetonitrile (2 mL).To the mixture was added sequenatlly K2CO3 ( 2.1 g , 15.1 mmol) and BnBr (0.95 g,5.5 mmol) and the resulting mixture was warmed to RT and stirred for 12 h.
  • Step 6 A solution of (R)-2-(l-benzylpiperidin-4-yl)-2-(4-bromophenyl)acetamide (1.8 g)
  • Step 7 To a solution of (R)-tert-butyl (2-(l-benzylpiperidin-4-yl)-2-(4- bromophenyl)ethyl) carbamate (700 mg, 1.5 mmol) in CH 2 C1 2 , was added TFA (2 mL) and the reaction was stirred for 2 h. After this time the mixture was concentrated in vacuo and the residue was dissolved in DMF cooled to O0C followed by the sequential addition of Intermediate A (500 mg, 1.5 mmol), triethyl amine (751 mg, 7.4 mmol) and HATU (1.13 g, 2.9 mmol).
  • Step 8 To a solution of (S)-ethyl 3-(4-(((R)-2-(l-benzylpiperidin-4-yl)-2-(4- bromophenyl) ethyl)carbamoyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (900 mg, 1.3 mmol) was added phenylboronic acid (317 mg, 2.6 mmol) and Pd(dppf)Cl2 (95 mg, 0.13 mmol) in dioxane (9.0 mL) /aq.NaC0 (2M,3.0 mL) and refluxed for 3 h.
  • Step 9 A solution of (S)-ethyl 3-(4-(((R)-2-([l,r-biphenyl]-4-yl)-2-(l-benzylpiperidin-4- yl)ethyl)carbamoyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (600 mg, 0.87 mmol) in ethanol (6 mL) was heated at 50 °C under 50 psi H 2 for 12 h. After this time, the mixture was filtered, concentrated and purified by flash to provide 300 mg intermediate.
  • Step 10 To a 0 °C solution of tert-butyl 4-((R)-l-([l,r-biphenyl]-4-yl)-2-(4-((S)-2-((tert- butoxycarbonyl)amino)-3-ethoxy-3-oxopropyl)benzamido)ethyl)piperidine-l-carboxylate (170 mg, 0.243 mmol) in CH 2 C1 2 (4 mL), TFA(1 mL) was added dropwise at 0 °C for 1 h and then the mixture was concentrated, and the pH adjusted to -6-7 with saturated aqueous NaHC0 .
  • Step 11 The title compound was prepared as described for (S)-3-(4-(((R)-2-([l, l'- biphenyl]-4-yl)-3-methylbutyl) carbamoyl)phenyl)-2-aminopropanoic acid (Example la, Step 4) via the hydrolysis of (S)-ethyl 3-(4-(((R)-2-([l, l'-biphenyl]-4-yl)-2-(piperidin-4- yl)ethyl)carbamoyl)phenyl)-2-aminopropanoate.
  • Step 1 To a 0 °C solution of ethyl 2-bromo-2-(4-bromophenyl)acetate (16.5 g, 93.8 mmol) and TEA (12.3 g, 121.9 mmol ) in THF (300 mL), was added 1-benzylpiperazine (30 g, 93.2 mmol). After addition, the mixture was warmed to room temperature and stirred for 12 h, after which time, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate and washed with aq. NaHC0 , and brine.
  • Step 2 A solution of ethyl 2-(4-benzylpiperazin-l-yl)-2-(4-bromophenyl)acetate (22 g, 52.8 mmol), phenylboronic acid (7.66 g, 63.3 mmol) and Pd (dppf)Cl 2 (3.86 g, 5.28 mmol) in dioxane (100 mL)/aq. NaC0 3 (2.0M, 100 mL) was heated at 80 °C for 12 h, then cooled to room temperature. After this time, the mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na 2 S04 and concentrated.
  • Step 4 To a solution of 2-([l,l'-biphenyl]-4-yl)-2-(4-benzylpiperazin-l-yl)acetic acid (1 g, 2.6 mmol) in CH 2 C1 2 (10 mL) was added (COCl) 2 (0.66 g, 5.2 mmol) dropwise at 0 °C. After the addition, the mixture was stirred at room temperature for 2 h after which time the solvent was removed in vacuo to provide 2-([l,l'-biphenyl]-4-yl)-2-(4-benzylpiperazin-l-yl)acetyl chloride as a yellow oil used without further purification.
  • Step 5 A solution of 2-([ 1 , 1 '-biphenyl]-4-yl)-2-(4-benzylpiperazin- 1 -yl)acetyl chloride (1 g, 2.5 mmol) in CH 2 C1 2 (10 mL) was added to 30% aqueous H 4 OH (10 mL). The mixture was stirred for 30 min and extracted with CH 2 C1 2 . The combined organic layers were washed with brine, dried over Na 2 SC"4 and concentrated to provide 2-([l, l'-biphenyl]-4-yl)-2-(4- benzylpiperazin-l-yl)acetamide as yellow oil used without further purification.
  • Step 7 To a solution of 2-([l,l'-biphenyl]-4-yl)-2-(4-benzylpiperazin-l-yl) (400 mg, 1.1 mmol), TEA (222 mg, 2.2 mmol) and Intermediate A (371 mg, 1.1 mmol) in DMF (10 mL) was added HATU (630 mg, 1.6 mmol) at 5 °C. The mixture was stirred at room temperature for 12 h, then diluted with water and extracted with ethyl acetate.
  • Step 8 A mixture of (2S)-ethyl 3-(4-((2-([l,l * -biphenyl]-4-yl)-2-(4-benzylpiperazin-l- yl)ethyl)carbamoyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (450 mg, 0.65 mmol) and 10% Pd(OH) 2 on activated carbon (20 mg ) in MeOH (lOmL) was stirred at room temperature under a hydrogen atmosphere (50 psi) for 12 h.
  • reaction mixture was filtered through a Celite pad, the filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica-gel to provide (2S)-ethyl 3-(4-((2-([l, l'-biphenyl]- 4-yl)-2-(piperazin-l-yl)ethyl)carbamoyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate as yellow oil.
  • Step 9 The title compound was made as described for the compound of Example la, Steps 3-4, starting with (2S)-ethyl 3-(4-((2-([l,l'-biphenyl]-4-yl)-2-(piperazin-l- yl)ethyl)carbamoyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate.

Abstract

The present invention is directed to amide compounds which are inhibitors of tryptophan hydroxylase (TPH), particularly isoform 1 (TPH1), that are useful in the treatment or prevention of diseases or disorders associated with peripheral serotonin including, for example, gastrointestinal, cardiovascular, pulmonary, inflammatory, metabolic, fibrotic, and low bone mass diseases, as well as cancer.

Description

AMIDE COMPOUNDS AS TRYPTOPHAN HYDROXYLASE INHIBITORS
CROSS-REFERENCE TO RELATED APPLICATIONS
The present application claims priority to U.S. Provisional Application Serial Nos.
62/097,701, filed on December 30, 2014 and 62/190,481, filed on July 9, 2015, the contents of which are hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
The present invention is directed to amide compounds which are inhibitors of tryptophan hydroxylase (TPH), particularly isoform 1 (TPHl), that are useful in the treatment or prevention of diseases or disorders associated with peripheral serotonin including, for example,
gastrointestinal, cardiovascular, pulmonary, inflammatory, metabolic, fibrotic, and low bone mass diseases, as well as cancer.
BACKGROUND OF THE INVENTION
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. In the central nervous system (CNS), 5-HT regulates mood, appetite, and other behavioral functions. In the GI system, 5-HT plays a general prokinetic role and is an important mediator of sensation (e.g., nausea and satiety) between the GI tract and the brain.
Dysregulation of the peripheral 5-HT signaling system has been reported to be involved in the etiology of several conditions (see for example: Mawe, G. M. & Hoffman, J. M. Serotonin Signalling In The Gut-functions, Dysfunctions And Therapeutic Targets. Nature Reviews.
Gastroenterology & Hepatology 10, 473-486 (2013); Gershon, M. D. 5-hydroxytryptamine (serotonin) In The Gastrointestinal Tract. Current Opinion in Endocrinology, Diabetes, and Obesity 20, 14-21 (2013); Lesurtel, M., Soil, C, Graf, R. & Clavien, P.-A. Role of Serotonin In The Hepato-gastrointestinal Tract: An Old Molecule For New Perspectives. Cellular And Molecular Life Sciences : CMLS 65, 940-52 (2008)). These include osteoporosis (e.g. Kode, A. et al. FOXOl Orchestrates The Bone-suppressing Function Of Gut-derived Serotonin. The Journal of Clinical Investigation 122, 3490-503 (2012); Yadav, V. K. et al. Pharmacological Inhibition Of Gut-derived Serotonin Synthesis Is A Potential Bone Anabolic Treatment For Osteoporosis. Nature Medicine 16, 308-12 (2010); Yadav, V. K. et al. Lrp5 Controls Bone Formation By Inhibiting Serotonin Synthesis In The Duodenum. Cell 135, 825-37 (2008)), cancer (e.g. Liang, C. et al. Serotonin Promotes The Proliferation Of Serum-deprived
Hepatocellular Carcinoma Cells Via Upregulation Of FOX03a. Molecular Cancer 12, 14 (2013); Soil, C. et al. Serotonin Promotes Tumor Growth In Human Hepatocellular Cancer. Hepatology 51, 1244-1254 (2010); Pai, V. P et al. Altered Serotonin Physiology In Human Breast Cancers Favors Paradoxical Growth And Cell Survival. Breast Cancer Research : BCR 11, R81 (2009); Engelman, K., Lovenberg, W. & Sjoerdsma, A. Inhibition Of Serotonin
Synthesis By Para-chlorophenylalanine In Patients With The Carcinoid Syndrome. The New England Journal of Medicine 277, 1103-8 (1967)), cardiovascular (e.g. Robiolio, P. A. et al. Carcinoid Heart Disease : Correlation of High Serotonin Levels With Valvular Abnormalities Detected by Cardiac Catheterization and Echocardiography. Circulation 92, 790-795 (1995).), diabetes (e.g. Sumara, G, Sumara, O., Kim, J. K. & Karsenty, G. Gut-derived Serotonin Is A Multifunctional Determinant To Fasting Adaptation. Cell Metabolism 16, 588-600 (2012)), atherosclerosis (e.g. Ban, Y. et al. Impact Of Increased Plasma Serotonin Levels And Carotid Atherosclerosis On Vascular Dementia. Atherosclerosis 195, 153-9 (2007)), as well as gastrointestinal (e.g. Manocha, M. & Khan, W. I. Serotonin and GI Disorders: An Update on Clinical and Experimental Studies. Clinical and Translational Gastroenterology 3, el3 (2012); Ghia, J.-E. et al. Serotonin Has A Key Role In Pathogenesis Of Experimental Colitis.
Gastroenterology 137, 1649-60 (2009); Sikander, A., Rana, S. V. & Prasad, K. K. Role Of Serotonin In Gastrointestinal Motility And Irritable Bowel Syndrome. Clinica Chimica Acta; International Journal of Clinical Chemistry 403, 47-55 (2009); Spiller, R. Recent Advances In Understanding The Role Of Serotonin In Gastrointestinal Motility In Functional Bowel Disorders: Alterations In 5-HT Signalling And Metabolism In Human Disease.
Neurogastroenterology and Motility: The Official Journal of The European Gastrointestinal Motility Society 19 Suppl 2, 25-31 (2007); Costedio, M. M., Hyman, N. & Mawe, G. M. Serotonin And Its Role In Colonic Function And In Gastrointestinal Disorders. Diseases of the Colon and Rectum 50, 376-88 (2007); Gershon, M. D. & Tack, J. The Serotonin Signaling System: From Basic Understanding To Drug Development For Functional GI Disorders. Gastroenterology 132, 397-414 (2007); Mawe, G. M., Coates, M. D. & Moses, P. L. Review Article: Intestinal Serotonin Signalling In Irritable Bowel Syndrome. Alimentary Pharmacology & Therapeutics 23, 1067-76 (2006); Crowell, M. D. Role Of Serotonin In The Pathophysiology Of The Irritable Bowel Syndrome. British Journal of Pharmacology 141, 1285-93 (2004)), pulmonary (e.g. Lau, W. K. W. et al. The Role Of Circulating Serotonin In The Development Of Chronic Obstructive Pulmonary Disease. PloS One 7, e31617 (2012); Egermayer, P., Town, G. I. & Peacock, A. J. Role Of Serotonin In The Pathogenesis Of Acute And Chronic Pulmonary Hypertension. Thorax 54, 161-168 (1999)), 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)), 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)), idiopathic pulmonary fibrosis (IPF) (e.g. Eickelberg, O. et al. Increased expression of 5- hydroxytryptamine2A/B receptors in idiopathic pulmonary fibrosis: a rationale for therapeutic intervention 65, 949-955 (2010); Dygai, A.M. Effects of antiserotonin drug on the development of lung fibrosis and blood system reactions after intratracheal administration of bleomycin 4, 519-523 (2012); Distler, J. H. W. Platelet-derived serotonin links vascular disease and tissue fibrosis 208, 961-972 (2011)), or Raynaud's syndrome (e.g. Black, CM. Treatment of Raynaud's phenomenon with the selective serotonin reuptake inhibitor fluoxetine 40, 1038-1043 (2001), Herrick, A. L. The pathogenesis, diagnosis and treatment of Raynaud phenomenon 8, 469-479)). The large number of pharmaceutical agents that block or stimulate the various 5-HT receptors is also indicative of the wide range of medical disorders that have been associated with 5-HT dysregulation (see for example: Wacker, D. et al. Structural Features For Functional Selectivity At Serotonin Receptors. Science (New York, N Y.) 340, 615-9 (2013)).
The rate-limiting step in 5-HT biosynthesis is the hydroxylation of tryptophan by dioxygen, which is catalyzed by tryptophan hydroxylase (TPH; EC 1.14.16.4) in the presence of the cofactor (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4). The resulting oxidized product, 5-hydroxytryptophan (5-HTT) is subsequently decarboxylated by an aromatic amino acid decarboxylase (AAAD; EC 4.1.1.28) to produce 5-HT. Together with phenylalanine hydroxylase (PheOH) and tyrosine hydroxylase (TH), TPH belongs to the pterin-dependent aromatic amino acid hydroxylase family.
Two vertebrate isoforms of TPH, namely TPH1 and TPH2, have been identified. TPH1 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 TPH1 in the gut.
A small number of phenylalanine-derived TPH1 inhibitors are known. One example, p- chlorophenylalanine (pCPA), a very weak and unselective irreversible inhibitor of TPH, has proven effective in treating chemotherapy-induced emesis, as well as diarrhea, in carcinoid tumor patients. However, pCPA is distibuted centrally and, as a result, its administration has been linked to the onset of depression and other alterations of CNS functions in patients and animals. p-Ethynyl phenylalanine is a more selective and more potent TPH inhibitor than pCPA (Stokes, A. H. et al. p-Ethynylphenylalanine: A Potent Inhibitor Of Tryptophan Hydroxylase. Journal of Neurochemistry 74, 2067-73 (2000), but also affects central 5-HT production and, like pCPA, is believed to irreversibly interfere with the synthesis of TPH (and possibly other proteins). For additional information related to pCPA, see Weber, L.J. "p-Chlorophenylalanine depletion of gastrointestinal 5-hydroxytryptamine," Biochem PharmacoJ 19, 2169-2172 (1970) and (Alpini, G. et al. "Serotonin metabolism is dysregulated in cholangiocarcinoma, which has implications for tumor growth," Cancer Res. 68, 9184-9193 (2008).
More recently, bulkier phenylalanine-derived TPH inhibitors have been reported to reduce intestinal 5-HT concentration without affecting brain 5-HT levels (Zhong, H. et al.
Molecular dynamics simulation of tryptophan hydroxylase- 1 : binding modes and free energy analysis to phenylalanine derivative inhibitors. International Journal of Molecular Sciences 14, 9947-62 (2013); Ouyang, L. et al. Combined Structure-Based Pharmacophore and 3D-QSAR Studies on Phenylalanine Series Compounds as TPH1 Inhibitors. International Journal of Molecular Sciences 13, 5348-63 (2012); Camilleri, M. LX-1031, A Tryptophan 5-hydroxylase Inhibitor, And Its Potential In Chronic Diarrhea Associated With Increased Serotonin. Neurogastroenterology and Motility: The Official Journal of The European Gastrointestinal Motility Society 23, 193-200 (2011); Cianchetta, G. et al. Mechanism of Inhibition of Novel Tryptophan Hydroxylase Inhibitors Revealed by Co-crystal Structures and Kinetic Analysis. Current chemical genomics 4, 19-26 (2010); Jin, H. et al. Substituted 3-(4-(l,3,5-triazin-2-yl)- phenyl)-2-aminopropanoic Acids As Novel Tryptophan Hydroxylase Inhibitors. Bioorganic & Medicinal Chemistry Letters 19, 5229-32 (2009); Shi, Z.-C. et al. Modulation Of Peripheral Serotonin Levels By Novel Tryptophan Hydroxylase Inhibitors For The Potential Treatment Of Functional Gastrointestinal Disorders. Journal of medicinal chemistry 51, 3684-7 (2008); Liu, Q. et al. Discovery And Characterization of Novel Tryptophan Hydroxylase Inhibitors That Selectively Inhibit Serotonin Synthesis In The Gastrointestinal Tract. The Journal of
Pharmacology and Experimental Therapeutics 325, 47-55 (2008)).
There is a current need to selectively reduce intestinal 5-HT levels as a means for treating and preventing 5-HT-associated diseases. The TPHl inhibitors described herein are intended to address this need.
SUMMARY OF THE INVENTION
The present invention relates to a TPH-inhibiting compound of Formula I:
Figure imgf000006_0001
I
or a pharmaceutically acceptable salt thereof, wherein constituent variables are defined herein.
The present invention further relates to a pharmaceutical composition comprising a TPH- inhibiting compound of the invention, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. The present invention further relates to a method of inhibiting TPH, such as TPH1, by contacting the TPH enzyme with a compound of Formula I, or a pharmaceutically acceptable salt thereof.
The present invention further relates to a method of lowering peripheral serotonin in a patient comprising administering to the patient an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
The present invention further relates to a method of treating or preventing a disease in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
The present invention further relates to a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of disease in a patient.
The present invention further relates to use of a compound of Formula I, or a
pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of disease in a patient.
DETAILED DESCRIPTION
Compounds
The present invention relates to a TPH-inhibiting compound of Formula I:
Figure imgf000007_0001
I
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is C3-14 cycloalkyl, C6-io aryl, 4 to 14-membered heterocycloalkyl, or 5 to 10- membered heteroaryl; Z is a bridging C3-14 cycloalkyl group, a bridging C6-io aryl group, a bridging 4 to 14- membered heterocycloalkyl group, or a bridging 5 to 10-membered heteroaryl group, each optionally substituted by 1, 2, or 3 substituents independently selected from Rz;
or Z is:
Figure imgf000008_0001
R1 is H, Ci-io alkyl, C3-10 cycloalkyl, phenyl, -(CR9R10)pOC(O)Ru, -(C R9R10)P RUR12, or -(C R9R10)pC(O) RuR12, 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, Ci-4 alkyl, and C1-4 haloalkyl;
R2 is H, Ci-4 alkyl, C(0)Rbl, C(0)NRclRdl, or C(0)ORal;
R3 and R4 are each independently selected from H, C1-4 alkyl, C1-4 haloalkyl, OH, and C1-4 alkoxy;
each R5 is independently selected from halo, C1-4 alkyl, and C1-4 alkoxy;
R6 is H or Ci-4 alkyl;
or R6 and Z, together with the N atom to which they are both attached, form a 4-7 membered heterocycloalkyl group optionally substituted by 1, 2, or 3 substituents independently selected from Rz;
each R7 is independently selected from H, halo, and C1-4 alkyl;
each R8 is independently selected from H, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C6-io aryl, C3 -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, 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;
wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 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 R8a, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 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; or R and R , when taken together with the single carbon atom to which they are both attached, form a C3-7 cycloalkyl group optionally substituted by 1, 2, or 3 substituents independently selected from halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, CN, NO2, ORa2, SRa2, C(0)Rb2, C(0) Rc2Rd2, C(0)ORa2, OC(0)Rb2, OC(0) Rc2Rd2, NRc2Rd2,
Rc2C(0)Rb2, NRc2C(0)ORa2, Rc2C(0) Rc2Rd2, Rc2S(0)Rb2, NRc2S(0)2Rb2,
Rc2S(0)2 Rc2Rd2, S(0)Rb2, S(0) Rc2Rd2, S(0)2Rb2, and S(0)2 Rc2Rd2;
each R8a is independently selected from C5-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C5-10 aryl-Ci-6 alkyl, C3-10 cycloalkyl-Ci-6 alkyl, 5- 10 membered hetero aryl- C 1-6 alkyl, and 4-10 membered heterocycloalkyl-Ci-6 alkyl, each of which is optionally substituted by 1 or 2 substituents independently selected from halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, CN, N02, ORa2, SR32, 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;
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, ORa3, and NRc Rd3;
R11 and R12 are each independently selected from H and Ci-6 alkyl;
RA is H, Cy1, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, CN, N02, ORa4, SRa4, C(0)RM, C(0)NRc4Rd4, C(0)ORa4, OC(0)Rb4, OC(0)NRc4Rd4, NRc4Rd4, NRc4C(0)Rb4, NRc4C(0)ORa4, NRc4C(0)NRc4Rd4, NRc4S(0)RM, NRc4S(0)2RM, NRc4S(0)2NRc4Rd4, S(0)RM, S(0)NRc4Rd4, S(0)2Rb4, or S(0)2NRc4Rd4, wherein said Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, 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, ORa4, SRa4, C(0)Rb4, C(0)NRc4Rd4, C(0)ORa4, OC(0)RM, OC(0)NRc4Rd4, NRc4Rd4, NRc4C(0)Rb4, NRc4C(0)ORa4, NRc4C(0)NRc4Rd4, NRc4S(0)RM, NRc4S(0)2RM, NRc4S(0)2NRc4Rd4, S(0)RM, S(0)NRc4Rd4, S(0)2RM, and
S(0)2NRc4Rd4;
RB is H, Cy2, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 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, or S(0)2NRc5Rd5, wherein said Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl 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, 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;
Rc and RD are each independently selected from H, halo, Ci-6 alkyl, C2-6 alkenyl, C2 -6 alkynyl, Ci-6 haloalkyl, CN, N02, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)ORa6, NRc6C(0)NRc6Rd6, NRc6S(0)Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, and S(0)2NRc6Rd6;
wherein said Ci-6 alkyl, C2 -6 alkenyl, and C2 -6 alkynyl 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, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)ORa6, NRc6C(0)NRc6Rd6, NRc6S(0)Rb6, NRc6S(0)2Rb6,
NRc6S(0)2NRc6Rd6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, and S(0)2NRc6Rd6;
each Rz is halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 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, wherein said Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with a substituent selected from halo, 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;
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 is independently selected from halo, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C5-10 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)-C 1 -4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, CN, N02, ORa7, SRa7, C(0)Rb7, C(0)NRc7Rd7, C(0)ORa7,
OC(0)Rb7, OC(0)NRc7Rd7, NRc7Rd7, NRc7C(0)Rb7, NRc7C(0)ORa7, NRc7C(0)NRc7Rd7, Rc7S(0)Rb7, NRc7S(0)2Rb7, NRc7S(0)2NRc7Rd7, S(0)Rb7, S(0)NRc7Rd7, S(0)2Rb7, and
S(0)2 Rc7Rd7, 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, C3-10 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 halo, Ci-6 alkyl, CN, N02, ORa7, SRa7, C(0)Rb7, C(0) Rc7Rd7, C(0)ORa7, OC(0)Rb7, OC(0) Rc7Rd7, Rc7Rd7, Rc7C(0)Rb7, Rc7C(0)ORa7, Rc7C(0) Rc7Rd7, Rc7S(0)Rb7, Rc7S(0)2Rb7, Rc7S(0)2 Rc7Rd7, S(0)Rb7, S(0) Rc7Rd7, S(0)2Rb7, and S(0)2 Rc7Rd7;
each Ral, Rbl, Rcl, and Rdl is independently selected from H, Ci-6 alkyl, CM haloalkyl, C6- 10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl;
or 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 halo, Ci-6 alkyl, and Ci-6 haloalkyl;
each Ra2, Ra3, Ra4, Ra5, Ra6, Ra7, Rb2, Rb4, Rb5, Rb6, Rb7, Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rd2, Rd3, Rd4, Rd5, Rd6, and Rd7 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-Ci-4 alkyl, C3-10 cycloalkyl-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, and (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, C3-10 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 CM alkyl, halo, CN, ORa8, C(0)Rb8, C(0)NRc8Rd8, C(0)ORa8, OC(0)Rb8, OC(0)NRc8Rd8, NRc8Rd8, NRc8C(0)Rb8, NRc8C(0)NRc8Rd8,
NRc8C(0)ORa8, S(0)Rb8, S(0)NRc8Rd8, S(0)2Rb8, NRc8S(0)2Rb8, NRc8S(0)2NRc8Rd8, and S(0)2NRc8Rd8;
each Ra8, Rb8, Rc8, and Rd8 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 CM 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, CM alkyl, Ci-4 alkoxy, C 1-4 alky lthio, CM alkylamino, and di(Ci-4 alkyl) amino; n is 0, 1, 2, 3, or
m is 1, 2, 3, or 4;
p is 1, 2, 3, or 4;
wherein:
(1) when Z is:
Figure imgf000012_0001
R2 is C(0)ORal, Ral is Ci-6 alkyl, m is 2, n is 0, R3 is H, R4 is H, R6 is H, R7 is H, Rs is H, RA is H, RB is H, Rc is H, and RD is H; then ring A is other than indolyl and naphthyl;
(2) when Z is:
Figure imgf000012_0002
R2 is C(0)ORal, Ral is Ci-6 alkyl, m is 2, n is 0, R3 is H, R4 is H, R6 is H, R7 is H, R8 is H, RA is cyclohexyl or phenyl, RB is H, Rc is H, and RD is H; then ring A is other than phenyl;
(3) when Z is unsubstituted bridging furanyl, R2 is H, n is 0, R3 is H, R4 is H, R6 is H, and one of RA, RB, Rc, and RD is methoxy; then ring A is other than phenyl; and
(4) when Z is bridging phenyl substituted by amino, R2 is H, n is 0, R3 is H, R4 is H, and R6 is H; then ring A is other than thienyl.
In some embodiments, the present invention relates to a TPH-inhibiting compound of
Formula I: R4 R3 O
O
I
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is C3-14 cycloalkyl, C6-io aryl, 4 to 14-membered heterocycloalkyl, or 5 to 10- membered heteroaryl;
Z is a bridging C3 -14 cycloalkyl group, a bridging C6-io aryl group, a bridging 4 to 14- membered heterocycloalkyl group, or a bridging 5 to 10-membered heteroaryl group, each optionally substituted by 1, 2, or 3 substituents independently selected from Rz;
or Z is:
Figure imgf000013_0001
R1 is H, Ci-io alkyl, C3-10 cycloalkyl, phenyl, -(CR9R10)pOC(O)Ru, -(C R9R10)P RUR12, or -(C R9R10)pC(O) RuR12, 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, Ci-4 alkyl, and C1-4 haloalkyl;
R2 is H, Ci-4 alkyl, C(0)Rbl, C(0)NRclRdl, or C(0)ORal;
R3 and R4 are each independently selected from H, C1-4 alkyl, C1-4 haloalkyl, OH, and C1-4 alkoxy;
each R5 is independently selected from halo, C1-4 alkyl, and C1-4 alkoxy;
R6 is H or Ci-4 alkyl;
or R6 and Z, together with the N atom to which they are both attached, form a 4-7 membered heterocycloalkyl group optionally substituted by 1, 2, or 3 substituents independently selected from Rz;
each R7 is independently selected from H, halo, and C1-4 alkyl; each R is independently selected from H, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C6-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, CN, N02, ORa2, SRa2, C(0)Rb2, C(0) Rc2Rd2, C(0)ORa2, OC(0)Rb2,
OC(0) Rc2Rd2, NRc2Rd2, NRc2C(0)Rb2, NRc2C(0)ORa2, NRc2C(0) Rc2Rd2, NRc2S(0)Rb2, Rc2S(0)2Rb2, Rc2S(0)2 Rc2Rd2, S(0)Rb2, S(0) Rc2Rd2, S(0)2Rb2, and S(0)2 Rc2Rd2;
wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 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, C2-6 alkenyl, C2-6 alkynyl, 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;
or R7 and R8, when taken together with the single carbon atom to which they are both attached, form a C3-7 cycloalkyl group optionally substituted by 1, 2, or 3 substituents independently selected from halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 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;
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, ORa3, and NRc Rd3;
R11 and R12 are each independently selected from H and Ci-6 alkyl;
RA is H, Cy1, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, CN, N02, ORa4, SRa4, C(0)RM, C(0)NRc4Rd4, C(0)ORa4, OC(0)RM, OC(0)NRc4Rd4, NRc4Rd4, NRc4C(0)RM, NRc4C(0)ORa4, NRc4C(0)NRc4Rd4, NRc4S(0)RM, NRc4S(0)2RM, NRc4S(0)2NRc4Rd4, S(0)RM, S(0)NRc4Rd4, S(0)2RM, or S(0)2NRc4Rd4, wherein said Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, 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, ORa4, SRa4, C(0)Rb4, C(0)NRc4Rd4, C(0)ORa4, OC(0)RM, OC(0)NRc4Rd4, NRc4Rd4, NRc4C(0)Rb4, NRc4C(0)ORa4, NRc4C(0)NRc4Rd4, NRc4S(0)RM, NRc4S(0)2RM, NRc4S(0)2NRc4Rd4, S(0)RM, S(0)NRc4Rd4, S(0)2RM, and
S(0)2NRc4Rd4; RB is H, Cy2, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 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, or S(0)2NRc5Rd5, wherein said Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl 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, 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;
Rc and RD are each independently selected from H, halo, Ci-6 alkyl, C2-6 alkenyl, C2 -6 alkynyl, Ci-6 haloalkyl, CN, N02, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)ORa6, NRc6C(0)NRc6Rd6, NRc6S(0)Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, and S(0)2NRc6Rd6;
wherein said Ci-6 alkyl, C2 -6 alkenyl, and C2 -6 alkynyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C6-io aryl, C3 -10 cycloalkyl, 5-10 membered heteroaiyl, 4-10 membered heterocycloalkyl, halo, Ci-6 alkyl, C2 -6 alkenyl, Ci-6 haloalkyl, CN, N02, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)ORa6, NRc6C(0)NRc6Rd6, NRc6S(0)Rb6, NRc6S(0)2Rb6,
NRc6S(0)2NRc6Rd6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, and S(0)2NRc6Rd6;
each Rz is halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 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, wherein said Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with a substituent selected from halo, 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;
Cy1 and Cy2 are each independently selected from C6-io aryl, C3 -10 cycloalkyl, 5-10 membered heteroaiyl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy; each is independently selected from halo, Ci-6 alkyl, Ci-6 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)-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, CN, N02, ORa7, SRa7, C(0)Rb7, C(0)NRc7Rd7, C(0)ORa7,
OC(0)Rb7, OC(0) Rc7Rd7, NRc7Rd7, NRc7C(0)Rb7, NRc7C(0)ORa7, Rc7C(0) Rc7Rd7,
Rc7S(0)Rb7, NRc7S(0)2Rb7, NRc7S(0)2 Rc7Rd7, S(0)Rb7, S(0) Rc7Rd7, S(0)2Rb7, and
S(0)2 Rc7Rd7, 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, C3-10 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 halo, Ci-6 alkyl, CN, N02, ORa7, SRa7, C(0)Rb7, C(0)NRc7Rd7, C(0)ORa7, OC(0)Rb7, OC(0)NRc7Rd7, NRc7Rd7, NRc7C(0)Rb7, NRc7C(0)ORa7, NRc7C(0)NRc7Rd7, NRc7S(0)Rb7, NRc7S(0)2Rb7, NRc7S(0)2NRc7Rd7, S(0)Rb7, S(0)NRc7Rd7, S(0)2Rb7, and S(0)2NRc7Rd7;
each Ral, Rbl, Rcl, and Rdl is independently selected from H, Ci-6 alkyl, CM haloalkyl, C6- 10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl;
or 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 halo, Ci-6 alkyl, and Ci-6 haloalkyl;
each Ra2, Ra3, Ra4, Ra5, Ra6, Ra7, Rb2, Rb4, Rb5, Rb6, Rb7, Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rd2, Rd3, Rd4, Rd5, Rd6, and Rd7 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-Ci-4 alkyl, C3-10 cycloalkyl-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, and (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, C3-10 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 CM alkyl, halo, CN, ORa8, C(0)Rb8, C(0)NRc8Rd8, C(0)ORa8, OC(0)Rb8, OC(0)NRc8Rd8, NRc8Rd8, NRc8C(0)Rb8, NRc8C(0)NRc8Rd8,
NRc8C(0)ORa8, S(0)Rb8, S(0)NRc8Rd8, S(0)2Rb8, NRc8S(0)2Rb8, NRc8S(0)2NRc8Rd8, and S(0)2NRc8Rd8; each RA8, RB8, RC8, and RD8 is independently selected from H, C 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, C 1-4 alkyl, Ci-4 alkoxy, C 1-4 alky lthio, C 1-4 alky lamino, and di(Ci-4 alkyl) amino;
n is 0, 1, 2, 3, or 4;
m is 1, 2, 3, or 4; and
p is 1, 2, 3, or 4;
wherein:
(1) when Z is:
Figure imgf000017_0001
R2 is C(0)ORal, Ral is Ci-6 alkyl, m is 2, n is 0, R3 is H, R4 is H, R6 is H, R7 is H, Rs is H, RA is H, RB is H, Rc is H, and RD is H; then ring A is other than indolyl and naphthyl;
(2) when Z is:
Figure imgf000017_0002
R2 is C(0)ORal, Ral is Ci-6 alkyl, m is 2, n is 0, R3 is H, R4 is H, R6 is H, R7 is H, R8 is H, RA is cyclohexyl or phenyl, RB is H, Rc is H, and RD is H; then ring A is other than phenyl;
(3) when Z is unsubstituted bridging furanyl, R2 is H, n is 0, R3 is H, R4 is H, R6 is H, and one of RA, RB, Rc, and RD is methoxy; then ring A is other than phenyl; and
(4) when Z is bridging phenyl substituted by amino, R2 is H, n is 0, R3 is H, R4 is H, and R6 is H; then ring A is other than thienyl.
In some embodiments, Ring A is C6-io aryl or 5 to 10-membered heteroaryl.
In some embodiments, Ring A is phenyl, naphthyl, pyridyl, indazolyl, or imidazolyl. In some embodiments, Ring A is phenyl.
In some embodiments, Z is a bridging C3-14 cycloalkyl group, a bridging C6-io aryl group, a bridging 4 to 14-membered heterocycloalkyl group, or a bridging 5 to 10-membered heteroaryl group, each optionally substituted by 1, 2, or 3 substituents independently selected from Rz.
In some embodiments, Z is a bridging C3-7 cycloalkyl group.
In some embodiments, Z is a bridging cyclobutyl group or bridging cyclohexyl group. In some embodiments, Z is:
Figure imgf000018_0001
In some embodiments, R6 and Z, together with the N atom to which they are both attached, form a 4-7 membered heterocycloalkyl group optionally substituted by 1, 2, or 3 substituents independently selected from Rz.
In some embodiments, R1 is H, Ci-10 alkyl, or C3-10 cycloalkyl.
In some embodiments, R1 is H or Ci-10 alkyl.
In some embodiments, R1 is H or C1-4 alkyl.
In some embodiments, R1 is H or ethyl.
In some embodiments, R1 is H.
In some embodiments, R1 is ethyl.
In some embodiments, R1 is Ci-10 alkyl or C3-10 cycloalkyl.
In some embodiments, R1 is ethyl, propyl, butyl, pentyl, or cyclopentyl.
In some embodiments, R2 is H, C alkyl, C(0)Rbl, or C(0) RclRdl.
In some embodiments, R2 is H.
In some embodiments, R3 and R4 are each independently selected from H and C1-4 In some embodiments, R3 and R4 are both H.
In some embodiments, R6 is H or methyl.
In some embodiments, R6 is H.
In some embodiments, each R7 is independently selected from H and C1-4 alkyl.
In some embodiments, each R7 is independently selected from H and methyl.
In some embodiments, R7 is H. In some embodiments, each R is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C6-io aryl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, and ORa2; wherein said Ci-6 alkyl, C6-io aryl, C3 -10 cycloalkyl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R8a, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, CN, N02, ORa2, SRa2, C(0)Rb2, C(0) Rc2Rd2, C(0)ORa2, OC(0)Rb2, OC(0) Rc2Rd2, NRc2Rd2, NRc2C(0)Rb2, NRc2C(0)ORa2, Rc2C(0) Rc2Rd2,
Rc2S(0)Rb2, Rc2S(0)2Rb2, Rc2S(0)2 Rc2Rd2, S(0)Rb2, S(0) Rc2Rd2, S(0)2Rb2, and
S(0)2 Rc2Rd2.
In some embodiments, each R8 is independently selected from H, Ci-6 alkyl, C3-10 cycloalkyl, and 4-10 membered heterocycloalkyl; wherein said Ci-6 alkyl, C3-10 cycloalkyl, and 4- 10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R8a, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, CN, N02, ORa2, SR32, 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.
In some embodiments, each R8 is independently selected from H, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C6-io aryl, C3 -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, N02, ORa2, SR32, 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; wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 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, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, CN, N02, OR32, 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.
In some embodiments, each R8 is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C6-io aryl, C3 -10 cycloalkyl, 4-10 membered heterocycloalkyl, and ORa2, wherein said Ci-6 alkyl, C6-io aryl, C3 -10 cycloalkyl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 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, Rc2S(0)Rb2, NRc2S(0)2Rb2, NRc2S(0)2 Rc2Rd2, S(0)Rb2, S(0) Rc2Rd2, S(0)2Rb2, and
S(0)2 Rc2Rd2.
In some embodiments, each R8 is independently selected from H, Ci-6 alkyl, or C3-10 cycloalkyl, wherein said Ci-6 alkyl and C3-10 cycloalkyl, are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, CN, N02, ORa2, SRa2, C(0)Rb2, C(0) Rc2Rd2, C(0)ORa2, OC(0)Rb2, OC(0) Rc2Rd2, Rc2Rd2, Rc2C(0)Rb2, Rc2C(0)ORa2, Rc2C(0) Rc2Rd2, Rc2S(0)Rb2, Rc2S(0)2Rb2, Rc2S(0)2 Rc2Rd2, S(0)Rb2, S(0) Rc2Rd2, S(0)2Rb2, and S(0)2 Rc2Rd2.
In some embodiments, each R8 is independently selected from H, Ci-6 alkyl, or C3-7 cycloalkyl, wherein said Ci-6 alkyl is optionally substituted by hydroxyl and said C3-7 cycloalkyl is optionally substituted by 1 or 2 methyl groups.
In some embodiments, each R8 is independently selected from H and 4-7 membered heterocycloalkyl optionally substituted with 1 or 2 substituents independently selected Ci-6 alkyl and benzyl.
In some embodiments, each R8 is independently selected from H, piperidinyl, and piperazinyl, each optionally substituted with 1 or 2 substituents independently selected Ci-6 alkyl and benzyl.
In some embodiments, each R8 is independently selected from H and Ci-6 alkyl.
In some embodiments, each R8 is independently selected from H and C3-7 cycloalkyl.
In some embodiments, each R8 is independently selected from H and 2-propyl.
In some embodiments, R7 and R8, when taken together with the single carbon atom to which they are both attached, form a C3-7 cycloalkyl group optionally substituted by 1, 2, or 3 substituents independently selected from halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 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.
In some embodiments, R7 and R8, when taken together with the single carbon atom to which they are both attached, form a C3-7 cycloalkyl group.
In some embodiments, R7 and R8, when taken together with the single carbon atom to which they are both attached, form a cyclopropyl group or a cyclobutyl group. In some embodiments, n is 0 or 1.
In some embodiments, n is 0.
In some embodiments, m is 1.
In some embodiments, m is 2.
In some embodiments, m is 3.
In some embodiments, m is 4.
In some embodiments, RA is H, Cy1, halo, C2-6 alkynyl, or ORa4, wherein said C2-6 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy1, halo, Ci-6 alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, N02, ORa4, SRa4, C(0)RM, C(0)NRc4Rd4, C(0)ORa4, OC(0)RM, OC(0)NRc4Rd4, NRc4Rd4, NRc4C(0)RM, NRc4C(0)ORa4,
NRc4C(0)NRc4Rd4, NRc4S(0)RM, NRc4S(0)2RM, NRc4S(0)2NRc4Rd4, S(0)RM, S(0)NRc4Rd4, S(0)2RM, and S(0)2NRc4Rd4.
In some embodiments, RA is Cy1, halo, C2-6 alkynyl, or ORa4, wherein said C2-6 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy1, halo, Ci-6 alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, N02, ORa4, SRa4, C(0)RM, C(0)NRc4Rd4, C(0)ORa4, OC(0)RM, OC(0)NRc4Rd4, NRc4Rd4, NRc4C(0)Rb4, NRc4C(0)ORa4, NRc4C(0)NRc4Rd4, NRc4S(0)RM, NRc4S(0)2RM, NRc4S(0)2NRc4Rd4, S(0)RM, S(0)NRc4Rd4, S(0)2RM, and
S(0)2NRc4Rd4.
