WO2015089137A1 - Acylguanidines as tryptophan hydroxylase inhibitors - Google Patents

Acylguanidines as tryptophan hydroxylase inhibitors Download PDF

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Publication number
WO2015089137A1
WO2015089137A1 PCT/US2014/069462 US2014069462W WO2015089137A1 WO 2015089137 A1 WO2015089137 A1 WO 2015089137A1 US 2014069462 W US2014069462 W US 2014069462W WO 2015089137 A1 WO2015089137 A1 WO 2015089137A1
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Prior art keywords
amino
phenyl
carbamoyl
methylene
propanoic acid
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PCT/US2014/069462
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French (fr)
Inventor
Stéphane De Lombaert
Daniel R. Goldberg
Kenneth Albert Brameld
Eric Brian Sjogren
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Karos Pharmaceuticals, Inc.
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Publication of WO2015089137A1 publication Critical patent/WO2015089137A1/en

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    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
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    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • 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.
  • R 12 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 c3 R d3 ;
  • R 8 is H.
  • the compounds of the invention have a Z configuration.
  • the term "Ci-j alkylthio,” employed alone or in combination with other terms 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.
  • 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.
  • Step 3 the nitrile is reduced to the corresponding benzyl amine via the use of a hydride reducing agent (e.g., LAH or BH3) or by transition metal-mediated hydrogenation (e.g., H 2 in the presence of Raney Nickel) to provide R.
  • a hydride reducing agent e.g., LAH or BH3
  • transition metal-mediated hydrogenation e.g., H 2 in the presence of Raney Nickel
  • 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 title compound can be prepared as described above (3-phenoxy-[l,l'-biphenyl]-2- yl)methanamine (Intermediate 60) using 2-chlorophenylboronic acid in place of phenylboronic acid (Step 1).

Abstract

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

Description

ACYLGUANIDINES AS TRYPTOPHAN HYDROXYLASE INHIBITORS
FIELD OF THE INVENTION
The present invention is directed to acylguanidines which are inhibitors of tryptophan hydroxylase (TPH), particularly isoform 1 (TPHl), that are useful in the treatment of diseases or disorders associated with peripheral serotonin including, for example, gastrointestinal, cardiovascular, pulmonary, inflammatory, metabolic, and low bone mass diseases, as well as serotonin syndrome, and 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)), or 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)). 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 hydro xylation 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 iso forms 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).
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 TPHl Inhibitors. InternationalJournal 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;
R1 is H, Ci-io alkyl, C3-10 cycloalkyl, phenyl, -(CR10Rn)POC(O)R12, -(CR10Rn)PNR13R14 , or -(CR10Rn)pC(O)NR13R14, wherein said C1-10 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 C haloalkyl;
R2 is H, CM alkyl, C(0)Rb, C(0)NRcRd, or C(0)ORa;
R3 and R4 are each independently selected from H, CM alkyl, CM haloalkyl, OH, and CM alkoxy;
R5 at each occurrence is independently selected from halo, CM alkyl, and CM alkoxy; R6 is H, CM alkyl, C(0)Rbl, C(0)NRclRdl, or C(0)ORal;
R7 is H or C M alkyl;
R8 at each occurrence is independently selected from H, halo, and CM alkyl;
R9 at each occurrence is independently selected from H, halo, CM alkyl, C2-6 alkenyl, C2-6 alkynyl, CM haloalkyl, C6-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO2, 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 CM 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, CM alkyl, C2-6 alkenyl, C2-6 alkynyl, CM haloalkyl, CN, NO2, ORa2, SRa2, C(0)Rb2, C(0)NRc2Rd2, C(0)ORa2, OC(0)Rb2, OC(0)NRc2Rd2, NR R , NRc2C(0)Rb2, NRc2C(0)ORa2, NRc2C(0)NRc2Rd2, NRc2S(0)Rb2, NRc2S(0)2Rb2, NRc2S(0)2NRc2Rd2, S(0)Rb2, S(0)NRc2Rd2, S(0)2Rb2, and S(0)2NRc2Rd2;
R10 and R1 1 are each independently selected from H and
Figure imgf000008_0001
alkyl;
R12 is Ci-6 alkyl optionally substituted by 1 , 2 or 3 substituents independently selected from Ci-6 haloalkyl, C3-10 cycloalkyl, ORa3, and NRc3Rd3;
R13 and R14 are each independently selected from H and Ci-6 alkyl;
RA is H, Cy1, halo, Ci_6 alkyl, C2-e alkenyl, CN, N02, ORa4, SRa4, C(0)Rb4, C(0)NRc4Rd4, C(0)ORa4, OC(0)Rb4, OC(0)NRc4Rd4, NRc4Rd4, NRc4C(0)Rb4, NRc4C(0)ORa4,
NRc4C(0)NRc4Rd4, NRc4S(0)Rb4, NRc4S(0)2Rb4, NRc4S(0)2NRc4Rd4, S(0)Rb4, S(0)NRc4Rd4, S(0)2Rb4, or S(0)2NRc4Rd4, wherein said Ci-e alkyl and C2-6 alkenyl are each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from Cy1, halo, Ci-6 alkyl, C2- 6 alkenyl, Ci_6 haloalkyl, CN, N02, ORa4, SRa4, C(0)Rb4, C(0)NRc4Rd4, C(0)ORa4, OC(0)Rb4, OC(0)NRc4Rd4, NRc4Rd4, NRc4C(0)Rb4, NRc4C(0)ORa4, NRc4C(0)NRc4Rd4, NRc4S(0)Rb4, NRc4S(0)2Rb4, NRc4S(0)2NRc4Rd4, S(0)Rb4, S(0)NRc4Rd4, S(0)2Rb4, and S(0)2NRc4Rd4;
RB is H, Cy2, halo, Ci_6 alkyl, C2-e 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, or S(0)2NRc5Rd5, wherein said Ci-6 alkyl and C2-6 alkenyl are each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from Cy2, halo, Ci-6 alkyl, C2- 6 alkenyl, Ci_6 haloalkyl, CN, N02, 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, 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 and C2-6 alkenyl are each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from C6-io aryl, C3-10 cycloalkyl, 5- 10 membered heteroaryl, 4-10 membered
heterocycloalkyl, halo, Ci_6 alkyl, C2-e 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;
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 RCy 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)-Ci_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,
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-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 Ra, Ral, Rb, Rbl, Rc , Rcl, Rd, and Rdl is independently selected from H, Ci_6 alkyl, Ci-4 haloalkyl, C6-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered hetero cyclo alkyl;
or Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6-, or 7- membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents
independently selected from halo, Ci-6 alkyl, and Ci-6 haloalkyl;
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, C haloalkyl, C2-e alkenyl, C6-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C6-io aryl-Ci-4 alkyl, C3-10 cyclo alkyl-C 1-4 alkyl, (5-10 membered heteroaryl)-Ci_ 4 alkyl, or (4-10 membered heterocycloalkyl)-Ci-4 alkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, C6- 10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-io aryl- C1-4 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 C 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;
or any of the following pairs of substituents: Rc2 and Rd2; Rc3 and Rd3; Rc4 and Rd4; Rc5 and Rd5; Rc6 and Rd6; and Rc7 and Rd7, together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered
heterocycloalkyl, C6-io aryl, 5-6 membered heteroaryl, halo, CN, ORa8, SRa8, 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, wherein said Ci_6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa8, SRa8, 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, CM alkyl, CM alkoxy, CM alkylthio, CM alkylamino, and di(Ci_4 alkyl) amino;
or any Rc8 and Rd8 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 OH, CN, amino, halo, CM alkyl, C alkoxy, CM alkylthio, CM alkylamino, and di(Ci_4 alkyl)amino; p is 1, 2, or 3;
n is 0, 1, 2, 3, or 4; and
m is 0, 1, 2, or 3. In some embodiments, R1 is H, Ci-io alkyl, C3-10 cycloalkyl, or -(CR^R11)POC(0)R12.
In some embodiments, R1 is H or C1-10 alkyl.
In some embodiments, R1 is C1-10 alkyl.
In some embodiments, R1 is ethyl.
In some embodiments, R1 is H.
In some embodiments, R2 is H.
In some embodiments, R3 and R4 are both H.
In some embodiments, R6 is H.
In some embodiments, R7 is H.
In some embodiments, R8 is H.
In some embodiments, R9 is H, Ci-6 alkyl, or phenyl, wherein said phenyl is optionally substituted with 1, 2, or 3 halo.
In some embodiments, R9 is H.
In some embodiments, n is 0.
In some embodiments, m is 0.
In some embodiments, m is 1.
In some embodiments, m is 2.
In some embodiments, m is 3.
In some embodiments, Ring A is C6-io aryl or 5 to 10-membered heteroaryl.
In some embodiments, Ring A is phenyl, naphthalenyl, benzo[d][l,3]dioxol-4-yl, 2,3- dihydrobenzo[b][l,4]dioxin-5-yl, 2,3-dihydro-lH-inden-l-yl, or 9H-fluoren-4-yl.
In some embodiments, Ring A is phenyl.
In some embodiments, the compounds of the invention have Formula II:
Figure imgf000012_0001
In some embodiments, the compounds of the invention have Formula III:
Figure imgf000012_0002
In some embodiments, the compounds of the invention have Formula IV:
Figure imgf000012_0003
In some embodiments, the compounds of the invention have Formula V:
Figure imgf000013_0001
In some embodiments, the compounds of the invention have Formula VI:
Figure imgf000013_0002
In some embodiments, RA includes at least one nitrogen atom.