In some embodiments, RA is Cy1.
In some embodiments, Cy1 is selected from phenyl, pyrazolyl, pyrimidinyl, pyridyl, cyclohexyl, cyclohexenyl, indazolyl, quinolyl, isoquinolyl, piperidinyl, thiazolyl, imidazolyl, benzimidazolyl, and benzo[d][l,3]dioxolyl, each of which is optionally substituted by 1, 2, or 3 substituents independently selected from RCy.
In some embodiments, Cy1 is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.
In some embodiments, is independently selected from halo, Ci-6 alkyl, Ci-6 haloalkyl, C6-io aryl, C3 -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, ORa7, C(0)NRc7Rd7, C(0)ORa7, and NRc7Rd7, wherein said Ci-6 alkyl is optionally substituted with 1 or 2 substituents independently selected from ORa7 and NRc7Rd7.
In some embodiments, is independently selected from F, CI, methyl, ethyl, propyl, butyl, trifluoromethyl, phenyl, cyclopropyl, cyclobutyl, imidazolyl, oxazolyl, pyrazolyl, CN, hydroxy, methoxy, ethoxy, amino, aminocarbonyl, methylaminocarbonyl,
dimethylaminocarbonyl, methoxymethyl, hydroxymethyl, hydroxyethyl, isopropyloxymethyl, aminomethyl, carboxyl, carboxy ethyl ester, oxetanyl, dimethylaminoethyloxy, t-butoxy, cyclopropyloxy,
In some embodiments, RB is H, halo, or ORa5.
In some embodiments, RB is H.
In some embodiments, Rc is H.
In some embodiments, RD is H.
In some embodiments, the compound has Formula II:
Figure imgf000022_0001
III.
In some embodiments, the compound has Formula IV:
Figure imgf000023_0001
In some embodiments, the compound has Formula VII:
Figure imgf000024_0001
VII
wherein q is 0, 1, 2, or 3.
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 Ci-4, Ci-6, and the like.
The term "n-membered" 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, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5- membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1, 2, 3, 4- tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.
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, «-propenyl, isopropenyl, «-butenyl, sec-butenyl, and the like.
As used herein, "Ci-j alkynyl", employed alone or in combination with other terms, refers to an alkyl group having one or more carbon-carbon triple bonds. In some embodiments, the alkynyl moiety contains 2 to 6 or 2 to 4 carbon atoms. Example alkynyl groups include, but are not limited to, ethynyl, propyn-l-yl, propyn-2-yl, and the like.
As used herein, the term "Ci-j alkylamino" refers to a group of formula - H(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 - H2.
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 C6-io aryl-Ci-3 alkyl. In some embodiments, arylalkyl is C6-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-Ci-3 alkyl, wherein the cycloalkyl portion is monocyclic. In some embodiments, cycloalkylalkyl is C3-7 cycloalkyl-Ci-4 alkyl.
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 trifluoro methyl. 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-£]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-Ci-4 alkyl, 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-C 1 -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.
As used herein, the term "bridging," when used to describe a cyclic group (as in a ring), is meant to refer to a ring that connects at least two portions of a molecule. For example, when Z is a bridging aryl group, the aryl group is linked to both Ring A (lefthand side of molecule) and the nitrogen atom of the NR6 moeity (righthand side of molecule) in compounds of Formula I. The two portions of the molecule which are linked via the bridging ring can be connected to the bridging ring at, for example, a single ring-forming atom of the bridging ring, adjacent ring- forming atoms of the bridging ring, or non-adjacent ring-forming atoms of the bridging ring.
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 4H- 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 (CH CN) 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, 66(1), 1-19, and in Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002).
The below Table is a key to abbreviations that may be used throughout.
Abbreviations
AIBN azobisisobutyronitrile
atm atmosphere
Boc tert-butyl-oxy-carbonyl
CAS# Chemical Abstract Service registry number
CBS Corey-Bakshi-Shibata (catalyst)
C¾CN acetonitrile
CBZ carbobenzyloxy
CsOAc cesium acetate
DIPEA N,N-diisopropylethylamine
DMAP 4-dimethylaminopyridine
DME dimethylether
DMF dimethylformamide
dppf 1 , 1 '-bis(diphenylphosphino)ferrocene
EDCI l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
ee enantiomeric excess
EtOAc ethyl acetate
h hour(s)
min minute(s)
Hex hexanes
HO AT l-hydroxy-7-azabenzotriazole
HO Ac acetic acid
HPLC high-performance liquid chromatography
IPA isopropyl acetate
iPr isopropyl
KOAc potassium acetate LAH lithium aluminum hydride
LDA lithium diisopropylamide
mCPBA 3-meta-chloroperoxybenzoic acid
MeOH methanol
MS mass spectrometry
MTBE methyl t-butyl ether
H4OH ammonium hydroxide
BS N-bromosuccinimide
NMP l-methyl-2-pyrrolidone
PAH pulmonary arterial hypertension
PCC pyridinium chlorochromate
PE petroleum ether
PheOH phenylalanine hydroxylase
Pr propyl
Prep-TLC preparative thin-layer chromatography
p-TSA para-toluene sulfonic acid
RT room temperature
SNAr nucleophilic aromatic substitution
TBAF tetrabutylammonium fluoride
TBME tert-butylmethyl ether
tBuOH tert-butanol
TBTU 0-(benzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate
TEA triethylamine
TFA trifluoroacetic acid
TH tyrosine hydroxylase
THF tetrahydrofuran
TLC thin-layer chromatography
TMSCN trimethylsilyl cyanide
TMS trimethylsilyl
TMSI trimethylsilyl iodide
TPH tryptophan hydroxylase Synthesis
Procedures for making compounds described herein are provided below with reference to Schemes 1-5. Optimum reaction conditions and reaction times may vary depending on the particular reactants used. Unless otherwise specified, solvents, temperatures, pressures and other reaction conditions are readily selected by one of ordinary skill in the art. Specific procedures are provided in the Examples section. Compounds are named using the "structure to name" function included in ChemDraw® v.12 (Perkin-Elmer).
Typically, reaction progress may be monitored by thin layer chromatography (TLC) or HPLC-MS if desired. Intermediates and products may be purified by chromatography on silica gel, recrystallization, HPLC and/or reverse phase HPLC. In the reactions described below, it may be necessary to protect reactive functional groups (such as hydroxy, amino, thio, or carboxy groups) to avoid their unwanted participation in the reactions. The incorporation of such groups, and the methods required to introduce and remove them are known to those skilled in the art (for example, see Greene, Wuts, Protective Groups in Organic Synthesis. 2nd Ed. (1999)). One or more deprotection steps in the synthetic schemes may be required to ultimately afford
compounds of Formula I. The protecting groups depicted in the schemes are used as examples, and may be replaced by other compatible alternative groups. Starting materials used in the following schemes can be purchased or prepared by methods described in the chemical literature, or by adaptations thereof, using methods known by those skilled in the art. The order in which the steps are performed can vary depending on the protecting or functional groups introduced and the reagents and reaction conditions used, but would be apparent to those skilled in the art.
Compounds of the invention can be prepared as shown in Scheme 1. Briefly, in Step 1, an amine (see, e.g., Intermediate B) is treated in DMF with Intermediate A in the presence of a coupling agent (e.g., HATU, Et3 ) to provide amide C. In Step 2, ethyl ester hydrolysis (e.g. with LiOH in aqueous THF) provides acid D. Various esters can be made by converting D to an acid chloride (e.g with SOCh) followed by the addition of another alcohol to provide E.
Removal of the the N-Boc protecting group can be accomplished with a strong acid (e.g. TFA) to provide F. Alternatively, the amino acid G, can be prepared directly from D in Step 4a via removal of the the N-Boc protecting group directly with strong acid (e.g. TFA).
Scheme 1
Figure imgf000035_0001
The acid intermediate A used in Scheme 1 can be prepared according to Scheme 2. Briefly, in Step 1, (S)-ethyl 2-amino-3-(4-hydroxyphenyl)propanoate (H) is reacted with (Boc)20 in the presence of a base (e.g., NaHC0 ) in a solvent (e.g., THF/MeOH) to provide J. In Step 2, the hydroxyl group is converted to a triflate (e.g., with Tf20) in the presence of a base (e.g., pyridine) at low to ambient temperature to provide K. In Step 3, palladium-catalyzed hydroxy carbonylation is accomplished with a catalytic amount of palladium catalyst (e.g., Pd(OAc)2) in the presence of CO (e.g., 1 atm) and a base (e.g., iPr2 Et), and then mixture is heated for a period of time (e.g. 12-24 h) to provide A.
Scheme 2
Figure imgf000036_0001
Amine N can be prepared as described in Scheme 3. Briefly, in Step 1, nitrile L is reacted with a base (e.g. LDA) at low temperature (e.g. -78 °C) in THF followed by the addition of an electrophilic reagent (e.g. R8-X) to provide M. Step 2, nitrile M is then reduced (e.g. with BH -THF) in THF at low temperature (e.g. 0 °C) to provide N.
Scheme 3
Figure imgf000037_0001
Amine T can be prepared as described in Scheme 4. Briefly, in Step 1, ethyl 2-(4- bromophenyl)acetate (O) is reacted with a base (e.g. NaH) at low temperature (e.g. -10 °C) in THF followed by addition of an electrophilic reagent (e.g. 2-bromopropane) to provide P. Step 2, the ethyl ester is hydrolyzed to the acid Q with base (e.g. KOH). In Step 3, diastereomeric salt formation and recrystallization (e.g. with R-(+)-phenylethylamine) provides R. Step 4, amide formation occurs via treating the acid with a coupling reagent (e.g. oxalyl chloride) and then treatment with H4OH to provide S. Step 5, amide S is reduced (e.g. with BH3-THF) in THF at low temperature (e.g. 0 °C) to provide T.
Scheme 4
Figure imgf000037_0002
Biaryl compounds (V) can be prepared as described in Scheme 5 (Ar is an aromatic moiety like, for example, substituted or unsubstituted phenyl). Briefly, in Step 1, amine T is treated with Intermediate A in the presence of a coupling agent (e.g., HATU, Et3 ) to provide amide S. Aryl coupling (e.g. Suzuki) can be accomplished by treating U with a boronic acid (e.g. ArB(OH)2) in the presence of a transition metal coupling agent (e.g. Pd(dppf)Cl2) and heated in dioxane for 12-24 h to provide T. Compounds of this type can then be converted to either the amino ester or amino acid as described in Scheme 1 (steps 2-4 or steps 2 & 4a).
Scheme 5
Figure imgf000038_0001
Alternatively, biaryl compounds (V) can be prepared as described in Scheme 6. Briefly, in Step 1, bromide U is treated with bis(pinacolato)diboron in the presence of a transition metal coupling agent (e.g., Pd(dppf)2) to provide amide W. Step 2, aryl coupling (e.g. Suzuki) can be accomplished by treating W and an aryl bromide (e.g. ArBr) in the presence of a transition metal coupling agent (e.g. Pd(dppf)Cl2) and heated in dioxane for 12-24 h to provide V. Compounds of this type can then be converted to either the amino ester or amino acid as described in Scheme 1.
Scheme 6
Figure imgf000039_0001
Figure imgf000039_0002
Certain compounds where Z is a bridging ring can be prepared as described in Scheme 7. Briefly, in Step 1, epoxide W is treated with a Grignard reagent in the presence of a transition metal (e.g., Cul) to provide amine X. Step 2, under Mitsunobu conditions with X in the presence of phthalimide, triphenyl phosphine and diisopropyl azodicarboxylate provides Y. In Step 3, aminolysis catalyzed by a lipase (e.g. lipase B from Candida antarctica) provides amino compound Z which can be used to prepare compounds of the invention by the methods described, for example, in Scheme 1.
Scheme 7
Figure imgf000040_0001
Compounds where Z is taken together with R6 to form a ring can be prepared as described in Scheme 8. Briefly, in Step 1, Suzuki coupling with pyridine boronic acid A' provide B'. In Step 2, reduction of the pyridine B' with lithium triethylborohydride in a solvent (e.g. THF) provides piperidine C In Step 3, chiral HPLC allows for the seperation of both enatiomers, as exmplified by D' which can be used to prepare compounds of the invention by the methods described, for example, in Scheme 1.
Scheme 8
Figure imgf000041_0001
Methods of Use
The compounds of the invention can be used to inhibit the activity of the TPHl enzyme in a cell by contacting the cell with an inhibiting amount of a compound of the invention. The cell can be part of the tissue of a living organism, or can be in culture, or isolated from a living organism. Additionally, the compounds of the invention can be used to inhibit the activity of the TPHl enzyme in an animal, individual, or patient, by administering an inhibiting amount of a compound of the invention to the cell, animal, individual, or patient.
Compounds of the invention can also lower peripheral serotonin levels in an animal, individual, or patient, by administering an effective amount of a compound of the invention to the animal, individual, or patient. In some embodiments, the compounds of the invention can lower levels of peripheral serotonin (e.g., 5-HT in the GI tract) selectively over non-peripheral serotonin (e.g., 5-HT in the CNS).
As TPHl inhibitors that can lower peripheral serotonin levels, the compounds of the invention are useful in the treatment and prevention of various diseases associated with abnormal expression or activity of the TPHl enzyme, or diseases associated with elevated or abnormal peripheral serotonin levels. In some embodiments, the treatment or prevention includes administering to a patient in need thereof a therapeutically effective amount of a TPHl inhibitor of the invention. In some embodiments, the disease or disorder treatable by administration of one or more of the compounds provided herein is characterized by an altered rate of the tryptophan-serotonin metabolism wherein the rate limiting step of tryptophan- serotonin metabolism is the hydroxylation of L-Tryp catalyzed by TPH (e.g., TPHl).
Biological assays, some of which are described herein, can be used to determine the inhibitory effect of compounds against TPH (such as TPHl) in vitro and/or in vivo. In vitro biochemical assays for human, mouse, and rat TPHl and human TPH2, PheOH, and TH may be used to measure inhibition of enzyme activity and the selectivity among TPHl, TPH2, PheOH, and TH. In addition, the efficacy of these compounds can be determined, for example, by measuring their effect on intestinal 5-HT levels in rodents after oral administration.
Diseases treatable or preventable by administering a TPHl inhibitor of the invention include bone disease such as, for example, osteoporosis, osteoporosis pseudoglioma syndrome (OPPG), osteopenia, osteomalacia, renal osteodystrophy, Paget's disease, fractures, and bone metastasis. In some embodiments, the disease is osteoporosis, such as primary type 1 (e.g., postmenopausal osteoporosis), primary type 2 (e.g., senile osteoporosis), and secondary (e.g., steroid- or glucocorticoid-induced osteoporosis).
The present invention further includes methods of treating or preventing bone fracture such as, for example, osteoporotic or traumatic fracture, or surgical fractures associated with an orthopedic procedure (e.g., limb lengthening, bunion removal, an increase in bone formation associated with a prosthesis, bone metastasis, or spinal fusion).
Further diseases treatable or preventable by the methods of the invention include cardiovascular diseases such as aortic and coronary artery diseases, atherosclerosis,
hypertentsion (acute or chronic), and pulmonary hypertension (PH), including idiopathic or familial PH, and also including PH associated with or brought on by other diseases or conditions. In some embodiments, the PH disease is pulmonary arterial hypertension (PAH). See, e.g., Ciuclan, L. et al. "Imatinib attenuates hypoxia-induced pulmonary arterial hypertension pathology via reduction in 5-hydroxytryptamine through inhibition of tryptophan hydroxylase 1 expression." Am J Respir Crit Care Med. 187(1): 78-89 (2013).
The types of PAH treatable or preventable according to the methods of the invention include (1) idiopathic (IP AH), (2) familial (FPAH), and (3) associated (APAH) which is the most common type of PAH. The latter is PAH which is associated with other medical conditions including, for example, (1) collagen vascular disease (or connective tissue disease) which include autoimmune diseases such as scleroderma or lupus; (2) congenital heart and lung disease; (3) portal hypertension (e.g., resulting from liver disease); (4) HIV infection; (5) drugs (e.g., appetite suppressants, cocaine, and amphetamines; (6) other conditions including thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia,
hemoglobinopathies, myeloproliferative disorders,and splenectomy. APAH can also be PAH associated with abnormal narrowing in the pulmonary veins and/or capillaries such as in pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis. Another type of PAH is associatead with persistent pulmonary hypertension of the newborn (PPHN). APAH can aslo be PAH associated with radiation pneumonitis.
Diseases treatable or preventable by administering a TPH1 inhibitor of the invention include fibrotic diseases, such as: pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), interstitial lung disease, etc.), skin fibrosis (e.g., scleroderma), fibrosis of various other organ tissues such as heart fibrosis (e.g. fibrosis of the heart valves), kidney fibrosis, liver fibrosis, etc. any of which may be caused by chronic diseases such as fatty liver disease (e.g., in the case of liver fibrosis) and diabetic nephropathy (e.g., in the case of kidney fibrosis). See, e.g., "Lung fibrosis by serotonin receptor antagonists in mice." Eur Respir J. 2008, 32(2):426-36; Konigshoff, M. et al. "5-Hydroxytryptamine 2A/B receptors in idiopathic pulmonary fibrosis." Thorax. 2010, 65(11):949— 55; "Scleroderma lung and skin fibrosis." Best Pr act Res Clin Rheumatol. 2011, 25(6):843-58; "Platelet-derived serotonin links vascular disease and tissue fibrosis." J Exp Med. 2011, 208(5):961-72; "Molecular targets for therapy in systemic sclerosis." Fibrogenesis Tissue Repair. 2012;5:S19; "New cellular and molecular mechanisms of lung injury and fibrosis in idiopathic pulmonary fibrosis." Lancet. 2012; 380 (9842):680-8; "Treating skin and lung fibrosis in systemic sclerosis: a future filled with promise?" Curr Opin Pharmacol . 2013; 13(3):455-62; Mann, D.A. et al. "Serotonin paracrine signaling in tissue fibrosis." Biochim Biophys Acta. 2013, 1832(7):905-10.
The compounds of the invention can be used in the treatment or prevention of liver disease including, for example, hepatitis. In some embodiments, the hepatitis is associated with or induced by an autoimmune process (e.g., autoimmune hepatitis or primary biliary cirrhosis). In some embodiments, the hepatitis is associated with or induced by alcoholic or toxic liver destruction. In some embodiments, the hepatitis is associated with or induced by a viral infection, such as an infection by HAV, HBV, HCV, HDV, HEV, or HGV. Further diseases treatable or preventable by the methods of the invention include metabolic diseases such as diabetes and hyperlipidemia; pulmonary diseases such as pulmonary embolism, adult respiratory distress syndrome (ARDS); gastrointestinal diseases such as inflammatory bowel diseases (IBD), irritable bowel syndrome (e.g., post-infectious), colitis (e.g., ulcerative colitis), chemotherapy-induced emesis, diarrhea, carcinoid syndrome, celiac disease, Crohn's disease, celiac disease, abdominal pain, dyspepsia, constipation (e.g., idiopathic constipation), lactose intolerance, necrotizing entercolitis, Ogilvie's syndrome, pancreatic cholera syndrome, pancreatic insufficiency, Zollinger-Ellison Syndrome, or other gastrointestinal inflammatory conditions; cancers such as liver cancer, breast cancer, cholangiocarcinoma, colon cancer, colorectal cancer, neuroendocrine tumors, pancreatic cancer, prostate cancer, and bone cancer (e.g., osteosarcoma, chrondro sarcoma, Ewings sarcoma, osteoblastoma, osteoid osteoma, osteochondroma, carcinoid tumors, enchondroma, chondromyxoid fibroma, aneurysmal bone cyst, unicameral bone cyst, giant cell tumor, and bone tumors); blood diseases (e.g.,
myeoloproliferative syndrome, myelodysplastic syndrome, Hodgkin's lymphoma, non- Hodgkin's lymphoma, myeloma, and anemia such as aplastic anemia and anemia assocated with kidney disease; and blood cancers (e.g., leukemias such as acute lymphocytic leukemia (ALL), chronic lymphocytic leukemica (CLL), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML)). See, e.g., Ghia, J. E. et al. "Serotonin has a key role in pathogenesis of experimental colitis." Gastroenterology 137(5): 1649-1660 (2009); Brown, P. M. et al. "The tryptophan hydroxylase inhibitor LX1031 shows clinical benefit in patients with
nonconstipating irritable bowel syndrome," Gastroenterology 141, 507-516 (2011);
Engelman, K., et al. "Inhibition of serotonin synthesis by para-chlorophenylalanine in patients with the carcinoid syndrome." NEnglJMed 277(21): 1103-1108 (1967); Pai VP et al. "Altered serotonin physiology in human breast cancers favors paradoxical growth and cell survival. " Breast Cancer Res. 11(6) (2009); Shinka T et al. " Serotonin synthesis and metabolism-related molecules in a human prostate cancer cell line." Oncol Lett. Mar;2(2):211-215 (2011); and Hicks, R.J. "Use of molecular targeted agents for the diagnosis, staging and therapy of neuroendocrine malignancy." Cancer Imaging . Oct 4; 10 Spec. no. AS83-91 (2010).
The compounds of the invention are also useful in the treatment or prevention of myxomatous mitral valve disease. Lacerda, C. M. et al. "Local serotonin mediates cyclic strain- induced phenotype transformation, matrix degradation, and glycosaminoglycan synthesis in cultured sheep mitral valves." Am J Physiol Heart Circ Physiol. 302(10): H1983-1990 (2012).
In some embodiments, the present invention includes methods of lowering plasma cholesterol, lowering plasma triglycerides, lowering plasma glycerol, lowering plasma free fatty acids in a patient by administering to said patient a therapeutically effective amount of a compound of the invention.
In some embodiments, the present invention includes methods of treating or preventing thrombosis, sleep disorders, pain, diabetes (type 1 or type 2), complications associated with liver transplantation or regeneration, serotonin syndrome, Raynaud's syndrome, subarachnoid hemorrhage, abdominal migraine, CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, telangiectasia), Gilbert's syndrome, nausea, multiple endocrine neoplasia (MEN) types I and II, pheochromacytoma, somatization disorder, functional anorectal disorders, functional bloating, immune tolerance and inflammatory diseases including, e.g. multiple sclerosis and systemic sclerosis. See, Nowak E.C. et al. "Tryptophan hydroxylase-1 regulates immune tolerance and inflammation." J Exp Med. Oct 22, 09(11):2127-35 (2012); Dees C. et al. "Platelet-derived serotonin links vascular disease and tissue fibrosis." J Exp Med. May 9, 208(5):961-72 (2011).
The compounds of the invention are also useful in the treatment or prevention of inflammatory disease, such as allergic airway inflammation (e.g., asthma). See, e.g., Durk, T. et al. "Production of serotonin by tryptophan hydroxylase 1 and release via platelets contribute to allergic airway inflammation." Am J Respir Crit Care Med. 187(5): 476-485 (2013).
As used herein, the term "cell" is meant to refer to a cell that is in vitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal.
As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" the enzyme with a compound of the invention includes the administration of a compound of the present invention to an individual or patient, such as a human, having the TPH1 enzyme, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the TPH1 enzyme. 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
One or more additional pharmaceutical agents or treatment methods can be used in combination with the compounds of the present invention for treatment or prevention of various diseases, disorders or conditions disclosed herein. The agents can be combined with the present compounds in a single dosage form, or the agents can be administered simultaneously or sequentially in separate dosage forms.
Example pharmaceutical agents that may be useful in a combination therapy for blood disorders like blood cancers include parathyroid hormone, anti-sclerostin antibodies, kathepsin K inhibitors, and anti-Dickopff 1.
Example pharmaceutical agents that may be useful in a combination therapy for cancer include leuprolide, goserelin, buserelin, flutamide, nilutamide, ketoconazole, aminoglutethimide, mitoxantrone, estramustine, doxorubicin, etoposide, vinblastine, paclitaxel, carboplatin, and vinorelbine. Therapies that can be combined with TPH inhibition include radiation therapy, high- intensity focused ultrasound, or surgery (e.g., removal of diseased tissues). Other drugs for use in treating cancer include testolactone, anastrozole, letrozole, exemestane, vorozole, formestane, fadrozole, GnRH-analogues, temozolomide, bavituximab, cyclophosphamide, fluorouracil, fulvestrant, gefitinib, trastuzumab, IGF-1 antibodies, lapatinib, methotrexate, olaparib, BSI-201, pazopanib, rapamycin, ribavirin, sorafenib, sunitinib, tamoxifen, docetaxel, vatalinib, bevacizumab, and octreotide.
Example pharmaceutical agents that may be useful in combination therapy for cardiovascular or pulmonary diseases include endothelin receptor antagonists such as
ambrisentan, BMS-193884, bosentan, darusentan, SB-234551, sitaxsentan, tezosentan and macitentan. Anticoagulants such as warfarin, acenocoumarol, phenprocoumon, phenindione, heparin, fondaparinux, argatroban, bivalirudin, lepirudin, and ximelagatran may also be useful in combination therapy. Pharmaceutical agents for combination therapy further include calcium channel blockers like amlodipine, felodipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, lacidipine, lercanidipine, phenylalkylamines, verapamil, gallopamil, diltiazem, and menthol. Prostacyclins like epoprostenol, iloprost and treprostinil may also be combined with the TPH inhibitors of the invention. Further pharmaceutical agents for combination therapy in cardiovascular or pulmonary diseases include PDE5 inhibitors like sildenafil, tadalafil, and vardenafil; diuretics like furosemide, ethacrynic acid, torasemide, bumetanide,
hydrochlorothiazide, spironolactone, mannitol, nitric oxide or nitric oxide releasers, and soluble guanylate cyclase stimulators, such as riociguat. Yet further pharmaceutical agents for combination therapy include APJ receptor agonists (WO 2013/111110); IP receptor agonists (WO 2013/105057; WO 2013/105066; WO 2013/105061; WO 2013/105063; WO 2013/105065; WO 2013/105058); and PDGF receptor inhibitors (WO 2013/030802).
Example pharmaceutical agents that may be useful in combination therapy for metabolic disorders include HSL inhibitors such as those disclosed in International Patent Publications WO2006/074957; WO2005/073199; WO2004/11 1031; WO2004/111004; WO2004/035550; WO2003/051841 ; WO2003/051842; and WO2001/066531.
Example pharmaceutical agents that may be useful in combination therapy for bone disorders and diseases include bisphosphantes such as etidronate, clodronate, tiludronate, pamidronate, neridronate, olpadronate, alendronate, ibandronate, risedronate, cimadronate, zoledronate, and the like. Serotonin receptor modulators, such as 5-HTIB , 5-HT2A, and 5-HT2B agonists or antagonists, may also be useful in combination therapy for bone disease. Other useful agents for combination therapy include selective serotonin reuptake inhibitors (SSRI), anti- serotonin antibodies, and beta blockers such as IPS339, ICI1 18,551, butaxamine, metipranolol, nadol, oxprenolol, penbutolol, pindolol, propranolol, timolol, and sotalol. Further useful agents for combination therapy for the treatment of bone disorders, such as osteoporosis, include teriparatide, strontium ranelate, raloxifene, and denosumab.
Administration, Pharmaceutical Formulations, Dosage Forms
The compounds of the invention can be administered to patients (animals and humans) in need of such treatment in appropriate dosages that will provide prophylactic and/or therapeutic efficacy. The dose 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 can be determined by the treating physician.
A compound of this invention can be administered orally, subcutaneously, topically, parenterally, by inhalation spray 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.
Treatment duration can be as long as deemed necessary by a treating physician. The compositions can be administered one to four or more times per day. 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 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.
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration can include, for example, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Suspensions can include one or more suspending agents
Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
Compositions and compounds of the present invention can be administered by aerosol which can be administered, for example, by a sonic nebulizer.
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 as described below.
EXAMPLES
The compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials.
¾ NMR Spectra were acquired on one or more of three instruments: (1) Agilent
Unitylnova 400 MHz spectrometer equipped with a 5 mm Automation Triple Broadband (ATB) probe (the ATB probe was simultaneously tuned to ¾, 19F and 1 C); (2) Agilent Unitylnova 500 MHz spectrometer; or (3) Varian Mercury Plus 400 MHz spectrometer. Several NMR probes were used with the 500 MHz NMR spectrometer, including both 3 mm and 5 mm ¾, 19F and 1 C probes and a 3 mm X'H19F NMR probe (usually X is tuned to 1 C). For typical ¾ NMR spectra, the pulse angle was 45 degrees, 8 scans were summed and the spectral width was 16 ppm (-2 ppm to 14 ppm). Typically, a total of about 32768 complex points were collected during the 5.1 second acquisition time, and the recycle delay was set to 1 second. Spectra were collected at 25 °C. ¾ NMR Spectra were typically processed with 0.3 Hz line broadening and zero-filling to about 131072 points prior to Fourier transformation. Chemical shifts were expressed in ppm relative to tetramethylsilane. The following abbreviations are used herein: br = broad signal, s = singlet, d = doublet, dd = double doublet, ddd = double double doublet, dt = double triplet, t = triplet, td = triple doublet, tt = triple triplet q = quartet, m = multiplet.
Liquid chromatography - mass spectrometry (LCMS) experiments to determine retention times and associated mass ions were performed using one or more of the following Methods A, B, and C:
Method A: Waters BEH C18, 3.0 x 30 mm, 1.7 μπι, was used at a temperature of 50 °C and at a flow rate of 1.5 mL/min, 2 μΐ^ injection, mobile phase: (A) water with 0.1% formic acid and 1% acetonitrile, mobile phase (B) MeOH with 0.1% formic acid; retention time given in minutes. Method A details: (I) ran on a Binary Pump G1312B with UV/Vis diode array detector G1315C and Agilent 6130 mass spectrometer in positive and negative ion electrospray mode with UV PDA detection with a gradient of 15-95%) (B) in a 2.2 min linear gradient (II) hold for 0.8 min at 95% (B) (III) decrease from 95-15% (B) in a 0.1 min linear gradient (IV) hold for 0.29 min at 15% (B);
Method B: An Agilent Zorbax Bonus RP, 2.1 x 50 mm, 3.5 μπι, was used at a temperature of 50 °C and at a flow rate of 0.8 mL/min, 2 μΐ^ injection, mobile phase: (A) water with 0.1%) formic acid and 1%> acetonitrile, mobile phase (B) MeOH with 0.1%> formic acid; retention time given in minutes. Method details: (I) ran on a Binary Pump G1312Bwith UV/Vis diode array detector G1315C and Agilent 6130 mass spectrometer in positive and negative ion electrospray mode with UV-detection at 220 and 254 nm with a gradient of 5-95% (B) in a 2.5 min linear gradient (II) hold for 0.5 min at 95% (B) (III) decrease from 95-5% (B) in a 0.1 min linear gradient (IV) hold for 0.29 min at 5% (B).
Method C: An API 150EX mass spectrometer linked to a Shimadzu LC-10AT LC system with a diode array detector was used. The spectrometer had an electrospray source operating in positive and negative ion mode. LC was carried out using an Agilent ZORBAX XDB 50 x 2.1 mm C18 column and a 0.5 mL/minute flow rate. Solvent A: 95% water, 5% acetonitrile containing 0.01% formic acid; Solvent B: acetonitrile. The gradient was shown as below. 0-0.5 min: 2% solvent (B); 0.5-2.5 min: 2% solvent B to 95% solvent (B); 2.5-4.0 min: 95% solvent (B); 4.0-4.2 min: 95% solvent (B) to 2% solvent B; 4.2-6.0 min: 2% solvent (B).
Microwave experiments were carried out using a Biotage Initiator™, which uses a single- mode resonator and dynamic field tuning. Temperatures from 40-250 °C were achieved, and pressures of up to 20 bars were reached.
Preparative HPLC purification was carried out using either a C18-reverse-phase column from Genesis (C18) or a C6-phenyl column from Phenomenex (C6 Ph) (100 x 22.5 mm i.d. with 7 micron particle size, UV detection at 230 or 254 nm, flow 5-15mL/min), eluting with gradients from 100-0 to 0-100 % water/acetonitrile or water/MeOH containing 0.1% formic acid. Fractions containing the required product (identified by LCMS analysis) were pooled, the organic fraction removed by evaporation, and the remaining aqueous fraction lyophilised, to give the product.
Chiral HPLC was carried out with one of the following two conditions:
A) Instrument: Agilent 1100 HPLC
Column: CHIRALCEL OD-H, 4.6*250 mm, 5μιη;
Mobil phase: Hex/Ethanol/TFA=99:0.5:0.1
Flow rate: 0.8 mL/min
Temperature: Room temperature
Wavelength: 220 nm
B) Instrument: Agilent 1100 HPLC
Column: CHIRALCEL OD-H, 4.6*250 mm, 5μιη;
Mobil phase: Hex/IP A/TFA=91 :9:0.1 or Hex/IP A/TFA=97 : 3 : 0.1 Flow rate: 0.8 mL/min
Temperature: Room temperature
Wavelength: 220 nm
Compounds which required column chromatography were purified manually or fully automatically using either a Biotage SP1™ Flash Purification system with Touch Logic Control™ or a Combiflash Companion® with pre-packed silica gel Isolute® SPE cartridge, Biotage SNAP cartridge or Redisep® Rf cartridge respectively.
Preparation of Amine Intermediates
The following amines shown in Table 1 were used in preparing the compounds of the invention. They are either commercially available or can be prepared by known synthetic procedures. CAS registry numbers are provided for each.
Table 1. Amine Intermediates
Figure imgf000052_0001
Figure imgf000053_0001
15 [l, l'-biphenyl]-3-methyl amine 177976-49-7
2-([ 1,
16 r-biphenyl]-2-yloxy)
23314-13-8 ethylamine
17 oar-""" 2-(4- 118468-18-1 phenoxyphenyl)ethanamine
2-([ 1 , r-biphenyl]-4-yl)-3 , 3 -
18 1528144-26-4 dimethylbutan- 1 -amine
2-([l,r-biphenyl]-4-yl)-2-
19 496860-99-2 phenylethanamine
19b [ 1 , -biphenyl]-2-ethanamine 252984-00-2
(S)-l-([l,l'-biphenyl]-4-
19c 869567-02-2 yl)propan-2-amine
Intermediate 20: (!-([!, l'-bipheny -4-yl)cyclobutyl)methanamine
Figure imgf000054_0001
Step 1 : To a solution of 2-([l,l*-biphenyl]-4-yl)acetonitiile (CAS# 31603-77-7, 500 mg, 2.6 mmol) in toluene (5 mL) was added sodium amide (222 mg, 10 mmol) at RT. The mixture was heated to 35 °C for 15 min. Then 1,3-diiodopropane (490 mg, 2.6 mmol) was added dropwwise and the reaction was stirred at 35 °C for 16 h. After this time, an additional equivalent of sodium amide was added and the reaction was heated to 50 °C for 4.5 h. The reaction was then cooled to RT, quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SC"4, filtered and concentrated in vacuo. Purification via normal phase column chromatography (heptanes: ethyl acetate /4: 1) provided 1- ([l, l'-biphenyl]-4-yl)cyclobutanecarbonitrile as a colorless oil.
Step 2: A solution of l-([l,l'-biphenyl]-4-yl)cyclobutanecarbonitrile (119 mg, 0.5 mmol) in ether (5 mL) was cooled to 0 °C followed by the dropwise addition of LAH (1 mL of a 1M ether solution). The reaction was warmed to RT and stirred for 2 h. After this time, the reaction was cooled to 0 °C and quenched sequentially with water, 15% NaOH, and water, and then extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated in vacuo. Purification via normal phase column chromatography
(CH2Cl2:MeOH: H2OH/90: 10: l) provided the title compound as a colorless oil. LCMS (MH+): 238.
Intermediate 21: 2-([l,l'-biphenyl]- -yl)-2-cyclopentylethanamine
Figure imgf000055_0001
Step 1 : A solution of diisopropyl amine (576 mg, 5.7 mmol) in THF (2.5 mL) was cooled to -78 °C and n-butyl lithium (2.5 M in hexanes, 1 mL) was added. The reaction was stirred for 30 min at -78 °C. After this time, 2-([l, l'-biphenyl]-4-yl)acetonitrile (CAS# 31603-77-7, 500 mg, 2.6 mmol) was added and the reaction was stirred for 5 min, then cyclopentyl bromide (CAS# 137-43-9, 467 mg, 3.1 mmol) was added. The reaction mixture was warmed to RT and stirred for 16 h. After this time, the reaction was quenched with HC1 (IN) and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SC"4, filtered and concentrated in vacuo. Purification via normal phase column chromatography (hexanes: ethyl acetate/4: 1) provided 2-([l, l'-biphenyl]-4-yl)-2-cyclopentylacetonitrile as a colorless oil.
Step 2: To a solution of 2-([l,l'-biphenyl]-4-yl)-2-cyclopentylacetonitrile (173 mg, 0.7 mmol) in THF (5 mL) was added borane in THF (1 M, 9.9 mL). The reaction mixture was heated to 65 °C for 2 h. After this time, the reaction was cooled to RT and quenched with HCl (1 N, 5 mL), and then the pH was adjusted to -8.5 with NaOH (IN) and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated in vacuo. Purification via normal phase column chromatography (CH2Cl2:MeOH:NH40H/ 90: 10: 1) provided the title compound as a colorless oil. LCMS (MH+): 266.
The following amine intermediates of Table 2 were prepared as described above for 2-
([1, l'-biphenyl]-4-yl)-2-cyclopentylethanamine (Intermediate 21).
Table 2. Amine Intermediates
Figure imgf000056_0001
Figure imgf000057_0001
54 2-([ 1 , 1 '-biphenyl]-4-yl)pentan- 1 -amine 240
2-([l,l'-biphenyl]-4-yl)-3-methylbutan-
55 240
1 -amine
Intermediate 31: 2-([l,l'-biphenyl]-4- l)-3,3,3-trifluoropropan-l-amine
Figure imgf000058_0001
Step 1 : To a solution of 2-([l,l'-biphenyl]-4-yl)acetonitrile (CAS# 31603-77-7, 250 mg, 1.3 mmol) in toluene (5 mL) was added sodium amide (0.1 mL, 1.3 mmol). After 20 min, 1- trifluoromethyl-l,2-benziodoxol-3-(lH)-one (CAS#: 887144-94-7, 440 mg, 1.4 mmol) was added dropwise and the reaction was stirred at RT for 16 h. After this time, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated in vacuo to provide 2-([l,l'-biphenyl]-4-yl)-3,3,3- trifluoropropanenitrile that was used without further purification.
Step 2: The tile compound was prepared as described for 2-([l,l'-biphenyl]-4-yl)-2- cyclopentylethanamine (step 2) as a colorless oil. LCMS (MH+): 266.
Intermediate 32: 5-([l,l'-biphenyl]-4-yl)-6-amino-4,4-dimethylhexan-2-ol
Diastereomer 1
Figure imgf000059_0001
Step 1 : A solution of diisopropyl amine (576 mg, 5.7 mmol) in THF (2.5 mL) was cooled to -78 °C and n-butyl lithium (2.3 M in hexanes, 1 mL) was added. The reaction was stirred for 30 min at -78 °C. After this time, 2-([l, l'-biphenyl]-4-yl)acetonitrile (1.0 g, 5.6 mmol) was added and the reaction was stirred for 15 min at -78 C. Then acetone (1.9 mL, 26 mmol) was added and the reaction was warmed to RT for 16 h. The reaction was then quenched with HCl (IN) and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated in vacuo. Purification via normal phase column
chromatography (heptanes: ethyl acetate/4: 1) provided 2-([l, l'-biphenyl]-4-yl)-3,3-dimethyl-5- oxohexanenitrile as a colorless oil.
Step 2: To a solution of 2-([l,l'-biphenyl]-4-yl)-3,3-dimethyl-5-oxohexanenitrile (700 mg, 2.4 mmol) in THF (5 mL) was added borane in THF (1 M, 24 mL) and the reaction mixture was heated to 65 °C for 2 h. After this time, the reaction was cooled to RT and quenched with HCl (1 N, 5 mL), and then the pH was adjusted to -8.5 with NaOH (IN) and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated in vacuo. Purification via normal phase column chromatography (CH2Cl2:MeOH:NH2OH/ 90: 10: 1) provided the first fraction (Rf = 0.14 in CH2Cl2:MeOH: NH2OH/90: 10: 1) as the title compound as a colorless oil. LCMS (MH+): 298. Intermediate 33: 5-([l,l'-biphenyl]-4-yl)-6-amino-4,4-dimethylhexan-2-ol
Diastereomer 2
Figure imgf000059_0002
The title compound was isolated as a colorless oil as the 2nd fraction from the reduction of 2-([l,r-biphenyl]-4-yl)-3,3-dimethyl-5-oxohexanenitrile (Step 2, Intermediate 32), (Rf = 0.10 in CH2Cl2:MeOH:NH2OH/90: 10: l). LCMS (MH+): 298.
Intermediate 34: 5-([l,l'-biphenyl]-4-yl)-6-amino-4,4-dimethylhexan-2-ol
Diastereomer 3 (stereochemistry not defined)
Figure imgf000060_0001
The title compound was isolated as a colorless oil as the 3rd fraction from the reduction of 2-([l,r-biphenyl]-4-yl)-3,3-dimethyl-5-oxohexanenitrile (Step 2, Intermediate 32), (Rf = 0.05 in CH2Cl2:MeOH:NH2OH/90: 10: l). LCMS (MH+): 298.