In some embodiments RA is diethylamino or a cyclic moiet selected from:
Figure imgf000013_0003
Figure imgf000013_0004
wherein each of the aforementioned cyclic moieties is optionally substituted by 1 or 2 RCy.
In some embodiments, RA is selected from:
Figure imgf000014_0001
Figure imgf000014_0002
wherein q is 0, 1, or 2.
In some embodiments, RD and Rc are both H.
In some embodiments, RB and Rc are both H.
In some embodimetns, RB is H.
In some embodiments, RB, Rc, and RD are each H.
In some embodiments, the compounds of the invention have an E configuration.
In some embodiments, the compounds of the invention have a Z configuration.
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.
It is further understood that, although depicted herein as E isomers, the acylguanidines of the invention can exist in various conformational, tautomeric, and protonation (e.g.,
acylguanidinium) states dictated by their specific chemical substitution, the receptor/enzyme binding site geometry, the solvent, the temperature, the existing hydrogen bond network, etc. (see schematic below) (see for example: Kleinmaier, R., et al. Conformations, Conformational Preferences, And Conformational Exchange Of N'-substituted N-acylguanidines: Intermolecular Interactions Hold The Key. Journal of the American Chemical Society 132, 11223-33 (2010)). It is intended that all acylguanidine conformations, tautomers, and protonation states are encompassed by the present invention. The representation of a compound of the invention by name or structure in this application in one form or state is intended to include the other conformational, tautomeric, and protonation (acylguanidinium) states unless otherwise specified.
Figure imgf000015_0001
Representative Conformational, Tautomeric, and Protonation States of Acylguanidines
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
Figure imgf000015_0002
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-chained 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, n-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," employed alone or in combination with other terms, refers to an unsaturated hydrocarbon group that may be straight-chained or branched 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, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.
As used herein, "Ci-j alkynyl," employed alone or in combination with other terms, refers to an unsaturated hydrocarbon group that may be straight-chained or branched having one or more triple carbon-carbon bonds and having i to j carbon atoms. In some embodiments, the alkynyl moiety contains 2 to 6 or to 2 to 4 carbon atoms.
As used herein, the term "Ci-j alkylamino," employed alone or in combination with other terms, refers to a group of formula -NH(alkyl), wherein the alkyl group has i to j carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
As used herein, the term "di-Ci-j-alkylamino," employed alone or in combination with other terms, 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 "Ci-j alkylthio," employed alone or in combination with other terms, 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," employed alone or in combination with other terms, refers to a group of formula -NH2.
As used herein, the term "Ci-j aryl," employed alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbon having i to j ring-forming carbon atoms, such as, but not limited to, phenyl, 1-naphthyl, 2- naphthyl, anthracenyl, phenanthrenyl, and the like. In some embodiments, aryl is C6-io aryl. In some embodiments, the aryl group is a naphthalene ring or phenyl ring. In some embodiments, the aryl group is phenyl.
As used herein, the term "arylalkyl," employed alone or in combination with other terms, 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 "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 unsaturations (e.g., double bonds) 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," employed alone or in combination with other terms, 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, "Ci-j haloalkoxy," employed alone or in combination with other terms, refers to a group of formula -O-haloalkyl having i to j carbon atoms. An example haloalkoxy group is OCF3. An additional example haloalkoxy group is OCHF2. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
As used herein, the term "halo," employed alone or in combination with other terms, 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, employed alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2s+l halogen atoms which may be the same or different, where "s" is the number of carbon atoms in the alkyl group, wherein the alkyl group has i to j carbon atoms. In some embodiments, the haloalkyl group is fluoromethyl, difluoromethyl, or trifluoromethyl. In some embodiments, the haloalkyl group is trifluoromethyl. In some embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms.
As used herein, the term "heteroaryl," employed alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic moiety, having one or more heteroatom ring members selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl group is a 5- to 10-membered heteroaryl ring which is monocyclic or bicyclic and which has 1 , 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl group is a 5- to 6-membered heteroaryl ring which is monocyclic and which has 1 , 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. The nitrogen atoms in the ring(s) of the heteroaryl group can be oxidized to form N-oxides. Example heteroaryl groups include, but are not limited to, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, azolyl, oxazole, thiazole, imidazole, furan, thiophene, quinoline, isoquinoline, indole, benzothiophene, benzo furan, benzisoxazole, imidazo[l ,2-¾]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," employed alone or in combination with other terms, refers to a group of formula—Ci-j alkyl-(heteroaryl). In some embodiments, 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.
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 unsaturations 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 group 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 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.
As used herein, the term "heterocycloalkylalkyl," employed alone or in combination with other terms, refers to a group of formula -Ci-j alkyl-(heterocycloalkyl). In some embodiments, heterocycloalkylalkyl is 5-10 membered heterocycloalkyl-Ci-3 alkyl or 5-10 membered heterocycloalkyl-Ci-4 alkyl, wherein the heterocycloalkyl portion is monocyclic or bicyclic and has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, heterocycloalkylalkyl is 5-6 membered heterocycloalkyl-Ci-4 alkyl wherein the heterocycloalkyl portion is monocyclic and has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereoisomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention may be isolated as a mixture of isomers or as separated isomeric forms.
Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. An example method includes fractional recrystallizaion 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. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of methylbenzyl- amine (e.g., S and R forms, or diastereomerically 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. 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.
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 is 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" as employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The expressions, "ambient temperature" and "room temperature," as used herein, are understood in the art, and refer generally to a temperature, e.g., a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a
temperature from about 20 °C to about 30 °C.
The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, EtOAc, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (CH3CN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19, and in Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). Table 1. Abbreviations
atm atmosphere BOC tert-butyl-oxy-carbonyl
CAS# Chemical Abstract Service registry number
DIPEA N,N-diisopropylethylamine
DMF dimethyl formamide
dppf 1 , 1 '-bis(diphenylphosphino)ferrocene
EDCI 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
EtOAc ethyl acetate
h hour(s)
min minute(s)
HO At 1 -hydroxy-7-azabenzotriazo le
HPLC high-performance liquid chromatography
KOAc potassium acetate
LAH lithium aluminum hydride
MeOH methanol
MS mass spectrometry
NH4OH ammonium hydroxide
PAH pulmonary arterial hypertension
P(Cy)3 tricyclohexyl phosphine
PheOH phenylalanine hydroxylase
Prep-TLC preparative thin-layer chromatography
RT room temperature
TFA trifluoro acetic acid
Tf20 trifluorometanesulfonic anhydride
TH tyrosine hydroxylase
THF tetrahydrofuran
TLC thin-layer chromatography
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 typically 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) in DMF is treated with Intermediate A in the presence of a base (e.g., Et3N), and heated for several hours (e.g. 6-12 h) at 110 °C to provide acylguanidine C. In Step 2, methyl 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 SOCl2) 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).
Figure imgf000025_0001
Scheme 1
The thiourea intermediate A used in Scheme 1 can be prepared according to Scheme 2. Briefly, in Step 1, (S)-methyl 2-amino-3-(4-hydroxyphenyl)propanoate (H) is reacted with (Boc)20 in the presence of a base (e.g., NaHC03) in a solvent (e.g., THF/MeOH). 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-catalysed hydroxycarbonylation is accomplished with a catalytic amount of palladium catalyst (e.g., Pd(OAc)2) in the presence of CO (e.g., 6 atm) and a base (e.g., KOAc), and then mixture is heated for a period of time (e.g. 12-24 h) to provide L. In Step 4, conversion to the thiourea can be accomplished by reaction with a coupling agent (e.g EDCI, HO At) and S- methylisothiouronium sulfate.
Figure imgf000026_0001
Scheme 2
Benzyl amine O can be prepared as described in Scheme 3. Briefly, in Step 1 nitrile M is reacted with an amine (HNR'Ri, where R1 and R> are optioanly substituted alkyl or are linked together to form an optionally substituted cyclic amind) in the presence of a base (e.g., NaH or K2CO3) in a solvent (e.g., DMF) and heated for a period of time (e.g., 12- 24 h). In Step 2, the nitrile N can be reduced to the corresponding benzyl amine via the use of a hydride reducing agent (e.g., LAH or BH3) or by transition metal-mediated hydrogenation (e.g., H2 in the presence of Raney Nickel).
Figure imgf000026_0002
Scheme 3
For certain substitutions on Ring A, palladium-mediated coupling reactions (e.g. Suzuki or Stille reactions) can be used, as shown in Scheme 4. Briefly, in Step 1, bromo-benzonitrile P in a solvent (e.g. aqueous dioxane) is added a boronic acid or boronate in the presence of a palladium catalyst (e.g., PdCl2(PPh3)2) and a base (e.g. CS2CO3), and the mixture is heated to reflux for several hours (e.g. 12-24) to provide a compound of formula Q. In Step 2, the nitrile can be reduced to the corresponding benzyl amine via the use of a hydride reducing agent (e.g. LAH or BH3) or by transition metal-mediated hydrogenation (e.g. H2 in the presence of Raney Nickel) to provide amine R.
Figure imgf000027_0001
P STEP 1 Q STEP 2 R
Scheme 4
Substituted benzyl amines V can be prepared as described in Scheme 5. Briefly, in Step 1, difluoro benzonitrile S is reacted with an amine (HNR'R") in the presence of a base (e.g., NaH or K2CO3) in a solvent (e.g., DMF) and heated for a period of time (e.g. 12-24 h) resulting in nitrile T. In Step 2, an alcohol (HOR, where R is alkyl, cycloalkyl, heterocycloalkyl, or similar, each optionally substituted) is added in the presence of a base (e.g., NaH) in a solvent (e.g,.
THF) and the reaction mixture is heated for some period of time (12-24 h). In Step 3, the nitrile is reduced to the corresponding benzyl amine via the use of a hydride reducing agent (e.g., LAH or BH3) or by transition metal-mediated hydrogenation (e.g., H2 in the presence of Raney Nickel) to provide R. In some cases, steps 1 and 2 can be reversed.
Figure imgf000027_0002
U STEP 3 V
Scheme 5
Methods of use
The compounds of the invention can be used to inhibit the activity of the TPH1 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). In some embodiments, the selectivity is 2-fold or more, 3- fold or more, 5-fold or more, 10-fold or more, 50-fold or more, or 100-fold or more.
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.
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 atherosclerosis 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).
The types of PAH treatable 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 associated with persistent pulmonary hypertension of the newborn (PPHN).
Further diseases treatable or preventable by the methods of the invention include metabolic diseases such as diabetes and hyper lipidemia; pulmonary diseases such as chronic obstructive pulmonary disease (COPD), and pulmonary embolism; gastrointestinal diseases such as IBD, colitis, chemotherapy-induced emesis, diarrhea, carcinoid syndrome, celiac disease,
Crohn's disease, abdominal pain, dyspepsia, constipation, lactose intolerance, MEN types I and II, Ogilvie's syndrome, pancreatic cholera syndrome, pancreatic insufficiency,
pheochromacytoma, scleroderma, somatization disorder, Zollinger-Ellison syndrome, or other gastrointestinal inflammatory conditions; liver diseases such as chronic liver disease; 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, 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)).
The compounds of the invention are also useful in the treatment and prevention of serotonin syndrome.
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.
The compounds of the invention are also useful in the treatment and prevention of inflammatory disease, such as allergic airway inflammation (e.g. asthma).
The compounds of the invention can also be used in the treatment 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.
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 who 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, ammoglutethimide, 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-FFT2A, 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.
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 1H 19F and 13C); (2) Agilent Unitylnova 400 MHz spectrometer; or (3) Varian Mercury Plus 400 MHz spectrometer. Several NMR probes were used with the 400 MHz NMR spectrometer, including both 3 mm and 5 mm 1H 19F and 13C probes and a 3 mm X'H^F NMR probe (usually X was tuned to 13C). For typical JH 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. JH 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 um, 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 G 1312B with UV/Vis diode array detector G 1315 C 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 μιη, 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 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 lyophilized, to give the product.
Chiral HPLC was carried out using a Chiralpak AD column, 4.4 mm x 250 mm, particle size 5 micron.
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
General Raney Nickel nitrile reduction to the corresponding benzyl amine: To a solution of the benzonitrile (0.9 mmol) in 20 mL of MeOH was added Raney Nickel (5%) and NH4OH (2 mL). The reaction was stirred under 1 atm of H2 at RT for 2 h, the solid was filtered away, and the filtrate was concentrated in vacuo to provide the amine. Intermediate 1: (2-(lH-l,2,3-triazol-l-yl)phenyl)methanamine
Figure imgf000037_0001
Step 1: To a solution of 2-fluorobenzonitrile (CAS# 394-47-8) (11 mmol) in 20 mL of DMF was added 1,2,3-triazole (11.8 mmol). The mixture was heated to 70 °C for 12 h, and then cooled to RT. The reaction was extracted with water and ethyl acetate, washed with brine and dried over Na2SC"4. Purification via prep-TLC provided 2-(2H-l,2,3-triazol-2-yl)benzonitrile.
Step 2: 2-(2H-l,2,3-triazol-2-yl)benzonitrile (2.6 mmol) was dissolved in 30 mL of THF. To this solution was added LAH (10.6 mmol). The mixture was stirred at RT for 12 h. The reaction was then quenched sequentially with water, 15% NaOH, and then water. The resulting solid was filtered, washed with THF, and the filtrate was concentrated in vacuo. The residue was purified by normal phase silica gel column chromatography to provide the title compound as a yellow oil. LCMS (MH+): 175.
Intermediate 2: (2-(4-methyl-lH-imidazol-l-yl)phenyl)methanamine:
Figure imgf000037_0002
The title compound can be prepared as described above for (2-(lH-l,2,3-triazol-l- yl)phenyl)methanamine using 4-methyl-lH-imidazole in the place of 1,2,3-triazole.
LCMS (MH+): 188.
Intermediate 3: (2-((3S,5S,7S)-adamantan-l- loxy)phenyl)methanamine;:
Figure imgf000037_0003
Step 1: To a 0 °C solution of adamantane-2-ol (2.5 mmol) in 30 mL of THF was added NaH (3 mmol). The reaction mixture was stirred for 1 h at 0 °C, and then 2-fluorobenzonitrile (2.5 mmol) was added. The reaction mixture was warmed to RT, then heated to 50 °C for 12 h. The reaction mixture was then cooled to RT then extracted with water and EtOAc, washed with brine, and dried over Na2S04. Concentration of the filtrate provided 2-((3S,5S,7S)-adamantan-l- yloxy)benzonitrile, which was used in step 2 without further purification.
Step 2: 2-((3S,5S,7S)-adamantan-l-yloxy)benzonitrile (0.8 mmol) was dissolved in 10 mL of THF. To this reaction mixture was added BH3-THF (4 mmol) and then the mixture was stirred at RT for 12 h. The solution was then quenched by dropwise addition of MeOH, then concentrated in vacuo to provide the title compound which was used without further purification.
LCMS (MH+): 258.
Intermediate 4: tert-butyl 4-(2-(aminomethyl)phenoxy)piperidine-l-carboxylate
Figure imgf000038_0001
The title compound can be prepared as described above for (2-((3S,5S,7S)-adamantan-l- yloxy)phenyl)methanamine, using tert-butyl 4-(2-(aminomethyl)phenoxy)piperidine-l- carboxylate (CAS# 109384-19-2) in place of adamantane-2-ol.
In this instance, the piperidine protecting group (N-Boc) was also removed in the final step (see, e.g., step 3, example 130) to make the fully elaborated molecule.
LCMS (MH+): 307.
Intermediate 5: (2-(4-phenylpiperidin-l-yl)phenyl)methanamine
Figure imgf000039_0001
Step 1: To a solution of 2-fluorobenzonitrile (4 mmol) and 4-phenyl-piperidine (CAS# 771-99-3) (4.5 mmol) in 10 mL of DMF was added K2CO3 (12 mmol). The reaction was stirred at 70 °C for 12 h, then cooled to RT. The reaction mixture was then extracted with water and EtOAc, washed with brine and dried over Na2S04, concentrated and purified by prep-TLC to provide 2- (4-phenylpiperidin-l-yl)benzonitrile as a white solid.
Step 2: The title compound was prepared by Raney Nickel nitrile reduction to the corresponding benzyl amine.
LCMS (MH+): 267.
The following intermediates of Table 2 were prepared as described above for 2-(4- phenylpiperidin-l-yl)phenyl)methanamine (Intermediate 5).
Table 2. Mono-substituted benzyl amines
Figure imgf000039_0002
Figure imgf000040_0001
Intermediate 12: (S)-tert-butyl 3-(2-(aminomethyl)phenoxy)pyrrolidine-l-carboxylate
Figure imgf000040_0002
Step 1: To a solution of 2-fluorobenzonitrile (3 mmol) and (R)-tert-butyl 3-hydroxypyrrolidine- 1-carboxylate (CAS# 109431-87-0) (3 mmol) in 20 mL of THF was added NaH (4.5 mmol). The reaction was stirred at 50 °C for 12 h, then cooled to RT. The reaction mixture was then extracted with water and EtOAc, washed with brine, dried over Na2S04, and concentrated in vacuo to provide (R)-tert-butyl 3-(2-cyanophenoxy)pyrrolidine- 1-carboxylate as a yellow oil which was used in Step 2 without further purification. Step 2: (R)-tert-butyl 3-(2-cyanophenoxy)pyrrolidine-l-carboxylate (2.4 mmol) in 30 mL of THF was added LAH (9.7 mmol), and the reaction was stirred at RT for 12 h. The reaction was then quenched sequentially with water, 15% NaOH, then more water. The resulting solid was filtered, washed with THF, and the filtrate was concentrated in vacuo. Purification by reverse phase column chromatography provided the title compound as a yellow oil. In this instance, the protecting group of the pyrolidine (N-Boc) was also removed in the final step (e.g. step 3, example 130) to make the fully elaborated molecule.
LCMS (MH+): 293. Intermediate 13: (2-(6-methoxy-2-methylpyridin-3-yl)phenyl)methanamine
Figure imgf000041_0001
Step 1: To a solution of 6-methoxy-2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine (CAS# 1080028-73-4) (2 mmol) and 2-bromobenzonitrile (2 mmol) in 50 mL of dioxane was added PdCl2(PPh3)2 (0.1 mmol) and CS2CO3 (4 mmol). The mixture was stirred at 100 °C for 12 h, then cooled to RT, filtered, and concentrated in vacuo to provide 2-(6-methoxy- 2-methylpyridin-3-yl)benzonitrile as a brown oil which was used without further purification. Step 2: The title compound was prepared by Raney Nickel nitrile reduction to the corresponding benzyl amine as a yellow oil.