Intermediate 35: 2-(2-chloro-[l,l'-biph nyl]-4-yl)ethanamine
Figure imgf000060_0002
Step 1 : A solution of l-bromo-2-chloro-4-methylbenzene (1.0 g, 4.90 mmol), BS (0.87 g, 4.90 mmol) and AIBN (1%) in CC14 (10 mL) was heated to reflux for 12 h. After cooling to RT, the reaction mixture was filtered and the filtrate was evaporated to provide l-bromo-4- (bromomethyl)-2-chlorobenzene as a yellow oil.
Step 2: A solution of l-bromo-4-(bromomethyl)-2-chlorobenzene (1.38 g, 4.90 mmol), TMSCN (0.58 g, 5.9 mmol) and K2C03 (0.81 g, 5.9 mmol) in CH CN (10 mL) was heated to 50 °C for 6 h. After this time, the reaction mixture was cooled to RT and concentrated in vacuo. The residue was extracted with ethyl acetate and the organic layer was washed with brine, dried over Na2SC"4, filtered and concentrated in vacuo to provide 2-(4-bromo-3-chlorophenyl) acetonitrile as a colorless oil.
Step 3 : To a solution of 2-(4-bromo-3-chlorophenyl) acetonitrile (800 mg, 3.47 mmol) and phenylboronic acid (508 mg, 4.16 mmol) in 1,4-dioxane (10 mL) was added aqueous Na2C03 (2M, 4mL) and PdCl2(PPh3)2 (3%), and the reaction was heated to 95 °for 12 h. After this time, the reaction mixture was cooled to RT and quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SC"4, filtered and concentrated in vacuo to provide. Purification via normal phase column chromatography (hexane/ethyl acetate: 40/1) provided 2-(2-chlorobiphenyl-4-yl)acetonitrile as a yellow oil.
Step 4: A solution of 2-(2-chlorobiphenyl-4-yl)acetonitrile (376 mg, 1.65 mmol) and Raney-Ni (190 mg) in a solution of H in CH OH (6 mL) was stirred at RT for 12 h under 1 atm of H2. After this time, the reaction mixture was filtered and the filtrate was concentrated in vacuo to provide the title compound as a yellow liquid. LCMS (MH+): 232.08.
Intermediate 36: 2-(3-methoxy-[l,l'-biphenyl]-4-yl)ethanamine
Figure imgf000061_0001
The title compound can be prepared as described for Intermediate 35: 2-(2-chloro-[l,l'- biphenyl]-4-yl)ethanamine starting with l-bromo-3-methoxy-4-methylbenzene. LCMS (MH+): 228.13.
Intermediate 37: 2-(6-phenylpyridin-3- l)ethanamine
Figure imgf000061_0002
The title compound can be prepared as described for Intermediate 35: 2-(2-chloro-[l,l' biphenyl]-4-yl)ethanamine starting with 2-bromo-5-methylpyridine. LCMS (MH+): 199.12.
Intermediate 38: 2-(l-([l,l'-biphenyl]-4-yl)-2-aminoethoxy)ethanol
Figure imgf000062_0001
Step 1 : To a solution of 4-bromobenzaldehyde (2.0 g, 10.8 mmol) and phenylboronic acid (1.58 g, 13.0 mmol) in 1,4-dioxane (10 mL) was added aqueous Na2C03 (2M, 4mL) and PdCl2(PPh3)2 (3%) and the reaction was heated to 95 °for 12 h. After this time, the reaction was cooled to RT and quenched with water, extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SC"4, filtered and concentrated in vacuo. Purification via normal phase column chromatography (hexane/ethyl acetate= 100/1) provided biphenyl-4- carbaldehyde as white solid.
Step 2: A solution of biphenyl-4-carbaldehyde (500 mg, 2.74 mmol), ethane- 1,2-diol (2 mL) and 4-methylbenzenesulfonic acid (47 mg, 0.274 mmol) in toluene (6 mL) was heated at 140 °C for 4 d. After this time, the reaction was cooled to RT and the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SC"4, filtered and concentrated in vacuo. Purification via normal phase column chromatography (hexane/ethyl acetate: 10/1) provided 2-(Biphenyl-4-yl)-l,3-dioxolane as a white solid.
Step 3 : A solution of 2-(biphenyl-4-yl)-l,3-dioxolane (460 mg, 2.03 mmol), TMSCN (242 mg, 2.44 mmol) and Znl2 (1.3 g, 4.06 mmol) in CH2C12 (10 mL) was stirred at RT for 3.5 h. After this time, the reaction mixture was quenched with saturated Na2C03 and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SC"4, filtered and concentrated in vacuo. Purification via normal phase column chromatography (hexane/ethyl acetate: 3/1) provided 2-(biphenyl-4-yl)-2-(2-hydroxyethoxy)acetonitrile as colorless gel.
Step 4: A solution of 2-(biphenyl-4-yl)-2-(2-hydroxyethoxy)acetonitrile (76 mg, 0.30 mmol) and Raney-Ni (50 mg) in a solution of H3 (7 N in CH3OH) (6 mL) was stirred at RT for 12 h under 1 atm of H2. After this time, the reaction was filtered and the filtrate was
concentrated in vacuo to afford the title compound as a white solid that was used without further purification. LCMS[M+1] : 258.3. Intermediate 39: (Z)-4-([l,l'-biphenyl -2-yl)but-3-en-l-amine
Figure imgf000063_0001
Stepl : A solution of N-(3-bromopropyl)phthalimide (CAS#: 5460-29-7 , 13.4 g, 5 mmol) and triphenyl phosphine (13.2 g, 5 mmol) in m-xylene (75 mL) was heated to 145 °C for 40 h. After this time, the reaction was cooled to RT, filtered, washed with ether and dried in vacuo to provide (3-(l,3-dioxoisoindolin-2-yl)propyl)triphenylphosphonium bromide as a white solid.
Step 2: A solution of (3-(l,3-dioxoisoindolin-2-yl)propyl)triphenylphosphonium bromide (2.7 g, 5 mmol) in THF (30 mL) was cooled to 0 °C and potassium t-butoxide (0.56 g, 5 mmol) was added solution was stirred at 0 °C for 15 min and then [l, l'-biphenyl]-2-carbaldehyde (CAS#: 1203-68-5, 0.91 g, 5 mmol) was added. The reaction was warmed to RT and stirred for 12 h. After this time, the reaction was filtered, washed with ether and concentrated in vacuo to provide (Z)-2-(4-([l,l'-biphenyl]-2-yl)but-3-en-l-yl)isoindoline-l,3-dione as a white solid.
Step 3 : A solution of (Z)-2-(4-([l, l'-biphenyl]-2-yl)but-3-en-l-yl)isoindoline-l,3-dione (550 mg, 1.56 mmol) in hydrazine (5 mL) and ethanol (10 mL) was heated to 75 °C for 2 h. After this time, the reaction was cooled to RT, concentrated in vacuo and purified directly via normal phase column chromatography (MeOH:CH2Cl2: Lt OH/98: 1 : 1) to provide the title compound as a clear oil. LCMS (MH+): 224.4.
Intermediate 40: 4-([l,l'-biphenyl]-2-yl)butan-l-amine
Figure imgf000063_0002
A solution of (Z)-4-([l, l'-biphenyl]-2-yl)prop-2-en-l -amine (Intermediate 39, 100 mg, 0.45 mmol) and 10% Pd/C (50 mg) in 2.5 mL of ethanol was stirred at RT for 12 h under 1 atm of H2. After this time, the reaction mixture was filtered through celite and concentrated in vacuo to provide the title compound as a clear oil that was used without further purification. LCMS (MH+): 226.1.
Intermediate 41: 3-([l,l'-biphenyl]-2-yl)cyclobutanamine
Figure imgf000064_0001
A solution of 3-(2-bromophenyl)-cyclobutanamine (CAS#: 1156289-16-5, 26 mg, 0.10 mmol), phenyl boronic acid (18 mg, 0.15 mmol), Pd(PPh )2Cl2 (3 mg, 0.005 mmol), and Na2C0 (21 mg, 0.2 mmol) in CH3CN/H20 (5 mL, 4: 1) was heated to 90 °C for 2 h. After this time, the reaction was cooled to RT, filtered through celite and concentrated in vacuo to provide the title compound as a colorless oil that was used without further purification. LCMS (MH+): 224.1.
Intermediate 42: 2-(l-phenyl-lH-indazol-5-yl)ethanamine
Figure imgf000064_0002
Step 1 : To a solution of 4-fluoro-3-formyl-benzonitrile (CAS#: 146137-79-3, 6 g, 40.2 mmol) in DMF (30 mL) was added phenylhydrazine hydrochloride (6.12 g, 42.3 mmol). The reaction mixture was stirred for 2 h at 80 °C. Then K2C0 (11.11 g, 80.5 mmol) was added and the reaction mixture was heated to 140 °C for an additional 12 h. After this time, the reaction was cooled to RT, and then poured into ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SC"4, filtered and concentrated in vacuo. Purification via normal phase column chromatography (hexane/ethyl acetate: 2/1) to provide 1-phenyl-lH- indazole-5-carbonitrile as light yellow solid.
Step 2: A solution of l-phenyl-lH-indazole-5-carbonitrile (2.1 g, 9.5 mmol) in EtOH (20 mL) and NaOH (40% in water, 20 mL) was heated to reflux for 12 h. After this time, the reaction was cooled to RT, and the reaction mixture was concentrated in vacuo. The pH of the residue was adjusted to ~3 by the addition of HC1 (6.0 N) to provide an off-white solid that filtered to provide 1 -phenyl- lH-indazole-5-carboxylic acid. Step 3 : To a solution of l-phenyl-lH-indazole-5-carboxylic acid (2.0 g, 8.4 mmol) was added BH3-THF (1.0 M, 20 mL) and the reaction mixture was heated to reflux for 12 h. After this time, the reaction was cooled to RT and the reaction mixture was quenched with
concentrated HC1 (10 mL) and then heated to reflux for an additional 3 h. The reaction mixture was then cooled to room temperature and NaHC03 (aq) was added dropwise to adjust the pH~7 and then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SC"4, filtered and concentrated in vacuo. Purification via normal phase column chromatography (hexane:ethyl acetate/2: 1) provided a -1 : 1 mixture of 5-(chloromethyl)-l-phenyl-lH-indazole and (1 -phenyl- lH-indazol-5-yl)methanol that was used in the next step directly.
Step 4: To the 1 : 1 mixture of 5 -(chloromethyl)-l -phenyl- lH-indazole and (1-phenyl-lH- indazol-5-yl) (1.0 g, 4.4 mmol) in DMF (10 mL) was added NaCN (428 mg, 8.7 mmol) and the reaction was heated to 50 °C for 48 h. After this time, the reaction mixture was cooled to RT and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated in vacuo. Purification via normal phase column chromatography (hexane/ethyl acetate: 2/1) provided 2-(l-phenyl-lH-indazol-5-yl)acetonitrile as an off-white solid.
Step 5: To a solution of 2-(l-phenyl-lH-indazol-5-yl)acetonitrile(730 mg, 3.13 mmol) in THF (10 mL) was added BH3-THF (1.0 M, 15 mL) and the reaction was heated to reflux for 12 h. After this time, the reaction was cooled to RT and HC1 (3.0 N, 10 mL) was added and the reaction mixture was then heated to reflux for 3 h. The reaction mixture was then cooled to RT and NaHC03 (aq) was added to adjust the pH~7. The reaction mixture was then extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SC"4, filtered and concentrated in vacuo. Purification via normal phase column chromatography (hexane:ethyl acetate/4: 1) provided the title compound as a yellow oil. LCMS (MH+): 238.1.
Intermediate 43: 2-(4-phenyl-lH-imidazol-2-yl)ethanamine
Figure imgf000065_0001
Step 1 : To a solution of 3-((tert-butoxycarbonyl)amino)propanoic acid (CAS#: 26250- 90-8, 2 g, 10.58 mmol) in DMF (20 mL) was added Cs2C03 (1.72 g, 5.28 mmol) and the reaction mixture was stirred at RT for 1 h. After this time, 2-bromo-l-phenylethanone (CAS#: 70-11-1, 2.1 g, 0.256 mmol) was added and the reaction mixture was stirred for an additional 12 h at RT. The solvent was then removed in vacuo and ethyl acetate was added (50 mL) and the resultant white solid was filtered away from the reaction mixture. The filtrate was concentrated in vacuo to provide 2-oxo-2-phenylethyl 3-((tert-butoxycarbonyl)amino)propanoate as a light yellow solid that was used without further purification.
Step 2: To a solution of 2-oxo-2-phenylethyl 3-((tert-butoxycarbonyl)amino)propanoate (3 g, 9.8 mmol) in xylene (25 mL) was added ammonium acetate (7.84 g, 102 mmol ). The reaction mixture was heated to 140 °C for 2 h. After this time, the reaction mixture was cooled to RT and then poured into saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SC"4, filtered and concentrated in vacuo. Purification via normal phase column chromatography (hexane:ethyl acetate/4: 1) provided tert- butyl (2-(4-phenyl-lH-imidazol-2-yl)ethyl)carbamate as a light yellow oil.
Step 3 : To a solution of tert-butyl (2-(4-phenyl-lH-imidazol-2-yl)ethyl)carbamate (200 mg, 0.7 mmol) in MeOH (2 mL) was added HC1 (3.6 M in MeOH, 10 mL) and stirred at RT for 3 h. After this time, the reaction mixture was concentrated in vacuo to provide the title compound as a yellow oil that was used without further purification. LCMS (MH+): 224.1.
Intermediate 44: (R)-2-(4-bromophenyl)-3-methylbutan-l-amine
Figure imgf000066_0001
Step 1 : A solution of ethyl 2-(4-bromophenyl)acetate (CAS#: 14062-25-0, 40 g, 164.5 mmol) in DMF (200 mL) was cooled to -10 °C followed by the slow addition of NaH (60% in oil, 4.34g, 181 mmol) in several portions. The reaction mixture was stirred for 15 min and 2- bromopropane (22.2 g, 181 mmol) was added dropwise over 10 min. The reaction mixture was allowed to warm to RT and stirred for 12 h. After this time, the reaction mixture was concentrated in vacuo and then extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated in vacuo. Purification via normal phase column chromatography (hexanes: ethyl acetate/ 4: 1) provided ethyl 2-(4-bromophenyl)-3- methylbutanoate as yellow oil. Step 2: To a solution of ethyl 2-(4-bromophenyl)-3-methylbutanoate (26 g, 91.2 mmol) in EtOH (50 mL) was added aq. KOH (5 N,50 mL) and the reaction was heated to reflux for 12 h. The reaction mixture was then cooled to RT, and concentrated in vacuo. To the oily reside was adjusted the pH to ~3 with HCl (6.0 N) and the resulting solid was filtered and dried to provide 2-(4-bromophenyl)-3-methylbutanoic acid as an off- white solid that was used without further purification.
Step 3 : To a solution of 2-(4-bromophenyl)-3-methylbutanoic acid (12.7 g, 49.4 mmol) in C¾CN (75 mL) was added R-(+)-l-phenylethylamine (3.0 g, 24.7 mmol) in C¾CN (50 mL). After 1 h, the crystalline precipitate was filtered off, washed with cold C¾CN and dried in vacuo. To obtain high enantioselectivity, the crystalline diastereomeric salt was recrystallized an additional 3 times from MeOH and DMF (1 : 1) (filtering drying and then subjecting to the process each time). The corresponding diastereomeric salt was suspended in ether and treated with 3 N HCl to adjust the pH to ~1. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated in vacuo to provide (R)-2-(4-bromophenyl)-3-methylbutanoic acid as an off-white solid in >99%ee. Chiral HPLC analysis: Chiralcel OD-H (4.6 x 250 mm, 5 uM); hexanes:ethanol:TFA/99:5: l, retention time of 35.16 min. Optical rotation [a]2oD = -41.4 (c = 0.408, CHC13).
Step 4: To a 0 °C solution of (R)-2-(4-bromophenyl)-3-methylbutanoic acid (6 g, 23.6 mmol) in CH2C12 (20 ml) was added oxalyl chloride (6 g, 47.2 mmol) dropwise over a 10 min period. After the complete addition of oxalyl chloride, DMF (2 drops) was added to and the reaction was warmed to RT for 2 h. After this time, the reaction mixture was then concentrated in vacuo and the residue was dissolved in CH2C12 (15 mL), cooled to 0 °C and poured directly into ammonium hydroxide (28% ¾ in water, 50 mL), warmed to RT and stirred for 2 h then concentrated in vacuo. To the residue was added HCl (3N) to adjust the pH to ~7 and the resulting solid was filtered, washed with water, and dried in vacuo to provide (R)-2-(4- bromophenyl)-3-methylbutanamide as a white solid that was used without further purification.
Step 5: To a solution of (R)-2-(4-bromophenyl)-3-methylbutanamide (5.5 g, 21.7 mmol) was added BH3-THF (50 mL) and then heated to reflux for 12 h. After this time, the reaction mixture was cooled to RT and a second addition of BH3-THF (50 mL) was added and the reaction mixture was heated to reflux for an additional 12 h. After this time, the reaction mixture was cooled to RT, and quenched with 3 N HCl, and then heated to reflux for 3 h. The reaction was then cooled to RT and 1 N NaOH was added dropwise to adjust the pH to ~7 and then the entire mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated in vacuo. Purification via normal phase column chromatography (CH2Cl2:MeOH/9: 1) provided the title compound as a light yellow oil. LCMS (MH+): 242.05.
Intermediate 45: (S)-2-(4-bromophenyl)-3-methylbutan-l-amine
Figure imgf000068_0001
The title compound was made as described in Intermediate 44: (R)-2-(4-bromophenyl)-3- methylbutan-1 -amine using S-(+)-l-phenylethylamine. Chiral HPLC analysis of (S)-2-(4- bromophenyl)-3-methylbutanoic: Chiralcel OD-H (4.6 x 250 mm, 5 uM);
hexanes:ethanol:TFA/99:5:, retention time of 30.94 min. Optical rotation [a]2oD = 40.0 (c = 1, MeOH). LCMS (MH+): 242.05. Intermediate 46: (R)-3-methyl-2-(naphthalen-2-yl)butan-l-amine
Figure imgf000068_0002
The title compound was made as described for Intermediate 44: starting with a-isopropyl- 2-naphthaleneacetic acid (CAS#: 64497-79-6 ) in place of 2-(4-bromophenyl)-3-methylbutanoic acid. LCMS (MH+): 214.15.
Intermediate 47: (R)-2-(4-bromophenyl)-2-cyclobutylethanamine
Figure imgf000068_0003
The title compound was made as described for Intermediate 44: (R)-2-(4 bromophenyl)- 3-methylbutan-l-amine using bromocyclobutane (CAS#: 4399-47-7 ) in place of 2- bromopropane. LCMS (MH+): 254.05.
Intermediate 48: (R)-2-(4-bromophenyl)-2-cyclopentylethanamine
Figure imgf000069_0001
The title compound was made as described for Intermediate 44: (R)-2-(4 bromophenyl)- 3-methylbutan-l-amine using bromocyclopentane (CAS#: 137-43-9) in place of 2- bromopropane. LCMS (MH+): 268.06.
Intermediate 49: (R)-2-(4-bromophenyl)-2-cyclohexylethanamine
Figure imgf000069_0002
The title compound was made as described for Intermediate 44: (R)-2-(4 bromophenyl)- 3-methylbutan-l-amine using bromocyclohexane (CAS#: 108-85-0) in place of 2-bromopropane. LCMS (MH+): 282.1.
Intermediate 50: (R)-2-(4-bromophenyl)-2-(4,4-dimethylcyclohexyl)ethanamine
Figure imgf000069_0003
The title compound was made as described for Intermediate 44: (R)-2-(4 bromophenyl)- 3-methylbutan-l-amine using 4-bro mo- 1, 1 -dimethyl- cyclohexane (CAS#: 25090-97-5) in place of 2-bromopropane. LCMS (MH+): 310.1. Intermediate 51: (R)-2-(4-bromophenyl)-2-cycloheptylethanamine
Figure imgf000070_0001
The title compound was made in the identical manner as described for Intermediate 44: (R)-2-(4 bromophenyl)-3-methylbutan-l -amine using bromocycloheptane (CAS#: 137-43-9 ) in place of 2-bromopropane. LCMS (MH+): 295.10.
Intermediate 52: (R)-2-(4-bromophenyl)-N,3-dimethylbutan-l-amine
Figure imgf000070_0002
Step 1 : To a solution of (R)-2-(4-bromophenyl)-3-methylbutan-l -amine (Intermediate 44„ 1 g, 4.1 mmol) in CH2C12 (10 mL) was added (Boc) 20 (1 g, 4.5 mmol) and TEA (1.2 mL, 8.2 mmol) The reaction mixture was stirred at RT for 3 h and then diluted with water and extracted with CH2C12. The organic layer was washed with brine, dried over Na2SC"4, filtered and concentrated in vacuo. Purification via normal phase column chromatography
(CH2Cl2:MeOH/9: l) provided (R)-tert-butyl (2-(4-bromophenyl)-3-methylbutyl)carbamate as a yellow oil.
Step 2: To a 0 °C solution of (R)-tert-butyl (2-(4-bromophenyl)-3-methylbutyl)carbamate (300 mg, 0.87 mmol) in DMF (5 mL) was added NaH (39 mg, 0.964 mmol) and the reaction was stirred for 15 min. After this time, methyl iodide (254.33 mg, 1.75 mmol) was added, and the reaction was warmed to RT and stirred for 2 h. Then, the reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SC"4, filtered and concentrated in vacuo. Purification via normal phase column chromatography (CH2Cl2:MeOH/10: l) provided (R)-tert-butyl (2-(4-bromophenyl)-3-methylbutyl) (methyl)carbamate as a yellow oil.
Step 3 : To a 0 °C solution of (R)-tert-butyl (2-(4-bromophenyl)-3-methylbutyl) (methyl) carbamate in CH2C12 (6 mL) was added TFA (1.5 mL) and the reaction mixture was stirred for 1 h at 0 °C. After this time, the reaction mixture was concentrated, and saturated aqueous
NaHCC was added to adjust the pH 6-7 and then extracted with CH2C12. The organic layer was washed with brine, dried over Na2SC"4, filtered and concentrated in vacuo to provide the title compound as a yellow solid that was used without further purification. LCMS (MH+): 256.10. Intermediate 53: (R)-2-(4-bromophenyl)-2-cyclopropylethanamine
Figure imgf000071_0001
The title compound was made as described for Intermediate 44: (R)-2-(4 bromophenyl)- 3-methylbutan-l-amine using bromocyclopropane (CAS#: 4333-56-6) in place of 2- bromopropane. LCMS (MH+): 240.03.
Intermediate 54: (R)-2-(4-bromophenyl)-3,3-dimethylbutan-l-amine
Figure imgf000071_0002
Step 1 : t-Butyl magnesium chloride in ether (2M, 61 ml) was added to a solution of 4- bromo benzaldehyde (15g) in THF (200 ml) at 0 °C. The mixture was allowed to warm RT and stirred for 5 h. Saturated H4CI solution was added and extracted with ethyl acetate. The organic layer was dried and concentrated. The crude was purified by flash chromatography (3% to 10% ethyl acetate in hexane) to provide (4-bromophenyl)(t-butyl)methanonol as a colorless oil. (7.9 g).
Step 2: To a solution of l-(4-bromophenyl)-2,2-dimethylpropan-l-ol (3.8 g, 15.7 mmol) in CH2C12 (20 ml) was added a homogeneous mixture of PCC (12 g) and silica gel (12 g). The mixture was stirred at room temperature for 4 h. Filtration of the reaction mixture through a short silica pad with excess CH2CI2 provided (4-bromophenyl)(t-butyl)methanone (3.4 g).
Step 3 : To a solution of methyl triphenylphosphonium bromide (8.8 g) in THF (100 mL) at -78 °C was added n-BuLi (2.5 M in hexane, 10.4 mL) slowly. The mixture was stirred at 0 °C for 30 min. To the reaction mixture was added a solution of (4-bromophenyl)(t-butyl)methanone (21) (5.3 g) in THF (10 mL). The mixture was allowed to warm to room temperature, stirred 24 h, and partitioned between TBME and saturated NH4CI solution. The combined organics were dried, filtered and concentrated in vacuo. The residue was purified by flash chromatography with 50: 1 hexane/EA to provide 3, 3 -dimethyl -2-(4-bromophenyl)-l-butene (3.7 g).
Step 4: To a solution of 3,3-dimethyl2-(4-bromophenyl)-l-butene(22) (2.5g) in THF at 0
°C, was added B¾ (1 M in THF, 18 mL) dropwise. The mixture was allowed to warm to room temperature, and stirred for 1 h. 1 M Aqueous NaOH solution (21 mL) and H2O2 (30% in water, 2.6g) was slowly added. The mixture was stirred at room temperature for 1 hr, and then partitioned between TBME (50 mL) and water (50 mL). The aqueous layer was extracted with TBME (50 mL x 2). The combined organic layers were washed with brine, dried, and
concentrated and then was purified by flash chromatography with 4: 1 hexane/EA to provide 3,3- dimethyl-2-(4-bromophenyl)butanol (1.8 g) as a white solid.
Step 5: To a mixture 3,3-dimethyl-2-(4-bromophenyl)butanol (1.81g) in DMF (20 mL) at room temperature was added PDC (8.2 g) in portions. The mixture was stirred at room temperature overnight, and then diluted with EA (100 mL), filtered through a celite pad. The filtrate was washed with water, brine and dried, filtered and concentrated to give the crude product which was purified by flash chromatography with 4: 1 hexane/EA to provide 3,3- dimethyl-2-(4-bromophenyl)butanoic acid as a white solid (0.7 g).
Step 6: A solution of 3,3-dimthyl-2-(4-bromophenyl)butanoic acid (0.7 g) in 4 mL of thionyl chloride was stirred at RT for 12 h. Thionyl chloride was removed under vacuum and chased twice with CH2CI2. After drying under vacuum, 2-(4-bromophenyl)-3,3-dimethylbutanoyl chloride was obtained as an oil (0.6 g).
Step 7: To a solution of (R)-4-benzyl-2-oxazolidinone (0.5 g) in THF (20 mL) was cooled to -78 °C and n-BuLi (2.5 M in hexane, 1.5 mL) was added drop-wise. The mixture was stirred 30 min then a solution of 2-(4-bromophenyl)-3,3-dimethylbutanoyl chloride (0.6 g) in THF (3 mL) was added at -78°C. The mixture was stirred for 1 h and the saturated H4CI solution (20 mL) was added. The organic layer was separated and the aqueous layer was extracted twice with TBME (10 mL). The combine organic extracts were dried, filtered and concentrated in vacuo. The resulting diasteromers were separated with flash chromatography by gradient of hexane, 50: 1 hexane/EA, then 10: 1 hexane/EA to give (4R)-4-benzyl-3-[(2R)-2-tert- butyl-2-(4-bromophenyl)acetyl]-1.3-oxazolidin-2-one as an oil (0.32 g) (up spot) and (4R)-4- benzyl-3-[(2S)-2-tert-butyl-2-(4-bromophenyl)acetyl]-1.3-oxazolidin-2-one as a white solid (0.31 g) (low spot).
Step 8: To a solution of (4R)-4-benzyl-3-[(2R)-2-tert-butyl-2-(4-bromophenyl)acetyl]- 1.3-oxazolidin-2-one (2 g, 4.65 mmol) in THF/water (60/20 mL) was added 30% H202 (3.8 mL) at 0 °C and stirred for 10 min. Then LiOH.H20 (400 mg, 9.3 mmol ) was added. The reaction mixture was stirred at RT overnight. After cooling to 0 °C, Na2S0 (4.8 g, 37.2 mmol) was added and the mixture was stirred for 30 min, and then extracted with EA. The aqueous layer was collected and acidified to pH=2 with 5% KHSO4, extracted with ethyl acetate, dried, filtered, and concentrated to afford (R)-2-(4-bromophenyl)-3,3-dimethylbutanoic acid (900 mg) as an oil.
Step 9: To a solution of (R)-2-(4-bromophenyl)-3,3-dimethylbutanoic acid (900 mg, 3.32 mmol) in CH2C12 (10 mL) was added (COCl)2 (1 mL) at 0 °C, then DMF (1 drop) was added and stirred for 2 h. After this time, the reaction mixture was concentrated, and the resulting residue was poured into H .H20 and filtered. The solid was collected to afford (R)-2-(4- bromophenyl)-3,3-dimethylbutanamide (600 mg) that was used in the next step without further purification.
Step 10: A solution of (R)-2-(4-bromophenyl)-3,3-dimethylbutanamide (600 mg, 2.22 mmol) in THF was cooled to 0 °C to which BH .THF (50 mL) was added slowly, then the mixture was refluxed for 12 h. After this time, the reaction was cooled to RT and 3 N HCl (10 mL) was added. The mixture was refluxed for 2 h, then cooled to RT. The pH was adjusted to ~8 with aqueous NaHC0 and then extracted with ethyl acetate, dried, filtered, concentrated, and purified by flash column (CH2C12 /MeOH= 15/1 v/v) to afford the title compound (450 mg) as an oil. LCMS (MH+): 256.1.
Intermediate 55: (R)-2-(4,4-dimethylcyclohexyl)-2-phenylethanamine
Figure imgf000074_0001
The title compound was made as described for Intermediate 44 ((R)-2-(4 bromophenyl)- 3-methylbutan-l-amine) using 4-bro mo- 1, 1 -dimethyl cyclohexane (CAS#: 25090-97-5) in place of 2-bromopropane and ethyl phenylacetate (CAS# 101-97-3) in place of ethyl 2-(4- bromophenyl)acetate. LCMS (MH+): 232.2.
Intermediate 56: (R)-2-(4,4-dimethylcyclohexyl)-2-(p-tolyl)ethanamine
Figure imgf000074_0002
The title compound was made as described for Intermediate 44 ((R)-2-(4 bromophenyl)- 3-methylbutan-l-amine) using 4-bro mo- 1, 1 -dimethyl cyclohexane (CAS#: 25090-97-5) in place of 2-bromopropane and ethyl 4-methylphenylacetate (CAS# 94-08-6) in place of ethyl 2-(4- bromophenyl)acetate. LCMS (MH+): 246.4.
Intermediate 57: (R)-2-(4,4-dimethylcyclohexyl)-2-(4-fluorophenyl)ethanamine
Figure imgf000074_0003
The title compound was made as described for Intermediate 44 ((R)-2-(4 bromophenyl)- 3-methylbutan-l-amine) using 4-bro mo- 1, 1 -dimethyl cyclohexane (CAS#: 25090-97-5) in place of 2-bromopropane and ethyl 4-fluorophenylacetate (CAS# 587-88-2) in place of ethyl 2-(4- bromophenyl)acetate. LCMS (MH+): 250.4. Intermediate 58: (R)-2-(4,4-dimethylcyclohexyl)-2-(4-methoxyphenyl)ethanamine
Figure imgf000075_0001
The title compound was made as described for Intermediate 44 ((R)-2-(4 bromophenyl)- 3-methylbutan-l-amine) using 4-bro mo- 1, 1 -dimethyl cyclohexane (CAS#: 25090-97-5) in place of 2-bromopropane and ethyl 4-methoxyphenylacetate (CAS# 14062-18-1) in place of ethyl 2- (4-bromophenyl)acetate. LCMS (MH+): 262.4.
Intermediate 59: (R)-2-(4,4-dimethylcyclohexyl)-2-(4-chlorophenyl)ethanamine
Figure imgf000075_0002
The title compound was made as described for Intermediate 44 ((R)-2-(4 bromophenyl)- 3-methylbutan-l-amine) using 4-bro mo- 1, 1 -dimethyl cyclohexane (CAS#: 25090-97-5) in place of 2-bromopropane and ethyl 4-chlorophenylacetate (CAS# 14062-24-9) in place of ethyl 2-(4- bromophenyl)acetate. LCMS (MH+): 266.8. Intermediate 60: (R)-2-(4,4-dimethylcyclohexyl)-2-(4-(trifluoromethyl)phenyl)-ethanamine
Figure imgf000075_0003
The title compound was made as described for Intermediate 44 ((R)-2-(4 bromophenyl)- 3-methylbutan-l-amine) using 4-bro mo- 1, 1 -dimethyl cyclohexane (CAS#: 25090-97-5) in place of 2-bromopropane and ethyl 4-(trifluoromethyl)phenylacetate (CAS# 721-63-1) in place of ethyl 2-(4-bromophenyl)acetate. LCMS (MH+): 300.4. Intermediate 61: (2R)-2-(4-bromophenyl)-2-(4-(tert-butyl)cyclohexyl)-ethanamine
Figure imgf000076_0001
The title compound was made as described for Intermediate 44 ((R)-2-(4 bromophenyl)- 3-methylbutan-l-amine) using l-bromo-4-(tert-butyl)cyclohexane (CAS#: 7080-86-6) in place of 2-bromopropane. LCMS (MH+): 339.14.
Intermediate 62: (2R)-2-(4-bromophen l)-2-(4-(trifluoromethyl) cyclohexyl) ethanamine
Figure imgf000076_0002
The title compound was made as described for Intermediate 44 ((R)-2-(4 bromophenyl)- 3 -methylbutan-1 -amine) using l-bromo-4-(trifluoromethyl)cyclohexane (CAS#: 30129-20-5 ) in place of 2-bromopropane. LCMS (MH+): 351.22.
Intermediate 63: (R)-2-(4-bromophe nan-7-yl)ethanamine
Figure imgf000076_0003
Step 1 : To a 0 °C solution of spiro[3.5]nonan-7-ol (CAS#: 1393450-96-8, 1 g, 140 mmol) in CH2CI2 was added triphenylphosphine (0.08 g, 0.28 mmol), imidazole (0.03 g, 0.43 mmol), and iodine (0.05 g, 0.03 mmol). The mixture was heated at 100 °C for 1 h then cooled to RT. The mixture was poured into a saturated solution of NaHC0 . Excess triphenylphosphine was destroyed by the addition of iodine until the iodine coloration persisted in the organic layer. The organic layer was washed twice with 5% (wt.) Na2S20 and brine, dried over MgS04, filtered, and concentrated in vacuo. The residue was purified on silica gel (hexanes/ethyl acetate, 8/1) to provide 7-iodospiro[3.5]nonane as as a light yellow oil.
Step 2: The title compound was made as described for Intermediate 44 ((R)-2-(4 bromophenyl)-3-methylbutan-l -amine) using 7-iodospiro[3.5]nonane in place of 2- bromopropane. LCMS (MH+): 322.11. Intermediate A: (S)-4-(2-((tert-butoxycarbonyl)amino)-3-ethoxy-3-oxopropyl)benzoic acid
Figure imgf000077_0001
Step 1 : To a 0 °C solution of (S)-ethyl 2-((tert-butoxycarbonyl)amino)-3-(4- hydroxyphenyl)propanoate (CAS#: 72594-77-5, 7 g, 22.7 mmol) in CH2C12 (70 mL), was added pyridine (8.95 g, 113.2 mmol) followed by the dropwise addition of trifluoromethanesulfonic anhydride (6.7 g, 23.7 mmol) over a 30 min period. After this time, the reaction was stirred at 0 °C for 5 h, then extracted with CH2C12. The organic layer was washed sequentially with a 0.5 N NaOH solution , water, 1 N HCl, and brine, then dried over Na2SC"4, filtered and concentrated in vacuo to provide (S)-ethyl 2-((tert-butoxycarbonyl)amino)-3-(4-(((trifluoromethyl)sulfonyl) oxy)phenyl)propanoate as an off-white solid that was used without further purification.
Step 2: To a solution of (S)-ethyl 2-((tert-butoxycarbonyl)amino)-3-(4-(((trifluoromethyl) sulfonyl)oxy)phenyl)propanoate (10 g, 22.6 mmol) in DMF/H20 (45 mL/15 mL) was added iPr2NEt(5.8 g, 45.2 mmol), l,3-bis(diphenylphosphino)propane (560 mg, 1.4 mmol), and
Pd(OAc)2 (152 mg, 0.68 mmol). The reaction was stirred at 70 °C under 1 atm of CO for 12 h. After this time, the reaction was cooled to RT and extracted with ethyl acetate. The organic layer was washed with NaHC0 , 3N HCl, brine and then dried over Na2S04, filtered and concentrated in vacuo to provide the title compound as a white solid that was used without further purification. ¾ NMR (500 MHz, CDC13) δ ppm: 8.09 - 8.03 (m, 2H), 7.46 (dt, J= 7.3, 1.1 Hz, 2H), 5.29 (t, J= 7.1 Hz, 1H), 4.19 (dq, J= 12.3, 8.0 Hz, 1H), 4.09 (dq, J= 12.5, 8.0 Hz, 1H), 3.37 (ddt, J= 12.4, 7.1, 1.0 Hz, 1H), 3.15 (ddt, J= 12.5, 7.2, 1.1 Hz, 1H), 1.44 (s, 9H), 1.18 (t, J= 8.0 Hz, 3H). LCMS (MH+): 338.
Intermediate B: (S)-ethyl 2-((tert-butoxycarbonyl)amino)-3-(4-(((R)-3-methyl-2-(4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)butyl)carbamoyl)phenyl)propanoate
Figure imgf000078_0001
To a solution of (S)-ethyl 3-(4-(((R)-2-(4-bromophenyl)-3-methylbutyl)
carbamoyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (from Step 1 of Example la, 2 g, 3.6 mmol) in dioxane (30 mL) was added Pd(dppf)Cl2 (260 mg, 0.36 mmol),
bis(pinacolato)diboron (1.8 g, 7.1 mmol), and KOAc (1.05 g, 10.68 mmol). The reaction mixture was heated to 90 °C for 12 h. After this time, the reaction was cooled to RT and extracted with ethyl acetate. The the organic layer was washed with NaHC0 , brine, dried over Na2S04, filtered, and concentrated in vacuo. Purification via normal phase column
chromatography (hexanes: ethyl acetate/2: 1 v/v) provided the title compound as an off-white solid (2.5 g). LCMS (MH+): 553.4.
Representative experimental procedure
Example la: (S)-3-(4-(((R)-2-([l,l'-biphenyl]-4-yl)-3-methylbutyl) carbamoyl)ph
aminopropanoic acid
Figure imgf000078_0002
Step 1 : To a solution of (S)-4-(2-((tert-butoxycarbonyl)amino)-3-ethoxy-3- oxopropyl)benzoic acid (Intermediate A, 200 mg, 0.82 mmol) in DMF (10 mL) was added (R)-2- (4-bromophenyl)-3-methylbutan-l -amine (Intermediate 44, 278 mg, 1.24 mmol), HATU (623 mg, 1.64 mmol), and TEA (166 mg, 1.64 mmol), and the reaction was stirred for 48 h at RT. After this time, the reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated in vacuo. Purification via normal phase column chromatography (hexanes: ethyl acetate/4: 1 v/v) provided (S)-ethyl 3- (4-(((R)-2-(4-bromophenyl)-3-methylbutyl)carbamoyl)phenyl)-2-((tert- butoxycarbonyl)amino)propanoate as a white solid.
Step 2: To a solution of (S)-ethyl 3-(4-(((R)-2-(4-bromophenyl)-3-methylbutyl) carbamoyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (200 mg, 0.36 mmol) in dioxane (5.0 mL)/Na2C03 (2.5 mL, 2.0 M, aq.) was added phenyl boronic acid (66 mg, 0.54 mmol) followed by Pd(dppf)Cl2 (26 mg, 0.036 mmol). The reaction was purged with N2 and then heated to 90 °C for 3 h. After this time, the reaction was cooled to RT and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SC"4, filtered and concentrated in vacuo. Purification via normal phase column chromatography (hexanes: ethyl acetate/4: 1) provided (S)-ethyl 3-(4-(((R)-2-([l, r-biphenyl]-4-yl)-3-methylbutyl)carbamoyl)phenyl)-2-((tert- butoxycarbonyl)amino)propanoate as an off-white solid.
Step 3 : To a 0 °C solution of (S)-ethyl 3-(4-(((R)-2-([l, l*-biphenyl]-4-yl)-3-methylbutyl) carbamoyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (150 mg, 0.27 mmol) in CH2C12 (6 mL), was added dropwise TFA (1.5 mL). The reaction was warmed to RT for 3 h, then concentrate in vacuo. To the resulting residue was added saturated aqueous solution of NaHC03 to adjust the pH to -7.5 and then extracted with CH2C12. The organic layer was washed with brine, dried over Na2SC"4, filtered and concentrated in vacuo to provide (S)-ethyl 3-(4-(((R)-2- ([l, l'-biphenyl]-4-yl)-3-methylbutyl)carbamoyl)phenyl)-2-aminopropanoate as an off-white solid.
Step 4: To a 0 °C solution of (S)-ethyl 3-(4-(((R)-2-([l, l'-biphenyl]-4-yl)-3-methylbutyl) carbamoyl)phenyl)-2-aminopropanoate (75 mg, 0.16 mmol) in MeOH (6 mL), was added dropwise 5 N NaOH (2 mL) and then the reaction mixture was warmed to RT for 3 h. After this time, the reaction mixture was acidified with 3N HC1 to adjust the pH to 6-7, the MeOH was removed in vacuo and the resultant solid was filtered, washed with H20, and dried in vacuo to provide the title compound as a white solid. 1H NMR (400 MHz, MeOH-d4): δ ppm 7.61-7.50 (m, 7H), 7.40 (t, J = 7.5 Hz, 3H), 7.29 (dd, J = 11.4, 7.3 Hz, 6H), 3.88 (dd, J = 13.5, 5.1 Hz, 2H), 3.75 (s, 1H), 3.62 (t, J = 11.7 Hz, 2H), 3.34 (s, 1H), 3.02 (s, 1H), 2.84 (s, 1H), 2.03-1.96 (m, 1H), 1.09 (d, J = 6.5 Hz, 4H), 0.82 (d, J = 6.5 Hz, 4H). LCMS (MH+): 430.54.
Example lb: (S)-3-(4-(((S)-2-([l,l'-biphenyl]-4-yl)-3-methylbutyl) carbamoyl)phenyl)-2- aminopropanoic acid
Figure imgf000080_0001
The title compound was prepared as described in Example la: (S)-3-(4-(((R)-2-([l, l'- biphenyl]-4-yl)-3-methylbutyl)carbamoyl)phenyl)-2-aminopropanoic acid, starting with (S)-2-(4- bromophenyl)-3-methylbutan-l -amine (Intermediate 45).
¾ NMR (400 MHz, DMSO-d6): δ ppm 7.56 (ddd, J = 12.9, 7.5, 3.2 Hz, 5H), 7.40 (t, J = 7.7 Hz, 2H), 7.29 (dd, J = 11.1, 8.0 Hz, 4H), 3.88 (dd, J = 13.3, 5.4 Hz, 1H), 3.74 (dd, J = 8.5, 4.5 Hz, 1H), 3.62 (dd, J = 13.3, 10.3 Hz, 1H), 3.01 (dd, J = 14.5, 8.6 Hz, 1H), 2.84 (td, J = 10.0, 9.2, 5.5 Hz, 1H), 2.00 (dq, J = 14.0, 7.0 Hz, 1H), 1.09 (d, J = 6.7 Hz, 3H), 0.82 (d, J = 6.7 Hz, 3H).
LCMS (MH+): 430.54.
The following compounds in Table 3a were prepared as described above for (S)-3-(4- (((R)-2-([l,l'-biphenyl]-4-yl)-3-methylbutyl)carbamoyl)phenyl)-2-aminopropanoic acid
(Example la). NMR data is provided in Table 3b.
Table 3a
Figure imgf000080_0002
Figure imgf000081_0001
Figure imgf000082_0001
(S)-2-amino-3 -(4-(((R)-2-(3 '-chloro-[ 1, 1'- biphenyl]-4-yl)-3-
465.98 methylbutyl)carbamoyl)phenyl)propanoic
acid
(S)-2-amino-3-(4-(((R)-2-(3'-methoxy-5'- methyl- [1, 1 '-bipheny 1] -4-yl)-3 -
475.59 methylbutyl)carbamoyl) phenyl)propanoic
acid
(S)-2-amino-3 -(4-(((R)-2-(3 *-(tert-butyl)-[ 1 , 1 '- biphenyl]-4-yl)-3-methylbutyl)carbamoyl) 487.65 phenyl)propanoic acid
(S)-2-amino-3-(4-(((R)-2-(3',5'-dimethyl-
[l,r-biphenyl]-4-yl)-3-
459.59 methylbutyl)carbamoyl)phenyl)propanoic
acid
(S)-2-amino-3 -(4-(((R)-2-(3 '-methoxy-[ 1 , 1 '- biphenyl]-4-yl)-3-
461.57 methylbutyl)carbamoyl)phenyl)propanoic
acid
(S)-2-amino-3 -(4-(((R)-2-(3 '-hydroxy-[ 1 , 1 '- biphenyl]-4-yl)-3-
447.54 methylbutyl)carbamoyl)phenyl)propanoic
OH acid
(S)-2-amino-3 -(4-(((R)-3-methyl-2-(3 '- (trifluoromethyl)-[ 1 , 1 '-biphenyl]-4- 499.54 yl)butyl)carbamoyl) phenyl)propanoic acid
(S)-2-amino-3 -(4-(((R)-2-(3 '-ethyl-[ 1 , 1 '- biphenyl]-4-yl)-3-methyl 459.59 butyl)carbamoyl)phenyl)propanoic acid
(S)-3-(4-(((R)-2-(4-(lH-indazol-6-yl)phenyl)- 3 -methyl butyl) carb amoyl)p heny l)-2- 471.56
N-N aminopropanoic acid
H
(S)-2-amino-3 -(4-(((R)-2-(4'-methoxy-[ 1 , 1 '- biphenyl]-4-yl)-3-
461.57 methylbutyl)carbamoyl)phenyl)propanoic
acid
(S)-2-amino-3 -(4-(((R)-2-(3 '-isopropyl-[ 1 , 1 '- biphenyl]-4-yl)-3-
472.62 methylbutyl)carbamoyl)phenyl)
propanoic acid
(S)-2-amino-3-(4-(((R)-2-(3'-cyclopropyl- [l,r-biphenyl]-4-yl)-3-
471.60 methylbutyl)carbamoyl)phenyl)
propanoic acid (S)-3-(4-(((R)-2-(3 '-( IH-pyrazol- 1 -yl)-[ 1 , 1 '- biphenyl]-4-yl)-3-
38 497.60 methylbutyl)carbamoyl)phenyl)-2- aminopropanoic acid
(S)-2-amino-3 -(4-(((R)-3-methyl-2-(3 '- (oxazol-2-yl)-[ 1 , 1 '-biphenyl]-4-
39 498.59 yl)butyl)carbamoyl)phenyl)
propanoic acid
(S)-2-amino-3-(4-(((R)-3-methyl-2-(4'- (trifluoromethyl)-[ 1 , 1 '-biphenyl]-4-
40 499.54 yl)butyl)carbamoyl)phenyl)
propanoic acid
(S)-2-amino-3 -(4-(((R)-2-(4'-ethoxy-[ 1 , 1 '- biphenyl]-4-yl)-3-
41 475.59 methylbutyl)carbamoyl)phenyl)
propanoic acid
(S)-2-amino-3 -(4-(((R)-2-(4'-fluoro-[ 1 , 1 '- biphenyl]-4-yl)-3-
42 449.53 methylbutyl)carbamoyl)phenyl)
propanoic acid
(S)-2-amino-3 -(4-(((R)-2-(4'-chloro-[ 1, 1'- biphenyl]-4-yl)-3-
43 465.98 methylbutyl)carbamoyl)phenyl)
propanoic acid
(S)-2-amino-3 -(4-(((R)-2-(4'-ethyl-[ 1 , 1 '- biphenyl]-4-yl)-3-
44 459.59 methylbutyl)carbamoyl)phenyl)propanoic
acid
(S)-2-amino-3 -(4-(((R)-2-(4'-isobutyl-[ 1 , 1 '- biphenyl]-4-yl)-3-
45 515.70 methylbutyl)carbamoyl)phenyl)propanoic
acid
(S)-3-(4-(((R)-2-(3 '-(IH-imidazol- 1 -yl)-[ 1 , 1 '- biphenyl]-4-yl)-3-
46 497.60 methylbutyl)carbamoyl)phenyl)-2- aminopropanoic acid
(S)-2-amino-3 -(4-(((R)-2-(4'-(tert-butyl)-[ 1 , 1 '- biphenyl]-4-yl)-3-
47 487.65 methylbutyl)carbamoyl)phenyl)propanoic
acid
(S)-2-amino-3-(4-(((R)-3-methyl-2-(4- (pyridin-4-
48 432.53 yl)phenyl)butyl)carbamoyl)phenyl)propanoic
acid
Figure imgf000085_0001
Figure imgf000086_0001
Table 3b
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Example 72: (S)-3-(4-(((R)-2-([l,l'-biphenyl]-4-yl)-2-cyclopropylethyl) carbamoyl)phenyl)- 2-aminopropanoic acid
Figure imgf000094_0002
The title compound was prepared as described for Example la: (S)-3-(4-(((R)-2-([l,l'- biphenyl]-4-yl)-3-methylbutyl) carbamoyl)phenyl)-2-aminopropanoic acid starting with (R)-2- (4-bromophenyl)-2-cyclopropylethanamine (Intermediate 53).
¾ NMR (400 MHz, DMSO-d6): δ ppm 7.73 (d, J = 7.8 Hz, 2H), 7.60 (dd, J = 19.6, 7.6 Hz, 4H), 7.43 (t, J = 7.6 Hz, 2H), 7.32 (dd, J = 18.8, 7.6 Hz, 5H), 4.22 (s, 1H), 3.62 (qd, J = 13.4, 7.4 Hz, 2H), 3.11 (t, J = 5.4 Hz, 2H), 2.26 (q, J = 8.3 Hz, 1H), 1.22 (s, 1H), 1.06 (s, lH), 0.57 (d, J = 7.4 Hz, 1H), 0.30 (dt, J = 13.6, 7.4 Hz, 2H). LCMS (MH+): 429.52.
Example 73: (S)-3-(4-(((R)-2-([l,l'-biphenyl]-4-yl)-2-cyclobutylethyl) carbamoyl)phenyl)- 2-aminopropanoic acid
Figure imgf000095_0001
The title compound was prepared as described for Example la: (S)-3-(4-(((R)-2-([l,l'- biphenyl]-4-yl)-3-methylbutyl) carbamoyl)phenyl)-2-aminopropanoic acid starting with (R)-2- (4-bromophenyl)-2-cyclobutylethanamine (Intermediate 47).
¾ NMR (400 MHz, DMSO-d6): δ ppm 7.68 (d, J = 8.0 Hz, 2H), 7.57 (dd, J = 22.4, 7.8 Hz, 3H), 7.42 (t, J = 7.6 Hz, 2H), 7.28 (dt, J = 16.1, 7.6 Hz, 4H), 4.18 (t, J = 6.5 Hz, 1H), 3.48 (dd, J = 13.3, 6.1 Hz, 2H), 3.36 (dd, J = 13.1, 8.4 Hz, 2H), 3.09 (dd, J = 6.6, 3.2 Hz, 2H), 2.97 (q, J = 8.4, 7.9 Hz, 2H), 2.63 - 2.53 (m, 2H), 2.12 (s, 1H), 1.80 (dt, J = 17.7, 8.9 Hz, 3H), 1.66 (s, 1H), 1.52 (q, J = 9.5 Hz, 2H). LCMS (MH+): 443.55.
Example 74: (S)-3-(4-(((R)-2-([l,l'-biphenyl]-4-yl)-3,3-dimethylbutyl) carbamoyl)phenyl)- 2-aminopropanoic acid
Figure imgf000095_0002
The title compound was prepared as described for Example la: (S)-3-(4-(((R)-2-([l,l'- biphenyl]-4-yl)-3-methylbutyl)carbamoyl)phenyl)-2-aminopropanoic acid starting with (R)-2-(4- bromophenyl)-3,3-dimethylbutan-l-amine (Intermediate 54).
¾ NMR (400 MHz, DMSO-d6): δ ppm 8.50 (m, 2H), 8.20 (d, J = 5.4 Hz, 2H), 8.12 (s, 1H), 7.66 - 7.52 (m, 3H), 7.42 (t, J = 7.6 Hz, 1H), 7.35 - 7.19 (m, 3H), 4.16 (d, J = 6.1 Hz, 1H), 3.72 (d, J = 6.4 Hz, 1H), 3.13 - 2.98 (m, 1H), 0.92 (s, 5H). LCMS (MH+): 445.57.
Example 75: (S)-2-amino-3-(4-(((R)-2-cyclobutyl-2-(3'-methyl-[l,l'-biph
yl)ethyl)carbamoyl)phenyl)propanoic acid
Figure imgf000096_0001
The title compound was made as described for (S)-3-(4-(((R)-2-([l, l'-biphenyl]-4-yl)-3- methylbutyl) carbamoyl)phenyl)-2-aminopropanoic acid (Example la) starting with (R)-2-(4- bromophenyl)-2-cyclobutylethanamine (Intermediate 47) and 3-methylphenyl bornic acid (CAS# 17933-03-8) in place of phenyl boronic acid.
¾ NMR (400 MHz, OMSO-d6): δ ppm 7.68 - 7.58 (m, 1H), 7.55 - 7.47 (m, 1H), 7.41 - 7.21 (m, 4H), 7.12 (d, J= 7.6 Hz, 1H), 3.76 (dd, J= 8.5, 4.5 Hz, 1H), 3.68 (dd, J= 13.3, 5.8 Hz, 1H), 3.44 (dd, J= 13.4, 9.1 Hz, 1H), 3.03 (dd, J= 14.6, 8.2 Hz, 2H), 2.69 (q, J= 9.2, 8.7 Hz, 1H), 2.38 (s, 2H), 2.03 - 1.75 (m, 4H), 1.64 (q, J= 9.2 Hz, 1H). LCMS (MH+): 457.58.
Example 76: (S)-2-amino-3-(4-(((R)-2-(4'-cyano-[l,l'-biphenyl]-4-yl)-2- cyclobutylethyl)carbamoyl)phenyl)propanoic acid
Figure imgf000096_0002
The title compound was made as described for (S)-3-(4-(((R)-2-([l, l'-biphenyl]-4-yl)-3- methylbutyl) carbamoyl)phenyl)-2-aminopropanoic acid (Example la) starting with (R)-2-(4- bromophenyl)-2-cyclobutylethanamine (Intermediate 47) and 4-cyanophenyl bornic acid (CAS# 126747-14-6) in place of phenyl boronic acid.
¾ NMR (400 MHz, OMSO-d6): δ ppm 8.32 (t, J= 5.6 Hz, 1H), 8.23 (d, J= 5.3 Hz, 1H), 7.86 (q, J= 8.4 Hz, 2H), 7.68 (dd, J= 19.3, 8.0 Hz, 2H), 7.30 (dd, J= 11.4, 8.0 Hz, 2H), 4.20 (d, J = 6.0 Hz, 1H), 3.50 (dt, J= 11.6, 5.5 Hz, 1H), 3.37 (dt, J= 13.5, 6.9 Hz, 1H), 3.17 - 2.95 (m, 2H), 2.61 (p, J= 8.8 Hz, 1H), 2.19 - 2.10 (m, 1H), 1.92 - 1.63 (m, 3H), 1.53 (q, J= 9.4 Hz, 1H), 1.34 (s, 1H). LCMS (MH+): 468.56. Example 77: (S)-2-amino-3-(4-(((R)-2-cyclobutyl-2-(4'-(hydroxymethyl)-[l,l'-biph yl)ethyl)carbamoyl)phenyl)propanoic acid
Figure imgf000097_0001
The title compound was made as described for (S)-3-(4-(((R)-2-([l, l'-biphenyl]-4-yl)-3- methylbutyl) carbamoyl)phenyl)-2-aminopropanoic acid (Example la) starting with (R)-2-(4- bromophenyl)-2-cyclobutylethanamine (Intermediate 47) and 4-hydroxymethylphenyl boronic acid (CAS# 59016-93-2) in place of phenyl boronic acid.
¾ MR (400 MHz, OMSO-d6): δ ppm 8.44 - 8.38 (m, 1H), 7.69 (d, J = 7.9 Hz, 4H), 7.54 (dd, J = 10.6, 7.9 Hz, 8H), 7.35 (d, J = 7.9 Hz, 4H), 7.26 (dd, J = 16.7, 7.9 Hz, 8H), 4.49 (s, 4H), 4.17 (t, J = 6.5 Hz, 3H), 3.48 (dd, J = 13.2, 6.1 Hz, 3H), 3.35 (dd, J = 13.3, 8.3 Hz, 3H), 3.11 (d, J = 6.5 Hz, 4H), 3.00 - 2.91 (m, 3H), 2.58 (q, J = 8.6 Hz, 3H), 2.14 (d, J = 7.3 Hz, 2H), 2.11 (s, 1H), 1.84 (d, J = 8.9 Hz, 2H), 1.80 (s, 2H), 1.78 - 1.61 (m, 7H), 1.52 (q, J = 9.4 Hz, 4H), 1.19 (s, 3H), 0.83 (d, J = 5.3 Hz, 2H).LCMS (MH+): 473.52.
Example 78: (S)-3-(4-(((R)-2-([l,l'-biphenyl]-4-yl)-2-cyclohexylethyl)-carbamoyl)phenyl)-2- aminopropanoic acid
Figure imgf000097_0002
The title compound was made as described for (S)-3-(4-(((R)-2-([l, l'-biphenyl]-4-yl)-3- methylbutyl) carbamoyl)phenyl)-2-aminopropanoic acid (Example la) starting with (R)-2-(4- bromophenyl)-2-cyclohexylethanamine (Intermediate 49).
¾ NMR (400 MHz, OMSO-d6): δ ppm 7.66 - 7.51 (m, 15H), 7.41 (t, J= 7.6 Hz, 5H), 7.35 - 7.19 (m, 13H), 4.15 (t, J= 6.5 Hz, 3H), 3.70 (dd, J= 13.4, 5.9 Hz, 4H), 3.53 (dd, J= 13.3, 9.2 Hz, 4H), 3.08 (d, J= 6.5 Hz, 5H), 2.87 (q, J= 7.1 Hz, 4H), 1.83 (d, J= 12.5 Hz, 3H), 1.67 (d, J = 12.8 Hz, 4H), 1.58 - 1.46 (m, 9H), 1.20 (s, 3H), 1.02 (dp, J= 38.2, 13.1, 12.0 Hz, 12H), 0.76 (q, J= 11.8, 11.1 Hz, 5H). LCMS (MH+): 471.60. Example 79: (S)-3-(4-(((R)-2-([l,l'-biphenyl]-4-yl)-2-(4,4-dimethylcyclohexyl)
ethyl)carbamoyl)phenyl)- -aminopropanoic acid
Figure imgf000098_0001
The title compound was made as described for (S)-3-(4-(((R)-2-([l, l'-biphenyl]-4-yl)-3- methylbutyl) carbamoyl)phenyl)-2-aminopropanoic acid (Example la, starting with (R)-2-(4- bromophenyl)-2-(4, 4-dimethylcyclohexyl)ethanamine (Intermediate 50) .
¾ MR (400 MHz, OMSO-d6): δ ppm 7.65 - 7.51 (m, 6H), 7.41 (t, J = 7.6 Hz, 2H), 7.28 (dd, j = 24.5, 6.9 Hz, 3H), 7.23 (d, J = 6.1 Hz, 2H), 4.15 (t, j = 6.5 Hz, 1H), 3.71 (dd, J = 13.0, 5.8 Hz, 1H), 3.58 - 3.47 (m, 1H), 3.08 (d, J = 6.5 Hz, 2H), 2.89 (q, J = 7.6 Hz, 1H), 1.38 - 1.10 (m, 5H), 1.00 (p, J = 12.7 Hz, 2H), 0.81 (s, 3H), 0.72 (s, 3H) LCMS (MH+): 499.66.
Example 80: (S)-3-(4-(((R)-2-([l,l'-biphenyl]-4-yl)-2-cyclopentylethyl) carbamoyl)phenyl)- 2-aminopropanoic acid
Figure imgf000098_0002
The title compound was prepared as described in Example la: (S)-3-(4-(((R)-2-([l, l'- biphenyl]-4-yl)-3-methylbutyl) carbamoyl)phenyl)-2-aminopropanoic acid, starting with (R)-2- (4-bromophenyl)-2-cyclopentylethanamine (Intermediate 48). ¾ NMR (400 MHz, DMSO-d6): δ ppm 7.63 - 7.49 (m, 10H), 7.40 (t, J= 7.6 Hz, 4H), 7.27 (dt, J= 18.9, 7.6 Hz, 9H), 4.12 (d, J= 6.6 Hz, 3H), 3.66 - 3.43 (m, 6H), 3.07 (d, J= 6.5 Hz, 4H), 2.80 (td, J= 9.6, 5.1 Hz, 3H), 2.05 (q, J= 9.0, 8.4 Hz, 3H), 1.92 (s, 2H), 1.39 - 1.21 (m, 8H), 1.16 (d, J= 19.3 Hz, 4H), 0.95 (dd, J= 12.7, 6.8 Hz, 3H), 0.74 (s, 1H). LCMS (MH+): 457.57.
Example 81: (S)-2-amino-3-(4-(((R)-2-(4'-cyano-[l,l'-biphenyl]-4-yl)-2- cyclopentylethyl)carbamo l)phenyl)propanoic acid
Figure imgf000099_0001
The title compound was prepared as described for Example la: (S)-3-(4-(((R)-2-([l,l'- biphenyl]-4-yl)-3-methylbutyl) carbamoyl)phenyl)-2-aminopropanoic acid starting with (R)-2- (4-bromophenyl)-2-cyclopentylethanamine (Intermediate 48) and 4-cyanophenyl boronic acid. ¾ NMR (400 MHz, DMSO-d6): δ ppm 7.75 (s, 3H), 7.55 (dd, J= 14.7, 7.9 Hz, 3H), 7.28 (d, J = 7.9 Hz, 2H), 7.21 (d, J= 7.9 Hz, 2H), 4.08 (t, J= 6.5 Hz, 1H), 3.60 (dd, J= 13.5, 5.0 Hz, 1H), 3.51 (t, J= 11.6 Hz, 1H), 3.07 (d, J= 6.5 Hz, 2H), 2.85 - 2.76 (m, 1H), 2.02 (d, J= 9.7 Hz, 1H), 1.89 (d, J= 9.6 Hz, 1H), 1.53 (s, 1H), 1.43 (s, 1H), 1.27 (s, 2H), 1.23 (d, J= 7.7 Hz, 1H), 0.90 (t, J= 10.3 Hz, 1H). LCMS (MH+): 482.59.
Example 82: (S)-2-amino-3-(4-(((R)-2-cyclopentyl-2-(4'-(hydroxymethyl)-[l,l'-biph l)ethyl)carbamoyl)phenyl)propanoic acid
Figure imgf000099_0002
The title compound was prepared as described for Example la: (S)-3-(4-(((R)-2-([l,l'- biphenyl]-4-yl)-3-methylbutyl) carbamoyl)phenyl)-2-aminopropanoic acid, starting with (R)-2- (4-bromophenyl)-2-cyclopentylethanamine (Intermediate 48) and 4-hydroxymethylphenyl boronic acid.
¾ NMR (400 MHz, DMSO-d6): δ ppm 7.59 - 7.49 (m, 3H), 7.34 (d, J= 8.0 Hz, 1H), 7.24 (dd, J= 8.2, 3.8 Hz, 2H), 4.48 (s, 1H), 3.65 - 3.56 (m, 2H), 3.52 - 3.41 (m, 2H), 3.36 (s, 1H), 3.06 (s, 1H), 2.77 (dd, J= 14.5, 8.0 Hz, 2H), 2.09 - 2.00 (m, 2H), 1.91 (s, 1H), 1.56 (s, 1H), 1.44 (s, 1H), 1.33 (s, 1H), 1.30 (s, 1H), 1.19 (s, 1H), 0.94 (s, 1H). LCMS (MH+): 487.60.
Example 83: (S)-2-amino-3-(4-(((R)-2-cyclopentyl-2-(3'-methyl-[l,l'-biphenyl]-4- yl)ethyl)carbamoyl)phen l)propanoic acid
Figure imgf000100_0001
The title compound was prepared as described for Example la: (S)-3-(4-(((R)-2-([l,l'- biphenyl]-4-yl)-3-methylbutyl) carbamoyl)phenyl)-2-aminopropanoic acid, starting with (R)-2- (4-bromophenyl)-2-cyclopentylethanamine (Intermediate 48) and 3-methylphenyl boronic acid. ¾ NMR (400 MHz, DMSO-d6): 8.22 (s, 4H), 7.66 (d, J = 7.9 Hz, 3H), 7.53 (d, J = 7.9 Hz, 3H), 7.45 - 7.36 (m, 3H), 7.35 - 7.22 (m, 8H), 7.13 (d, J = 7.5 Hz, 2H), 4.19 (d, J = 6.2 Hz, 2H), 3.71 - 3.60 (m, 3H), 3.48 (td, J = 13.7, 11.1, 6.5 Hz, 3H), 3.16 - 3.00 (m, 5H), 2.97 (s, 1H), 2.82 (td, J = 9.6, 5.0 Hz, 3H), 2.34 (s, 4H), 2.10 (q, J = 8.3 Hz, 3H), 1.97 (q, J = 5.2, 4.5 Hz, 3H), 1.60 (s, 2H), 1.50 (s, 2H), 1.42 - 1.24 (m, 7H), 0.96 (dt, J = 11.3, 8.2 Hz, 3H). LCMS (MH+): 471.60. Example 84: (S)-3-(4-(((R)-2-([l,l'-biphenyl]-4-yl)-2-cycloheptylethyl) carbamoyl)phenyl)- 2-aminopropanoic acid
Figure imgf000100_0002
The title compound was prepared as described for Example la: (S)-3-(4-(((R)-2-([l,l'- biphenyl]-4-yl)-3-methylbutyl)carbamoyl)phenyl)-2-aminopropanoic acid, starting with (R)-2- (4-bromophenyl)-2-cycloheptylethanamine (Intermediate 51).
¾ NMR (400 MHz, DMSO-d6): δ ppm 7.62 (t, J= 8.2 Hz, 2H), 7.54 (d, J= 7.8 Hz, 1H), 7.41 (t, J= 7.6 Hz, 1H), 7.35 - 7.21 (m, 3H), 4.15 (t, J= 6.6 Hz, 1H), 3.67 (dd, J= 13.5, 5.9 Hz, 1H), 3.55 (t, J= 11.4 Hz, 1H), 3.11 - 3.05 (m, 1H), 2.98 (d, J= 7.9 Hz, 1H), 1.78 (s, 1H), 1.60 (s, 1H), 1.49 (s, 1H), 1.36 (d, J= 9.0 Hz, 2H), 1.20 (s, 1H), 1.12 - 1.02 (m, 1H). LCMS (MH+): 485.63. Example 85: (S)-2-amino-3-(4-(((R)-2-(4'-cyano-[l,l'-biphenyl]-4-yl)-2- cycloheptylethyl)carbamoyl)phenyl)propanoic acid
Figure imgf000101_0001
The title compound was prepared as described for Example la: (S)-3-(4-(((R)-2-([l,l'- biphenyl]-4-yl)-3-methylbutyl) carbamoyl)phenyl)-2-aminopropanoic acid, starting with (R)-2- (4-bromophenyl)-2-cycloheptylethanamine (Intermediate 51) and 4-cyanophenyl boronic acid. ¾ NMR (400 MHz, DMSO-d6): δ ppm 7.79 (s, 3H), 7.57 (dd, J= 20.7, 7.8 Hz, 4H), 7.29 (d, J = 7.9 Hz, 2H), 7.22 (d, J= 8.0 Hz, 2H), 4.09 - 4.01 (m, 34H), 3.60 (qd, J= 13.5, 7.8 Hz, 3H), 3.07 (d, J= 6.6 Hz, 2H), 1.73 (d, J= 11.1 Hz, 2H), 1.57 (d, J= 18.6 Hz, 2H), 1.48 - 1.39 (m, 3H), 1.35 - 1.26 (m, 4H), 1.20 (s, 1H). LCMS (MH+): 510.64.
Example 86: (S)-2-amino-3-(4-(((R)-2-cycloheptyl-2-(4'-(hydroxymethyl)-[l,l'-biphenyl]-4- yl)ethyl)carbamoyl)phenyl)propanoic acid
Figure imgf000102_0001
The title compound was prepared as described for Example la: (S)-3-(4-(((R)-2-([l,l'- biphenyl]-4-yl)-3-methylbutyl) carbamoyl)phenyl)-2-aminopropanoic acid, starting with (R)-2- (4-bromophenyl)-2-cycloheptylethanamine (Intermediate 51) and 4-hydroxymethyl phenyl boronic acid.
¾ NMR (400 MHz, DMSO-d6): δ ppm 7.67 - 7.50 (m, 5H), 7.35 (d, J = 7.7 Hz, 2H), 7.25 (t, J = 6.3 Hz, 3H), 4.49 (s, 2H), 4.14 (d, J = 6.4 Hz, 1H), 3.67 (dd, J = 13.7, 5.5 Hz, 1H), 3.55 (s, 1H), 3.10 (d, J = 6.4 Hz, 2H), 2.98 (d, J = 8.0 Hz, 1H), 1.78 (s, 1H), 1.60 (s, 1H), 1.47 (d, J = 13.9 Hz, 2H), 1.36 (d, J = 8.9 Hz, 3H), 1.25 (s, 1H), 1.19 (s, 1H), 1.06 (d, J = 11.4 Hz, 1H). LCMS (MH+): 515.66.
Example 87: (S)-2-amino-3-(4-(((R)-2-cycloheptyl-2-(3'-methyl-[l,l'-biphenyl]-4- yl)ethyl)carbamoyl)phenyl)propanoic acid
Figure imgf000102_0002
The title compound was prepared as described for Example la: (S)-3-(4-(((R)-2-([l,l'- biphenyl]-4-yl)-3-methylbutyl) carbamoyl)phenyl)-2-aminopropanoic acid starting with (R)-2- (4-bromophenyl)-2-cycloheptylethanamine (Intermediate 51) and 4-hydroxymethyl phenyl boronic acid.
¾ NMR (400 MHz, DMSO-d6): δ ppm 7.55 (dd, J = 37.6, 8.0 Hz, 7H), 7.38 (d, J = 11.6 Hz, 4H), 7.11 (d, J = 7.5 Hz, 2H), 4.24 - 4.06 (m, 3H), 3.99 - 3.82 (m, 1H), 3.70 - 3.50 (m, 3H), 3.08 (d, J = 6.5 Hz, 4H), 2.97 (s, 2H), 2.31 (s, 5H), 1.76 (s, 3H), 1.58 (s, 1H), 1.47 (s, 5H), 1.34 (d, J = 8.8 Hz, 5H), 1.23 (d, J = 9.2 Hz, 1H), 1.04 (q, J = 10.2, 9.8 Hz, 2H). LCMS (MH+): 499.66.
Example 88: (S)-2-amino-3-(4-(((R)-3-methyl-2-(naphthalen-2-yl) butyl) carbamoyl) phenyl)propanoic acid
Figure imgf000103_0001
The title compound was prepared as described for Example la: (S)-3-(4-(((R)-2-([l,l'- biphenyl]-4-yl)-3-methylbutyl)carbamoyl)phenyl)-2-aminopropanoic acid, starting with (R)-3- methyl-2-(naphthalen-2-yl)butan-l -amine (Intermediate 46).
¾ MR (400 MHz, DMSO-d6): δ ppm 8.34 - 8.23 (m, 2H), 7.81 (dd, J= 10.8, 7.6 Hz, 2H), 7.67 - 7.58 (m, 2H), 7.48 - 7.42 (m, 1H), 7.38 (dd, J= 15.3, 7.3 Hz, 1H), 7.23 (d, J= 8.0 Hz, 1H), 4.14 (q, J= 6.0 Hz, 1H), 3.77 (dt, J= 13.3, 5.4 Hz, 1H), 3.62 (ddd, J= 13.8, 9.2, 6.3 Hz, 1H), 3.08 (d, J= 6.4 Hz, 1H), 2.96 (q, J= 7.4 Hz, 1H), 2.01 (h, J= 6.8 Hz, 1H), 0.98 (d, J= 6.6 Hz, 2H), 0.73 (d, J= 6.7 Hz, 2H). LCMS (MH+): 405.50
Example 89: (S)-2-amino-3-(4-(((R)-2-(4-(3-hydroxyprop-l-yn-l-yl)phenyl)-3- methylbutyl)carbamoyl henyl)propanoic acid
Figure imgf000103_0002
Step 1 : To a solution of (S)-ethyl 3-(4-(((R)-2-(4-bromophenyl)-3-methylbutyl) carbamoyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (Example la, Step 2, (200 mg, 0.36 mmol) in DMF (10 mL) was add Pd(PPh3)2Cl2 (38 mg, 0.054 mmol), Cul (14 mg, 0.072 mmol) and PPh3 (19 mg, 0.072 mmol). After stirring for 5 min, prop-2-yn-l-ol (CAS#: 107-19- 7, 61 mg, 1.08 mmol) and diethyl amine (53 mg, 0.72 mmol) were added and the reaction was heated to 80 °C for 12 h. After this time, the reaction was cooled to RT and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated in vacuo. Purification via normal phase column chromatography (hexanes: ethyl acetate/4: 1) provided (S)-ethyl 2-((tert-butoxycarbonyl)amino)-3 -(4-(((R)-2-(4-(3-hydroxyprop- 1 -yn- 1 - yl)phenyl)-3-methylbutyl)carbamoyl)phenyl)propanoate as a yellow oil. LCMS (MH+): 537.3.
The title compound was produced by following Steps 3-4 as described for Example la to provide a white solid.
¾ MR (400 MHz, MeOH-d4): δ ppm 7.49 (d, J = 7.8 Hz, 3H), 7.30 (dd, J = 24.4, 7.8 Hz, 6H), 7.17 (d, J = 7.8 Hz, 3H), 4.37 (s, 3H), 3.82 (dd, J = 13.3, 5.3 Hz, 2H), 3.57 (t, J = 11.8 Hz, 2H), 3.45 (s, 1H), 3.30 (s, 5H), 3.10 (d, J = 13.6 Hz, 2H), 2.79 (t, J = 9.8 Hz, 3H), 2.01 (s, 1H), 1.98 - 1.86 (m, 3H), 1.30 (d, J = 15.1 Hz, 6H), 1.05 (d, J = 6.6 Hz, 5H), 0.89 (s, 1H), 0.76 (d, J = 6.6 Hz, 5H). LCMS (MH+): 409.5.
Example 90: (S)-2-amino-3-(4-(((R)-3-methyl-2-(4-(pyridin-2-yl)phenyl)butyl)
carbamoyl)phenyl)propanoic acid
Figure imgf000104_0001
Step 1 : A solution of Intermediate B: (S)-ethyl 2-((tert-butoxycarbonyl)amino)-3-(4- (((R)-3-methyl-2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)butyl)carbamoyl)phenyl) propanoate (200 mg, 0.33 mmol), 2-bromopyridine ( 80 mg, 0.493 mmol), Pd(dppf)C12 (24 mg, 0.0329 mmol) and 2M Na2C03 (1 mL) in dioxane (3 mL) was purged with N2 and then heated at 80 °C for 3 h. After this time, the reaction mixture was cooled to RT and the mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2S04 and concentrated. The residue was purified by flash column to provide (S)-ethyl 2-((tert-butoxycarbonyl)amino)-3-(4- (((R)-3-methyl-2-(4-(pyridin-2-yl)phenyl)butyl)carbamoyl)phenyl)propanoate (105 mg) as a yellow solid.
Steps 2 & 3 : The title compound was produced by following Steps 3-4 as described for Example la to provide a white solid. ¾ MR (400 MHz, DMSO-d6): δ ppm 8.60 (dt, J = 4.6, 1.5 Hz, 1H), 7.99 - 7.78 (m, 4H), 7.53 (d, J = 8.0 Hz, 2H), 7.33 - 7.23 (m, 3H), 7.20 (d, J = 7.9 Hz, 2H), 3.74 - 3.59 (m, 1H), 3.57 - 3.43 (m, 2H), 3.03 - 2.95 (m, 1H), 2.84 (q, J = 7.1 Hz, 1H), 2.54 (s, 1H), 1.94 (dt, J = 13.4, 6.7 Hz, 1H), 0.94 (d, J = 6.7 Hz, 3H), 0.72 (d, J = 6.7 Hz, 3H). LCMS (MH+): 432.53.
Example 91: (S)-3-(4-(((R)-2-([l,l'-biphenyl]-4-yl)-3-methylbutyl) (methyl)
carbamoyl)phenyl)-2-aminopropanoic acid
Figure imgf000105_0001
The title compound was prepared as described for Example la: (S)-3-(4-(((R)-2-([l,l'- biphenyl]-4-yl)-3-methylbutyl)carbamoyl)phenyl)-2-aminopropanoic acid starting with (R)-2-(4- bromophenyl)-N,3-dimethylbutan-l-amine (Intermediate 52).
¾ MR (400 MHz, DMSO-d6): δ ppm 7.73 (d, J = 7.8 Hz, 2H), 7.60 (dd, J = 19.6, 7.6 Hz, 4H), 7.43 (t, J = 7.6 Hz, 2H), 7.32 (dd, J = 18.8, 7.6 Hz, 5H), 4.22 (s, 1H), 3.62 (qd, J = 13.4, 7.4 Hz, 2H), 3.11 (t, J = 5.4 Hz, 2H), 2.26 (q, J = 8.3 Hz, 1H), 1.22 (s, 1H), 1.06 (s, 1H), 0.57 (d, J = 7.4 Hz, 1H), 0.30 (dt, J = 13.6, 7.4 Hz, 2H)LCMS (MH+): 429.5.
Example 92: (S)-3-(4-(((lS,2S)-2-([l,l'-biphenyl]-4-yl)cyclohexyl)carbamoyl) phenyl)-2- aminopropanoic acid
Figure imgf000105_0002
The title compound was prepared as described for Example la: (S)-3-(4-(((R)-2-([l,l'- biphenyl]-4-yl)-3-methylbutyl)carbamoyl)phenyl)-2-aminopropanoic acid starting with (I S, 2S)- 2-(4-iodophenyl)cyclohexylamine (CAS# 1389386-47-3). ¾ MR (400 MHz, DMSO-d6): δ ppm 7.56 - 7.43 (m, 6H), 7.40 - 7.14 (m, 8H), 4.08 (q, J = 6.6, 5.5 Hz, 2H), 3.05 (d, J = 6.5 Hz, 2H), 2.76 (td, J = 11.7, 3.3 Hz, 1H), 1.87 (s, 1H), 1.78 (d, J = 14.9 Hz, 2H), 1.71 (d, J = 13.7 Hz, 2H), 1.57 - 1.41 (m, 1H), 1.41 (s, 2H), 1.30 (d, J = 11.7 Hz, 1H).. LCMS (MH+): 443.5.
Example 93: (S)-2-amino-3-(4-((2-(4'-methoxy-[l,l'-biphenyl]-4- yl)ethyl)carbamoyl)phen l)propanoic acid
Figure imgf000106_0001
Step 1 : To a solution of (S)-4-(2-((tert-butoxycarbonyl)amino)-3-ethoxy-3- oxopropyl)benzoic acid (Intermediate A, 200 mg, 0.82 mmol) in DMF (10 mL) was added 2-(4- bromophenyl)ethanamine (200 mg, 1.0 mmol), HATU (623 mg, 1.64 mmol), and TEA (166 mg, 1.64 mmol), and the reaction was stirred for 48 h at RT. After this time, the reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SC"4, filtered and concentrated in vacuo. Purification via normal phase column
chromatography (hexanes: ethyl acetate/4: 1) provided (S)-ethyl 3-(4-((4-bromophenethyl) carbamoyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate as a white solid.
Step 2: To a solution of (S)-ethyl 3-(4-((4-bromophenethyl)carbamoyl)phenyl)-2-((tert- butoxycarbonyl)amino)propanoate (200 mg, 0.38 mmol) in dioxane (5.0 mL)/Na2C03 (2.5 mL, 2.0 M, aq.) was added 4-methoxy phenyl boronic acid (70 mg, 0.55 mmol) followed by
Pd(dppf)Cl2 (30 mg, 0.038 mmol). The reaction was purged with N2 and then heated to 90 °C for 3 h. After this time, the reaction was cooled to RT and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SC"4, filtered and concentrated in vacuo. Purification via normal phase column chromatography (hexanes: ethyl acetate/4: 1) provided (S)- ethyl 2-((tert-butoxycarbonyl)amino)-3-(4-((2-(4'-methoxy-[l, l'-biphenyl]-4-yl)ethyl) carbamoyl)phenyl)propanoateas an off-white solid. Step 3 : To a 0 °C solution of (S)-ethyl 2-((tert-butoxycarbonyl)amino)-3-(4-((2-(4'- methoxy-[l, l'-biphenyl]-4-yl)ethyl)carbamoyl)phenyl)propanoate (125 mg, 0.23 mmol) in CH2CI2 (6 mL), was added dropwise TFA (1.5 mL). The reaction was warmed to RT for 3 h, then concentrate in vacuo. To the resulting residue was added saturated aqueous solution of NaHCC to adjust the pH to -7.5 and then extracted with CH2CI2. The organic layer was washed with brine, dried over Na2SC"4, filtered and concentrated in vacuo to provide (S)-ethyl 2- amino-3-(4-((2-(4'-methoxy-[l, l'-biphenyl]-4-yl)ethyl)carbamoyl)phenyl)propanoate as an off- white solid that was used without further purification.
Step 4: To a 0 °C solution of (S)-ethyl 2-amino-3-(4-((2-(4'-methoxy-[l, l'-biphenyl]-4- yl)ethyl)carbamoyl)phenyl)propanoate (75 mg, 0.16 mmol) in MeOH (6 mL), was added dropwise 5 N NaOH (2 mL) and then the reaction mixture was warmed to RT for 3 h. After this time, the reaction mixture was acidified with 3N HC1 to adjust the pH to 6-7, the MeOH was removed in vacuo and the resultant solid was filtered, washed with H2O, and dried in vacuo to provide the title compound as a white solid.