LCMS (MH+): 267.
The following intermediates of Table 3 were prepared as described above for (2-(6- methoxy-2-methylpyridin-3-yl)phenyl)methanamine (Intermediate 13).
Table 3: Aryl substituted benzyl amines
Figure imgf000041_0002
Figure imgf000042_0001
Intermediate 21 : (3 '-(piperidin-l -ylmethyl)- [1,1 '-biphenyl] -4-yl)methanamine
Figure imgf000043_0001
Step 1: To a solution of l-(3-bromobenzyl)piperidine (CAS#: 59507-40-3) (6 mmol), bis(pinacolato)diboron (7.2 mmol), potassium acetate (12 mmol) in 20 mL of acetonitrile was added Pd(OAc)2 (0.12 mmol) and P(Cy)3 (0.3 mmol). The mixture was stirred at 80 °C for 2 h, then filtered and concentrated in vacuo to provide l-(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)benzyl)piperidine as a yellow solid.
Step 2: To a solution of l-(3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)benzyl)piperidine (3 mmol) in 10 mL of ethanol and 2 mL of water was added (4-bromophenyl)methanamine (3 mmol), PdCl2(PPh3)2 (0.06 mmol) and K2C03 (6 mmol). The reaction was stirred at 75 °C for 2 h, then filtered and concentrated in vacuo and then purified by normal phase silica gel column chromatography to provide the title compound as a yellow solid.
LCMS (MH+): 281. Intermediate 22: (4-methoxy-2-(piperidin-l- l)phenyl)methanamine
Figure imgf000043_0002
Step 1: To a solution of 2-fluoro-4-methoxybenzonitrile (CAS# 94610-82-9) (2 mmol) and piperidine (2.2 mmol) in 10 mL of DMF was added K2C03 (6 mol). The mixture was stirred at 70 °C for 12 h, then filtered and extracted with EtOAc, washed with brine, and dried over Na2SC"4, then concentrated in vacuo and purified by normal phase silica gel column
chromatography to provide 4-methoxy-2-(piperidin-l-yl)benzonitrile as a yellow oil.
Step 2: The title compound was prepared by Raney Nickel nitrile reduction to the corresponding benzyl amine as a yellow solid.
LCMS (MH+): 221. Intermediate 23: (5-bromo-2-(piperidin-l-yl)phenyl)methanamine
Figure imgf000044_0001
Step 1: To a solution of 5-bromo-2-fluorobenzonitrile (CAS# 179897-89-3) (18 mmol) and piperidine (72 mmol) in 20 mL of DMF was added K2CO3 (36 mmol). The mixture was stirred at 80 °C for 12 h, then poured into 150 mL of water, extracted with EtOAc, washed with brine, dried over Na2S04, concentrated in vacuo, then purified by prep-TLC to provide 5-bromo-2- (piperidin-l-yl)benzonitrile as a yellow oil. Step 2: The title compound was prepared by Raney Nickel nitrile reduction to the corresponding benzyl amine as a yellow solid.
LCMS (MH+): 269.
Intermediate 24: (3-(piperidin-l-yl)-[l, '-biphenyl]-2-yl)methanamine
Figure imgf000044_0002
Step 1: To a solution of 2-bromo-6-(piperidin-l-yl)benzonitrile (CAS#: 1260649-11-3) (0.6 mmol) and phenyl boronic acid (0.7 mmol) in 20 mL of CH3CN and 1 mL of water was added PdCl2(PPh3)2 (0.006 mmol) and Cs2C03 (1.7 mmol). The mixture was stirred at 70 °C for 12 h, then cooled to RT. The mixture was then filtered and concentrated in vacuo to provide 3- (piperidin-l-yl)-[l, -biphenyl]-2-carbonitrile as a yellow oil which was used in Step 2 without further purification. Step 2: The title compound was prepared by Raney Nickel nitrile reduction to the correspond benzyl amine as a white solid.
LCMS (MH+): 269.
Intermediate 25: (2-chloro-6-(3-methyl-lH- razol-l-yl)phenyl)methanamine
Figure imgf000045_0001
Step 1: To a solution of 2-chloro-6-fluorobenzonitrile (CAS# 668-45-1) (4 mmol) and 3-methyl- lH-pyrazole (6 mmol) in 10 mL of DMF was added K2CO3 (8 mmol). The mixture was stirred at 70 °C for 12 h, then cooled to RT. The mixture was filtered and extracted with water and EtOAc, washed with brine, dried over Na2S04, concentrated in vacuo, and purified by prep-TLC to provide 2-chloro-6-(3-methyl-lH-pyrazol-l-yl)benzonitrile as a yellow solid.
Step 2: The title compound was prepared by Raney Nickel nitrile reduction to the corresponding benzyl amine as a yellow oil.
LCMS (MH+): 222.
Intermediate 26: (2-(cyclopentyloxy)-6-methoxyphenyl)methanamine
Figure imgf000045_0002
Step 1: To a 0 °C solution of cyclopentanol (10 mmol) in 50 mL of THF was added NaH (11 mmol). The reaction mixture was stirred for 1 h at 0 °C, and then 2,6-difluorobenzonitrile
(CAS# 1897-52-5) (10 mmol) was added. The reaction mixture was warmed to RT, then heated to 50 °C for 12 h. After this time, the reaction was cooled to 0 °C. Water was added then the reaction mixture was extracted with EtOAc, washed with brine, and dried over NaS04. Concentration of the filtrate in vacuo provided 2-(cyclopentyloxy)-6-fluorobenzonitrile which was used in Step 2 without further purification.
Step 2: 2-(Cyclopentyloxy)-6-fluorobenzonitrile (3 mmol) was dissolved in 15 mL of MeOH followed by the addition of NaOMe (15 mmol). The reaction was heated to reflux for 12 h, then cooled to RT. Concentration of the reaction mixture in vacuo, followed by purification on silica gel chromatography provided 2-(cyclopentyloxy)-6-methoxybenzonitrile as a yellow oil.
Step 3: 2-(Cyclopentyloxy)-6-methoxybenzonitrile (3 mmol) was dissolved in 15 mL of THF. To this reaction mixture was added BH3-THF (15 mmol), then the mixture was heated to reflux for 12 h. The reaction was then cooled to RT, then quenched by dropwise addition of MeOH.
The solvent was evaporated in vacuo, the residue dissolved in 20 mL of IN HC1, then extracted with CH2CI2. Concentration in vacuo provided the title compound which was used without further purification.
LCMS (MH+): 222.
Intermediate 27: (2-(cyclopentyloxy)-6-fluoro henyl)methanamine
Figure imgf000046_0001
Step 1: To a 0 °C solution of cyclopentanol (10 mmol) in 50 mL of THF was added NaH (11 mmol). The reaction mixture was stirred for 1 h at 0 °C, then 2,6-difluorobenzonitrile (10 mmol) was added. The reaction mixture was warmed to RT, then heated to 50 °C for 12 h. After this time, the reaction was cooled to 0 °C. Water was added then the reaction mixture was extracted with EtOAc, washed with brine, and dried over NaS04. Concentration of the filtrate in vacuo provided 2-(cyclopentyloxy)-6-fluorobenzonitrile which was used in Step 2 without further purification.
Step 2: 2-(cyclopentyloxy)-6-fluorobenzonitrile (3 mmol) was dissolved in 15 mL of THF. To this reaction mixture was added BH3-THF (15 mmol), then the mixture was heated to reflux for 12 h. The reaction was then cooled to RT, and quenched by dropwise addition of MeOH. The solvent was evaporated in vacuo, the residue dissolved in 20 mL of IN HC1, then extracted with CH2CI2. Concentration in vacuo provided the title compound which was used without further purification.
LCMS (MH+): 210.
Intermediate 28: (2-fluoro-6-(2H-l,2,3-triazol-2- l)phenyl)methanamine
Figure imgf000047_0001
Step 1: To a solution of 2,6-difluorobenzonitrile (5 mmol) and 1,2,3-triazole (5 mmol) in 20 mL of DMF was added K2CO3 (20 mmol). The reaction was heated to 70 °C for 12 h, then cooled to RT. The reaction mixture was then extracted with water and EtOAc, washed with brine, and dried over Na2S04, then concentrated in vacuo. Purification via prep-TLC provided 2-fluoro-6- (2H- 1 ,2,3-triazol-2-yl)benzonitrile. Step 2: The title compound was prepared by the general Raney Nickel nitrile reduction to the corresponding benzyl amine as a yellow oil.
LCMS (MH+): 193.
Intermediate 39: (2-fluoro-6-(lH-pyrazol-l- l)phenyl) methanamine
Figure imgf000047_0002
The title compound can be prepared as described above for (2-fluoro-6-(2H-l,2,3-triazol- 2-yl)phenyl)methanamine (Intermediate 28), using pyrazole in place of 1,2,3-triazole.
LCMS (MH+): 192. Intermediate 249: (2-fluoro-6-morpholinophenyl)methanamine
Figure imgf000048_0001
The title compound can be prepared as described above for (2-fluoro-6-(2H-l,2,3-triazol- 2-yl)phenyl)methanamine (Intermediate 28), using morpholine in place of 1,2,3-triazole.