¾ NMR (400 MHz, MeOH-d4): δ ppm 2.87 (t, J=7.3 Hz, 2 H) 3.15 (dd, J=6.2, 4.5 Hz, 2 H) 3.49 - 3.55 (m, 2 H) 3.78 (s, 3 H) 4.20 - 4.27 (m, 1 H) 7.00 (q, J=5.2 Hz, 2 H) 7.29 (d, J=8.3 Hz, 2 H), 7.35 (d, J=8.3 Hz, 2 H) 7.52 - 7.55 (m, 2 H) 7.57 (q, J=5.2 Hz, 2 H) 7.81 (d, J=8.4 Hz, 2 H) 8.31 (d, J=4.5 Hz, 3 H) 8.58 (t, J=5.6 Hz, 1 H). LCMS (MH+): 419.5. The following compounds in Table 4a were prepared as described above for Example 93 using the appropriate boronic acid. NMR data is provided in Table 4b.
Table 4a
Figure imgf000107_0001
Figure imgf000107_0002
Figure imgf000108_0001
(S)-2-amino-3-(4-((2-(3'- (dimethylcarbamoyl)-[ 1 , 1 '-biphenyl]-4-
107 460.54 yl)ethyl) carbamoyl)phenyl)propanoic
acid
1
H2N (S)-2-amino-3-(4-((2-(3'-carbamoyl-
108 [l,r-biphenyl]-4-yl)ethyl) 432.48 carbamoyl )phenyl)propanoic acid
Table 4b
Figure imgf000109_0001
2 H) 3.56 (q, J=6.6 Hz, 2 H) 4.13 - 4.23 (m, 1 H) 7.36 (d, J=8.1 Hz, 2 H) 7.50 (d, J=7.9 Hz, 2 H) 7.81 (d, J=8.1 Hz, 2 H) 7.98 (d, J=7.3 Hz, 2 H) 8.28 - 8.36 (m, 2 H) 8.50 (br. s., 3 H) 8.67 (d, J=4.1 Hz, 1 H), 8.90 (d, J=4.0 Hz, 2 H)
105 D (not determined)
IH NMR 400 DMSO-d6): δ ppm 8.03 (s, 1H), 7.75 (d, J = 7.0 Hz, 3H),
106 7.62 (d, J = 7.7 Hz, 2H), 7.52 (d, J = 8.8 Hz, 1H), 7.32 (t, J = 10.5 Hz, 4H), 4.17
(s, 1H), 3.51 (s, 2H), 3.12 (d, J = 6.5 Hz, 2H), 2.87 (s, 2H), 2.78 (s, 3H
IH NMR 400 DMSO-d6): δ ppm 7.79 (d, J = 7.9 Hz, 2H), 7.69 (d, J = 7.8 Hz, 1H), 7.64-7.57 (m, 2H), 7.49 (t, J = 7.7 Hz, 1H), 7.33 (d, J = 7.9 Hz, 3H),
107
4.21 (d, J = 6.4 Hz, 1H), 3.51 (t, J = 7.3 Hz, 2H), 3.13 (d, J = 6.5 Hz, 2H), 2.98 (s, 2H), 2.94-2.83 (m, 4H)
IH NMR 400 DMSO-d6): δ ppm 8.10 (s, 1H), 7.79 (dd, J = 11.9, 7.7 Hz, 3H), 7.64 (d, J = 7.9 Hz, 2H), 7.51 (t, J = 7.7 Hz, 1H), 7.33 (t, J = 8.1 Hz, 3H),
108
4.20 (t, J = 6.5 Hz, 1H), 3.90 (s, 1H), 3.51 (t, J = 7.3 Hz, 2H), 3.13 (d, J = 6.5 Hz, 2H), 2.88 (t, J = 7.3 Hz, 2H)
Example 109: (S)-3-(4-((2-([l,l'-biphenyl]-4-yl)ethyl)carbamoyl)phenyl)-2-aminopropanoic acid
Figure imgf000110_0001
Step 1 : To a solution of (S)-4-(2-((tert-butoxycarbonyl)amino)-3-ethoxy-3- oxopropyl)benzoic acid (Intermediate A, 200 mg, 0.82 mmol) in DMF (10 mL) was added (2- ([l, l'-biphenyl]-4-yl)ethanamine (Intermediate 5, 236 mg, 1.2 mmol), HATU (623 mg, 1.64 mmol) and TEA (166 mg, 1.64 mmol) and the mixture was stirred for 48 h at RT. After this time, the reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated in vacuo. Purification via normal phase column chromatography (hexanes: ethyl acetate/4: 1 v/v) provided (S)-ethyl 3-(4- ((2-([l, l'-biphenyl]-4-yl)ethyl) carbamoyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate as a white solid.
Step 2: To a 0 °C solution of (S)-ethyl 3-(4-((2-([l,l'-biphenyl]-4-yl)ethyl)carbamoyl) phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (150 mg, 0.29 mmol) in CH2CI2 (6 mL), was added dropwise TFA (1.5 mL). The reaction was warmed to RT for 3 h, then concentrated in vacuo. To the resulting residue was added saturated aqueous solution of NaHC0 to adjust the pH to -7.5 and then extracted with CH2CI2. The organic layer was washed with brine, dried over Na2SC"4, filtered and concentrated in vacuo to provide (S)-ethyl 3-(4-((2-([l, l'-biphenyl]-4- yl)ethyl)carbamoyl)phenyl)-2-aminopropanoate as an off-white solid that was used without further purification.
Step 3 : To a 0 °C solution of (S)-ethyl 3-(4-((2-([l,l*-biphenyl]-4-yl)ethyl)carbamoyl) phenyl)-2-aminopropanoate 75 mg, 0.18 mmol) in MeOH (6 mL), was added dropwise NaOH (5N, 2 mL) and the reaction mixture was warmed to RT for 3 h. After this time, the reaction mixture was acidified with HC1 (3N) to adjust the pH to 6-7, then the MeOH was removed in vacuo and the resultant solid was filtered, washed with H2O, and dried in vacuo to provide the title compound as a white solid. LCMS (MH+): 388.46. ¾ NMR (400 MHz, DMSO-d6): δ ppm 7.70 (s, 2 H),7.57-7.48 (m,6H),7.36-7.33 (t, J = 8.0 Hz, 2 H),7.29-7.25 (m,3H),4.64(s, l H), 3.95 (s, 2H), 3.64-3.61 (m, 1H), 3.43-3.39 (m, 1H), 3.06 (s, 2 H).
The compounds in Table 5a were made following the procedure for Example 109 starting with the appropriate amine intermediate indicated in the table. NMR data is provided in Table 5b.
Table 5a
Figure imgf000111_0001
Figure imgf000111_0002
(2S)-3-(4-((2-([l, l'-biphenyl]-4- yl)-5-hydroxy-3,3-
112 34 dimethy lhexy 1) carb amoyl) 488.62 phenyl)-2-aminopropanoic acid
(Stereoisomer 3)
(2S)-3-(4-((2-([l,r-biphenyl]-4- yl)-3-methylbutyl)
113 55 430.54 carbamoyl)phenyl)-2- aminopropanoic acid
(2S)-3-(4-((2-([l,r-biphenyl]-4- yl)-2-cycloheptylethyl)
114 28 484.63 carbamoyl)phenyl)-2- aminopropanoic acid
(2S)-3-(4-((2-([l,r-biphenyl]-4- yl)-2-cyclohexylethyl)
115 24 470.6 carbamoyl)phenyl)-2- aminopropanoic acid
(2S)-3-(4-((2-([l,r-biphenyl]-4- yl)-2-cyclopentylethyl)
116 21 456.58 carbamoyl)phenyl)-2- aminopropanoic acid
(2S)-3-(4-((2-([l,r-biphenyl]-4- yl)-2-cyclobutylethyl)
117 30 442.55 carbamoyl)phenyl)-2- aminopropanoic acid
(2S)-3-(4-((2-([l,r-biphenyl]-4- yl)-3-methylpentyl)
118 23 444.57 carbamoyl)phenyl)-2- aminopropanoic acid
(2S)-3-(4-((2-([l,r-biphenyl]-4- yl)-4,4-dimethylpentyl)
119 26 458.59 carbamoyl) phenyl)-2- aminopropanoic acid (2S)-3-(4-((2-([l, l'-biphenyl]-4-
120 3 a0"" yl)butyl)carbamoyl)phenyl)-2- 416.51 aminopropanoic acid
(2S)-3-(4-((2-([l,r-biphenyl]-4- yl)-2-(tetrahydro-2H-pyran-4-
121 29 472.58 yl)ethyl)carbamoyl)phenyl)-2- aminopropanoic acid
(2S)-3-(4-((2-([l,r-biphenyl]-4- yl)-4-methylpentyl)
122 22 444.57 carbamoyl)phenyl)-2- aminopropanoic acid
F
(2S)-3-(4-((2-([l,r-biphenyl]-4- yl)-3 , 3 ,3 -trifluoropropyl)
123 31 456.46 carbamoyl)phenyl)-2- aminopropanoic acid
(2S)-3-(4-((2-([l,r-biphenyl]-4-
124 27 yl)hexyl)carbamoyl)phenyl)-2- 444.57 aminopropanoic acid
(S)-3 -(4-((( 1 -([ 1 , 1 '-biphenyl] -4-
125 20 yl)cyclobutyl)methyl)carbamoyl 428.52
)phenyl)-2-aminopropanoic acid
(2S)-3-(4-((2-([l, l'-biphenyl]-4-
126 2 yl)propyl)carbamoyl)phenyl)-2- 402.49 aminopropanoic acid
(2S)-3-(4-((2-([l,r-biphenyl]-4-
127 54 yl)pentyl)carbamoyl)phenyl)-2- 430.54 aminopropanoic acid (S)-3 -(4-((( 1 -([ 1 , 1 '-biphenyl] -4- yl)cyclopropyl)methyl)carbamo
128 4 414.5 yl)phenyl)-2-aminopropanoic
acid
(S)-3-(4-((3-([l,r-biphenyl]-2-
129 41 yl)cyclobutyl)carbamoyl)phenyl 414.5
)-2-aminopropanoic acid
(2S)-3-(4-((l-([l,r-biphenyl]-4-
130 1 yl)propan-2-yl)carbamoyl) 402.49 phenyl)-2-aminopropanoic acid
(S)-3-(4-((2-([l, l'-biphenyl]-3-
131 6 yl)ethyl)carbamoyl)phenyl)-2- 388.46 aminopropanoic acid
(S)-2-amino-3-(4-((2- (naphthalen-2-yl)ethyl)
132 7 362.42 carbamoyl)phenyl)propanoic
acid
(S)-3-(4-((2-([l, l'-biphenyl]-4- yl)-2-methylpropyl)
133 8 416.51 carbamoyl)phenyl)-2- aminopropanoic acid
(S)-3-(4-((3-([l,r-biphenyl]-4-
134 9 yl)propyl)carbamoyl)phenyl)-2- 402.49 aminopropanoic acid
(S)-3-(4-((4-([l,r-biphenyl]-2-
135 40 yl)butyl)carbamoyl)phenyl)-2- 416.51 aminopropanoic acid
(S)-2-amino-3-(4-((2-(6- phenylpyridin-3 -yl)
136 37 389.45 ethyl)carbamoyl)phenyl)
propanoic acid
(2S)-3-(4-((2-([l,r-biphenyl]-4- yl)-2-(2-hydroxyethoxy)
137 38 448.51 ethyl)carbamoyl)phenyl)-2- aminopropanoic acid
Figure imgf000115_0001
Figure imgf000116_0001
Table 5b
Figure imgf000116_0002
1H NMR (400 MHz, DMSO-d6): δ ppm 0.92 (s, 3 H) 0.97 (s, 3 H) 1.06 (d, J=6.15 Hz, 3 H) 1.28 (dd, J=14.23, 2.46 Hz, 1 H) 1.45 (dd, J=14.35, 7.96 Hz, 1 H) 2.98 -
112 3.15 (m, 3 H) 3.68 - 3.84 (m, 2 H) 3.85 - 3.95 (m, 1 H) 4.18 (m, J=5.70 Hz, 1 H) 7.25 (dd, J=13.32, 8.05 Hz, 4 H) 7.30 - 7.37 (m, 1 H) 7.43 (t, J=7.64 Hz, 2 H) 7.58 (dd, J=11.13, 8.25 Hz, 4 H) 7.63 - 7.69 (m, 2 H) 8.12 (br. s., 1 H) 8.21 (br. s., 3 H)
1H NMR (400 MHz, DMSO-d6): δ ppm 0.72 (d, J=6.74 Hz, 3 H) 0.93 (d, J=6.64 Hz, 3 H) 1.83 - 2.01 (m, 1 H) 2.75 - 2.89 (m, 1 H) 3.09 (d, J=6.54 Hz, 2 H) 3.50 (td,
113 J=13.58, 5.93 Hz, 1 H) 3.69 (dd, J=12.84, 5.52 Hz, 1 H) 4.14 (br. s., 1 H) 7.18 - 7.34 (m, 5 H) 7.40 (t, J=7.64 Hz, 2 H) 7.54 (d, J=8.15 Hz, 2 H) 7.60 (d, J=7.37 Hz, 2 H) 7.66 (s, 2 H) 8.20 - 8.42 (m, 4 H)
1H NMR (400 MHz, DMSO-d6): δ ppm 1.00 - 1.17 (m, 1 H) 1.20 - 1.45 (m, 5 H) 1.45 - 1.73 (m, 5 H) 1.82 (br. s., 2 H) 2.92 - 3.03 (m, 1 H) 3.04 - 3.18 (m, 2 H) 3.46 -
114 3.63 (m, 1 H) 3.64 - 3.79 (m, 1 H) 4.21 (d, J=5.42 Hz, 1 H) 7.23 - 7.37 (m, 5 H) 7.43 (t, J=7.64 Hz, 2 H) 7.57 (d, J=8.20 Hz, 2 H) 7.64 (d, J=7.32 Hz, 2 H) 7.69 (d, J=8.20 Hz, 2 H) 8.16 - 8.33 (m, 4 H)
1H NMR (400 MHz, DMSO-d6): δ ppm 0.64 - 0.84 (m, 1 H) 0.86 - 1.28 (m, 4 H) 1.43 - 1.62 (m, 4 H) 1.66 (d, J=12.98 Hz, 1 H) 1.83 (d, J=l 1.81 Hz, 1 H) 2.79 - 2.92
115 (m, 1 H) 3.09 (d, J=6.35 Hz, 2 H) 3.45 - 3.53 (m, 2 H) 3.64 - 3.78 (m, 1 H) 4.13 (d, J=5.03 Hz, 1 H) 7.13 - 7.34 (m, 5 H) 7.36 - 7.45 (m, 2 H) 7.53 (d, J=8.20 Hz, 2 H) 7.57 - 7.68 (m, 4 H) 8.24 (t, J=5.52 Hz, 1 H) 8.33 (br. s., 3 H)
1H NMR (400 MHz, DMSO-d6): δ ppm 0.85 - 1.10 (m, 1 H) 1.24 - 1.73 (m, 6 H) 1.90 - 2.04 (m, 1 H) 2.05 - 2.21 (m, 1 H) 2.83 (td, J=9.53, 5.49 Hz, 1 H) 2.97 - 3.19
116 (m, 2 H) 3.39 - 3.58 (m, 1 H) 3.59 - 3.75 (m, 1 H) 4.21 (d, J=5.42 Hz, 1 H) 7.28 (dd, J=8.27, 2.56 Hz, 4 H) 7.30 - 7.38 (m, 1 H) 7.44 (t, J=7.64 Hz, 2 H) 7.57 (d, J=8.25 Hz, 2 H) 7.61 - 7.65 (m, 2 H) 7.69 (s, 2 H) 8.16 - 8.34 (m, 4 H)
1H NMR (400 MHz, DMSO-d6): δ ppm.45 - 1.61 (m, 1 H) 1.63 - 1.95 (m, 4 H) 2.09 - 2.21 (m, 1 H) 2.55 - 2.71 (m, 1 H) 2.94 - 3.04 (m, 1 H) 3.05 - 3.19 (m, 2 H) 3.28 -
117 3.44 (m, 1 H) 3.46 - 3.59 (m, 1 H), 4.15 - 4.30 (m, 1 H) 7.20 - 7.38 (m, 5 H) 7.39 - 7.48 (m, 2 H) 7.57 (d, J=8.25 Hz, 2 H) 7.64 (d, J=1.32 Hz, 2 H) 7.73 (d, J=8.25 Hz, 2 H) 8.26 (d, J=3.66 Hz, 3 H) 8.34 (t, J=5.59 Hz, 1 H)
1H NMR (400 MHz, DMSO-d6): δ ppm 0.75 (d, J=6.64 Hz, 1 H) 0.78 - 0.86 (m, 2 H) 0.87 - 1.01 (m, 4 H) 1.32 - 1.54 (m, 1 H) 1.64 - 1.83 (m, 1 H) 3.02 (dd, J=17.84,
118 7.44 Hz, 1 H) 3.13 (d, J=5.52 Hz, 2 H) 3.56 (d, J=6.20 Hz, 1 H) 3.70 (dd, J=12.74, 5.91 Hz, 1 H) 4.16 (br. s., 1 H) 7.20 - 7.38 (m, 5 H) 7.44 (t, J=7.15 Hz, 2 H) 7.57 (d, J=7.86 Hz, 2 H) 7.61 - 7.77 (m, 4 H) 8.15 - 8.59 (m, 4 H)
1H NMR (400 MHz, DMSO-d6): δ ppm 0.78 (s, 9 H) 1.54 - 1.82 (m, 2 H) 3.12 (br. s., 3 H) 3.36 (br. s., 2 H) 4.23 (br. s., 1 H) 7.33 (dd, J=12.18, 7.98 Hz, 6 H) 7.44 (t,
119
J=7.57 Hz, 2 H) 7.62 (dd, J=19.96, 7.71 Hz, 4 H) 7.73 (d, J=8.00 Hz, 2 H) 8.27 (br. s., 3 H) 8.46 (br. s., 1 H)
1H NMR (400 MHz, DMSO-d6): δ ppm 0.76 (t, J=7.35 Hz, 3 H) 1.49 - 1.68 (m, 1 H) 1.69 - 1.87 (m, 1 H) 2.83 - 2.97 (m, 1 H) 3.16 (d, J=6.20 Hz, 2 H) 3.48 - 3.58 (m,
120
2 H) 4.18 (br. s., 1 H) 7.26 - 7.38 (m, 5 H) 7.45 (t, J=7.64 Hz, 2 H) 7.53 - 7.70 (m, 4 H) 7.76 (d, J=8.25 Hz, 2 H) 8.41 (br. s., 3 H) 8.48 (t, J=5.56 Hz, 1 H)
1H NMR (400 MHz, DMSO-d6): δ ppm 0.94 - 1.13 (m, 1 H) 1.15 - 1.34 (m, 2 H)
121 1.66 - 1.93 (m, 2 H) 2.76 - 2.91 (m, 1 H) 2.96 - 3.33 (m, 4 H) 3.41 - 3.58 (m, 1 H) 3.72 (d, J=7.52 Hz, 2 H) 3.82 (d, J=9.27 Hz, 1 H) 4.17 (d, J=5.32 Hz, 1 H) 7.17 -
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Example 153: (S)-2-amino-3-(4-((3-(2-(isoquinolin-7-yl)phenyl)propyl)
carbamoyl)phenyl)propanoic acid
Figure imgf000120_0002
Step 1 : A solution of (S)-2-amino-3-(4-((3-(2-bromophenyl)propyl) carbamoyl) phenyl)propanoic acid (Example 145, 140 mg, 0.27 mmol), CsOAc (99 mg, 0.51 mmol), Pd(dppf)Cl2 (38 mg, 0.051 mmol) and isoquinolin-7-ylboronic acid (88 mg, 0.51 mmol) in THF (3 mL) was purged with N2 and then heated to 90 °C for 3 h. After this time, the reaction was cooled to RT and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2S04, and filtered and concentrated in vacuo. Purification via normal phase column chromatography (hexanes: ethyl acetate/4: 1) provided (S)-ethyl 2-((tert-butoxycarbonyl)amino)- 3-(4-((3-(2-(isoquinolin-7-yl)phenyl)propyl)carbamoyl)phenyl)propanoate as an off- white solid. Step 2: To a 0 °C solution of (S)-ethyl 2-((tert-butoxycarbonyl)amino)-3-(4-((3-(2- (isoquinolin-7-yl)phenyl)propyl)carbamoyl)phenyl)propanoate (100 mg, 0.17 mmol) in CH2CI2 (5 mL), was added dropwise TFA (1.2 mL). The reaction was warmed to RT for 3 h, then concentrate in vacuo. To the resulting residue was added saturated aqueous solution of NaHC0 to adjust the pH to -7.5 and then extracted with CH2CI2. The organic layer was washed with brine, dried over Na2SC"4, filtered and concentrated in vacuo to provide (S)-ethyl 2-amino-3-(4- ((3-(2-(isoquinolin-7-yl)phenyl)propyl)carbamoyl)phenyl)propanoate as an off- white solid that was used without further purification.
Step 3 : To a 0 °C solution of (S)-ethyl 2-amino-3-(4-((3-(2-(isoquinolin-7- yl)phenyl)propyl)carbamoyl)phenyl)propanoate (75 mg, 0.16 mmol) in MeOH (6 mL), was added dropwise 5 N NaOH (2 mL) and then the reaction mixture was warmed to RT for 3 h. After this time, the reaction mixture was acidified with 3N HC1 to adjust the pH to 6-7, the MeOH was removed in vacuo and the resultant solid was filtered, washed with H2O, and dried in vacuo to provide the title compound as a white solid. LCMS (M+H): 453.53.
The following compounds in Table 6a were prepared as described above for Example 153 using the appropriate boronic acid. MR data is provided in Table 6b.
Table 6a
Figure imgf000121_0001
Figure imgf000121_0002
Figure imgf000122_0001
Table 6b
Figure imgf000122_0002
Example 160: (S)-3-(4-(((R)-2-([l,l'-biphenyl]-4-yl)-2-(piperidin carbamoyl)phenyl)-2-aminopropanoic acid
Figure imgf000123_0001
Step 1 : To a solution of ethyl 2-(4-bromophenyl)acetate (CAS#: 77143-76-1, 38 g, 0.16 mol) in DMF (380 mL), NaH ( 6.9 g,0.173 mol, 60% in oil ) was added at -20 °CEbver 1 h and then the mixture was stirred at the same temperature for 2 h. After this time, tert-butyl 4- iodopiperidine-l-carboxylate (CAS#: 301673-14-3, 53.5 g,0.17 mol) was added dropwise at -10 °C. After addition, the mixture was stirred at RT for 12 h, then poured into ice/water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SC"4 and concentrated, then purified by silica gel chromatography to provide tert-butyl 4-(l- (4-bromophenyl)-2-ethoxy-2-oxoethyl)piperidine-l-carboxylate (60 g) as an off-white solid.
Step 2: To a solution of tert-butyl 4-(l-(4-bromophenyl)-2-ethoxy-2-oxoethyl)piperidine-
1-carboxylate (65 g, 0.15 mol) in ethanol //water (600 mL,v/v=l : l), KOH (25.70 g,0.458 mol) was added at RT and then the mixture was stirred at the same temperature for 12 h. The mixture was concentrated and adjusted pH=2. The solid was filtered, washed with water and dried under vacuum to provide 2-(4-bromophenyl)-2-(l-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid as a white solid.
Step 3 : To a solution of 2-(4-bromophenyl)-2-(l-(tert-butoxycarbonyl)piperidin-4- yl)acetic acid (10 g, 0.025 mol) in DMF (100 mL) was added (R)-l-phenylethanamine (1.52 g, 0.013 mol) and the mixture was stirred at RT for lh. The solid was filtered, washed with water and dried under vacuum to provide (R)-l-phenylethanamine (R)-2-(4-bromophenyl)-2-(l-(tert- butoxycarbonyl)piperidin-4-yl)acetate. The salt was dissolved in water, and the pH adjusted to 2 by the slow addition of HC1, and then then extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2S04 and concentrated under vacuum to provide (R)-2-(4- bromophenyl)-2-(l-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid as a white solid (98% ee by HRLC).
Step 4: To a solution of (R)-2-(4-bromophenyl)-2-(l-(tert-butoxycarbonyl)piperidin-4- yl)acetic acid (4.5 g, 11.2 mmol) in THF (400 mL) was added a solution of (Boc)20 (3.20 g, 14.7 mmol) in THF (50 mL) at OSC over 30 min and then pyridine (581 mg,7.3 mmol) and H4CO3 ( 1.16 g, 14.6 mmol) was added at O°C0 The mixture was warmed to RT and stirred for 12 h, then poured into water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SC"4 and concentrated. The residue was purified by silica gel chromatography to provide (R)-tert-butyl 4-(2-amino-l-(4-bromophenyl)-2-oxoethyl)piperidine- 1-carboxylate as an off-white solid.
Step 5: To a solution of (R)-tert-butyl 4-(2-amino-l-(4-bromophenyl)-2- oxoethyl)piperidine-l-carboxylate (2 g, 5.1 mmol) in CH2CI2 (20 mL) was added TFA (5 mL) dropwise at 0SC. The mixture was warmed to RT and then stirred for 2h, and then concentrated and dissolved in acetonitrile (2 mL).To the mixture was added sequenatlly K2CO3 ( 2.1 g , 15.1 mmol) and BnBr (0.95 g,5.5 mmol) and the resulting mixture was warmed to RT and stirred for 12 h. After this time the mixture was diluted with water and extracted with ethyl acetate, the combined organic layer was washed with brine, dried over Na2S04 and concentrated to provide (R)-2-(l-benzylpiperidin-4-yl)-2-(4-bromophenyl)acetamide as a white solid.
Step 6: A solution of (R)-2-(l-benzylpiperidin-4-yl)-2-(4-bromophenyl)acetamide (1.8 g„
3.5 mmol) in THF (18 mL) was cooled to 0°C and a solution of borane in THF (1M/20 mL) was added dropwise. The resulting mixture was warmed to RT and then heated at reflux for 12 h. After this time, the reaction was cooled to RT and concentrated in vacuo. The residue was dissolved in 6 N HC1 (20 mL), and then heated at 70°C for 3 h after which the reaction was cooled to RT and concentrated in vacuo. The residue was dissolved in methanol and then triethyl amine (1.7 g , 17.4 mmol) and (Boc)20 (3.8 g, 17.431) were added. The mixture was stirred at RT for 12 h, then diluted with water and extracted with CH2Cl2.The organic layer was washed with brine, dried over Na2SC"4 and concentrated. The residue was purified by silica gel
chromatography to provide (R)-tert-butyl (2-(l-benzylpiperidin-4-yl)-2-(4-bromophenyl)ethyl) carbamate as a light yellow semi-solid.
Step 7: To a solution of (R)-tert-butyl (2-(l-benzylpiperidin-4-yl)-2-(4- bromophenyl)ethyl) carbamate (700 mg, 1.5 mmol) in CH2C12, was added TFA (2 mL) and the reaction was stirred for 2 h. After this time the mixture was concentrated in vacuo and the residue was dissolved in DMF cooled to O0C followed by the sequential addition of Intermediate A (500 mg, 1.5 mmol), triethyl amine (751 mg, 7.4 mmol) and HATU (1.13 g, 2.9 mmol). The mixture was stirred at RT for 12 h, then diluted with water and extracted with CH2C12. The combined organic layer was washed with brine, dried over Na2SC"4 and concentrated. The residue was purified by silica gel chromatography to provide (S)-ethyl 3-(4-(((R)-2-(l- benzylpiperidin-4-yl)-2-(4-bromophenyl)ethyl)carbamoyl)phenyl)-2-((tert- butoxycarbonyl)amino)propanoate as a yellow solid.
Step 8: To a solution of (S)-ethyl 3-(4-(((R)-2-(l-benzylpiperidin-4-yl)-2-(4- bromophenyl) ethyl)carbamoyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (900 mg, 1.3 mmol) was added phenylboronic acid (317 mg, 2.6 mmol) and Pd(dppf)Cl2 (95 mg, 0.13 mmol) in dioxane (9.0 mL) /aq.NaC0 (2M,3.0 mL) and refluxed for 3 h. After this time, the reaction was cooled to RT, diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2S04 and concentrated. The residue was purified by silica gel chromatography to provide (S)-ethyl 3-(4-(((R)-2-([l,l'-biphenyl]-4-yl)-2-(l- benzylpiperidin-4-yl)ethyl)carbamoyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate as an off-white solid.
Step 9: A solution of (S)-ethyl 3-(4-(((R)-2-([l,r-biphenyl]-4-yl)-2-(l-benzylpiperidin-4- yl)ethyl)carbamoyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (600 mg, 0.87 mmol) in ethanol (6 mL) was heated at 50 °C under 50 psi H2 for 12 h. After this time, the mixture was filtered, concentrated and purified by flash to provide 300 mg intermediate. The intermediate (150 mg) was dissolved in CH2Cl2and triethyl amine and (Boc)20 stirred at rt overnight. The mixture was concentrated and purified by silica gel chromatography to provide tert-butyl 4-((R)- l-([l,l'-biphenyl]-4-yl)-2-(4-((S)-2-((tert-butoxycarbonyl)amino)-3-ethoxy-3-oxopropyl) benzamido)ethyl)piperidine-l-carboxylate as a white solid.
Step 10: To a 0 °C solution of tert-butyl 4-((R)-l-([l,r-biphenyl]-4-yl)-2-(4-((S)-2-((tert- butoxycarbonyl)amino)-3-ethoxy-3-oxopropyl)benzamido)ethyl)piperidine-l-carboxylate (170 mg, 0.243 mmol) in CH2C12 (4 mL), TFA(1 mL) was added dropwise at 0 °C for 1 h and then the mixture was concentrated, and the pH adjusted to -6-7 with saturated aqueous NaHC0 . The mixture was concentrated and purified by Prep-HPLC to afford (S)-ethyl 3-(4-(((R)-2-([l, l'- biphenyl]-4-yl)-2-(piperidin-4-yl)ethyl)carbamoyl)phenyl)-2-aminopropanoate as a yellow solid.
Step 11 : The title compound was prepared as described for (S)-3-(4-(((R)-2-([l, l'- biphenyl]-4-yl)-3-methylbutyl) carbamoyl)phenyl)-2-aminopropanoic acid (Example la, Step 4) via the hydrolysis of (S)-ethyl 3-(4-(((R)-2-([l, l'-biphenyl]-4-yl)-2-(piperidin-4- yl)ethyl)carbamoyl)phenyl)-2-aminopropanoate. ¾ NMR (400 MHz, DMSO-d6): δ ppm 7.55 (d, J = 7.8 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 7.9 Hz, 2H), 7.08 (d, J = 8.1 Hz, 2H), 4.13 (s, 1H), 3.62 (d, J = 9.9 Hz, 1H), 3.49 (t, J = 11.6 Hz, 1H), 3.08 (d, J = 6.5 Hz, 1H), 2.81 (s, 1H), 1.62 (s, 1H), 1.40 (s, 1H), 1.17 (s, 2H), 1.09 (d, J = 7.5 Hz, 1H), 1.00 - 0.83 (m, 1H), 0.78 (s, 2H), 0.69 (s, 2H). LCMS (MH+): 434.33.
Example 161: (S)-3-(4-(((R)-2-([l,l'-biphenyl]-4-yl)-2-(l-benzylpiperidin-4- yl)ethyl)carbamoyl)phenyl)-2-aminopropanoic acid
Figure imgf000126_0001
The title compounds was prepared as described above starting from (S)-ethyl 3-(4-(((R)-
2-([l,l'-biphenyl]-4-yl)-2-(l-benzylpiperidin-4-yl)ethyl)carbamoyl)phenyl)-2-((tert- butoxycarbonyl)amino) propanoate (Example 160, Step 8) and following the procedure as outlined in (S)-3-(4-(((R)-2-([l,r-biphenyl]-4-yl)-3-methylbutyl)carbamoyl)phenyl)-2- aminopropanoic acid (Example la, Steps 3-4).
¾ NMR (400 MHz, DMSO-d6): δ ppm 7.60 - 7.47 (m, 6H), 7.40 (t, J = 7.6 Hz, 7H), 7.36 - 7.22 (m, 3H), 7.20 (d, J = 8.0 Hz, 2H), 4.10 - 4.00 (m, 3H), 3.71 - 3.55 (m, 1H), 3.54 (s, 1H), 3.04 - 2.89 (m, 1H), 2.90 (s, 1H), 2.00 (d, J = 12.0 Hz, 2H), 1.49 (t, J = 13.9 Hz, 1H), 1.1 1 (t, J = 7.1 Hz, 1H). LCMS (MH+): 471.59.
Example 162: (S)-3-(4-(((R)-2-([l,l'-biphenyl]-4-yl)-2-(l-methylpiperidin
yl)ethyl)carbamoyl)phenyl)-2-aminopropanoic acid
Figure imgf000127_0001
The title compound was prepared as described for the compound of Example 160 starting with 4-iodo-l-methylpiperidine (CAS#: 90485-32-8).
¾ NMR (400 MHz, MEOH-d4): δ ppm 7.63 - 7.47 (m, 6H), 7.47 - 7.36 (m, 2H), 7.30 (td, J = 8.5, 7.9, 1.5 Hz, 5H), 3.91 (dd, J= 13.3, 5.5 Hz, 1H), 3.76 - 3.57 (m, 1H), 3.26 (dd, J= 14.5, 4.6 Hz, 1H), 3.12 - 2.95 (m, 2H), 2.95 (s, OH), 2.93 (s, 1H), 2.36 (s, 2H), 2.29 (t, J= 11.7 Hz, 1H), 2.21-2.05 (m, 2H), 1.76 (d,J=8.3Hz, 1H), 1.53 (t, J= 17.1 Hz, 2H), 1.26 (d,J=18.3Hz, 1H). LCMS (MH+): 486.62. Example 163: (S)-3-(4-(((R)-2-([l,l'-biphenyl]-4-yl)-2-(l-ethylpiperidin-4- yl)ethyl)carbamoyl)phen -2-aminopropanoic acid
Figure imgf000127_0002
The title compound was prepared as described for the compound of Example 160 starting with l-ethyl-4-bromopiperidine (CAS#: 90633-19-5).
¾ NMR (400 MHz, MEOH-d4): 7.56 (ddd,J= 8.1, 6.9, 1.4 Hz, 6H), 7.51-7.35 (m, 2H), 7.35 - 7.25 (m, 5H), 3.91 (dd, J= 13.3, 5.5 Hz, 1H), 3.68 - 3.57 (m, 1H), 3.22 (dd, J= 14.2, 4.7 Hz, 1H),3.11 (d,J= 11.8 Hz, 1H), 3.00 - 2.87 (m, 1H), 2.47 (q,J=7.1Hz, 1H), 2.18-2.06 (m, 1H), 2.07- 1.95 (m, 1H), 1.76 (d,J=9.0Hz, 1H), 1.52 (dd,J=27.3, 12.9 Hz, 1H), 1.24 (dd,J = 24.3, 12.9 Hz, 1H), 1.09 (t, J= 7.2 Hz, 2H).
LCMS (MH+): 500.64. Example 164: (2S)-3-(4-((2-([l,l'-biphenyl]-4-yl)-2-(piperazin-l- yl)ethyl)carbamoyl)phenyl)-2-aminopropanoic acid
Figure imgf000128_0001
Step 1 : To a 0 °C solution of ethyl 2-bromo-2-(4-bromophenyl)acetate (16.5 g, 93.8 mmol) and TEA (12.3 g, 121.9 mmol ) in THF (300 mL), was added 1-benzylpiperazine (30 g, 93.2 mmol). After addition, the mixture was warmed to room temperature and stirred for 12 h, after which time, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate and washed with aq. NaHC0 , and brine. The organic layer was dried over Na2SC"4, concentrated and the residue was purified by silica gel chromatography to provide ethyl 2-(4-benzylpiperazin- l-yl)-2-(4-bromophenyl)acetate as a yellow solid.
Step 2: A solution of ethyl 2-(4-benzylpiperazin-l-yl)-2-(4-bromophenyl)acetate (22 g, 52.8 mmol), phenylboronic acid (7.66 g, 63.3 mmol) and Pd (dppf)Cl2 (3.86 g, 5.28 mmol) in dioxane (100 mL)/aq. NaC03 (2.0M, 100 mL) was heated at 80 °C for 12 h, then cooled to room temperature. After this time, the mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2S04 and concentrated. The residue was purified by silica gel chromatography to provide ethyl 2-([l, l'-biphenyl]-4-yl)-2-(4- benzylpiperazin-l-yl)acetate as light yellow oil.
Step 3 : A solution of ethyl 2-([l,l'-biphenyl]-4-yl)-2-(4-benzylpiperazin-l-yl)acetate (20 g, 48.3 mmol), KOH (8.12 g, 145 mmol) in EtOH/water (60 mL/ 20 mL) was heated at 80 °C for 2 h. After this time, the reaction was cooled to room temperature and the mixture was concentrated, diluted with water and adjusted pH=6-7 with 3 N HC1 and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SC"4 and concentrated to provide 2-([l, l'-biphenyl]-4-yl)-2-(4-benzylpiperazin-l-yl)acetic acid as a light yellow solid that was used without further purification.
Step 4: To a solution of 2-([l,l'-biphenyl]-4-yl)-2-(4-benzylpiperazin-l-yl)acetic acid (1 g, 2.6 mmol) in CH2C12 (10 mL) was added (COCl)2 (0.66 g, 5.2 mmol) dropwise at 0 °C. After the addition, the mixture was stirred at room temperature for 2 h after which time the solvent was removed in vacuo to provide 2-([l,l'-biphenyl]-4-yl)-2-(4-benzylpiperazin-l-yl)acetyl chloride as a yellow oil used without further purification.
Step 5 : A solution of 2-([ 1 , 1 '-biphenyl]-4-yl)-2-(4-benzylpiperazin- 1 -yl)acetyl chloride (1 g, 2.5 mmol) in CH2C12 (10 mL) was added to 30% aqueous H4OH (10 mL).The mixture was stirred for 30 min and extracted with CH2C12. The combined organic layers were washed with brine, dried over Na2SC"4 and concentrated to provide 2-([l, l'-biphenyl]-4-yl)-2-(4- benzylpiperazin-l-yl)acetamide as yellow oil used without further purification.
Step 6: To a solution of 2-([l,l'-biphenyl]-4-yl)-2-(4-benzylpiperazin-l-yl)acetamide (0.8 g, 2.1 mmol) in THF (10 mL) was added BH3-THF (IN, 15 mL) drop wise at 0 °C. The reaction mixture was warmed to room temperature and then heated to reflux for 12 h. After this time, the reaction mixture was cooled to room temperature, 6N HC1 (5 mL) was added and then the reaction mixture was refluxed for 2 h. The mixture was then cooled and concentrated in vacuo diluted with water, adjusted pH=7-8 with aqueous NaHC03 and extracted with ethyl acetate. The combined organic layers were dried over Na2SC"4, concentrated, and the residue was purified by silica gel chromatography to provide 2-([l, l'-biphenyl]-4-yl)-2-(4-benzylpiperazin-l- yl)ethanamine as a yellow oil.
Step 7: To a solution of 2-([l,l'-biphenyl]-4-yl)-2-(4-benzylpiperazin-l-yl) (400 mg, 1.1 mmol), TEA (222 mg, 2.2 mmol) and Intermediate A (371 mg, 1.1 mmol) in DMF (10 mL) was added HATU (630 mg, 1.6 mmol) at 5 °C. The mixture was stirred at room temperature for 12 h, then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over Na2SC"4, concentrated and purified by flash column to provide (2S)-ethyl 3-(4-((2-([l, l'-biphenyl]-4-yl)-2-(4-benzylpiperazin-l- yl)ethyl)carbamoyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate as a yellow oil.
Step 8: A mixture of (2S)-ethyl 3-(4-((2-([l,l*-biphenyl]-4-yl)-2-(4-benzylpiperazin-l- yl)ethyl)carbamoyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (450 mg, 0.65 mmol) and 10% Pd(OH)2 on activated carbon (20 mg ) in MeOH (lOmL) was stirred at room temperature under a hydrogen atmosphere (50 psi) for 12 h. After this time, the reaction mixture was filtered through a Celite pad, the filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica-gel to provide (2S)-ethyl 3-(4-((2-([l, l'-biphenyl]- 4-yl)-2-(piperazin-l-yl)ethyl)carbamoyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate as yellow oil.
Step 9: The title compound was made as described for the compound of Example la, Steps 3-4, starting with (2S)-ethyl 3-(4-((2-([l,l'-biphenyl]-4-yl)-2-(piperazin-l- yl)ethyl)carbamoyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate.
¾ NMR (400 MHz, MEOH-d4): 7.74 - 7.56 (m, 6H), 7.45 - 7.29 (m, 7H), 4.24 (t, J = 6.7 Hz, 1H), 4.10 (dd, J = 13.5, 7.0 Hz, 1H), 3.96 (t, J = 7.4 Hz, 1H), 3.69 (dd, J = 13.5, 7.5 Hz, 1H), 3.21 (m, 4H), 2.89 - 2.81 (m, 6H). LCMS (MH+): 473.58. Example 165: (S)-2-amino-3-(4-(((R)-2-(4-bromophenyl)-2-(4,4- dimethylcyclohexyl)ethyl)carbamoyl)phenyl)propanoic acid
Figure imgf000130_0001
The title compound was made as described for the compound of Example la starting with (R)-2-(4-bromophenyl)-2-(4,4-dimethylcyclohexyl)ethanamine (Intermediate 50).