LCMS (MH+): 211
Intermediate 29: (2,6-di(2H-l,2,3-triaz l-2-yl)phenyl)methanamine
Figure imgf000048_0002
Step 1: To a solution of 2,6-difluorobenzonitrile (10 mmol) and 1,2,3-triazole (20 mmol) in 20 mL of DMF was added K2CO3 (40 mmol). The reaction was heated to 80 °C for 12 h, then cooled to RT. The reaction mixture was then extracted with water and EtOAc, washed with brine, dried over Na2S04, then concentrated in vacuo. Purification via prep-TLC provided 2,6- di(2H- 1 ,2,3-triazol-2-yl)benzonitrile.
Step 2: The title compound was prepared by the general Raney Nickel nitrile reduction to the corresponding benzyl amine as a yellow solid.
LCMS (MH+): 242.
Intermediate 30: (2-(piperidin-l-yl)-6-(trifluoromethyl)phenyl)methanamine
Figure imgf000048_0003
Step 1: To a solution of 2-fluoro-6-(trifluoromethyl)benzonitrile (CAS#: 133116-83-3) (2 mmol) and piperidine (2.2 mmol) in 10 mL of DMF was added K2CO3 (12 mmol). The reaction was stirred at 70 °C for 12 h, then cooled to RT. The reaction mixture was then extracted with water and EtOAc, washed with brine, dried over Na2S04, concentrated in vacuo, then purified by prep- TLC to provide 2-(piperidin-l-yl)-6-(trifluoromethyl)benzonitrile as a white solid. Step 2: To 2-(piperidin-l-yl)-6-(trifluoromethyl)benzonitrile (1.2 mmol) in 20 mL of EtOH was added NiCl2 (2.4 mmol) and NaBH4 (3.5 mmol). The reaction was stirred at RT for 12 h, quenched with water. The solid was filtered away and the filtrate extracted with CH2C12, washed with brine, dried over Na2S04, concentrated in vacuo, then purified by prep-TLC to provide the title compound as a yellow oil.
LCMS (MH+): 259.
The following intermediates of Table 4 were prepared as described above for (2- (piperidin- 1 -yl)-6-(trifluoromethyl)phenyl)methanamine (Intermediate 30) .
Table 4. Di-substituted benzyl amines
Figure imgf000049_0001
Figure imgf000050_0001
Intermediate 41 : l-(2-(aminomethyl)-3-methoxyphenyl)piperidin-4-ol
Figure imgf000051_0001
Step 1: To a solution of 2-methoxy-6-fluorobenzonitrile (CAS#: 94088-46-7) (3 mmol) and 4- hydroxypiperidine (3.6 mmol) in 10 mL of DMF was added K2CO3 (6 mmol). The reaction was stirred at 80 °C for 4 h, then cooled to RT. The reaction mixture was then extracted with water and EtOAc, washed with brine, dried over Na2S04, concentrated in vacuo, then purified by prep- TLC to provide 2-(4-hydroxypiperidin-l-yl)-6-methoxybenzonitrile as a yellow solid.
Step 2: The title compound was prepared by Raney Nickel nitrile reduction to the corresponding benzyl amine as a yellow solid.
LCMS (MH+): 236.
The following intermediates of Table 5 were prepared as described above for l-(2- (aminomethyl)-3-methoxyphenyl)piperidin-4-ol (Intermediate 41). Table 5. Methoxy substituted benzyl amines
Figure imgf000051_0002
Figure imgf000052_0001
Intermediate 54: (3-methoxy-2-(piperidin-l-yl)phenyl)methanamine
Figure imgf000052_0002
Step 1: To a solution of 2-fluoro-3-methoxybenzonitrile (CAS#: 198203-94-0) (3 mmol) and piperidine (3.6 mmol) in 10 mL of DMF was added K2CO3 (6 mmol). The reaction was stirred at 80 °C for 4 h, then cooled to RT. The reaction mixture was then extracted with water and EtOAc, washed with brine, dried over Na2S04, concentrated in vacuo, then purified by prep-TLC to provide 3-methoxy-2-(piperidin-l-yl)benzonitrile as a yellow solid. Step 2: The title compound was prepared by Raney Nickel nitrile reduction to the correspond benzyl amine as a white solid.
LCMS (MH+): 221.
Intermediate 55: (2-(azepan-l-yl)-3-methoxyphenyl)methanamine
Figure imgf000053_0001
The title compound can be prepared as described above for (3-methoxy-2-(piperidin-l- yl)phenyl)methanamine (Intermediate 54), using homopiperidine in place of piperidine.
LCMS (MH+): 235.
Intermediate 68: (2-methoxy-6-(2-methylpiperidin-l-yl)phenyl)methanamine
Figure imgf000053_0002
The title compound can be prepared as described above for l-(2-(aminomethyl)-3- methoxyphenyl)piperidin-4-ol (Intermediate 41), using 2-methylpiperidine (CAS#: 109-05-7) in place of piperidine.
LCMS (MH+): 236.
Intermediate 46: (2-ethoxy-6-(piperidi -l-yl)phenyl)methanamine
Figure imgf000053_0003
The title compound can be prepared as described above for l-(2-(aminomethyl)-3- methoxyphenyl)piperidin-4-ol (Intermediate 41), using 2-ethoxy-6-fluorobenzonitrile (CAS#: 119584-73-5) in place of 2-methoxy-6-fluorobenzonitrile.
LCMS (MH+): 236.
Intermediate 48: (5-methyl-2-(piperidi -l-yl)phenyl)methanamine
Figure imgf000054_0001
Step 1: To a solution of 2-fluoro-5-methylbenzonitrile (CAS# 64113-84-4) (3 mmol) and piperidine (3 mmol) in 10 mL of DMF was added K2CO3 (6 mmol). The reaction was stirred at 80 °C for 12 h, then cooled to RT. The reaction mixture was then extracted with water and EtOAc, washed with brine, dried over Na2S04, concentrated in vacuo, then purified by prep-TLC to provide 5-methyl-2-(piperidin-l-yl)benzonitrile as a yellow solid.
Step 2: The title compound was prepared by Raney Nickel nitrile reduction to the corresponding benzyl amine as a yellow solid.
LCMS (MH+): 205.
The following intermediates of Table 6 were prepared as described above for (5-methyl- 2-(piperidin-l-yl)phenyl)methanamine (Intermediate 48) .
Table 6. Di-substituted benzyl amines
LCMS
No. Name Structure
(MH+)
(5-methoxy-2-(piperidin-l-yl)phenyl)
Intermediate 49 H2 220 methanamine kJ N
0
Figure imgf000055_0001
Intermediate 52: (3-chloro-2-(piperidin- -yl)phenyl)methanamine
Figure imgf000055_0002
Step 1: To a solution of 3-chloro-2-fluorobenzonitrile (CAS# 94087-40-8) (2.3 mmol) and piperidine (2.8 mmol) in 10 mL of DMF was added K2CO3 (4.6 mmol). The reaction was stirred at RT for 12 h, then the reaction mixture was extracted with water and EtOAc, washed with brine, dried over Na2S04, then concentrated in vacuo to provide 3-chloro-2-(piperidin-l- yl)benzonitrile as a yellow solid which was used in Step 2 without further purification. Step 2: To 3-chloro-2-(piperidin-l-yl)benzonitrile (1.65 mmol) in 5 mL of EtOH was added
N1CI2 (5 mmol) and NaBH4 (5 mmol). The reaction was stirred at RT for 4 h then quenched with water. The solid was filtered and the reaction mixture extracted with CH2CI2, washed with brine, dried over Na2S04, concentrated in vacuo, then purified by prep-TLC to provide the title compound as a yellow oil.
LCMS (MH+): 225.
Intermediate 53: (2-methyl-6-(piperidin-l-yl)phenyl)methanamine
Figure imgf000056_0001
The title compound can be prepared as described above for (3-chloro-2-(piperidin-l- yl)phenyl)methanamine (Intermediate 52 ) using 2-fluoro-6-methylbenzonitrile (CAS#: 198633- 76-0) in the place of 3-chloro-2-fluorobenzonitrile.
LCMS (MH+): 205.
Intermediate 57: (4-(piperidin-l-yl)-[l, '-biphenyl]-3-yl)methanamine
Figure imgf000056_0002
Step 1: To a solution of 5-bromo-2-(piperidin-l-yl)benzonitrile (CAS# 876918-30-8) (4 mmol) and phenyl boronic acid (4 mmol) in 30 mL of CH3CN and 10 mL of water was added
PdCl2(PPh3)2 (0.08 mmol) and Na2C03 (8 mmol). The mixture was stirred at 70 °C for 12 h, then cooled to RT. The mixture was then filtered and concentrated in vacuo to provide 4-(piperidin- l-yl)-[l,l'-biphenyl]-3-carbonitrile as a yellow solid which was used in Step 2 without further purification.
Step 2: The title compound was prepared by Raney Nickel nitrile reduction to the corresponding benzyl amine as a yellow solid.
LCMS (MH+): 267. Intermediate 58: (4-(azepan-l-yl)-[l,l'-biphenyl]-3-yl)methanamine
Figure imgf000057_0001
The title compound can be prepared as described above for (4-(piperidin-l-yl)-[l, - biphenyl]-3-yl)methanamine (Intermediate 57) using 5-bromo-2-(hexahydro-lH-azepin-l- yl)benzonitrile (CAS#: 1260805-75-1) in place of 5-bromo-2-(piperidin-l-yl)benzonitrile.
LCMS (MH+): 281.