¾ NMR (400 MHz, DMSO-d6): δ ppm 7.64 (d, J = 7.9 Hz, 3H), 7.57 (dd, J = 12.6, 7.8 Hz, 6H), 7.40 (t, J = 7.6 Hz, 3H), 4.64 - 4.49 (m, 1H), 4.46 - 4.26 (m, 2H), 4.13 (t, J = 6.4 Hz, 2H), 3.86 - 3.64 (m, 2H), 3.54 (dd, J = 13.3, 8.8 Hz, 2H), 3.24 (d, J = 12.0 Hz, 2H), 3.13 (s, 3H), 3.19 - 3.04 (m, 2H), 2.96 - 2.66 (m, 4H), 2.00 (d, J = 13.2 Hz, 1H), 1.93 - 1.86 (m, 1H), 1.57 (d, J = 13.5 Hz, 2H), 1.47 - 1.33 (m, 1H), 1.27 - 1.15 (m, 1H). LCMS (MH+): 472.59.
Example 166: (S)-2-amino-3-(4-(((R)-2-(4,4-dimethylcyclohexyl)-2-phenylethyl)
carbamoyl)phenyl)propanoic acid
Figure imgf000130_0002
The title compound was made as described for the compound of (Example la, starting with (R)-2-(4,4-dimethylcyclohexyl)-2-phenylethanamine (Intermediate 55).
¾ MR (400 MHz, DMSO-d6) δ 7.57 (d, J = 8.0 Hz, 2H), 7.28 - 7.18 (m, 4H), 7.13 (dd, J = 7.5, 4.7 Hz, 2H), 5.00 (d, J = 5.7 Hz, 1H), 4.15 (t, J = 6.4 Hz, 1H), 3.67 (dd, J = 13.3, 5.9 Hz, 1H), 3.52 (dd, J = 13.2, 9.5 Hz, 1H), 3.10 (d, J = 6.5 Hz, 1H), 2.83 (q, J = 7.3 Hz, 1H), 1.63 (s, 1H), 1.44 (d, J = 9.4 Hz, 1H), 1.32 (d, J = 8.4 Hz, 1H), 1.21 (d, J = 11.3 Hz, 1H), 1.12 (s, 1H), 0.96 (ddd, J = 28.2, 18.3, 11.1 Hz, 1H), 0.79 (s, 3H), 0.69 (s, 3H). LCMS (MH+): 423.56.
Example 167: (S)-2-amino-3-(4-(((R)-2-(4,4-dimethylcyclohexyl)-2-(p-tolyl)ethyl) carbamoyl)phenyl)propanoic acid
Figure imgf000131_0001
The title compound was made as described for the compound of Example la, starting with (R)-2-(4,4-dimethylcyclohexyl)-2-(p-tolyl)ethanamine (Intermediate 56).
¾ MR (400 MHz, Methanol-d4) δ 7.59 - 7.52 (m, 5H), 7.35 - 7.24 (m, 2H), 7.11 - 6.98 (m, 2H), 2.27 (s, 3H), 1.78 (d, J = 12.5 Hz, 1H), , 1.42 (dd, J = 12.4, 9.0 Hz, 1H), 1.36 - 1.16 (m, 2H), 0.79 (s, 3H), 0.69 (s, 3H)LCMS (MH+): 437.59
Example 168: (S)-2-amino-3-(4-(((R)-2-(4,4-dimethylcyclohexyl)-2-(4- fluorophenyl)ethyl)carbamoyl)phenyl)propanoic acid
Figure imgf000131_0002
The title compound was made as described for the compound of Example la starting with (R)-2-(4,4-dimethylcyclohexyl)-2-(4-fluorophenyl)ethanamine (Intermediate 57). ¾ NMR (400 MHz, Methanol-d4) δ 7.49 (d, J = 8.3 Hz, 2H), 7.25 - 7.13 (m, 2H), 7.04 - 6.94 (m, 2H), 4.08 (q, J = 7.1 Hz, 1H), 3.85 (dd, J = 13.3, 5.5 Hz, 1H), 3.69 (t, J = 6.7 Hz, 1H), 3.53 (dd, J = 13.3, 10.3 Hz, 1H), 2.99 (td, J = 12.9, 12.2, 6.8 Hz, 1H), 2.96 - 2.78 (m, 1H), 1.80 (d, J = 10.9 Hz, 1H), 1.56 - 1.50 (m, 1H), 1.28 (s, 3H), 1.32 - 1.10 (m, 2H), 1.14 - 0.96 (m, 1H), 0.87 (s, 3H), 0.82 (s, 3H). LCMS (MH+): 441.55
Example 169: (S)-2-amino-3-(4-(((R)-2-(4,4-dimethylcyclohexyl)-2-(4- methoxyphenyl)ethyl)carbamoyl)phenyl)propanoic acid
Figure imgf000132_0001
The title compound was made as described for the compound of Example la, starting with (R)-2-(4,4-dimethylcyclohexyl)-2-(4-methoxyphenyl)ethanamine (Intermediate 58).
¾ NMR (400 MHz, Methanol-d4) δ 7.49 (d, J = 8.3 Hz, 2H), 7.25 - 7.13 (m, 4H), 7.04 - 6.94 (m, 2H), 4.2 (t, J = 7.1 Hz, 2H), 3.85 (dd, J = 13.3, 5.5 Hz, 1H), 3.69 (t, J = 6.7 Hz, 1H), 3.53 (dd, J = 13.3, 10.3 Hz, 1H), 2.99 (m, 3H), 2.96 - 2.78 (m, 1H), 1.80 (d, J = 10.9 Hz, 1H), 1.56 - 1.50 (t, 3H), 1.28 (s, 3H), 1.32 - 1.10 (m, 2H), 1.14 - 0.96 (m, 1H), 0.87 (s, 3H), 0.82 (s, 3H). LCMS (MH+): 453.56.
Example 170: (S)-2-amino-3-(4-(((R)-2-(4,4-dimethylcyclohexyl)-2-(4- chlorophenyl)ethyl)carbamoyl)phenyl)propanoic acid
Figure imgf000132_0002
The title compound was made as described for the compound of Example la, starting with (R)-2-(4,4-dimethylcyclohexyl)-2-(4-chlorophenyl)ethanamine (Intermediate 59). ¾ NMR (400 MHz, DMSO-d6) δ 7.63 (d, J = 8.0 Hz, 2H), 7.29 (dd, J = 8.2, 5.6 Hz, 4H), 7.18 (d, J = 8.4 Hz, 2H), 3.68 (dd, J = 13.3, 5.6 Hz, 1H), 3.50 (ddd, J = 13.5, 9.2, 5.0 Hz, 1H), 3.15 (d, J = 11.6 Hz, 2H), 2.86 (dt, J = 9.1, 6.5 Hz, 1H), 1.22 (d, J = 12.4 Hz, 1H), 1.21 - 1.10 (m, 1H), 0.87 (s, 3H), 0.79 (s, 3H). LCMS (MH+): 458.01.
Example 171: (S)-2-amino-3-(4-(((R)-2-(4,4-dimethylcyclohexyl)-2-(4- trifluoromethylphenyl)ethyl)carbamoyl)phenyl)propanoic acid
Figure imgf000133_0001
The title compound was made as described for the compound of Example la, starting with (R)-2-(4,4-dimethylcyclohexyl)-2-(4-trifluoromethylphenyl)ethanamine (Intermediate 60). ¾ NMR (400 MHz, Methanol-d4) δ 7.57 (d, J = 8.0 Hz, 2H), 7.51 - 7.44 (m, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.24 - 7.17 (m, 1H), 3.73 - 3.54 (m, 1H), 3.05 - 2.89 (m, 1H), 1.60 (d, J = 9.6 Hz, 1H), 1.28 (dt, J = 22.5, 11.6 Hz, 1H), 0.97 (m, 3H), 0.85 (d, J = 19.3 Hz, 3H). LCMS (MH+): 491.56.
Example 172: (2S)-2-amino-3-(4-(((2R)-2-(4-bromophenyl)-2-(4- (trifluoromethyl)cyclohexyl ethyl)carbamoyl)phenyl)propanoic acid
Figure imgf000133_0002
The title compound was made as described for the compound of Example la, starting with (2R)-2-(4-bromophenyl)-2-(4-(trifluoromethyl) cyclohexyl)ethanamine (Intermediate 62). ¾ NMR (400 MHz, DMSO-d6) δ ppm 7.69 - 7.65 (m, 1H), 7.42 (m, 5H), 7.25 (m, 2H), 3.72 (dd, J = 13.4, 6.1 Hz, 2H), 3.52 (dd, J = 13.3, 8.9 Hz, 1H), 3.08 (t, J = 5.8 Hz, 2H), 2.86 (q, J = 7.2 Hz, 1H), 2.11 (s, 1H), 2.00 (d, J = 10.0 Hz, 1H), 1.87 (d, J = 12.6 Hz, 1H), 1.78 (d, J = 12.8 Hz, 1H), 1.61 (d, J = 11.6 Hz, 1H), 1.23 (d, J = 13.4 Hz, 2H), 1.07 (dt, J = 36.1, 11.8 Hz, 1H), 0.93 - 0.79 (m, 2H). LCMS (MH+): 542.40.
Example 173: (2S)-2-amino-3-(4-(((2R)-2-(4-bromophenyl)-2-(4-(tert-butyl)
cyclohexyl)ethyl)carbamoyl)phenyl)propanoic acid
Figure imgf000134_0001
The title compound was made as described for the compound of Example la, starting with (2R)-2-(4-bromophenyl)-2-(4-(tert-butyl)cyclohexyl)ethanamine (Intermediate 61).
¾ MR (400 MHz, DMSO-d6) δ ppm 7 7.61 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.3 Hz, 2H), 7.12 - 7.04 (m, 2H), 4.19 (t, J = 6.5 Hz, 1H), 3.63 (m, 2H), 3.08 (dd, J = 6.5, 3.9 Hz, 2H), 2.77 (dt, J = 9.3, 6.3 Hz, 1H), 1.90 (d, J = 11.5 Hz, 1H), 1.71 (d, J = 11.4 Hz, 1H), 1.62 (d, J = 10.2 Hz, 1H), 1.49 (d, J = 3.0 Hz, 1H), 1.47 (s, 2H), 1.43 (d, J = 7.5 Hz, 1H), 1.32 (s, 1H), 1.21 (d, J = 6.0 Hz, 1H), 0.97 - 0.75 (m, 14H). LCMS (MH+): 530.51.
Example 174: (2S)-3-(4-(((2R)-2-([l,l'-biphenyl]-4-yl)-2-(4-(tert- butyl)cyclohexyl)ethyl)carbamoyl)phenyl)-2-aminopropanoic acid
Figure imgf000134_0002
The title compound was prepared as described for Example la starting with (2R)-2-(4- bromophenyl)-2-(4-(tert-butyl)cyclohexyl)ethanamine (Intermediate 61) and phenyl boronic acid. ¾ NMR (400 MHz, DMSO-d6): δ ppm 8.25 (s, 1H), 7.68 - 7.56 (m, 4H), 7.54 (d, J= 8.3 Hz, 2H), 7.42 (t, J= 7.7 Hz, 2H), 7.36 - 7.18 (m, 5H), 3.88 (s, 1H), 3.71 (dt, J= 12.0, 5.6 Hz, 1H), 3.60 - 3.48 (m, 1H), 3.11 (dd, J= 14.3, 5.7 Hz, 1H), 2.99 (dd, J= 14.4, 7.2 Hz, 1H), 2.85 (q, J = 7.1 Hz, 1H), 1.93 (s, 1H), 1.72 (s, 1H), 1.63 (s, 1H), 1.51 (s, 1H), 1.21 (s, 1H), 0.91 (dd, J= 19.8, 10.1 Hz, 1H), 0.81 (s, 1H), 0.76 (s, 12H). LCMS (MH+): 528.71.
Example 175: (2S)-3-(4-(((2R)-2-([l,l'-biphenyl]-4-yl)-2-(4-(trifluoromethyl)
cyclohexyl)ethyl)carbamoyl)phenyl)-2-aminopropanoic acid
Figure imgf000135_0001
The title compound was prepared as described for the compound of Example la starting with (2R)-2-(4-bromophenyl)-2-(4-(trifluoromethyl)cyclohexyl)ethanamine (Intermediate 62) and phenyl boronic acid.
¾ NMR (400 MHz, DMSO-d6): δ ppm 7.69 - 7.53 (m, 4H), 7.42 (t, J = 7.7 Hz, 2H), 7.36 - 7.20 (m, 2H), 7.19 (m, 4H), 4.20 (t, J = 6.5 Hz, 1H), 3.72 (dd, J = 13.4, 6.1 Hz, 1H), 3.52 (dd, J = 13.3, 8.9 Hz, 1H), 3.08 (t, J = 5.8 Hz, 2H), 2.86 (q, J = 7.2 Hz, 1H), 2.11 (s, 1H), 2.00 (d, J =
10.0 Hz, 1H), 1.87 (d, J = 12.6 Hz, 1H), 1.78 (d, J = 12.8 Hz, 1H), 1.61 (d, J = 11.6 Hz, 1H), 1.23 (d, J = 13.4 Hz, 2H), 1.07 (dt, J = 36.1, 11.8 Hz, 1H), 0.93 - 0.79 (m, 2H). LCMS (MH+):
540.60. Example 176: (S)-3-(4-(((R)-2-([l,l'-biphenyl]-4-yl)-2-(spiro[3.5]nonan-7- yl)ethyl)carbamoyl)phenyl)-2-aminopropanoic acid
Figure imgf000136_0001
The title compound was prepared as described for the compound of Example la starting with (R)-2-(4-bromophenyl)-2-(spiro[3.5]nonan-7-yl)ethanamine (Intermediate 63)
¾ NMR (400 MHz, DMSO-d6): δ ppm 1H NMR (400 MHz, DMSO-d6) δ 7.62 - 7.50 (m, 6H), 7.41 (t, J = 7.6 Hz, 2H), 7.34 - 7.18 (m, 5H), 4.18 (t, J = 6.4 Hz, 1H), 3.70 (dd, J = 13.2, 5.6 Hz, 1H), 3.48 (dd, J = 13.3, 9.4 Hz, 1H), 3.07 (t, J = 5.2 Hz, 2H), 2.82 (q, J = 7.6 Hz, 1H), 1.72 (q, J = 7.0, 6.2 Hz, 4H), 1.65 - 1.52 (m, 5H), 1.50 (m, 3H), 1.32 - 1.14 (m, 2H), 1.02 (m, 2 H).LCMS (MH+): 511.67.
Example 177: (S)-3-(4-(((lS,2S)-2-([l,l'-biphenyl]-4-yl)cyclopentyl) carbamoyl)phenyl)-2- aminopropanoic acid
Figure imgf000136_0002
The title compound was prepared as described for the compound of Example la starting with (I S, 2S)-2-(4-bromo)cyclopentylamine (CAS# 1388847-75-3).
¾ NMR (400 MHz, DMSO-d6): δ ppm 7.52 (d, J = 7.9 Hz, 2H), 7.40 (ddd, J = 20.9, 16.1, 7.7 Hz, 6H), 7.27 (d, J = 8.1 Hz, 3H), 7.16 (d, J = 7.7 Hz, 2H), 4.59 (q, J = 6.9 Hz, 1H), 4.08 (d, J = 6.5 Hz, 1H), 3.33 (q, J = 8.3 Hz, 1H), 3.04 (d, J = 6.6 Hz, 2H), 2.04 (dt, J = 17.3, 8.7 Hz, 4H), 1.72 (dq, J = 13.9, 7.6, 7.0 Hz, 2H). LCMS (MH+): 429.52. Example 178: (2S)-3-(4-((2-([l,l'-biphenyl]-4-yl)cycloheptyl)carbamoyl)-phenyl)-2- aminopropanoic acid
Figure imgf000137_0001
The title compound was prepared as described for the compound of Example la starting with 2-(4-chlorophenyl)cyclohexylamine (CAS# 1249261-65-1).
¾ MR (400 MHz, DMSO-d6): δ ppm 7.64 - 7.46 (m, 6H), 7.46 (d, J = 2.4 Hz, 2H), 7.38 (q, J = 9.4, 8.5 Hz, 3H), 7.35 - 7.19 (m, 2H), 4.43 (d, J = 6.3 Hz, 1H), 4.17 (t, J = 6.5 Hz, 1H), 3.94 (m, 1H), 3.17 (m, 2H), 2.32 - 2.21 (m, 1H), 1.89 - 1.78 (m, 6H), 1.48 (s, 2H), 1.45 (m, 3H). LCMS (MH+): 485.63.
Preparation of prodrugs:
Example Pla: (S)-ethyl 3-(4-(((R)-2-([l,l'-biphenyl]-4-yl)-3-methylbutyl)
carbamoyl)phenyl)-2-aminopropanoate
Figure imgf000137_0002
Step 1 : To a solution of (S)-4-(2-((tert-butoxycarbonyl)amino)-3-ethoxy-3- oxopropyl)benzoic acid (Intermediate A, 200 mg, 0.82 mmol) in DMF (10 mL) was added (R)-2- (4-bromophenyl)-3-methylbutan-l -amine (Intermediate 44, 278 mg, 1.24 mmol), HATU (623 mg, 1.64 mmol), and TEA (166 mg, 1.64 mmol). The reaction was stirred for 48 h at RT. After this time, the reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated in vacuo. Purification via normal phase column chromatography (hexanes: ethyl acetate/4: 1 v/v) provided (S)-ethyl 3-(4- (((R)-2-(4-bromophenyl)-3-methylbutyl)carbamoyl)phenyl)-2-((tert- butoxycarbonyl)amino)propanoate as a white solid.
Step 2: To a solution of (S)-ethyl 3-(4-(((R)-2-(4-bromophenyl)-3-methylbutyl) carbamoyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (200 mg, 0.36 mmol) in dioxane (5.0 mL)/Na2C03 (2.5 mL, 2.0 M, aq.) was added phenyl boronic acid (66 mg, 0.54 mmol) followed by Pd(dppf)Cl2 (26 mg, 0.036 mmol). The reaction was purged with N2 and then heated to 90 °C for 3 h. After this time, the reaction was cooled to RT and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated in vacuo. Purification via normal phase column chromatography (hexanes: ethyl acetate/4: 1 v/v) provided (S)-ethyl 3-(4-(((R)-2-([l, r-biphenyl]-4-yl)-3-methylbutyl)carbamoyl)phenyl)-2-((tert- butoxycarbonyl)amino)propanoate as an off-white solid.
Step 3 : To a 0 °C solution of (S)-ethyl 3-(4-(((R)-2-([l, l*-biphenyl]-4-yl)-3-methylbutyl) carbamoyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (150 mg, 0.27 mmol) in CH2C12 (6 mL), was added dropwise TFA (1.5 mL). The reaction was warmed to RT for 3 h, then concentrated in vacuo. To the resulting residue was added saturated aqueous solution of
NaHCC to adjust the pH to -7.5 and then extracted with CH2C12. The organic layer was washed with brine, dried over Na2SC"4, filtered and concentrated in vacuo to provide (S)-ethyl 3-(4-(((R)- 2-([l,l'-biphenyl]-4-yl)-3-methylbutyl)carbamoyl)phenyl)-2-aminopropanoate as an off- white solid.
1H NMR (400 MHz, MeOH-d4): δ ppm 7.62 - 7.46 (m, 5H), 7.40 (t, J = 7.7 Hz, 2H), 7.34 -
7.24 (m, 3H), 7.19 (d, J = 8.3 Hz, 2H), 4.05 (qd, J = 7.1, 1.2 Hz, 2H), 3.88 (dd, J = 13.3, 5.5 Hz, 1H), 3.72 - 3.54 (m, 2H), 3.04 - 2.78 (m, 3H), 2.00 (dq, J = 13.7, 6.9 Hz, 1H), 1.16 - 1.05 (m, 5H), 0.82 (d, J = 6.7 Hz, 2H). LCMS (M+H): 459.59.
The compounds shown in Table 7a were made using the method described above starting with the appropriate ethyl ester. NMR data is provided in Table 7b.
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
phenyl)propanoate
Figure imgf000141_0001
propanoate (S)-ethyl 2-amino-3-(4-((2-(3'- (methylcarbamoyl)- [1,1 '-biphenyl] -4-
P106 H 473.56 yl)ethyl)carbamoyl)
phenyl)propanoate
1
(S)-ethyl 2-amino-3-(4-((2-(3'- (dimethylcarbamoyl)-[ 1 , 1 '-biphenyl]-
P107 H 488.59
4-yl)ethyl)carbamoyl)
phenyl)propanoate
1
(S)-ethyl 2-amino-3-(4-((4-
P150 H phenoxyphenethyl)carbamoyl) 433.51 phenyl)propanoate
(S)-ethyl 2-amino-3 -(4-((2-( 1 -phenyl-
P148 H 1 H-indazol- 5 -yl)ethy 1) carb amoyl) 457.54 phenyl)propanoate
hyl 2-amino-3 -(4-((2-(4-phenyl-
P149 o~c (S)-et
H lH-imidazol-2-yl)ethyl) 407.47 carbamoyl)phenyl)propanoate
(S)-ethyl 3-(4-(((R)-2-([l, l'- biphenyl] -4-yl)-2-
P73 H 443.55 cyclobutylethyl)carbamoyl) phenyl)- 2-aminopropanoate
(S)-ethyl 2-amino-3-(4-(((R)-3-
P88 H methyl-2-(naphthalen-2-yl)butyl) 433.56 carbamoyl)phenyl)propanoate
(S)-ethyl 3-(4-(((R)-2-([l, l'- biphenyl]-4-yl)-2-cyclopentylethyl)
P80 H 485.63 carbamoyl)phenyl)-2- aminopropanoate
(S)-ethyl 3-(4-(((R)-2-([l, l'- biphenyl]-4-yl)-2-cycloheptylethyl)
P84 H 513.68 carbamoyl)phenyl)-2- aminopropanoate (2S)-ethyl 3 -(4-((2-([ 1 , 1 '-biphenyl]- 4-yl)-3 , 3 -dimethylbutyl)
P151 H 473.62 carbamoyl)phenyl)-2- aminopropanoate
(S)-ethyl 2-amino-3-(4-(((R)-3- methyl-2-(2'-methyl-[ 1 , 1 '-biphenyl]-
P24 H 473.62
4-yl)butyl)carbamoyl)
phenyl)propanoate
(S)-ethyl 2-amino-3-(4-(((R)-2- cyclobutyl-2-(3'-methyl-[l, Γ-
P75 H biphenyl]-4-yl)ethyl)carbamoyl) 485.63 phenyl)propanoate
(S)-ethyl 2-amino-3 -(4-(((R)-2-(4'- cyano-[ 1 , 1 '-biphenyl]-4-yl)-2-
P76 H 495.61 cyclobutylethyl)carbamoyl)phenyl)- propanoate
P78 ?- (S)-ethyl 3-(4-(((R)-2-([l, l'- biphenyl]-4-yl)-2-
H 498.66 cyclohexylethyl)carbamoyl)phenyl)- 2-aminopropanoate
(S)-ethyl 2-amino-3 -(4-(((R)-2-(4'- cyano-[ 1 , 1 '-biphenyl]-4-yl)-2-
P81 H 510.64 cyclopentylethyl)carbamoyl)phenyl)- propanoate
(S)-ethyl 2-amino-3-(4-(((R)-2- cyclobutyl-2-(4'-(hydroxymethyl)-
P77 H [1, 1 '-biphenyl] -4-yl)ethyl)carbamoyl) 501.63 phenyl)propanoate (S)-ethyl 2-amino-3-(4-(((R)-2- cyclopentyl-2-(4'-(hydroxymethyl)-
P82 H 515.66
[1, 1 '-biphenyl]-4-yl)ethyl)carbamoyl)
phenyl)propanoate
(S)-ethyl 2-amino-3 -(4-(((R)-2-(4'- cyano-[ 1 , 1 '-biphenyl]-4-yl)-2-
P85 H 538.69 cycloheptylethyl)carbamoyl)phenyl)- propanoate
(S)-ethyl 2-amino-3-(4-(((R)-2-(3'- fluoro- [ 1 , 1 '-bipheny l]-4-yl)-3 -
P25 H 477.58 methylbutyl)carbamoyl)phenyl)- propanoate
(S)-ethyl 2-amino-3-(4-(((R)-2- cyclopentyl-2-(3 '-methyl-[ 1 , 1 '-
P83 H 499.66 biphenyl]-4-yl)ethyl)carbamoyl)
phenyl)propanoate
(S)-ethyl 2-amino-3-(4-(((R)-2-(3'- chloro-[l, l'-biphenyl]-4-yl)-3-
P26 H 494.04 methylbutyl)carbamoyl)phenyl)
propanoate
^^^^^^^
(S)-ethyl 3 -(4-((2-([ 1 , 1 *-biphenyl]-4- yl)-2-
P152 H 493.61 phenylethyl)carbamoyl)phenyl)-2- aminopropanoate
(S)-ethyl 2-amino-3-(4-(((R)-2- cycloheptyl-2-(4'-(hydroxymethyl)-
P86 H 534.71
[l, r-biphenyl]-4-yl)ethyl)
carbamoyl)phenyl)propanoate
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
aminopropanoate
Figure imgf000148_0001
Figure imgf000149_0001
propanoate
Figure imgf000150_0001
propanoate (S)-ethyl 2-amino-3-(4-(((R)-3- methyl-2-(4'-(oxetan-3 -yl)-[ 1 , 1 '-
P68 H biphenyl]-4- 515.66 yl)butyl)carbamoyl)phenyl)- propanoate
(S)-ethyl 3-(4-(((R)-2-([l, l'- biphenyl]-4-yl)-3,3-
P74 H 445.56 dimethylbutyl)carbamoyl)pheny)-2- aminopropanoate
(S)-ethyl 2-amino-3 -(4-(((R)-2-(4'-(2- (dimethylamino)ethoxy)-[ 1 , 1 '-
P67 H biphenyl]-4-yl)-3- 546.71 methylbutyl)carbamoyl)phenyl)- y — — propanoate
(S)-ethyl 2-amino-3-(4-(((R)-3- methyl-2-(4-(thiazol-2-
P69 H 466.61 yl)phenyl)butyl)carbamoyl)
phenyl)propanoate
(S)-ethyl 2-amino-3-(4-(((R)-3- methyl-2-(4-(thiazol-4-
P70 H 466.61 yl)phenyl)butyl)carbamoyl)
phenyl)propanoate
(S)-ethyl 2-amino-3 -(4-(((R)-2-(4'- amino-3 '-hydroxy- [ 1 , 1 '-biphenyl]-4-
Qi H 490.61 yl)-3 -methylbutyl)carbamoyl)
phenyl)propanoate
OH
(S)-ethyl 3-(4-(((lS,2S)-2-([l,r- biphenyl]-4-
P92 H 471.60 yl)cyclohexyl)carbamoyl)pheny)-2- aminopropanoate
Figure imgf000152_0001
Figure imgf000153_0001
Table 7b
Figure imgf000153_0002
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
IH NMR (400 MHz, MeOH-d4): δ ppm 7.62 - 7.45 (m, 5H), 7.40 (t, J= 7.6 Hz, 2H), 7.29 (dd, J= 7.9, 6.1 Hz, 2H), 7.19 (d, J= 8.0 Hz, 2H), 4.05 (q, J= 7.1 Hz,
P84 2H), 3.88 (dd, J= 13.3, 5.5 Hz, IH), 3.70 - 3.54 (m, 2H), 2.96 (ddq, J= 27.2,
13.5, 6.8 Hz, 3H), 1.94 (dt, J= 24.0, 8.1 Hz, 2H), 1.68 (d, J= 21.1 Hz, 2H), 1.60 (s, IH), 1.50 (d, J= 7.8 Hz, 2H), 1.31 - 1.07 (m, 4H)
IH NMR (400 MHz, MeOH-d4): δ ppm 7.62 - 7.50 (m, 3H), 7.40 (dt, J= 7.6, 3.6 Hz, 3H), 7.30 (dd, J= 13.4, 7.4 Hz, 3H), 7.15 (d, J= 8.0 Hz, 2H), 4.07 - 3.96
P151
(m, 2H), 3.87 (d, J= 8.0 Hz, 2H), 3.63 (t, J= 6.7 Hz, IH), 3.02 - 2.84 (m, 3H), 1.29 (s, IH), 1.09 (td, J= 7.2, 1.9 Hz, 3H), 1.01 (s, 8H)
IH NMR (400 MHz, MeOH-d4): δ ppm 7.49 (d, J= 8.2 Hz, 2H), 7.29 - 7.08 (m, 7H), 4.07 (q, J= 7.0 Hz, 2H), 3.88 (dd, J= 13.3, 5.6 Hz, IH), 3.72 - 3.56 (m,
P24
2H), 3.05 - 2.75 (m, 4H), 2.19 (s, 2H), 2.00 (dp, J= 14.1, 7.0 Hz, 2H), 1.29 (d, J = 4.7 Hz, IH), 1.19 - 1.02 (m, 5H), 0.84 (d, J= 6.7 Hz, 2H)
IH NMR (400 MHz, MeOH-d4): δ 7.64 - 7.47 (m, 4H), 7.41 - 7.31 (m, 2H), 7.31 - 7.14 (m, 6H), 7.11 (d, J= 7.5 Hz, IH), 4.07 (q, J= 7.2 Hz, 2H), 3.73 -
P75 3.62 (m, 2H), 3.42 (dd, J= 13.4, 9.0 Hz, IH), 3.07 - 2.88 (m, 4H), 2.77 - 2.61
(m, 2H), 2.38 (s, 3H), 2.23 (ddd, J= 13.4, 8.4, 5.1 Hz, 2H), 2.03 - 1.72 (m, 6H),
1.63 (p, J= 8.8 Hz, 2H), 1.14 (t, J= 7.2 Hz, 3H)
IH NMR (400 MHz, MeOH-d4): δ ppm 7.77 (s, 2H), 7.60 (dd, J= 8.2, 3.0 Hz, 2H), 7.34 (d, 7= 8.0 Hz, IH), 7.24 (d, J= 8.0 Hz, IH), 4.07 (q, J= 7.1 Hz, IH),
P76 3.72 - 3.61 (m, IH), 3.46 (dd, J= 13.3, 9.0 Hz, IH), 2.98 (ddt, J= 28.6, 13.5, 7.2
Hz, 2H), 2.70 (q, J= 8.9 Hz, IH), 2.04 - 1.73 (m, 3H), 1.63 (q, J= 9.4 Hz, IH), 1.14 (t, 7= 7.1 Hz, 2H)
IH NMR (400 MHz, MeOH-d4): δ ppm 7.61 - 7.46 (m, 5H), 7.39 (t, 7= 7.7 Hz, 2H), 7.33 - 7.15 (m, 4H), 4.05 (q, 7= 7.1 Hz, 2H), 3.90 (dd, 7= 13.3, 5.5 Hz,
P78 IH), 3.71 - 3.52 (m, 2H), 3.03 - 2.80 (m, 3H), 2.00 (d, 7= 12.9 Hz, IH), 1.79 (d,
7= 13.1 Hz, IH), 1.73 - 1.52 (m, 4H), 1.40 - 1.26 (m, 2H), 1.26 - 1.03 (m, 6H), 0.88 (td, 7= 12.2, 9.1 Hz, IH)
IH NMR (400 MHz, MeOH-d4): δ ppm 7.77 (d, 7= 1.7 Hz, 9H), 7.64 - 7.45 (m, 10H), 7.35 (d, 7= 8.3 Hz, 5H), 7.29 (s, IH), 7.20 (d, 7= 8.0 Hz, 5H), 4.06 (q, 7 =
P81 7.1 Hz, 5H), 3.83 (dd, 7= 13.3, 4.8 Hz, 3H), 3.66 (t, 7= 6.7 Hz, 3H), 3.56 (dd, 7
= 13.3, 10.3 Hz, 3H), 3.04 - 2.81 (m, 9H), 2.18 (h, 7= 8.9 Hz, 4H), 1.77 - 1.68 (m, 3H), 1.60 (s, 2H), 1.57 - 1.36 (m, 11H), 1.17 - 1.01 (m, 10H)
IH NMR (400 MHz, MeOH-d4): δ ppm 7.64 - 7.50 (m, 5H), 7.40 (d, 7= 7.9 Hz, 2H), 7.25 (dd, 7= 14.3, 7.9 Hz, 4H), 4.63 (s, 2H), 4.07 (q, 7= 7.2 Hz, 2H), 3.68
P77 (dt, 7= 14.2, 6.4 Hz, 2H), 3.43 (dd, 7= 13.3, 8.9 Hz, IH), 2.98 (qd, 7= 13.8, 7.2
Hz, 3H), 2.69 (h, 7= 8.4, 7.6 Hz, IH), 2.26 - 2.19 (m, IH), 2.04 - 1.83 (m, 3H), 1.78 (d, 7= 10.1 Hz, 2H), 1.63 (p, 7= 8.2, 7.2 Hz, 2H), 1.14 (t, 7= 7.1 Hz, 2H)
IH NMR (400 MHz, MeOH-d4): δ ppm 7.60 - 7.49 (m, 6H), 7.40 (d, 7= 7.9 Hz, 2H), 7.28 (d, 7= 7.9 Hz, 2H), 7.19 (d, 7= 7.9 Hz, 2H), 4.63 (s, 2H), 4.05 (q, 7 =
P82 7.3 Hz, 2H), 3.84 (dd, 7= 13.5, 4.6 Hz, IH), 3.65 (d, 7= 6.8 Hz, IH), 3.31 (s,
IH), 3.04 - 2.78 (m, 4H), 2.17 (q, 7= 8.6 Hz, IH), 2.10 - 1.99 (m, 2H), 1.71 (s, IH), 1.67 - 1.51 (m, 3H), 1.46 (s, 2H), 1.11 (q, 7= 14.3, 10.8 Hz, 4H)
IH NMR (400 MHz, MeOH-d4): δ ppm 7.82 - 7.72 (m, 2H), 7.61 (d, J = 7.9 Hz,
P85 IH), 7.51 (d, J = 7.9 Hz, IH), 7.35 (d, J = 7.9 Hz, IH), 7.20 (d, J = 7.9 Hz, IH),
4.06 (q, J = 7.1 Hz, IH), 3.64 (dt, J = 13.3, 8.5 Hz, IH), 3.31 (s, 3H), 3.07 - 2.87
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Example Rla: (S)-propyl 3-(4-(((R)-2-([l,l'-biphenyl]-4-yl)-3-methylbutyl) carbamoyl)phenyl)-2-aminopropanoate
Figure imgf000165_0001
Step 1 : To a O°C solution of (S)-ethyl 3-(4-(((R)-2-([l, l'-biphenyl]-4-yl)-3- methylbutyl)carbamoyl) phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (Example la, Step 2, 800 mg, 1.51 mmol) in DMF (8 mL) was added TEA (762 mg, 7.536 mmol) and HATU (1.15 g, 3.026 mmol) and the reaction mixture was warmed to RT and stirred for 12 h. The reaction was then diluted with water (10 mL) and extracted with CH2CI2. The combined organic layers were washed with brine, dried over Na2S04 and concentrated. Purification via normal phase column chromatography (hexanes: ethyl acetate/4: 1 v/v) provided (S)-propyl 3-(4-(((R)-2-([l,l'- biphenyl]-4-yl)-3-methylbutyl)carbamoyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate as a yellow solid.
Step 2: To a 0°CSolution of (S)-propyl 3-(4-(((R)-2-([l, l*-biphenyl]-4-yl)-3-methylbutyl) carbamoyl) phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (1.0 g, 1.7 mmol) in dioxane (4 mL), was added HC1 in dioxane (1 M, 10 mL). The reaction mixture was stirred for 2 h 0 °C and then an additional 2 h at RT. After this time, the reaction mixture was concentrated in vacuo and the resulting solid was washed with ether to provide the title compound as a white solid.
The compounds shown in Table 8a were made using the method described above for Example Rla starting with the appropriate alcohol. NMR data is provided in Table 8b.
Table 8a
Figure imgf000165_0002
Figure imgf000166_0001
amnopropanoate
Table 8b
Figure imgf000166_0002
Example P166: (S)-ethyl 2-amino-3-(4-(((R)-2-(4,4-dimethylcyclohexyl)-2- phenylethyl)carbamoyl)phenyl)propanoate
Figure imgf000167_0001
The title compound was prepared as described for the compound of Example Rla starting with (R)-2-(4,4-dimethylcyclohexyl)-2-phenylethanamine (Interrmediate 55).
The compounds shown in Table 9a were made using the method according to Example PI 66 above starting with the appropriate intermediate.
Table 9a
Figure imgf000167_0002
Figure imgf000167_0003
Figure imgf000168_0001
Table 9b
Figure imgf000168_0002
3.73 - 3.54 (m, 1H), 3.05 - 2.89 (m, 1H), 1.60 (d, J = 9.6 Hz, 1H), 1.50 - 1.42 (m, 3H), 1.28 (dt, J = 22.5, 11.6 Hz, 1H), 0.97 (m, 3H), 0.85 (d, J = 19.3 Hz, 3H)
Example A: In vitro Inhibition Assays
TPH1 Assay
Recombinant human TPH1 (rTPHl GenBank TM accession no. P 004179) was expressed by cloning full length human TPH1 cDNA in to a bacterial pMAL-c5E expression vector to produce maltose-binding protein (MBP) TPH1 fusion proteins. E.coli BL21 (DE3) containing pMAL-c5E-TPHl was used for protein generation and the recombinant protein was purified utilizing standard column chromatography techniques. The MBP tagged TPH1 (MBP- TPH1) was used directly to screen compounds as described below.
TPH1 activities were measured in an assay containing 200 mM ammonium sulfate, 7 mM DTT, 50 μg/mL catalase, 25 μΜ ammonium iron sulfate, 50 mM MES, pH 7.1. Test compounds were diluted in 100% DMSO and added to the assay plate in 1 μΙ_, aliquots at lOOx final concentration. Fifty microliters of assay buffer containing 30 nM TPH1 enzyme (MBP tagged) were added to the plate wells containing the test compound by the use of an Eppendorf repeater pipette. The reaction was initiated by the addition of 50 μΙ_, of assay buffer containing 60 μΜ tryptophan and 72 μΜ 6-6-methyltetra-hydropterin (2x final concentration) by the use of a Multidrop (LabSystems). Final reaction conditions were 15 nM TPH1 enzyme, 30 μΜ tryptophan, 36 μΜ 6-methyltetra-hydropterin, 200 mM ammonium sulfate, 7 mM DTT, 25 μg/mL catalase, 25 μΜ ferrous ammonium sulfate, 50 mM MES, pH 7.1, with atmospheric oxygen at room temperature. The plate was immediately placed onto an M5 plate reader (Molecular Devices) for kinetic fluorescence measurement using an excitation setting of 300 nm and an emission setting of 335 nm. Fluorescence reads are recorded in kinetic mode for 300 seconds (5 minutes).
Kinetic assay data for compounds at specific concentrations was translated into slopes using the Softmax Pro software on a Spectramax reader, and compound inhibition slopes were compared with wells containing enzyme, substrate and cofactor in the absence of inhibitor (100%), and wells containing substrate and cofactor in the absence of enzyme (0%). DMSO concentration in the assay was 1%. Typically, in the absence of enzyme, reaction slopes were ~0. ICso' s were determined using Graphpad Prism.
Compounds having an IC50 of 10,000 nM or less were considered active.
Data related to TPHl inhibition activity of the compounds of the invention according to this assay is provided below in Table 10. Compounds that inhibit TPHl with an IC50 from 3,000 nM to 10,000 nM are indicated by +. Compounds that inhibit TPHl with an IC50 of less than 3,000 nM but more than 300 nM are indicated by ++. Compounds that inhibit TPHl from 50 nM to 300 nM are indicated by +++. Compounds that inhibit TPHl with an IC50 less than 50 nM are indicated by ++++.
Table 10. TPHl Inhibition Data
Figure imgf000170_0001
21 ++++
22 ++
23 ++
24 +++
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44 +++
46 ++++
47 ++
48 +++
49 +++
50 ++
51 +++ 52 ++++
53 ++++
54 ++
55 +++
56 ++++
57 ++++
58 +++
59 +++
60 ++
61 +++
62 ++++
63 ++
64 ++
65 +++
66 ++++
67 +
68 +++
69 +++
70 ++++
71 +
72 +++
73 ++++
74 ++++
75 ++++
76 ++++
77 ++++
78 ++++
79 ++++
80 ++++
81 ++++ 82 ++++
83 ++++
84 ++++
85 ++++
86 ++++
87 +++
88 ++++
89 ++
90 +++
91 +++
92 +++
93 ++
94 +++
95 ++
96 ++
97 ++
98 ++
99 +
100 +
101 +
102 +
103 +
104 +
105 +
106 ++
107 +
108 ++
109 ++
110 ++++
111 ++++ 112
113
114
115
116
117
118
119
120
121
122
123
124
125 ++
126 ++
127 ++
128 ++
129 ++
130 ++
131 ++
132 ++
133 ++
134 ++
135 ++
136 ++
137 ++
138 ++
139 +
140 +
141 + 142 +
143 +
144 +
145 +
146 +
147 +
148 ++
149 +
150 +
151 ++++
152 +++
153 ++
154 ++
155 ++
156 ++
157 +
158 +
159 +
160 +
178 +++
152a +++
174 ++++
175 ++++
172 +++
173 ++++
160 +++
161 ++++
177 ++++
176 ++++
162 ++++ 163 ++++
164 ++
165 ++++
166 +++
167 +++
168 +++
169 +++
170 ++++
171 +++
Example B: Intestinal 5-HT depletion assay
The efficacy of the TPH1 inhibitors of the invention can be assessed for the ability to decrease intestinal serotonin concentration in mice. Mice (C57 BL6) are administered a single 150 mg/kg dose of test article by oral gavage. Each animal is euthanized by exsanguination under isoflurane anesthesia. Jejunal intestinal mucosa is isolated and homogenized in 300 μΙ_, of a buffer containing 0.3M trichloroacetic acid, 0.1M sodium acetate, 10 mM EDTA, 20 mM sodium bisulfate and 50 mM ascorbic acid. Following centrifugation the 5-HT levels in the supematants are measured by HPLC. The remaining mucosal pellet is solubilized overnight at 37 °C in a 0.1% sodium dodecyl sulfate buffer in 0.1N NaOH followed by determination of protein concentrations using a BCA protein assay (Pierce, Rockford, II. 5-HT levels were normalized to protein and data were expressed as mean percent reduction of mucosal 5-HT levels relative to vehicle control ± SEM (percent 5-HT reduction). All animal studies are carried out with protocols approved by the Institutional Animal Care and Use Committee.
Example C: Reduction of mucosal 5-HT concentrations
The efficacy of the TPH1 inhibitors of the invention can be assessed for the ability to decrease intestinal serotonin concentration in mice. Mice (C57 BL6) are administered an oral dose of 10 or 50 mg/kg of the test article in the evening. Approximately 16 h following the first dose, mice are administered a second oral dose of 50 mg/kg of the appropriate compound. A third oral dose of 50 mg/kg of the appropriate test article is administered 12 h after dose 2. Following an overnight fast, each animal is euthanized by exsanguination under isoflurane anesthesia. Jejunal intestinal mucosa is isolated and homogenized in 300 mL of a buffer containing 0.3 M trichloroacetic acid, 0.1 M sodium acetate, 10 mM EDTA, 20 mM sodium bisulfate and 50 mM ascorbic acid. Following centrifugation the 5-HT levels in the supernatants are measured by HPLC. The remaining mucosal pellet is solubilized overnight at 37 °C in a 0.1% sodium dodecyl sulfate buffer in 0. IN NaOH followed by determination of protein concentrations using a BCA protein assay (Pierce, Rockford, IL). 5-HT levels are normalized to protein and data are expressed as mean percent reduction of mucosal 5-HT levels relative to vehicle control ± SEM (percent 5-HT reduction). All animal studies are carried out with protocols approved by the Institutional Animal Care and Use Committee.
Certain compounds of the invention were tested in the above assay and found to be active in decreasing intestinal serotonin concentration. Tested compounds are indicated in Table 1 1 showing statistical significance (P -values) of the obtained data (ANOVA): * refers to P<0.05, ** refers to P<0.01, *** refers to P<0.005, and **** refers to P<0.0005.
Table 11.
Figure imgf000177_0001
Example D: In vivo assay for inflammatory bowel diseases
The utility of the compounds of the invention for the treatment of inflammatory bowel diseases can be measured, for example, using the experimental models of colitis induced by trinitrobenzene sulfonic acid (TNBS), dinitrobenzene sulfonic acid (DNBS), and dextran sodium sulfate (DSS), as described by Ghia, J.-E. et al. in Gastroenterol. 137, 1649-60 (2009). Example E: In vivo assay for low bone mass diseases The utility of the compounds of the invention for the treatment of low bone mass diseases, such as osteoporosis, can be measured, for example, using the ovariectomy-induced osteopenia rat model, as described by Yadav, V. K. et al. in Nature Med. 16, 308-12 (2010). Example F: In vivo assay for PAH
The utility of the compounds of the invention for the treatment or prevention of pulmonary arterial hypertension (PAH), can be measured, for example, using the hypoxia mouse model, as described by Abid, S. et al. m Am. J. Physiol, Lung Cellular and Molecular
Physiology 303, L500-8 (2012), or using the rat monocrotaline-induced PAH or the rat chronic hypoxia model, as described by Kay, J. M. et al. Respiration 47, 48-56 (1985).
Example G: In vivo assay for allergic airway inflammation
The utility of the compounds of the invention for the treatment of allergic airway inflammation, can be measured, for example, using the mouse model of allergic asthma, as described by Diirk, T. et al. m Am. J. Respir. Crit. Care Med. 187, 476-485 (2013).
Example H: In vivo assay for gastrointestinal disorders
The utility of the compounds of the invention for the treatment of gastrointestinal disorders associated with dysregulation of the GI serotonergic system, such as chemotherapy- induced emesis and irritable bowel syndrome, can be measured, for example, using the a ferret model of chemotherapy-induced emesis, as described by Liu, Q. et al. in J. Pharmacol. Exp. Ther. 325, 47-55 (2008).
Example I: In vivo assay for tumor growth
The utility of the compounds of the invention for the treatment of tumor growth, can be measured, for example, using the the xenograft model of cholangiocarcinoma tumor growth, as described by Alpini, G. et al. in Cancer Res. 68, 9184-93 (2008).
Example J: In vivo assay for leukemia
The utility of the compounds of the invention for the treatment and prevention of leukemia and other cancers of the blood, can be measured, for example, using the mouse leukemia model, the osteoblast-deficient mouse model, or the murine model of acute myeloid leukemia, as described in WO 2013/074889.
Example K: In vivo assay for atherosclerosis
The utility of the compounds of the invention for the treatment or prevention of atherosclerosis, and the reduction of plasma cholesterol and triglyceride levels, can be measured, for example, using the Apo E -/- or LDLR -/- mouse models of atherosclerotic plaque development, as described in WO 2012/058598. Example L: In vivo assay for necrotizing enterocolitis
The utility of the compounds of the invention for the treatment or prevention of of necrotizing enterocolitis can be assessed, for example, using SERT knockout mice, as described in WO 2013/148978. Example M: In vivo assay for pulmonary fibrosis
The utility of the compounds of the invention for the treatment or prevention of pulmonary fibrosis (e.g., IPF) can be assessed, for example, using a bleomycin mouse model, as described in Fabre, A. et al. "Modulation of bleomycin-induced lung fibrosis by serotonin receptor antagonists in mice." Eur. Respir. J. 2008; 32; 426-436. Additional useful preclinical models and methods for testing the compounds of the invention for usefulness in the treatment or prevention of IPF are described in Moeller, A. et al. "The bleomycin animal model: a useful tool to investigate treatment options for idiopathic pulmonary fibrosis?" Int. J. Biochem. Cell Biol. 40, 362-82 (2008) and Mouratis, et al. "Modeling pulmonary fibrosis with bleomycin." Curr. Opin. Pulm. Med. 17, 355-61 (2011).
Example M: Preclinical model for systemic sclerosis (scleroderma)
The utility of the compounds of the invention for the treatment or prevention of scleroderma can be assessed, for example, according to the preclinical models and methods described in Derrett-Smith, E. C. et al. "Animal models of scleroderma: lessons from transgenic and knockout mice." Curr. Opin. Rheumatol. 21, 630-5 (2009) and Artlett, C. M. "Animal models of scleroderma: fresh insights." Curr. Opin. Rheumatol. 22, 677-82 (2010). Example N: Preclinical model for liver fibrosis
The utility of the compounds of the invention for the treatment or prevention of liver fibrosis can be assessed, for example, according to the preclinical models and methods described in Liedtke, C. et al. "Experimental liver fibrosis research: update on animal models, legal issues and translational aspects." Fibrogenesis Tissue Repair 6, 19 (2013) and Iredale, J. P. "Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ." J. Clin. Invest. I ll, 539-48 (2007).
Example O: Preclinical model for renal fibrosis
The utility of the compounds of the invention for the treatment or prevention of renal fibrosis can be assessed, for example, using the preclinical in vivo animal model and methods described in Johnson, T.S., J Clin Invest. Jun 15, 1997; 99(12): 2950-2960.
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

is claimed is:
A compound of Formula I:
Figure imgf000181_0001
I
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is C3-14 cycloalkyl, C6-io aryl, 4 to 14-membered heterocycloalkyl, or 5 to 10- membered heteroaryl;
Z is a bridging C3 -14 cycloalkyl group, a bridging C6-io aryl group, a bridging 4 to 14- membered heterocycloalkyl group, or a bridging 5 to 10-membered heteroaryl group, each optionally substituted by 1, 2, or 3 substituents independently selected from Rz;
or Z is:
Figure imgf000181_0002
R1 is H, Ci-io alkyl, C3-10 cycloalkyl, phenyl, -(CR9R10)pOC(O)Ru, -(C R9R10)P RUR12, or -(C R9R10)pC(O) RuR12, 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, Ci-4 alkyl, and C1-4 haloalkyl;
R2 is H, Ci-4 alkyl, C(0)Rbl, C(0)NRclRdl, or C(0)ORal;
R3 and R4 are each independently selected from H, C1-4 alkyl, C1-4 haloalkyl, OH, and C1-4 alkoxy;
each R5 is independently selected from halo, C1-4 alkyl, and C1-4 alkoxy;
R6 is H or Ci-4 alkyl; or R6 and Z, together with the N atom to which they are both attached, form a 4-7 membered heterocycloalkyl group optionally substituted by 1, 2, or 3 substituents independently selected from Rz;
each R7 is independently selected from H, halo, and Ci-4 alkyl;
each R8 is independently selected from H, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C6-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, CN, N02, ORa2, SRa2, C(0)Rb2, C(0) Rc2Rd2, C(0)ORa2, OC(0)Rb2,
OC(0) Rc2Rd2, NRc2Rd2, NRc2C(0)Rb2, NRc2C(0)ORa2, NRc2C(0) Rc2Rd2, NRc2S(0)Rb2, Rc2S(0)2Rb2, Rc2S(0)2 Rc2Rd2, S(0)Rb2, S(0) Rc2Rd2, S(0)2Rb2, and S(0)2 Rc2Rd2;
wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 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 R8a, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 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;
or R7 and R8, when taken together with the single carbon atom to which they are both attached, form a C3-7 cycloalkyl group optionally substituted by 1, 2, or 3 substituents independently selected from halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 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;
each R8a is independently selected from C6-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-io aryl-Ci-6 alkyl, C3-10 cycloalkyl-Ci-6 alkyl, 5- 10 membered heteroaryl-Ci-6 alkyl, and 4-10 membered heterocycloalkyl-Ci-6 alkyl, each of which is optionally substituted by 1 or 2 substituents independently selected from halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, CN, N02, ORa2, SR32, 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;
R9 are each independently selected from H and C1-4 alkyl; R is Ci-6 alkyl optionally substituted by 1, 2 or 3 substituents independently selected from Ci-6 haloalkyl, C3-10 cycloalkyl, ORa3, and NRc Rd3;
R11 and R12 are each independently selected from H and Ci-6 alkyl;
RA is H, Cy1, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, CN, N02, ORa4, SRa4, C(0)RM, C(0) Rc4Rd4, C(0)ORa4, OC(0)RM, OC(0) Rc4Rd4, NRc4Rd4, NRc4C(0)RM, Rc4C(0)ORa4, Rc4C(0) Rc4Rd4, Rc4S(0)RM, Rc4S(0)2RM, Rc4S(0)2 Rc4Rd4, S(0)RM, S(0) Rc4Rd4, S(0)2RM, or S(0)2 Rc4Rd4, wherein said Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, 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, ORa4, SRa4, C(0)RM, C(0)NRc4Rd4, C(0)ORa4, OC(0)RM, OC(0)NRc4Rd4, NRc4Rd4, NRc4C(0)Rb4, NRc4C(0)ORa4, NRc4C(0)NRc4Rd4, NRc4S(0)RM, NRc4S(0)2RM, NRc4S(0)2NRc4Rd4, S(0)RM, S(0)NRc4Rd4, S(0)2RM, and
S(0)2NRc4Rd4;
RB is H, Cy2, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 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, or S(0)2NRc5Rd5, wherein said Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl 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, 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;
Rc and RD are each independently selected from H, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, CN, N02, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)ORa6, NRc6C(0)NRc6Rd6, NRc6S(0)Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, and S(0)2NRc6Rd6;
wherein said Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl 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, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)ORa6, NRc6C(0)NRc6Rd6, NRc6S(0)Rb6, NRc6S(0)2Rb6,
NRc6S(0)2NRc6Rd6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, and S(0)2NRc6Rd6; each Rz is halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, CN, N02, ORa2, SRa2, C(0)Rb2, C(0) Rc2Rd2, C(0)ORa2, OC(0)Rb2, OC(0) Rc2Rd2, NRc2Rd2, NRc2C(0)Rb2, Rc2C(0)ORa2, Rc2C(0) Rc2Rd2, Rc2S(0)Rb2, NRc2S(0)2Rb2, Rc2S(0)2 Rc2Rd2, S(0)Rb2, S(0) Rc2Rd2, S(0)2Rb2, and S(0)2 Rc2Rd2, wherein said Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with a substituent selected from halo, 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;
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 is independently selected from halo, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C5-10 aryl, C3 -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-io aryl-Ci- 4 alkyl, C3 -10 cycloalkyl-C 1-4 alkyl, (5-10 membered heteroaryl)-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl, CN, N02, ORa7, SRa7, C(0)Rb7, C(0)NRc7Rd7, C(0)ORa7,
OC(0)Rb7, OC(0)NRc7Rd7, NRc7Rd7, NRc7C(0)Rb7, NRc7C(0)ORa7, NRc7C(0)NRc7Rd7,
NRc7S(0)Rb7, NRc7S(0)2Rb7, NRc7S(0)2NRc7Rd7, S(0)Rb7, S(0)NRc7Rd7, S(0)2Rb7, and
S(0)2NRc7Rd7, 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, C3-10 cycloalkyl-C 1-4 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 halo, Ci-6 alkyl, CN, N02, ORa7, SRa7, C(0)Rb7, C(0)NRc7Rd7, C(0)ORa7, OC(0)Rb7, OC(0)NRc7Rd7, NRc7Rd7, NRc7C(0)Rb7, NRc7C(0)ORa7, NRc7C(0)NRc7Rd7, NRc7S(0)Rb7, NRc7S(0)2Rb7, NRc7S(0)2NRc7Rd7, S(0)Rb7, S(0)NRc7Rd7, S(0)2Rb7, and S(0)2NRc7Rd7;
each Ral, Rbl, Rcl, and Rdl is independently selected from H, Ci-6 alkyl, CM haloalkyl, C6- 10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl;
or 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 halo, Ci-6 alkyl, and Ci-6 haloalkyl;
each Ra2, Ra3, Ra4, Ra5, Ra6, Ra7, Rb2, Rb4, Rb5, Rb6, Rb7, Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rd2, Rd3, Rd4, Rd5, Rd6, and Rd7 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-Ci-4 alkyl, C3-10 cycloalkyl-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, and (4-10 membered heterocycloalkyl)-C 1-4 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)-C 1-4 alkyl, and (4-10 membered heterocycloalkyl)-Ci-4 alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from CM alkyl, halo, CN, ORa8, C(0)Rb8, C(0) Rc8Rd8, C(0)ORa8, OC(0)Rb8, OC(0) Rc8Rd8, Rc8Rd8, NRc8C(0)Rb8, NRc8C(0) Rc8Rd8,
Rc8C(0)ORa8, S(0)Rb8, S(0) Rc8Rd8, S(0)2Rb8, Rc8S(0)2Rb8, Rc8S(0)2 Rc8Rd8, and S(0)2 Rc8Rd8;
each Ra8, Rb8, Rc8, and Rd8 is independently selected from H, C 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-4 alkoxy, C 1-4 alky lthio, C 1-4 alky lamino, and di(Ci-4 alkyl)amino;
n is 0, 1, 2, 3, or 4;
m is 1, 2, 3, or 4; and
p is 1, 2, 3, or 4;
wherein:
(3) when Z is:
Figure imgf000185_0001
R2 is C(0)ORal, Ral is Ci-6 alkyl, m is 2, n is 0, R3 is H, R4 is H, R6 is H, R7 is H, R8 is H, RA is H, RB is H, Rc is H, and RD is H; then ring A is other than indolyl and naphthyl;
(4) when Z is:
Figure imgf000186_0001
R2 is C(0)ORal, Ral is Ci-6 alkyl, m is 2, n is 0, R3 is H, R4 is H, R6 is H, R7 is H, R8 is H, RA is cyclohexyl or phenyl, RB is H, Rc is H, and RD is H; then ring A is other than phenyl;
(3) when Z is unsubstituted bridging furanyl, R2 is H, n is 0, R3 is H, R4 is H, R6 is H, and one of RA, RB, Rc, and RD is methoxy; then ring A is other than phenyl; and
(4) when Z is bridging phenyl substituted by amino, R2 is H, n is 0, R3 is H, R4 is H, and R6 is H; then ring A is other than thienyl.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
Ring A is C3-14 cycloalkyl, C5-10 aryl, 4 to 14-membered heterocycloalkyl, or 5 to 10- membered heteroaryl;
Z is a bridging C3-14 cycloalkyl group, a bridging C6-io aryl group, a bridging 4 to 14- membered heterocycloalkyl group, or a bridging 5 to 10-membered heteroaryl group, each optionally substituted by 1, 2, or 3 substituents independently selected from Rz;
or Z is:
Figure imgf000186_0002
R1 is H, Ci-10 alkyl, C3-10 cycloalkyl, phenyl, -(CR9R10)pOC(O)Ru, -(C R9R10)P RUR12, or -(C R9R10)pC(O) RuR12, 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, Ci-4 alkyl, and C1-4 haloalkyl;
R2 is H, Ci-4 alkyl, C(0)Rbl, C(0)NRclRdl, or C(0)ORal;
R3 and R4 are each independently selected from H, C1-4 alkyl, C1-4 haloalkyl, OH, and C1-4 alkoxy;
each R5 is independently selected from halo, C1-4 alkyl, and C1-4 alkoxy;
R6 is H or Ci-4 alkyl; or R6 and Z, together with the N atom to which they are both attached, form a 4-7 membered heterocycloalkyl group optionally substituted by 1, 2, or 3 substituents independently selected from Rz;
each R7 is independently selected from H, halo, and Ci-4 alkyl;
each R8 is independently selected from H, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C6-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, CN, N02, ORa2, SRa2, C(0)Rb2, C(0) Rc2Rd2, C(0)ORa2, OC(0)Rb2,
OC(0) Rc2Rd2, NRc2Rd2, NRc2C(0)Rb2, NRc2C(0)ORa2, NRc2C(0) Rc2Rd2, NRc2S(0)Rb2, Rc2S(0)2Rb2, Rc2S(0)2 Rc2Rd2, S(0)Rb2, S(0) Rc2Rd2, S(0)2Rb2, and S(0)2 Rc2Rd2;
wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 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, C2-6 alkenyl, C2-6 alkynyl, 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;
or R7 and R8, when taken together with the single carbon atom to which they are both attached, form a C3-7 cycloalkyl group optionally substituted by 1, 2, or 3 substituents independently selected from halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 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;
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, ORa3, and NRc Rd3;
R11 and R12 are each independently selected from H and Ci-6 alkyl;
RA is H, Cy1, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, CN, N02, ORa4, SRa4, C(0)RM, C(0)NRc4Rd4, C(0)ORa4, OC(0)RM, OC(0)NRc4Rd4, NRc4Rd4, NRc4C(0)Rb4, NRc4C(0)ORa4, NRc4C(0)NRc4Rd4, NRc4S(0)RM, NRc4S(0)2RM, NRc4S(0)2NRc4Rd4, S(0)RM, S(0)NRc4Rd4, S(0)2Rb4, or S(0)2NRc4Rd4, wherein said Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, 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, ORa4, SRa4, C(0)Rb4, C(0)NRc4Rd4, C(0)ORa4, OC(0)RM, OC(0)NRc4Rd4, NR R , NRc4C(0)RM, NRc4C(0)ORa4, NRc4C(0)NRc4Rd4, Rc4S(0)RM, NRc4S(0)2RM, NRc4S(0)2 Rc4Rd4, S(0)RM, S(0) Rc4Rd4, S(0)2RM, and
S(0)2 Rc4Rd4;
RB is H, Cy2, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 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, or S(0)2NRc5Rd5, wherein said Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl 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, 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;
Rc and RD are each independently selected from H, halo, Ci-6 alkyl, C2-6 alkenyl, C2 -6 alkynyl, Ci-6 haloalkyl, CN, N02, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)ORa6, NRc6C(0)NRc6Rd6, NRc6S(0)Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, and S(0)2NRc6Rd6;
wherein said Ci-6 alkyl, C2 -6 alkenyl, and C2 -6 alkynyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C6-io aryl, C3 -10 cycloalkyl, 5-10 membered heteroaiyl, 4-10 membered heterocycloalkyl, halo, Ci-6 alkyl, C2 -6 alkenyl, Ci-6 haloalkyl, CN, N02, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)ORa6, NRc6C(0)NRc6Rd6, NRc6S(0)Rb6, NRc6S(0)2Rb6,
NRc6S(0)2NRc6Rd6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, and S(0)2NRc6Rd6;
each Rz is halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 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, wherein said Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with a substituent selected from halo, 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; Cy1 and Cy2 are each independently selected from C6-io aryl, C3-io 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 is independently selected from halo, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C6-io aryl, C3-io 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)-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, CN, N02, ORa7, SRa7, C(0)Rb7, C(0)NRc7Rd7, C(0)ORa7,
OC(0)Rb7, OC(0) Rc7Rd7, NRc7Rd7, NRc7C(0)Rb7, NRc7C(0)ORa7, Rc7C(0) Rc7Rd7,
Rc7S(0)Rb7, Rc7S(0)2Rb7, Rc7S(0)2 Rc7Rd7, S(0)Rb7, S(0) Rc7Rd7, S(0)2Rb7, and
S(0)2 Rc7Rd7, 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, C3-10 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 halo, Ci-6 alkyl, CN, N02, ORa7, SRa7, C(0)Rb7, C(0)NRc7Rd7, C(0)ORa7, OC(0)Rb7, OC(0)NRc7Rd7, NRc7Rd7, NRc7C(0)Rb7, NRc7C(0)ORa7, NRc7C(0)NRc7Rd7, NRc7S(0)Rb7, NRc7S(0)2Rb7, NRc7S(0)2NRc7Rd7, S(0)Rb7, S(0)NRc7Rd7, S(0)2Rb7, and S(0)2NRc7Rd7;
each Ral, Rbl, Rcl, and Rdl is independently selected from H, Ci-6 alkyl, CM haloalkyl, C6- 10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl;
or 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 halo, Ci-6 alkyl, and Ci-6 haloalkyl;
each Ra2, Ra3, Ra4, Ra5, Ra6, Ra7, Rb2, RM, Rb5, Rb6, Rb7, Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rd2, Rd3, Rd4, Rd5, Rd6, and Rd7 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-Ci-4 alkyl, C3-10 cycloalkyl-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, and (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, C3-10 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 CM alkyl, halo, CN, ORa8, C(0)Rb8, C(0)NRc8Rd8, C(0)ORa8, OC(0)Rb8, OC(0)NRc8Rd8, NRc8Rd8, NRc8C(0)Rb8, NRc8C(0)NRc8Rd8, Rc8C(0)ORa8, S(0)Rb8, S(0) Rc8Rd8, S(0)2Rb8, Rc8S(0)2Rb8, Rc8S(0)2 Rc8Rd8, and S(0)2 Rc8Rd8;
each Ra8, Rb8, Rc8, and Rd8 is independently selected from H, C 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-4 alkoxy, C 1-4 alky lthio, C 1-4 alky lamino, and di(Ci-4 alkyl)amino;
n is 0, 1, 2, 3, or 4;
m is 1, 2, 3, or 4; and
p is 1, 2, 3, or 4;
wherein:
(5) when Z is:
Figure imgf000190_0001
R2 is C(0)ORal, Ral is Ci-6 alkyl, m is 2, n is 0, R3 is H, R4 is H, R6 is H, R7 is H, Rs is H, RA is H, RB is H, Rc is H, and RD is H; then ring A is other than indolyl and naphthyl;
(6) when Z is:
Figure imgf000190_0002
R2 is C(0)ORal, Ral is Ci-6 alkyl, m is 2, n is 0, R3 is H, R4 is H, R6 is H, R7 is H, R8 is H, RA is cyclohexyl or phenyl, RB is H, Rc is H, and RD is H; then ring A is other than phenyl;
(3) when Z is unsubstituted bridging furanyl, R2 is H, n is 0, R3 is H, R4 is H, R6 is H, and one of RA, RB, Rc, and RD is methoxy; then ring A is other than phenyl; and
(4) when Z is bridging phenyl substituted by amino, R2 is H, n is 0, R3 is H, R4 is H, and R6 is H; then ring A is other than thienyl.
3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Ring A is C6-io aryl or 5 to 10-membered heteroaryl.
4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, naphthyl, pyridyl, indazolyl, or imidazolyl.
5. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl.
6. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Z is a bridging C3-14 cycloalkyl group, a bridging C6-io aryl group, a bridging 4 to 14-membered heterocycloalkyl group, or a bridging 5 to 10-membered heteroaryl group, each optionally substituted by 1, 2, or 3 substituents independently selected from Rz.
7. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Z is a bridging C3-7 cycloalkyl group.
8. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Z is a bridging cyclobutyl group or bridging cyclohexyl group.
9. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Z is:
Figure imgf000191_0001
10. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R6 and Z, together with the N atom to which they are both attached, form a 4-7 membered heterocycloalkyl group optionally substituted by 1, 2, or 3 substituents independently selected from Rz.
1 1. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R1 is H or Ci-io alkyl.
12. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R1 is H or Ci-4 alkyl.
13. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R1 is H or ethyl.
14. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R1 is H.
15. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R1 is ethyl.
16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R2 is H, C alkyl, C(0)Rbl, or C(0) RclRdl.
17. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R2 is H.
18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 are each independently selected from H and Ci-4 alkyl.
19. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 are both H.
20. The compound of any one of claims 1 to 9 and 1 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R6 is H or methyl.
21. The compound of any one of 1 to 9 and 11 to 19, or a pharmaceutically acceptable salt thereof, wherein R6 is H.
22. The compound of any one of claims 1 to 5, 9, and 11 to 21, or a pharmaceutically acceptable salt thereof, wherein each R7 is independently selected from H and Ci-4 alkyl.
23. The compound of any one of claims 1 to 5, 9, and 11 to 21, or a pharmaceutically acceptable salt thereof, wherein each R7 is independently selected from H and methyl.
24. The compound of any one of claims 1 to 5, 9, and 11 to 21, or a pharmaceutically acceptable salt thereof, wherein R7 is H.
25. The compound of any one of claims 1 to 5, 9, and 11 to 24, or a pharmaceutically acceptable salt thereof, wherein each R8 is independently selected from H, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C6-io aryl, C3 -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, N02, ORa2, SR32, C(0)Rb2, C(0) Rc2Rd2, C(0)ORa2, OC(0)Rb2, OC(0) Rc2Rd2, NRc2Rd2, NRc2C(0)Rb2, NRc2C(0)ORa2, Rc2C(0) Rc2Rd2,
Rc2S(0)Rb2, NRc2S(0)2Rb2, NRc2S(0)2 Rc2Rd2, S(0)Rb2, S(0) Rc2Rd2, S(0)2Rb2, and S(0)2 Rc2Rd2; wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 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, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, CN, N02, OR32, 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.
26. The compound of any one of claims 1 to 5, 9, and 11 to 24, or a pharmaceutically acceptable salt thereof, wherein each R8 is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C6-io aryl, C3 -10 cycloalkyl, 4-10 membered heterocycloalkyl, and ORa2, wherein said Ci-6 alkyl, C6-io aryl, C3 -10 cycloalkyl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 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, Rc2S(0)Rb2, NRc2S(0)2Rb2, NRc2S(0)2 Rc2Rd2, S(0)Rb2, S(0) Rc2Rd2, S(0)2Rb2, and
S(0)2 Rc2Rd2.
27. The compound of any one of claims 1 to 5, 9, and 11 to 24, or a pharmaceutically acceptable salt thereof, wherein each R8 is independently selected from H, Ci-6 alkyl, or C3-10 cycloalkyl, wherein said Ci-6 alkyl and C3-10 cycloalkyl, are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, CN, N02, ORa2, SRa2, C(0)Rb2, C(0) Rc2Rd2, C(0)ORa2, OC(0)Rb2, OC(0) Rc2Rd2, Rc2Rd2, Rc2C(0)Rb2, Rc2C(0)ORa2, Rc2C(0) Rc2Rd2, Rc2S(0)Rb2, Rc2S(0)2Rb2, Rc2S(0)2 Rc2Rd2, S(0)Rb2, S(0) Rc2Rd2, S(0)2Rb2, and S(0)2 Rc2Rd2.
28. The compound of any one of claims 1 to 5, 9, and 11 to 24, or a pharmaceutically acceptable salt thereof, wherein each R8 is independently selected from H, Ci-6 alkyl, or C3-7 cycloalkyl, wherein said Ci-6 alkyl is optionally substituted by hydroxyl and said C3-7 cycloalkyl is optionally substituted by 1 or 2 methyl groups.
29. The compound of any one of claims 1 to 5, 9, and 11 to 24, or a pharmaceutically acceptable salt thereof, wherein each R8 is independently selected from H and Ci-6 alkyl.
30. The compound of any one of claims 1 to 5, 9, and 11 to 24, or a pharmaceutically acceptable salt thereof, wherein each R8 is independently selected from H and C3-7 cycloalkyl.
31. The compound of any one of claims 1 to 5, 9, and 11 to 24, or a pharmaceutically acceptable salt thereof, wherein each R8 is independently selected from H and 2-propyl.
32. The compound of any one of claims 1 to 5, 9, and 11 to 24, or a pharmaceutically acceptable salt thereof, wherein R7 and R8, when taken together with the single carbon atom to which they are both attached, form a C3-7 cycloalkyl group optionally substituted by 1, 2, or 3 substituents independently selected from halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, CN, N02, ORa2, SRa2, C(0)Rb2, C(0)NRc2Rd2, C(0)ORa2, OC(0)Rb2, OC(0)NRc2Rd2, RC R , Rc2C(0)Rb2, NRc2C(0)ORa2, NRc2C(0) Rc2Rd2, NRc2S(0)Rb2, NRc2S(0)2Rb2, Rc2S(0)2 Rc2Rd2, S(0)Rb2, S(0) Rc2Rd2, S(0)2Rb2, and S(0)2 Rc2Rd2.
33. The compound of any one of claims 1 to 5, 9, and 1 1 to 24, or a pharmaceutically acceptable salt thereof, wherein R7 and R8, when taken together with the single carbon atom to which they are both attached, form a C3-7 cycloalkyl group.
34. The compound of any one of claims 1 to 5, 9, and 1 1 to 24, or a pharmaceutically acceptable salt thereof, wherein R7 and R8, when taken together with the single carbon atom to which they are both attached, form a cyclopropyl group or a cyclobutyl group.
35. The compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.
36. The compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein n is 0.
37. The compound of any one of claims 1 to 5, 9, and 1 1 to 36, or a pharmaceutically acceptable salt thereof, wherein m is 1.
38. The compound of any one of claims 1 to 5, 9, and 1 1 to 36, or a pharmaceutically acceptable salt thereof, wherein m is 2.
39. The compound of any one of claims 1 to 5, 9, and 1 1 to 36, or a pharmaceutically acceptable salt thereof, wherein m is 3.
40. The compound of any one of claims 1 to 5, 9, and 1 1 to 36, or a pharmaceutically acceptable salt thereof, wherein m is 4.
41. The compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein RA is H, Cy1, halo, C2-6 alkynyl, or ORa4, wherein said C2 -6 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy1, halo, Ci-6 alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, N02, ORa4, SRa4, C(0)RM, C(0)NRc4Rd4, C(0)ORa4, OC(0)RM, OC(0)NRc4Rd4, NRc4Rd4, NRc4C(0)RM, NRc4C(0)ORa4, NRc4C(0)NRc4Rd4, NRc4S(0)RM, NRc4S(0)2RM, NRc4S(0)2NRc4Rd4, S(0)RM, S(0)NRc4Rd4, S(0)2RM, and S(0)2NRc4Rd4.
42. The compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein RA is Cy1, halo, C2-6 alkynyl, or ORa4, wherein said C2-6 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy1, halo, Ci-6 alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, N02, ORa4, SRa4, C(0)RM, C(0)NRc4Rd4, C(0)ORa4, OC(0)RM, OC(0)NRc4Rd4, NRc4Rd4, NRc4C(0)RM, NRc4C(0)ORa4, NRc4C(0)NRc4Rd4, NRc4S(0)RM, NRc4S(0)2RM, NRc4S(0)2NRc4Rd4, S(0)RM, S(0)NRc4Rd4, S(0)2RM, and S(0)2NRc4Rd4.
43. The compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein RA is Cy1.
44. The compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein Cy1 is selected from phenyl, pyrazolyl, pyrimidinyl, pyridyl, cyclohexyl, cyclohexenyl, indazolyl, quinolyl, isoquinolyl, piperidinyl, thiazolyl, imidazolyl, benzimidazolyl, and benzo[d][l,3]dioxolyl, each of which is optionally substituted by 1, 2, or 3 substituents independently selected from RCy.
45. The compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein Cy1 is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from K^.
46. The compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, wherein each is independently selected from halo, Ci-6 alkyl, Ci-6 haloalkyl, C5-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaiyl, 4-10 membered heterocycloalkyl, CN, ORa7, C(0)NRc7Rd7, C(0)ORa7, and NRc7Rd7, wherein said Ci-6 alkyl is optionally substituted with 1 or 2 substituents independently selected from ORa7 and NRc7Rd7.
47. The compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, wherein each is independently selected from F, CI, methyl, ethyl, propyl, butyl, trifluoromethyl, phenyl, cyclopropyl, cyclobutyl, imidazolyl, oxazolyl, pyrazolyl, CN, hydroxy, methoxy, ethoxy, amino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxymethyl, hydroxymethyl, hydroxyethyl, isopropyloxymethyl, aminomethyl, carboxyl, carboxy ethyl ester, oxetanyl, dimethylaminoethyloxy, t-butoxy, cyclopropyloxy,
48. The compound of any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, wherein RB is H, halo, or ORa5.
49. The compound of any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, wherein RB is H.
50. The compound of any one of claims 1 to 49, or a pharmaceutically acceptable salt thereof, wherein Rc is H.
51. The compound of any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof, wherein RD is H.
52. The compound of any one of claims 1 to 5, 9, and 11 to 51, or pharmaceutically acceptable salt thereof, having Formula II:
Figure imgf000197_0001
II.
53. The compound of any one of claims 1 to 5, 9, and 11 to 51, or pharmaceutically acceptable salt thereof, having Formula III:
Figure imgf000198_0001
Figure imgf000198_0002
Figure imgf000198_0003
56. The compound of any one of claims 1 to 5, 9, and 11 to 51, or pharmaceutically acceptable salt thereof, having Formula VI:
Figure imgf000199_0001
VI
wherein q is 0, 1, 2, or 3.
57. The compound of any one of claims 1 to 5, 9, and 11 to 51, or pharmaceutically acceptable salt thereof, having Formula VII:
Figure imgf000199_0002
VII
wherein q is 0, 1, 2, or 3.