Intermediate 59: (2-(piperidin-l-yl)-5-(thiazol-2-yl)phenyl)methanamine
Figure imgf000057_0002
Step 1: To a solution of 5-bromo-2-(piperidin-l-yl)benzonitrile (CAS# 876918-30-8) (1 mmol) and 2-(tributylstannyl)thiazole (1 mmol) in 10 mL of toluene was added PdCl2(PPh3)2 (0.05 mmol). The mixture was stirred at 1 10 °C for 12 h, then cooled to RT. The reaction mixture was filtered, concentrated in vacuo, and purified by prep-TLC to provide 2-(piperidin-l-yl)-5- (thiazol-2-yl)benzonitrile as an oil.
Step 2: The title compound was prepared by Raney Nickel nitrile reduction to the corresponding benzyl amine as a white solid.
LCMS (MH+): 274.
Intermediate 60: (3-phenoxy-[l,l'-biphenyl]-2-yl)methanamine
Figure imgf000058_0001
Step 1: To a solution of 2-bromo-6-fluorobenzonitrile (CAS# 79544-27-7) (11.9 mmol) and phenyl boronic acid (13.1 mmol) in 50 mL of acetonitrile and 10 mL of water was added PdCl2(PPh3)2 (0.35 mmol) and Na2C03 (23.8 mmol). The mixture was stirred at 80 °C for 12 h, then cooled to RT. The reaction mixture was then extracted with water and EtOAc, washed with brine, dried over Na2S04, then concentrated in vacuo to provide 3-fluoro-[l,l'-biphenyl]-2- carbonitrile as an oil which was used in Step 2 without further purification.
Step 2: To a solution of phenol (12 mmol) was added NaH (12 mmol) in 20 mL of DMF at 0 C. To this solution was added 3-fluoro-[l, -biphenyl]-2-carbonitrile (8 mmol). The reaction was warmed to RT, then stirred for 12 h. The reaction mixture was then extracted with water and EtOAc, washed with brine, dried over Na2S04, concentrated in vacuo, then purified by prep-TLC to provide 3-phenoxy-[l, l'-biphenyl]-2-carbonitrile as an oil. Step 3: The title compound was prepared as a yellow solid by Raney Nickel reduction of 3- phenoxy-[l, l'-biphenyl]-2-carbonitrile, as described for (2-chloro-6-(3 -methyl- lH-pyrazo 1-1- yl)phenyl)methanamine (Intermediate 25, Step 2).
LCMS (MH+): 276. Intermediate 65: (2'-chloro-3-phenoxy- '-biphenyl]-2-yl)methanamine
Figure imgf000058_0002
The title compound can be prepared as described above (3-phenoxy-[l,l'-biphenyl]-2- yl)methanamine (Intermediate 60) using 2-chlorophenylboronic acid in place of phenylboronic acid (Step 1).
LCMS (MH+): 310.
Intermediate 64: (3-methoxy-[l,l'-biphenyl]-2-yl)methanamine
Figure imgf000059_0001
Step 1: To a solution of 2-bromo-6-fluorobenzonitrile (11.9 mmol) and phenyl boronic acid (13 mmol) in 50 mL of CH3CN and 10 mL of water was added PdCl2(PPh3)2 (0.4 mmol) and Na2C03 (24 mmol). The reaction mixture was heated to 80 °C for 12 h, then cooled to RT. The reaction was filtered and extracted with water and EtOAc, washed with brine, dried over Na2S04, then concentrated in vacuo to provide 3-fluoro-[l, -biphenyl]-2-carbonitrile as an oil which was used in Step 2 without further purification. Step 2: To a solution of 3-fluoro-[l, -biphenyl]-2-carbonitrile (5.0 mmol) in 100 mL of methanol was added NaOMe (25 mmol). The reaction was heated to reflux for 12 h, then cooled to RT. Concentration of the reaction mixture in vacuo, followed by purification on silica gel chromatography (20: 1 /petroleum ethenether) provided 3-methoxy-[l,l'-biphenyl]-2-carbonitrile as a white solid.
Step 3: The title compound was prepared by Raney Nickel nitrile reduction to the corresponding benzyl amine as a white solid.
LCMS (MH+): 214. The following intermediates of Table 7 were prepared as described above for (3- methoxy-[l, -biphenyl]-2-yl)methanamine (Intermediate 64). Table 7. Methoxy substituted benzyl amines
Figure imgf000060_0003
Intermediate 66 : (2 '-chloro-3-ethoxy- [1 '-biphenyl] -2-yl)methanamine
Figure imgf000060_0001
The title compound can be prepared as described above for (3-methoxy-[l,l'-biphenyl]-2- yl)methanamine (Intermediate 64), using 2-chlorophenylboronic acid in place of phenyl boronic acid (Step 1) and NaOEt in place of NaOMe (Step 2).
LCMS (MH+): 262. Intermediate 67: (2,-chloro-3-isopropo -[l,l'-biphenyl]-2-yl)methanamine
Figure imgf000060_0002
The title compound can be prepared as described above for (3-methoxy-[l,l'-biphenyl]-2- yl)methanamine (Intermediate 64 ), using 2-chlorophenylboronic acid in place of phenylboronic acid (Step 1) and NaOiPr in place of NaOMe (Step 2).
LCMS (MH+): 276.
Intermediate 56: (6-methoxy-[l,l'-biphenyl]-2-yl)methanamine
Figure imgf000061_0001
Step 1: To a solution of 2-bromo-3-methoxybenzonitrile (CAS# 1261816-95-8) (11.9 mmol) and phenyl boronic acid (13 mmol) in 50 mL of CH3CN and 10 mL of water was added PdCl2(PPh3)2 (0.4 mmol) and Na2C03 (24 mmol). The reaction mixture was heated to 80 °C for 12 h, then cooled to RT. The reaction was filtered and extracted with water and EtOAc, washed with brine, dried over Na2S04, then concentrated in vacuo to provide 6-methoxy-[l, l'-biphenyl]-2- carbonitrile as an oil which was used in Step 2 without further purification.
Step 2: The title compound was prepared by the general Raney Nickel nitrile reduction to the corresponding benzyl amine as a yellow solid.
LCMS (MH+): 213.
Intermediate 62 : (2 '-chloro-6-methoxy- 1,1 '-biphenyl] -2-yl)methanamine
Figure imgf000061_0002
The title compound can be prepared as described above for (6-methoxy-[l,l'-biphenyl]-2- yl)methanamine (Intermediate 56), using 2-chlorophenyl boronic acid in place of phenyl boronic acid.
LCMS (MH+): 247.
Intermediate 69: (2-isopropoxy-6-(piperidin-l-yl)phenyl)methanamine
Figure imgf000062_0001
Step 1: A solution of 2,6-difluorobenzonitrile (29 mmol) and piperidine (28 mmol) in 80 mL of DMF is stirred at RT for 3 h. The reaction mixture was then extracted with water and EtOAc, washed with brine, dried over Na2S04, then concentrated in vacuo to provide 2-fluoro-6- (piperidin-l-yl)benzonitrile as a yellow oil which was used in Step 2 without further purification.
Step 2: To a solution of 2-fluoro-6-(piperidin-l-yl)benzonitrile (3.2 mmol) in 50 mL of isopropanol was added NaOH (6.37 mmol). The reaction was heated to 85 °C for 12 h, then cooled to RT, concentrated in vacuo, then purified on silica gel to provide 2-isopropoxy-6- (piperidin-l-yl)benzonitrile as an oil.
Step 3: The title compound was prepared by the general Raney Nickel nitrile reduction to the corresponding benzyl amine as yellow solid.
LCMS (MH+): 249.
Intermediate 70: (2-(cyclohexyloxy)-6-(piperidin-l-yl)phenyl)methanamine
Figure imgf000062_0002
Step 1: To a solution of cyclohexanol (4.5 mmol) in 60 mL of DMF was added NaH (60%, 6.0 mmol) at 0 °C. The reaction was stirred for 1 h, then 2-fluoro-6-(piperidin-l-yl)benzonitrile (CAS# 646989-68-6) (3.0 mmol) was added, and the reaction stirred for 48 h at RT. The reaction mixture was then extracted with water and EtOAc, washed with brine, dried over Na2SC"4, then concentrated in vacuo. The crude material was purified by chromatography on silica gel to provide 2-(cyclohexyloxy)-6-(piperidin-l-yl)benzonitrile as a white solid.
Step 2: The title compound was prepared by Raney Nickel nitrile reduction to the corresponding benzyl amine as an off-white solid.
LCMS (MH+): 289.
The following intermediates of Table 8 were prepared as described above for (2- (cyclohexyloxy)-6-(piperidin-l-yl)phenyl)methanamine (Intermediate 70). For intermediates 72, 73, 84 & 88-92, 2-fiuoro-6-(hexahydro-lH-azepin-l-yl)benzonitrile (CAS# 1260780-80-0) was substituted for 2-fluoro-6-(piperidin-l-yl)benzonitrile (CAS# 646989-68-6).
Table 8. Alkoxy substituted benzyl amines
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Intermediates 93 & 94: 3-(aminomethyl)-l-methyl-4-phenylpiperidin-2-one and 3- (aminomethyl)-l-methyl-4-phenylpyridin-2(lH)-one
Figure imgf000068_0002
The title compounds were prepared as a 1 : 1 mixture of amines via Raney Nickel nitrile reduction of l-methyl-2-oxo-4-phenyl-l,2-dihydropyridine-3-carbonitrile (CAS# 130879-53-7. These two amines were separated via normal phase silica gel column chromatography.