58. The compound of claim 1 selected from:
(S)-3-(4-(((R)-2-([l,r-biphenyl]-4-yl)-3-methylbutyl) carbamoyl)phenyl)-2- aminopropanoic acid;
(S)-3-(4-(((S)-2-([l,r-biphenyl]-4-yl)-3-methylbutyl) carbamoyl)phenyl)-2- aminopropanoic acid; (S)-2-amino-3-(4-(((R)-3-methyl-2-(4-(pyrimidin-5-yl)
phenyl)butyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(((R)-3-methyl-2-(4-(l-methyl-lH-pyrazol-4- yl)phenyl)butyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(((R)-2-(4'-hydroxy-[l,r-biphenyl]-4-yl)-3- methy lbutyl)carb amoy l)p heny l)propanoic aci d ;
(S)-2-amino-3-(4-(((R)-2-(4-(2-aminopyrimidin-5-yl)phenyl)-3- methy lbutyl)carb amoy l)p heny l)propanoic aci d ;
(S)-2-amino-3 -(4-(((R)-2-(2'-cyano- [1,1 '-biphenyl] -4-yl)-3 - methy lbutyl)carb amoy l)p heny l)propanoic aci d ;
(S)-2-amino-3 -(4-(((R)-2-(3 '-cyano- [1,1 '-biphenyl] -4-yl)-3 - methy lbutyl)carb amoy l)p heny l)propanoic aci d ;
(S)-2-amino-3 -(4-(((R)-2-(4'-cyano- [1,1 '-biphenyl] -4-yl)-3 - methy lbutyl)carb amoy l)p heny l)propanoic aci d ;
(S)-2-amino-3 -(4-(((R)-2-(4'-ethyl-[ 1 , 1 '-biphenyl]-4-yl)-3 - methy lbutyl)carb amoy l)p heny l)propanoic aci d ;
(S)-2-amino-3-(4-(((R)-2-(3'-(hydroxymethyl)-[l,l'-biphenyl]-4-yl)-3-methylbutyl) carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(((R)-2-(4'-(hydroxymethyl)-[l,l'-biphenyl]-4-yl)-3-methylbutyl) carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3 -(4-(((R)-2-(4'-carbamoyl-[ 1 , 1 '-biphenyl]-4-yl)-3 - methy lbutyl)carb amoy l)p heny l)propanoic aci d ;
4'-((R)- 1 -(4-((S)-2-amino-2-carboxyethyl)benzamido)-3 -methy lbutan-2-yl)-[ 1 , 1 '- biphenyl]-4-carboxylic acid;
(S)-2-amino-3-(4-(((R)-2-(4'-(ethoxycarbonyl)-[l,l'-biphenyl]-4-yl)-3-methylbutyl) carbamoyl)phenyl)propanoic acid;
(S)-3-(4-(((R)-2-(4-(lH-pyrazol-4-yl)phenyl)-3-methylbutyl) carbamoyl)phenyl)-2- aminopropanoic acid;
(S)-2-amino-3 -(4-(((R)-2-(3 '-(aminomethyl)-[ 1 , 1 '-biphenyl]-4-yl)-3 - methylbutyl)carbamoyl) phenyl)propanoic acid; (S)-2-amino-3 -(4-(((R)-2-(2'-(hydroxymethyl)-[ 1 , 1 *-biphenyl]-4-yl)-3 - methylbutyl)carbamoyl) phenyl)propanoic acid;
(S)-2-amino-3-(4-(((R)-3-methyl-2-(2',3',4',5'-tetrahydro-[l,r-biphenyl]-4- yl)butyl)carbamoyl) phenyl) propanoic acid;
(S)-2-amino-3-(4-(((R)-3-methyl-2-(3'-methyl-[l,r-biphenyl]-4- yl)butyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(((R)-3-methyl-2-(4'-methyl-[l,r-biphenyl]-4- yl)butyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(((R)-2-(4'-(aminomethyl)-[l,r-biphenyl]-4-yl)-3-methylbutyl) carbamoyl) phenyl)propanoic acid;
(S)-2-amino-3-(4-(((R)-2-(2'-(aminomethyl)-[l,r-biphenyl]-4-yl)-3-methylbutyl) carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(((R)-3-methyl-2-(2'-methyl-[l,r-biphenyl]-4- yl)butyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3 -(4-(((R)-2-(3 '-fluoro- [1, 1 '-biphenyl] -4-yl)-3 - methy lbutyl)carb amoy l)p heny l)propanoic aci d ;
(S)-2-amino-3 -(4-(((R)-2-(3 '-chloro-[ 1 , 1 '-biphenyl]-4-yl)-3 - methy lbutyl)carb amoy l)p heny l)propanoic aci d ;
(S)-2-amino-3-(4-(((R)-2-(3'-methoxy-5'-methyl-[l,r-biphenyl]-4-yl)-3- methylbutyl)carbamoyl) phenyl)propanoic acid;
(S)-2-amino-3-(4-(((R)-2-(3'-(tert-butyl)-[l,r-biphenyl]-4-yl)-3-methylbutyl)carbamoyl) phenyl)propanoic acid;
(S)-2-amino-3 -(4-(((R)-2-(3 5'-dimethyl-[ 1 , 1 '-biphenyl]-4-yl)-3 - methy lbutyl)carb amoy l)p heny l)propanoic aci d ;
(S)-2-amino-3 -(4-(((R)-2-(3 '-methoxy-[ 1 , 1 '-biphenyl]-4-yl)-3 - methy lbutyl)carb amoy l)p heny l)propanoic aci d ;
(S)-2-amino-3-(4-(((R)-2-(3'-hydroxy-[l,r-biphenyl]-4-yl)-3- methy lbutyl)carb amoy l)p heny l)propanoic aci d ;
(S)-2-amino-3 -(4-(((R)-3-methyl-2-(3 '-(trifluoromethyl)-[ 1 , 1 '-biphenyl]-4- yl)butyl)carbamoyl) phenyl)propanoic acid; (S)-2-amino-3 -(4-(((R)-2-(3 *-ethyl-[ 1 , 1 *-biphenyl]-4-yl)-3 -methyl butyl)carbamoyl)phenyl)propanoic acid;
(S)-3-(4-(((R)-2-(4-(lH-indazol-6-yl)phenyl)-3-methyl butyl)carbamoyl)phi aminopropanoic acid;
(S)-2-amino-3 -(4-(((R)-2-(4'-methoxy-[ 1 , 1 *-biphenyl]-4-yl)-3 - methy lbutyl)carb amoy l)p heny l)propanoic aci d ;
(S)-2-amino-3 -(4-(((R)-2-(3 *-isopropyl-[ 1 , 1 *-biphenyl]-4-yl)-3 - methy lbutyl)carb amoy l)p heny l)propanoic aci d ;
(S)-2-amino-3 -(4-(((R)-2-(3 '-cyclopropyl-[ 1 , 1 *-biphenyl]-4-yl)-3 - methy lbutyl)carb amoy l)p heny l)propanoic aci d ;
(S)-3-(4-(((R)-2-(3 '-( IH-pyrazol- 1 -yl)-[ 1 , 1 *-biphenyl]-4-yl)-3 - methylbutyl)carbamoyl)phenyl)-2-aminopropanoic acid;
(S)-2-amino-3 -(4-(((R)-3-methyl-2-(3 *-(oxazol-2-y l)-[ 1 , 1 *-biphenyl]-4- yl)butyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3 -(4-(((R)-3-methyl-2-(4'-(trifluoromethyl)-[ 1 , 1 '-biphenyl]-4- yl)butyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3 -(4-(((R)-2-(4'-ethoxy-[ 1 , 1 *-biphenyl]-4-yl)-3 - methy lbutyl)carb amoy l)p heny l)propanoic aci d ;
(S)-2-amino-3 -(4-(((R)-2-(4'-fluoro- [1, 1 '-biphenyl] -4-yl)-3 - methy lbutyl)carb amoy l)p heny l)propanoic aci d ;
(S)-2-amino-3 -(4-(((R)-2-(4'-chloro-[ 1 , 1 '-bipheny l]-4-yl)-3 - methy lbutyl)carb amoy l)p heny l)propanoic aci d ;
(S)-2-amino-3 -(4-(((R)-2-(4'-ethyl-[ 1 , 1 *-biphenyl]-4-yl)-3 - methy lbutyl)carb amoy l)p heny l)propanoic aci d ;
(S)-2-amino-3 -(4-(((R)-2-(4'-isobutyl-[ 1 , 1 *-biphenyl]-4-yl)-3 - methy lbutyl)carb amoy l)p heny l)propanoic aci d ;
(S)-3-(4-(((R)-2-(3 '-(IH-imidazol- 1 -yl)-[ 1 , 1 *-biphenyl]-4-yl)-3- methylbutyl)carbamoyl)phenyl)-2-aminopropanoic acid;
(S)-2-amino-3 -(4-(((R)-2-(4'-(tert-butyl)-[ 1 , 1 *-biphenyl]-4-yl)-3 - methy lbutyl)carb amoy l)p heny l)propanoic aci d ; (S)-2-amino-3-(4-(((R)-3-methyl-2-(4-(pyridin-4- yl)phenyl)butyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(((R)-3-methyl-2-(4-(pyridin-3- yl)phenyl)butyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3 -(4-(((R)-3-methyl-2-(4'-propyl-[ 1 , 1 '-biphenyl]-4- yl)butyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(((R)-2-(4'-(methoxymethyl)-[l,r-biphenyl]-4-yl)-3- methylbutyl)carbamoyl) phenyl)propanoic acid;
(S)-2-amino-3 -(4-(((R)-2-(2'-fluoro- [1, 1 '-biphenyl] -4-yl)-3 - methy lbutyl)carb amoy l)p heny l)propanoic aci d ;
(S)-2-amino-3 -(4-(((R)-3-methyl-2-(3 '-propyl-[ 1 , 1 '-biphenyl]-4- yl)butyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(((R)-2-(4'-butyl-[l,r-biphenyl]-4-yl)-3-methylbutyl)
carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(((R)-2-(4'-isopropyl-[l,r-biphenyl]-4-yl)-3-methylbutyl) carbamoyl)phenyl)propanoic acid;
(S)-3 -(4-(((R)-2-([ 1 , Γ :3 1 "-terphenyl]-4-yl)-3 -methylbutyl)carbamoyl)phenyl)-2- aminopropanoic acid;
(S)-2-amino-3-(4-(((R)-2-(4'-cyclopropoxy-[l,r-biphenyl]-4-yl)-3-methylbutyl) carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3 -(4-(((R)-2-(4'-cyclobutyl-[ 1 , 1 '-biphenyl]-4-yl)-3 - methy lbutyl)carb amoy l)p heny l)propanoic aci d ;
(S)-2-amino-3 -(4-(((R)-2-(2'-chloro-[ 1 , 1 '-biphenyl]-4-yl)-3 - methy lbutyl)carb amoy l)p heny l)propanoic aci d ;
(S)-2-amino-3-(4-(((R)-2-(4'-(isopropoxymethyl)-[l,r-biphenyl]-4-yl)-3-methylbutyl) carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3 -(4-(((R)-2-(4'-cyclopropyl-[ 1 , 1 '-biphenyl]-4-yl)-3 - methy lbutyl)carb amoy l)p heny l)propanoic aci d ;
(S)-3-(4-(((R)-2-(4-(lH-benzo[d]imidazol-5-yl)phenyl)-3- methylbutyl)carbamoyl)phenyl)-2-aminopropanoic acid; (S)-2-amino-3-(4-(((R)-2-(4'-(2-hydroxyethyl)-[l,r-biphenyl]-4-yl)-3-methylbutyl) carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3 -(4-(((R)-2-(4'-(tert-butoxy)-[ 1 , 1 '-biphenyl]-4-yl)-3 - methy lbutyl)carb amoy l)p heny l)propanoic aci d ;
(S)-2-amino-3-(4-(((R)-2-(3'-(2-(dimethylamino)ethoxy)-[l,r-biphenyl]-4-yl)-3- methy lbutyl)carb amoy l)p heny l)propanoic aci d ;
(S)-2-amino-3 -(4-(((R)-3 -methyl-2-(3 ',4', 5 '-tnfluoro- [1, 1 '-biphenyl] -4- yl)butyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(((R)-2-(4'-(2-(dimethylamino)ethoxy)-[l, l'-biphenyl]-4-yl)-3- methy lbutyl)carb amoy l)p heny l)propanoic aci d ;
(S)-2-amino-3 -(4-(((R)-3-methyl-2-(4'-(oxetan-3 -yl)-[ 1 , 1 '-biphenyl]-4- yl)butyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(((R)-3-methyl-2-(4-(thiazol-2-yl)phenyl)
butyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(((R)-3-methyl-2-(4-(thiazol-4-yl)phenyl)butyl)
carbamoyl)phenyl)propanoic acid;
(S)-3-(4-(((R)-2-(4-(lH-imidazol-2-yl)phenyl)-3-methylbutyl)carbamoyl)phenyl)-2- aminopropanoic acid; End Table 3
(S)-3-(4-(((R)-2-([l,l'-biphenyl]-4-yl)-2-cyclopropylethyl) carbamoyl)phenyl)-2- aminopropanoic acid;
(S)-3-(4-(((R)-2-([l, l'-biphenyl]-4-yl)-2-cyclobutylethyl) carbamoyl)phenyl)-2- aminopropanoic acid;
(S)-3 -(4-(((R)-2-([ 1 , 1 '-biphenyl]-4-yl)-3 , 3 -dimethylbutyl) carbamoyl)phenyl)-2- aminopropanoic acid;
(S)-2-amino-3 -(4-(((R)-2-cyclobutyl-2-(3 '-methyl- [1, 1 '-biphenyl] -4- yl)ethyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3 -(4-(((R)-2-(4'-cyano-[ 1 , 1 '-biphenyl]-4-yl)-2- cyclobutylethyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(((R)-2-cyclobutyl-2-(4'-(hydroxymethyl)-[l, l'-biphenyl]-4- yl)ethyl)carbamoyl)phenyl)propanoic acid; (S)-3-(4-(((R)-2-([l,r-biphenyl]-4-yl)-2-cyclohexylethyl)-carbamoyl)phenyl)-2- aminopropanoic acid;
(S)-3-(4-(((R)-2-([l,r-biphenyl]-4-yl)-2-(4,4-dimethylcyclohexyl)
ethyl)carbamoyl)phenyl)-2-aminopropanoic acid;
(S)-3-(4-(((R)-2-([l,r-biphenyl]-4-yl)-2-cyclopentylethyl) carbamoyl)phenyl)-2- aminopropanoic acid;
(S)-2-amino-3 -(4-(((R)-2-(4'-cyano-[ 1 , 1 '-biphenyl]-4-yl)-2- cyclopentylethyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(((R)-2-cyclopentyl-2-(4'-(hydroxymethyl)-[l,r-biphenyl]-4- yl)ethyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(((R)-2-cyclopentyl-2-(3'-methyl-[l,r-biphenyl]-4- yl)ethyl)carbamoyl)phenyl)propanoic acid;
(S)-3-(4-(((R)-2-([l,r-biphenyl]-4-yl)-2-cycloheptylethyl) carbamoyl)phenyl)-2- aminopropanoic acid;
(S)-2-amino-3 -(4-(((R)-2-(4'-cyano-[ 1 , 1 '-biphenyl]-4-yl)-2- cycloheptylethyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(((R)-2-cycloheptyl-2-(4'-(hydroxymethyl)-[l,r-biphenyl]-4- yl)ethyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(((R)-2-cycloheptyl-2-(3'-methyl-[l,r-biphenyl]-4- yl)ethyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(((R)-3-methyl-2-(naphthalen-2-yl)butyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3 -(4-(((R)-2-(4-(3 -hydroxyprop- 1 -yn- 1 -yl)phenyl)-3 - methy lbutyl)carb amoy l)p heny l)propanoic aci d ;
(S)-2-amino-3-(4-(((R)-3-methyl-2-(4-(pyridin-2-yl)phenyl)butyl)
carbamoyl)phenyl)propanoic acid;
(S)-3-(4-(((R)-2-([l,r-biphenyl]-4-yl)-3-methylbutyl) (methyl) carbamoyl)phenyl)-2- aminopropanoic acid;
(S)-3-(4-(((l S,2S)-2-([l,r-biphenyl]-4-yl)cyclohexyl)carbamoyl) phenyl)-2- aminopropanoic acid; (S)-2-amino-3 -(4-((2-(4'-methoxy-[ 1 , 1 '-biphenyl]-4- yl)ethyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-((2-(3'-chloro-[l,l'-biphenyl]-4-yl)ethyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-((2-(3'-methoxy-[l,r-biphenyl]-4- yl)ethyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-((2-(2'-chloro-[l,l'-biphenyl]-4-yl)ethyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3 -(4-((2-(2'-methoxy-[ 1 , 1 '-biphenyl]-4- yl)ethyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-((4-(benzo[d][l,3]dioxol-5-yl)phenethyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-((4-(quinolin-8-yl)phenethyl)carbamoyl)phenyl) propanoic acid;
(S)-2-amino-3-(4-((4-(isoquinolin-5-yl)phenethyl)carbamoyl)phenyl)propanoic acid; (S)-2-amino-3-(4-((4-(quinolin-3-yl)phenethyl)-carbamoyl)-phenyl) propanoic acid; (S)-2-amino-3-(4-((4-(2-methoxypyridin-3-yl)phenethyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-((4-(l-methyl-lH-pyrazol-4-yl)phenethyl)carbamoyl) phenyl)propanoic acid;
(S)-2-amino-3-(4-((4-(pyridin-4-yl)phenethyl)carbamoyl)phenyl) propanoic acid;
(S)-2-amino-3-(4-((4-(isoquinolin-7-yl)phenethyl)carbamoyl)phenyl) propanoic acid;
S)-2-amino-3-(4-((2-(3'-(methylcarbamoyl)-[l, -biphenyl]-4-yl)ethyl)carbamoyl) phenyl)propanoic acid;
(S)-2-amino-3-(4-((2-(3'-(dimethylcarbamoyl)-[l,r-biphenyl]-4-yl)ethyl)
carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3 -(4-((2-(3 '-carbamoyl- [ 1 , 1 '-biphenyl]-4- yl)ethyl)carbamoyl)phenyl)propanoic acid;
(S)-3-(4-((2-([l,l'-biphenyl]-4-yl)ethyl)carbamoyl)phenyl)-2-aminopropanoic acid;
(2S)-3-(4-((2-([l,r-biphenyl]-4-yl)-5-hydroxy-3,3-dimethylhexyl)carbamoyl)phenyl)-2- aminopropanoic acid (Stereoisomer 1); (2S)-3-(4-((2-([l,r-biphenyl]-4-yl)-5-hydroxy-3,3-dimethylhexyl)carbamoyl)phenyl)-2- aminopropanoic acid (Stereoisomer 2);
(2S)-3-(4-((2-([l,r-biphenyl]-4-yl)-5-hydroxy-3,3-dimethylhexyl)carbamoyl)phenyl)-2- aminopropanoic acid (Stereoisomer 3);
(2S)-3-(4-((2-([l,l'-biphenyl]-4-yl)-3-methylbutyl) carbamoyl)phenyl)-2-aminopropanoic acid;
(2S)-3-(4-((2-([l,r-biphenyl]-4-yl)-2-cycloheptylethyl) carbamoyl)phenyl)-2- aminopropanoic acid;
(2S)-3-(4-((2-([l,r-biphenyl]-4-yl)-2-cyclohexylethyl) carbamoyl)phenyl)-2- aminopropanoic acid;
(2S)-3-(4-((2-([l,r-biphenyl]-4-yl)-2-cyclopentylethyl) carbamoyl)phenyl)-2- aminopropanoic acid;
(2S)-3-(4-((2-([l,r-biphenyl]-4-yl)-2-cyclobutylethyl) carbamoyl)phenyl)-2- aminopropanoic acid;
(2S)-3-(4-((2-([l,r-biphenyl]-4-yl)-3-methylpentyl) carbamoyl)phenyl)-2- aminopropanoic acid;
(2S)-3-(4-((2-([l,r-biphenyl]-4-yl)-4,4-dimethylpentyl) carbamoyl) phenyl)-2- aminopropanoic acid;
(2S)-3-(4-((2-([l,l'-biphenyl]-4-yl)butyl)carbamoyl)phenyl)-2-aminopropanoic acid;
(2S)-3-(4-((2-([l,r-biphenyl]-4-yl)-2-(tetrahydro-2H-pyran-4- yl)ethyl)carbamoyl)phenyl)-2-aminopropanoic acid;
(2S)-3-(4-((2-([l,r-biphenyl]-4-yl)-4-methylpentyl) carbamoyl)phenyl)-2- aminopropanoic acid;
(2S)-3 -(4-((2-([ 1 , 1 '-biphenyl]-4-yl)-3 , 3 ,3 -trifluoropropyl) carbamoyl)phenyl)-2- aminopropanoic acid;
(2S)-3-(4-((2-([l,l'-biphenyl]-4-yl)hexyl)carbamoyl)phenyl)-2-aminopropanoic acid;
(S)-3-(4-(((l-([l,r-biphenyl]-4-yl)cyclobutyl)methyl)carbamoyl)phenyl)-2- aminopropanoic acid;
(2S)-3-(4-((2-([l,l'-biphenyl]-4-yl)propyl)carbamoyl)phenyl)-2-aminopropanoic acid;
(2S)-3-(4-((2-([l,l'-biphenyl]-4-yl)pentyl)carbamoyl)phenyl)-2-aminopropanoic acid; (S)-3-(4-(((l-([l, l'-biphenyl]-4-yl)cyclopropyl)methyl)carbamoyl)phenyl)-2- aminopropanoic acid;
(S)-3 -(4-((3 -([1,1 '-biphenyl]-2-yl)cyclobutyl)carbamoyl)phenyl)-2-aminopropanoic acid; (2S)-3-(4-((l-([l,l'-biphenyl]-4-yl)propan-2-yl)carbamoyl) phenyl)-2-aminopropanoic acid;
(S)-3-(4-((2-([l,l'-biphenyl]-3-yl)ethyl)carbamoyl)phenyl)-2-aminopropanoic acid;
(S)-2-amino-3-(4-((2-(naphthalen-2-yl)ethyl) carbamoyl)phenyl)propanoic acid;
(S)-3-(4-((2-([l,r-biphenyl]-4-yl)-2-methylpropyl) carbamoyl)phenyl)-2- aminopropanoic acid;
(S)-3-(4-((3-([l,l'-biphenyl]-4-yl)propyl)carbamoyl)phenyl)-2-aminopropanoic acid;
(S)-3-(4-((4-([l,l'-biphenyl]-2-yl)butyl)carbamoyl)phenyl)-2-aminopropanoic acid;
(S)-2-amino-3-(4-((2-(6-phenylpyridin-3-yl) ethyl)carbamoyl)phenyl)propanoic acid;
(2S)-3-(4-((2-([l,r-biphenyl]-4-yl)-2-(2-hydroxyethoxy) ethyl)carbamoyl)phenyl)-2- aminopropanoic acid;
(S)-2-amino-3-(4-((2-(2-chloro-[l,l'-biphenyl]-4-yl) ethyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-((2-(3-methoxy-[l,r-biphenyl]-4-yl)
ethyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-((4-(tert-butyl)phenethyl)carbamoyl)phenyl)propanoic acid;
(S)-3-(4-((2-([l,l'-biphenyl]-4-yl)-2-isopropyl-3 -methyl butyl)carbamoyl)phenyl)-2- aminopropanoic acid;
(S)-3-(4-((2-([l,l'-biphenyl]-2-yl)ethyl)carbamoyl)phenyl)-2-aminopropanoic acid;
(S)-2-amino-3-(4-((2-(naphthalen-l-yl)ethyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-((2-(piperidin-l-yl)benzyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3 -(4-((3 -(2-bromophenyl)propyl)carbamoyl)phenyl)propanoic acid;
(2S)-3 -(4-(( 1 -([ 1 , 1 '-biphenyl]-4-yl)butan-2-yl) carbamoyl)phenyl)-2-aminopropanoic acid;
(S)-3-(4-(([l, l'-biphenyl]-3-ylmethyl)carbamoyl)phenyl)-2-aminopropanoic acid;
(S)-2-amino-3-(4-((2-(l-phenyl-lH-indazol-5-yl)ethyl)carbamoyl)phenyl)propanoic acid; (S)-2-amino-3-(4-((2-(4-phenyl-lH-imidazol-2-yl) ethyl)carbamoyl)phenyl)propanoic acid; (S)-2-amino-3-(4-((4-phenoxyphenethyl)carbamoyl)phenyl)propanoic acid; (2S)-3 -(4-((2-([ 1 , 1 '-biphenyl]-4-yl)-3 , 3 -dimethylbutyl) carbamoyl)phenyl)-2- aminopropanoic acid;
(S)-3-(4-((2-([l,l'-biphenyl]-4-yl)-2-phenylethyl)carbamoyl) phenyl)-2-aminopropanoic acid;
(S)-2-amino-3-(4-((3-(2-(isoquinolin-7-yl)phenyl)propyl) carbamoyl)phenyl)propanoic acid;
(S)-3-(4-((3-([l,l'-biphenyl]-2-yl)propyl)carbamoyl)phenyl)-2-aminopropanoic acid;
(S)-2-amino-3-(4-((3-(2-(quinolin-8-yl)phenyl)propyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-((3-(2-(benzo[d][l,3]dioxol-5- yl)phenyl)propyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-((3-(2-(quinolin-3-yl)phenyl)propyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-((3-(2-(2,4-dimethylthiazol-5-yl)phenyl)propyl)carbamoyl)- phenyl)propanoic acid;
(S)-2-amino-3-(4-((3-(2-(quinolin-6-yl)phenyl)propyl)carbamoyl)phenyl)propanoic acid; and
(S)-2-amino-3 -(4-((3 -(2-( 1 -isobutyl- lH-pyrazol-4-yl)phenyl)propyl)- carbamoyl)phenyl)propanoic acid;
or a pharmaceutically acceptable salt of any of the aforementioned.
59. A compound of claim 1 selected from:
(S)-ethyl 3-(4-(((R)-2-([l, l'-biphenyl]-4-yl)-3-methylbutyl) carbamoyl)phenyl)-2- aminopropanoate;
(S)-ethyl 3-(4-(((S)-2-([l,r-biphenyl]-4-yl)-3-methylbutyl)carbamoyl)phenyl)-2- aminopropanoate;
(S)-ethyl 2-amino-3-(4-(((R)-3-methyl-2-(4-(pyrimidin-5- yl)phenyl)butyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-3-methyl-2-(4-(l-methyl-lH-pyrazol-4- yl)phenyl)butyl)carbamoyl) phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(4'-hydroxy-[l,r-biphenyl]-4-yl)-3- methylbutyl)carbamoyl)phenyl)propanoate; (S)-ethyl 2-amino-3-(4-(((R)-2-(4-(2-aminopyrimidin-5-yl)phenyl)-3- methylbutyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(2,-cyano-[l, l*-biphenyl]-4-yl)-3- methylbutyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3 -(4-(((R)-2-(3 *-cyano-[ 1 , 1 '-biphenyl]-4-yl)-3 - methylbutyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(4,-cyano-[l, l*-biphenyl]-4-yl)-3- methylbutyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(4*-ethyl-[l, l,-biphenyl]-4-yl)-3- methylbutyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(4'-(aminomethyl)-[l,r-biphenyl]-4-yl)-3-methylbutyl) carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3 -(4-(((R)-2-(3 '-(aminomethyl)- [1, 1 '-biphenyl] -4-y l)-3 -methylbutyl) carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3 -(4-(((R)-2-(2'-(aminomethyl)- [1, 1 '-biphenyl] -4-y l)-3 - methylbutyl)carbamoyl) phenyl)propanoate;
(S)-ethyl 2-amino-3 -(4-(((R)-2-(3 '-(hy droxymethyl)- [ 1 , 1 '-biphenyl]-4-yl)-3 - methylbutyl)carbamoyl) phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(4*-(hydroxymethyl)-[l, l,-biphenyl]-4-yl)-3- methylbutyl)carbamoyl) phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(2*-(hydroxymethyl)-[l, l,-biphenyl]-4-yl)-3- methylbutyl)carbamoyl) phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(4,-caibamoyl-[l, l*-biphenyl]-4-yl)-3- methylbutyl)carbamoyl)phenyl)propanoate;
4'-((R)-l-(4-((S)-2-amino-3-ethoxy-3-oxopropyl)benzamido)-3-methylbutan-2-yl)-[l, l'- biphenyl]-4-carboxylic acid;
ethyl 4'-((R)-l-(4-((S)-2-amino-3-ethoxy-3-oxopropyl)benzamido)-3-methylbutan-2-yl)- [1, 1 '-biphenyl]-4-carboxylate;
(S)-ethyl 3-(4-(((R)-2-(4-(lH-pyrazol-4-yl)phenyl)-3-methylbutyl)carbamoyl)phenyl)-2- aminopropanoate; (S)-ethyl 2-amino-3-(4-(((R)-3-methyl-2-(3,-methyl-[l, l*-biphenyl]-4- yl)butyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-3-methyl-2-(4,-methyl-[l, l*-biphenyl]-4- yl)butyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-((2-(3'-(methylcarbamoyl)-[l, -biphenyl]-4-yl)ethyl)carbamoyl) phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-((2-(3'-(dimethylcarbamoyl)-[l,r-biphenyl]-4- yl)ethyl)carbamoyl) phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-((4-phenoxyphenethyl)carbamoyl)phenyl)propanoate
(S)-ethyl 2-amino-3-(4-((2-(l-phenyl-lH-indazol-5- yl)ethyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-((2-(4-phenyl-lH-imidazol-2-yl)ethyl)
carbamoyl)phenyl)propanoate;
(S)-ethyl 3-(4-(((R)-2-([l, l*-biphenyl] -4-yl)-2-cyclobutylethyl)carbamoyl) phenyl)-2- aminopropanoate;
(S)-ethyl 2-amino-3-(4-(((R)-3-methyl-2-(naphthalen-2-yl)butyl)
carbamoyl)phenyl)propanoate;
(S)-ethyl 3-(4-(((R)-2-([l, l*-biphenyl]-4-yl)-2-cyclopentylethyl) carbamoyl)phenyl)-2- aminopropanoate;
(S)-ethyl 3-(4-(((R)-2-([l, l*-biphenyl]-4-yl)-2-cycloheptylethyl) carbamoyl)phenyl)-2- aminopropanoate;
(2S)-ethyl 3-(4-((2-([l, l*-biphenyl]-4-yl)-3,3-dimethylbutyl) carbamoyl)phenyl)-2- aminopropanoate;
(S)-ethyl 2-amino-3-(4-(((R)-3-methyl-2-(2,-methyl-[l, l*-biphenyl]-4- yl)butyl)carbamoyl) phenyl)propanoate;
(S)-ethyl 2-amino-3 -(4-(((R)-2-cyclobutyl-2-(3 *-methyl-[ 1 , 1 '-biphenyl]-4- yl)ethyl)carbamoyl) phenyl)propanoate;
(S)-ethyl 2-amino-3 -(4-(((R)-2-(4'-cyano-[ 1 , 1 '-biphenyl]-4-yl)-2- cyclobutylethyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 3-(4-(((R)-2-([l, l*-biphenyl]-4-yl)-2-cyclohexylethyl)carbamoyl)phenyl)-2- aminopropanoate; (S)-ethyl 2-amino-3 -(4-(((R)-2-(4'-cyano-[ 1 , 1 '-biphenyl]-4-yl)-2- cyclopentylethyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-cyclobutyl-2-(4'-(hydroxymethyl)-[l,r-biphenyl]-4- yl)ethyl)carbamoyl) phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-cyclopentyl-2-(4'-(hydroxymethyl)-[l,r-biphenyl]-4- yl)ethyl)carbamoyl) phenyl)propanoate;
(S)-ethyl 2-amino-3 -(4-(((R)-2-(4'-cyano-[ 1 , 1 '-biphenyl]-4-yl)-2- cycloheptylethyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(3'-fluoro-[l,r-biphenyl]-4-yl)-3- methylbutyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3 -(4-(((R)-2-cyclopentyl-2-(3 '-methyl-[ 1 , 1 '-biphenyl]-4- yl)ethyl)carbamoyl) phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(3'-chloro-[l,r-biphenyl]-4-yl)-3- methylbutyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 3-(4-((2-([l,r-biphenyl]-4-yl)-2-phenylethyl)carbamoyl)phenyl)-2- aminopropanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-cycloheptyl-2-(4'-(hydroxymethyl)-[l,r-biphenyl]-4- yl)ethyl) carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(3'-methoxy-5'-methyl-[l,r-biphenyl]-4-yl)-3- methylbutyl) carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(3'-(tert-butyl)-[l,r-biphenyl]-4-yl)-3- methylbutyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(3',5'-dimethyl-[l,r-biphenyl]-4-yl)-3- methylbutyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(3'-methoxy-[l,r-biphenyl]-4-yl)-3- methylbutyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(3'-hydroxy-[l,r-biphenyl]-4-yl)-3- methylbutyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-cycloheptyl-2-(3'-methyl-[l,r-biphenyl]-4-yl)ethyl) carbamoyl)phenyl)propanoate; (S)-ethyl 2-amino-3-(4-(((R)-3-methyl-2-(3'-(trifluoromethyl)-[l,r-biphenyl]-4- yl)butyl)carbamoyl) phenyl)propanoate;
(S)-ethyl 2-amino-3 -(4-(((R)-2-(3 '-ethyl-[ 1 , 1 '-biphenyl]-4-yl)-3 - methylbutyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 3-(4-(((R)-2-([l,r-biphenyl]-4-yl)-2-(4,4- dimethylcyclohexyl)ethyl)carbamoyl)phenyl)-2-aminopropanoate;
(S)-ethyl 3-(4-(((R)-2-(4-(lH-indazol-6-yl)phenyl)-3-methylbutyl)carbamoyl)phenyl)-2- aminopropanoate;
(S)-ethyl 2-amino-3 -(4-(((R)-3 -methyl-2-(3 '-(oxazol-2-yl)-[ 1 , 1 '-biphenyl]-4- yl)butyl)carbamoyl) phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(4'-chloro-[l,r-biphenyl]-4-yl)-3- methylbutyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(4'-methoxy-[l,r-biphenyl]-4-yl)-3- methylbutyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4 ((R)-3-methyl-2-(4'-(trifluoromethyl)-[l,r-biphenyl]-4-yl)butyl) carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(3'-isopropyl-[l,r-biphenyl]-4-yl)-3- methylbutyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 3-(4-(((R)-2-([l,r:3',l M-terphenyl]-4-yl)-3-methylbutyl)carbamoyl)phenyl)-2- aminopropanoate;
(S)-ethyl 3-(4-(((R)-2-([l,r-biphenyl]-4-yl)-3-methylbutyl)(methyl)carbamoyl)phenyl)- 2-aminopropanoate;
(S)-ethyl 2-amino-3-(4-(((R)-3-methyl-2-(3'-propyl-[l,r-biphenyl]-4-yl)butyl) carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3 -(4-(((R)-2-(3 '-cyclopropyl- [1, 1 '-biphenyl] -4-yl)-3 - methylbutyl)carbamoyl) phenyl)propanoate;
(S)-ethyl 3 -(4-(((R)-2-(3 '-( IH-pyrazol- 1 -yl)-[ 1 , 1 '-biphenyl]-4-yl)-3 - methylbutyl)carbamoyl) phenyl)-2-aminopropanoate;
(S)-ethyl 3 -(4-(((R)-2-(3 '-( IH-imidazol- 1 -yl)-[ 1 , 1 '-biphenyl]-4-yl)-3 -methylbutyl) carbamoyl)phenyl)-2-aminopropanoate; (S)-ethyl 2-amino-3-(4-(((R)-2-(4'-(methoxymethyl)-[l,r-biphenyl]-4-yl)-3-methylbutyl) carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(4,-butyl-[l, l*-biphenyl]-4-yl)-3- methylbutyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(4*-ethyl-[l, l,-biphenyl]-4-yl)-3- methylbutyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(4,-ethoxy-[l, l*-biphenyl]-4-yl)-3- methylbutyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(4,-isopropyl-[l, l*-biphenyl]-4-yl)-3- methylbutyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(4,-fluoro-[l,l*-biphenyl]-4-yl)-3- methylbutyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-3-methyl-2-(4-(pyridin-4- yl)phenyl)butyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(4,-isobutyl-[l, l*-biphenyl]-4-yl)-3- methylbutyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 3-(4-(((R)-2-([l, l'-biphenyl]-4-yl)-2-cyclopropylethyl)carbamoyl)phenyl)-2- aminopropanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(4,-(tert-butyl)-[l, l*-biphenyl]-4-yl)-3- methylbutyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(2,-chloro-[l,l*-biphenyl]-4-yl)-3- methylbutyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-3-methyl-2-(4-(pyridin-3- yl)phenyl)butyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-3-methyl-2-(4*-propyl-[l, l*-biphenyl]-4- yl)butyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(2,-fluoro-[l,l*-biphenyl]-4-yl)-3- methylbutyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(4,-cyclobutyl-[l, l*-biphenyl]-4-yl)-3- methylbutyl)carbamoyl)phenyl)propanoate; (S)-ethyl 2-amino-3-(4-(((R)-2-(4'-(isopropoxymethyl)-[l,r-biphenyl]-4-yl)-3- methylbutyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(4*-cyclopropyl-[l, l*-biphenyl]-4-yl)-3- methylbutyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(4'-(2-hydroxyethyl)-[l,r-biphenyl]-4-yl)-3- methylbutyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 3-(4-(((R)-2-(4-(lH-benzo[d]imidazol-5-yl)phenyl)-3- methylbutyl)carbamoyl)phenyl)-2-aminopropanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(3'-(2-(dimethylamino)ethoxy)-[l,r-biphenyl]-4-yl)-3- methylbutyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-3-methyl-2-(4-(pyridin-2- yl)phenyl)butyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-3-methyl-2-(3',4',5'-trifluoro-[l,r-biphenyl]-4- yl)butyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-3-methyl-2-(4'-(oxetan-3-yl)-[l,r-biphenyl]-4- yl)butyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 3-(4-(((R)-2-([l,r-biphenyl]-4-yl)-3,3-dimethylbutyl)carbamoyl)pheny)-2- aminopropanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(4'-(2-(dimethylamino)ethoxy)-[l,r-biphenyl]-4-yl)-3- methylbutyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-3-methyl-2-(4-(thiazol-2- yl)phenyl)butyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-3-methyl-2-(4-(thiazol-4- yl)phenyl)butyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(4'-amino-3'-hydroxy-[l,r-biphenyl]-4-yl)-3- methylbutyl)carbamoyl) phenyl)propanoate; and
(S)-ethyl 3-(4-(((l S,2S)-2-([l, r-biphenyl]-4-yl)cyclohexyl)carbamoyl)pheny)-2- aminopropanoate;
or a pharmaceutically acceptable salt of any of the aforementioned.
60. A compound of claim 1 selected from: (S)-3-(4-(((S)-l-([l, l'-biphenyl]-4-yl)propan-2-yl) carbamoyl)phenyl)-2-aminopropanoic acid;
(S)-3 -(4-(((R)-2-([ 1 , 1 '-biphenyl] -4-y l)-2-(piperidin-4-yl)ethyl) carbamoyl)phenyl)-2- aminopropanoic acid;
(S)-3-(4-(((R)-2-([l,r-biphenyl]-4-yl)-2-(l-benzylpiperidin-4- yl)ethyl)carbamoyl)phenyl)-2-aminopropanoic acid;
(S)-3 -(4-(((R)-2-([ 1 , 1 '-biphenyl]-4-yl)-2-(l -methylpiperidin-4- yl)ethyl)carbamoyl)phenyl)-2-aminopropanoic acid;
(S)-3 -(4-(((R)-2-([ 1 , 1 '-biphenyl]-4-yl)-2-(l -ethylpiperidin-4-yl)ethyl)carbamoyl)phenyl)- 2-aminopropanoic acid;
(2S)-3-(4-((2-([l,r-biphenyl]-4-yl)-2-(piperazin-l -yl)ethyl)carbamoyl)phenyl)-2- aminopropanoic acid;
(S)-2-amino-3-(4-(((R)-2-(4-bromophenyl)-2-(4,4- dimethylcyclohexyl)ethyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(((R)-2-(4,4-dimethylcyclohexyl)-2-phenylethyl)
carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(((R)-2-(4,4-dimethylcyclohexyl)-2-(p-tolyl)ethyl)
carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(((R)-2-(4,4-dimethylcyclohexyl)-2-(4- fluorophenyl)ethyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(((R)-2-(4,4-dimethylcyclohexyl)-2-(4- methoxyphenyl)ethyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(((R)-2-(4,4-dimethylcyclohexyl)-2-(4- chlorophenyl)ethyl)carbamoyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(((R)-2-(4,4-dimethylcyclohexyl)-2-(4- trifluoromethylphenyl)ethyl)carbamoyl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(((2R)-2-(4-bromophenyl)-2-(4- (trifluoromethyl)cyclohexyl)ethyl)carbamoyl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(((2R)-2-(4-bromophenyl)-2-(4-(tert-butyl)
cyclohexyl)ethyl)carbamoyl)phenyl)propanoic acid; (2S)-3-(4-(((2R)-2-([l,r-biphenyl]-4-yl)-2-(4-(tert- butyl)cyclohexyl)ethyl)carbamoyl)phenyl)-2-aminopropanoic acid;
(2S)-3-(4-(((2R)-2-([l,r-biphenyl]-4-yl)-2-(4-(trifluoromethyl)
cyclohexyl)ethyl)carbamoyl)phenyl)-2-aminopropanoic acid;
(S)-3-(4-(((R)-2-([l,r-biphenyl]-4-yl)-2-(spiro[3.5]nonan-7-yl)ethyl)carbamoyl)phenyl)- 2-aminopropanoic acid;
(S)-3-(4-(((l S,2S)-2-([l,r-biphenyl]-4-yl)cyclopentyl) carbamoyl)phenyl)-2- aminopropanoic acid; and
(2S)-3-(4-((2-([l,l'-biphenyl]-4-yl)cycloheptyl)carbamoyl)-phenyl)-2-aminopropanoic acid;
or a pharmaceutically acceptable salt of any of the aforementioned.
61. A compound of claim 1 selected from:
(2S)-ethyl 3-(4-((2-([l,r-biphenyl]-4-yl)cycloheptyl)carbamoyl)phenyl)-2- aminopropanoate;
(S)-ethyl 3 -(4-(((S)- 1 -([ 1 , 1 '-biphenyl]-4-yl)propan-2-yl)carbamoyl)phenyl)-2- aminopropanoate;
(2S)-ethyl 3-(4-(((2R)-2-([l, r-biphenyl]-4-yl)-2-(4-(tert- butyl)cyclohexyl)ethyl)carbamoyl) phenyl)-2-aminopropanoate;
(2S)-ethyl 3-(4-(((2R)-2-([l, r-biphenyl]-4-yl)-2-(4- (trifluoromethyl)cyclohexyl)ethyl)carbamoyl)phenyl)-2-aminopropanoate;
(S)-ethyl 3-(4-(((l S,2S)-2-([l, r-biphenyl]-4-yl)cyclopentyl)carbamoyl)phenyl)-2- aminopropanoate;
(S)-ethyl 3-(4-(((R)-2-([l,r-biphenyl]-4-yl)-2-(spiro[3.5]nonan-7- yl)ethyl)carbamoyl)phenyl)-2-aminopropanoate;
(S)-ethyl 3-(4-(((R)-2-([l,r-biphenyl]-4-yl)-2-(l-methylpiperidin-4- yl)ethyl)carbamoyl)phenyl)-2-aminopropanoate;
(S)-ethyl 3-(4-(((R)-2-([l,r-biphenyl]-4-yl)-2-(l-ethylpiperidin-4- yl)ethyl)carbamoyl)phenyl)-2-aminopropanoate;
(2S)-ethyl 3 -(4-((2-([ 1 , 1 '-biphenyl]-4-yl)-2-(4-methylpiperazin- 1 - yl)ethyl)carbamoyl)phenyl)-2-aminopropanoate; (S)-propyl 3-(4-(((R)-2-([l, l*-biphenyl]-4-yl)-3-methylbutyl) carbamoyl)phenyl)-2- aminopropanoate;
(S)-neopentyl 3-(4-(((R)-2-([l, l*-biphenyl]-4-yl)-3-methylbutyl) carbamoyl)phenyl)-2- aminopropanoate;
(S)-butyl 3-(4-(((R)-2-([l, r-biphenyl]-4-yl)-3-methylbutyl) carbamoyl)phenyl)-2- aminopropanoate;
(S)-cyclopentyl 3-(4-(((R)-2-([l, l*-biphenyl]-4-yl)-3-methylbutyl)carbamoyl)phenyl)-2- aminopropanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(4,4-dimethylcyclohexyl)-2- phenylethyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(4,4-dimethylcyclohexyl)-2-(p-tolyl)ethyl)carbamoyl) phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(4,4-dimethylcyclohexyl)-2-(4- fluorophenyl)ethyl)carbamoyl) phenyl) propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(4,4-dimethylcyclohexyl)-2-(4- methoxyphenyl)ethyl)carbamoyl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(((R)-2-(4-chlorophenyl)-2-(4,4- dimethylcyclohexyl)ethyl)carbamoyl)phenyl)propanoate; and
(S)-ethyl 2-amino-3-(4-(((R)-2-(4,4-dimethylcyclohexyl)-2-(4- (trifluoromethyl)phenyl)ethyl)carbamoyl)phenyl)propanoate;
or a pharmaceutically acceptable salt of any of the aforementioned.
62. A pharmaceutical composition comprising a compound of any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
63. A method of inhibiting TPHl comprising contacting said TPHl with a compound of any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof.
A method of lowering peripheral serotonin in a patient comprising administering to said a compound of any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof.
65. A method of treating or preventing a disease in a patient, wherein said disease is selected from bone disease, cardiovascular disease, metabolic disease, pulmonary disease, gastrointestinal disease, liver disease, cancer, inflammatory disease, and fibrotic disease comprising
administering to said patient a therapeutically effective amount of a compound of any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof.
66. The method of claim 65 wherein said bone disease is osteoporosis, osteoporosis pseudoglioma syndrome (OPPG), osteopenia, osteomalacia, renal osteodystrophy, Paget's disease, bone fracture, and bone metastasis.
67. The method of claim 65 wherein said osteoporosis is primary type 1 osteoporosis.
68. The method of claim 65 wherein said cardiovascular disease is pulmonary arterial hypertension (PAH).
69. The method of claim 68 wherein said PAH is associated pulmonary arterial hypertension (APAH).
70. The method of claim 65 wherein said metabolic disease is diabetes or hyperlipidemia.
71. The method of claim 65 wherein said pulmonary disease is chronic obstructive pulmonary disease (COPD) or pulmonary embolism.
72. The method of claim 65 wherein said gastrointestinal disease is irritable bowel disease (IBD).
73. The method of claim 65 wherein said liver disease is hepatitis.
74. The method of claim 65 wherein said cancer is liver cancer, breast cancer,
cholangiocarcinoma, colon cancer, colorectal cancer, neuroendocrine tumors, pancreatic cancer, prostate cancer, bone cancer, or blood cancer.
75. The method of claim 65 wherein said inflammatory disease is allergic airway inflammation.
76. The method of claim 65 wherein said fibrotic disease is scleroderma, idiopathic pulmonary fibrosis (IPF), heart valve fibrosis, kidney fibrosis, or liver fibrosis.
77. A method of treating or preventing Raynaud's syndrome in a patient
comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof.
78. A method of treating or preventing carcinoid syndrome in a patient comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof.
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