LCMS (MH+): 218 & 214. Intermediate 95: (2-chloro-3-methyl-6-(piperidin-l-yl)phenyl)methanamine
Figure imgf000068_0003
Step 1: To a solution of 2-chloro-6-fluoro-3-methylbenzonitrile (CAS# 886500-98-7) (1 mmol) and piperidine (1.5 mmol) in 10 mL of DMF was added K2CO3 (2 mmol). The mixture was stirred at 90 °C for 12 h, then cooled to RT. The reaction mixture was then extracted with water and EtOAc, washed with brine, dried over Na2S04, then concentrated in vacuo to provide (2- chloro-3-methyl-6-(piperidin-l-yl)phenyl)carbonitrile as an oil which was used in Step 2 without further purification.
Step 2: The title compound was prepared by Raney Nickel nitrile reduction to the corresponding benzyl amine as a yellow solid.
LCMS (MH+): 239.
The following intermediates of Table 9 were prepared as described above for (2-chloro-3- methyl-6-(piperidin-l-yl)phenyl)methanamine (Intermediate 95).
Table 9. Tri-substituted benzyl amines
Figure imgf000069_0001
Intermediate 99: (5-(piperidin-l-yl)benzo d] [l,3]dioxol-4-yl)methanamine
Figure imgf000070_0001
Step 1: To a suspension of 5-bromobenzo[d][l,3]dioxole-4-carbaldehyde (CAS#: 72744-54-8) (1.5 mmol) in 1 mL of THF was added h (1.65 mmol) and 10 mL of NH3-H2O. The mixture was stirred at RT for 12 h, then filtered. The residue was rinsed with water to provide 5- bromobenzo[d][l,3]dioxole-4-carbonitrile as a yellow oil which was used in Step 2 without further purification.
Step 2: To a solution of 5-bromobenzo[d][l,3]dioxole-4-carbonitrile (1.5 mmol) in 30 mL of toluene was added piperidine (3.0 mmol), sodium tert-butoxide (3.75 mmol), 2-dicyclo- hexylphosphino-2',4',6'-triisopropylbiphenyl (0.15 mmol), and Pd2(dba)3 (0.15 mmol). The reaction was heated to 110 °C for 12 h, then cooled to RT, concentrated in vacuo, and purified by silica gel chromatography to provide 5-(piperidin-l-yl)benzo[d][l,3]dioxole-4-carbonitrile as an oil.
Step 3: The title compound was prepared by Raney Nickel nitrile reduction to the corresponding benzyl amine as a yellow oil.
LCMS (MH+): 235. Intermediate 100: (6-(azepan-l-yl)-2,3-dihydrobenzo[b] [l,4]dioxin-5-yl)methanamine
Figure imgf000070_0002
The title compound can be prepared as described above for (5-(piperidin-l- yl)benzo[d][l,3]dioxol-4-yl)methanamine (Intermediate 99), using 6-bromo-2,3-dihydro -1,4- benzodioxin-5-carboxaldehyde (CAS#: 249636-65-5) in place of 5-bromobenzo[d] [l,3]dioxole- 4-carbaldehyde (Step 1) and homopiperidine in place of piperidine (Step 2).
LCMS (MH+): 263. Intermediate 101: (2-(azepan-l-yl)-3-chloro-6-methox phenyl)methanamine
Figure imgf000071_0001
Step 1: To a solution of 3-chloro-2,6-difluorobenzonitrile (CAS# 86225-73-2) (3 mmol) and homopiperidine (3.6 mmol) in 10 mL of DMF was added K2CO3 (6 mmol). The reaction was stirred at 80 °C for 4 h, then cooled to RT. The reaction mixture was then extracted with water and EtOAc, washed with brine, dried over Na2S04, concentrated in vacuo, then purified by prep- TLC to provide 2-(azepan-l-yl)-3-chloro-6-fluorobenzonitrile as a yellow solid.
Step 2: To a solution of 2-(azepan-l-yl)-3-chloro-6-fluorobenzonitrile (5.0 mmol) in 100 mL of methanol was added NaOMe (25 mmol). The reaction was heated to reflux for 12 h, then cooled to RT. Concentration of the reaction mixture in vacuo, followed by purification by silica gel chromatography (20: 1 /petroleum ethenether) provided 2-(azepan-l-yl)-3-chloro-6- methoxybenzonitrile as a white solid.
Step 3: The title compound was prepared by Raney Nickel nitrile reduction to the corresponding benzyl amine as a yellow oil.
LCMS (MH+): 268.
Intermediate 102 : (2-methoxy-3 '-methyl-4-(piperidin- 1-yl)- [1 , 1 '-biphenyl] -3- yl)methanamine NH2
Step 1: To a solution of 3-bromo-2,6-diflu 0orobenzonitrile (CAS# 1250444-23-5) (2 mmol) in methanol (10 mL) was added NaOMe (2.2. mmol) at 0 °C. The reaction was stirred at 0 °C for 3 h, concentrated in vacuo, then purified by prep-TLC to provide 3-bromo-6-fluoro-2- methoxybenzonitrile as yellow solid.
Step 2: To a solution of 3-bromo-6-fluoro-2 -methoxybenzonitrile (0.5 mmol) and piperidine (1.5 mmol) in 5 mL of DMF was added K2CO3 (1 mmol). The mixture was stirred at 80 °C for 12 h, then cooled to RT. The reaction mixture was then extracted with water and EtOAc, washed with brine, dried over Na2S04, then concentrated in vacuo. Purification by silica gel chromatography provided 3-bromo-2-methoxy-6-(piperidin-l-yl)benzonitrile as a white solid.
Step 3: To a solution of 3-bromo-2-methoxy-6-(piperidin-l-yl)benzonitrile (0.07 mmol) and m- tolylboronic acid (0.1 mmol) in 3 mL of CH3CN and 1 mL of water was added PdCl2(PPh3)2 (0.007 mmol) and Na3P03 (0.20 mmol). The mixture was stirred at 70 °C for 12 h, then cooled to RT. The material was filtered and extracted with water and EtOAc, washed with brine, dried over Na2S04, then concentrated in vacuo to provide 2-methoxy-3'-methyl-4-(piperidin-l-yl)- [l , l'-biphenyl]-3-carbonitrile as an oil which was used in Step 4 without further purification. Step 4: The title compound was prepared by Raney Nickel nitrile reduction to the corresponding benzyl amine as a yellow oil.
LCMS (MH+): 311.
Intermediate 103: (6-(azepan-l-yl)-3-chloro-2-phenoxyphenyl)methanamine
Figure imgf000073_0001
Step 1: To a solution of 3-chloro-2,6-difluorobenzonitrile (CAS# 86225-73-2) (1.2 mmol) and homopiperidine (1.4 mmol) in 5 mL of DMF was added K2CO3 (1.7 mmol). The mixture was stirred at 80 °C for 12 h, then cooled to RT. The reaction mixture was then extracted with water and EtOAc, washed with brine, dried over Na2S04, concentrated in vacuo, then purified by prep- TLC to provide 2-(azepan-l-yl)-3-chloro-6-fluorobenzonitrile as a yellow solid.
Step 2: To a solution of phenol (3.9 mmol) in 15 mL of DMF at 0 °C was added NaH (3.9 mmol). Then, 2-(azepan-l-yl)-3-chloro-6-fluorobenzonitrile (2.0 mmol) was added and the reaction mixture warmed to RT, then stirred for 12 h. The reaction mixture was then poured into water and filtered to provide 2-(azepan-l-yl)-3-chloro-6-methoxybenzonitrile as a yellow solid which was used in Step 2 without further purification.
Step 3: The title compound was prepared by Raney Nickel nitrile reduction to the corresponding benzyl amine as a white solid.
LCMS (MH+): 330.
Intermediate 104: (5-phenylbenzo[d] [l,3 dioxol-4-yl)methanamine
Figure imgf000073_0002
Step 1: To a solution of 5-bromobenzo[d][l,3]dioxole-4-carbonitrile (product from step 1,
Intermediate 99) (11.9 mmol) and phenyl boronic acid (13 mmol) in 50 mL of CH3CN and 10 mL of water was added PdCl2(PPh3)2 (0.4 mmol) and Na2C03 (24 mmol). The reaction mixture was heated to 80 °C for 12 h, then cooled to RT. The reaction was filtered and extracted with water and EtOAc, washed with brine, dried over Na2S04, then concentrated in vacuo to provide 5-phenylbenzo[d][l,3]dioxole-4-carbonitrile as an oil which was used in Step 2 without further purification.
Step 2: The title compound was prepared by Raney Nickel nitrile reduction to the corresponding benzyl amine as a yellow solid.
LCMS (MH+): 311.
The following amines shown in Table 10 are useful in preparing specific 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 10. Commercially available or known amines
Figure imgf000074_0001
Figure imgf000075_0001
o -to lylmethanamine 127 89-93-0
NH2
(2- 128 243863-36-7
(difluoromethoxy)phenyl)methanamine
NH2
(2-phenoxyphenyl)methanamine 129 107624-14-6
(2-(piperidin- 1 -yl)phenyl)methanamine 130 72752-54-6
(2-morpholinophenyl)methanamine 131 20407-48-8
(2-(pyrrolidin-l-
132 72752-53-5 yl)phenyl)methanamine
(2-(lH-pyrazol-l-
133 449758-13-8 yl)phenyl)methanamine
(2-(lH-imidazol-l-
134 25373-55-1 yl)phenyl)methanamine
(2-(3 -methyl- 1 H-pyrazo 1- 1 -
135 1006442-61-0 yl)phenyl)methanamine
(2-(lH-l,2,4-triazol-l-
136 449756-97-2 yl)phenyl)methanamine
NH2
(2- 137 943117-99-5
(cyclopentyloxy)phenyl)methanamine
NH2
(2-(( 1 -methylpiperidin-4-
138 870062-44-5 yl)oxy)phenyl)methanamine
(2-(piperazin-l-
139 190017-89-1 yl)phenyl)methanamine
Figure imgf000077_0001
(aminomethyl)phenoxy)acetate
Figure imgf000078_0001
2-(naphthalen-2-yl)ethanamine 162 2017-68-7
Figure imgf000079_0001
yl)phenyl)methanamine
Figure imgf000080_0001
yl)methanamine (4'-chloro-[l, l'-biphenyl]-2-
185 153850-88-5 yl)methanamine
(2'-chloro-[l , r-biphenyl]-2-
186 876170-46-6 yl)methanamine
(4'-methyl-[l , l'-biphenyl]-2-
187 40694-54-0 yl)methanamine
(4'-methoxy-2'-methyl-[ 1 , 1 '-biphenyl]-
188 946726-94-9 2-yl)methanamine
(2-(naphthalen- 1 -
189 1184587-27-6 yl)phenyl)methanamine
(2*,3*-dimethoxy-[ 1 , 1 *-biphenyl]-2-
190 63506-50-3 yl)methanamine
(4'-(trifluoromethyl)-[ 1 , 1 '-biphenyl]-2-
191 771582-31-1 yl)methanamine
(2'-(trifluoromethoxy)-[ 1 , 1 '-biphenyl]-
192 1184022-24-9 2-yl)methanamine
F
(4-(3-
193 864263-10-5 chlorophenoxy)phenyl)methanamine
[1,1 '-biphenyl] -4-ylmethanamine 194 712-76-5 θ :: (2-(thiazol-2-yl)phenyl)methanamine 195 927802-41-3 (3 -(thiazo l-2-yl)p heny l)methanamine 196 672324-88-8
(3 -(thiazo l-4-yl)p heny l)methanamine 197 1083369-01-0
O
2-(2-
(aminomethyl)phenyl)isothiazolidine 198 1016506-51-6
1,1 -dioxide
O T- Naphthalen-2-ylmethanamine 199 2018-90-8
(3 ,4-dimethylphenyl)methanamine 200 102-48-7
(2,5-dimethoxyphenyl)methanamine 201 3275-95-4
(2,3-dichlorophenyl)methanamine 202 39226-95-4
CI
(2,4-dichlorophenyl)methanamine 203 95-00-1
(3,5-dimethoxyphenyl)methanamine 204 20781-20-8
Figure imgf000082_0001
NH2
Οό 2,3-dihydro- 1 H-inden- 1 -amine 205 34698-41-4
(2-chloro-4-fluorophenyl)methanamine 206 15205-11-5
(2,4-dimethoxyphenyl)methanamine 207 20781-20-8
(2,5-dimethylphenyl)methanamine 208 93-48-1 ft (2-chloro-6-
209 57264-46-7 methylphenyl)methanamine
CI
Figure imgf000083_0001
Figure imgf000084_0001
(9H-fluoren-4-yl)methanamine 232 344887-28-1
8-phenyl-l,2,3,4-
233 69381-55-1 tetrahydroisoquino line
YY Mesitylmethanamine 234 40393-99-5
Intermediate A: (S,E)-methyl 3-(4-((amino(methylthio)methylene)carbamoyl)phenyl)-2- ((tert-butoxycarbonyl)amino)propanoate
Figure imgf000085_0001
Step 1: To a mixture of L-tyrosine methyl ester (6 mol) and NaHC03 (13.2 mol) in 13 L of THF/MeOH (3: 1) was added dropwise a solution of (Boc)20 (6.6 mol) in 2L THF at 0 °C. The reaction was warmed to RT and stirred for 12 h. Then the reaction mixture was concentrated in vacuo. The residue was dissolved in water and extracted with EtOAc. The combined organic layers were concentrated in vacuo to afford (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4- hydroxyphenyl) propanoate as white solid which was used in Step 2 without further purification.
Step 2: To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-hydroxyphenyl) (1 mol) in 240 mL of pyridine and 600 mL of CH2C12 was added dropwise Tf20 (1.2 mol) at 0 °C. The reaction was then warmed to RT and stirred for 12 h. Then, the reaction mixture was quenched with 1 N HC1, and the organic layers washed with saturated NaHC03, brine, then dried over NaSC"4 and concentrated in vacuo. The residue was purified by silica gel chromatography (PE/EtOAc = 4:1) to afford (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(((trifluoromethyl) sulfonyl)oxy) phenyl)propanoate as a pale yellow solid. Step 3: To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(((trifluoromethyl) sulfonyl)oxy)phenyl)propanoate (0.79 mol) in 1L of DMF was added Pd(OAc)2 (0.12 mol), dppf (130.8 g, 0.236 mol) and KOAc (3.9 mol). The reaction was charged with CO (g) and heated at 60 °C under 6 atm of CO for 24 h. Then, the reaction mixture was cooled to RT, and saturated NaHC03 was added to adjust the solution to pH > 7. The mixture was stirred for 30 min, washed with CH2C12, then the aqueous layer was acidified with citric acid to pH = 5-6, and filtered to provide (S)-4-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)benzoic acid as a white solid. Step 4: To a solution of (S)-4-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)benzoic acid (0.63 mol) in 3L CH2CI2 was added S-methylisothiouronium sulfate (0.95 mol), EDCI (1.3 mol), HO At (1.3 mol), and DIPEA (2.5 mol). The reaction mixture was stirred for 12 h at RT. Water was then added, and the reaction was extracted with CH2CI2, dried over Na2S04, concentrated in vacuo, and purified by chromatography on silica gel (gradient from CH2CI2 to CH2CI2: MeOH =100: 1) to provide a viscous yellow oil. The oil was washed with Et20 several times to afford the title compound as a pale yellow solid.
Ή NMR (Chloroform-d): δ ppm 1.41 (s, 9H), 2.60 (s, 3H), 3.13 (qd, J = 13.8, 6.1 Hz, 2H), 3.70 (s, 3H), 4.61 (q, J = 6.6 Hz, 1H), 5.00 (d, J = 8.3 Hz, 1H), 7.17 (d, J = 7.9 Hz, 2H), 8.18 (m, 2H) LCMS (MH+): 396
Representative experimental procedure for the preparation of acylguanidines of the invention (depicted as E isomers) Example 130: (S,E)-2-amino-3-(4-((amino((2-(piperidin-l-yl)benzyl)amino)methylene) carbamoyl)phenyl)propanoic acid
Figure imgf000086_0001
Step 1: To a mixture of (S,E)-methyl 3-(4-((amino(methylthio)methylene)carbamoyl)phenyl)-2- ((tert-butoxycarbonyl)amino)propanoate (Intermediate A) (5 mmol) in 10 mL of toluene was added (2-(piperidin-l-yl)phenyl)methanamine (7.6 mmol) followed by triethylamine (15.2 mmol). The mixture was heated to 110 °C for 6 h, then cooled to RT. The reaction mixture was then concentrated in vacuo and purified on ISCO combi- flash (Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: CH3CN Gradient: 5%-95% B in 1.5 min; Flow Rate:
2.0ml/min) to provide (S,E)-methyl 3-(4-((amino((2-(piperidin-l-yl)benzyl)amino)methylene) carbamoyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate as a white solid. Step 2: To a solution of (S,E)-methyl 3-(4-((amino((2-(piperidin-l-yl)benzyl)amino)
methylene)carbamoyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (3.4 mmol) in 50 mL of THF was added a solution of lithium hydroxide (402 mg, 16.8 mmol) in 3 mL water. The mixture was stirred at 50 °C for 6 h, then cooled to RT. The mixture was then filtered and concentrated in vacuo to provide (S,E)-3-(4-((amino((2-(piperidin-l-yl)benzyl)amino)methylene) carbamoyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid as a yellow solid which was used in Step 3 without further purification.
Step 3: To a solution of (S,E)-3-(4-((amino((2-(piperidin-l-yl)benzyl)amino)methylene) carbamoyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (2.87 mmol) in 50 mL of CH2CI2 was added 10 mL of TFA, then the solution was stirred for 6 h at RT. The reaction mixture was concentrated in vacuo and the residue purified by prep-HPLC (Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: CH3CN Gradient: 5%-95% B in 1.5 min; Flow Rate: 2.0 mL/min) to provide the title compound as a white solid.
Table 11.
Figure imgf000087_0001
LCMS
EX# R Name MW
(MH+)
Figure imgf000088_0001
Figure imgf000089_0001
acid
Figure imgf000090_0001
Figure imgf000091_0001
propanoic acid
Figure imgf000092_0001
Figure imgf000093_0001
propanoic acid
Figure imgf000094_0001
acid
Figure imgf000095_0001
Figure imgf000096_0001
ac
Figure imgf000097_0001
(S,E)-2-amino-3-(4-((amino((2-
HN. (piperidin- 1 -yl)-6-(p-
75 to ly lo xy)benzy l)amino)- 529.63 530.3
X r° methylene)carbamoyl)phenyl)- propanoic acid
Ύ (S,E)-2-amino-3-(4-((amino((2- (4-methoxyphenoxy)-6- (piperidin- 1 -yl)benzyl)amino)-
76 545.63 546.3 methylene)carbamoyl)phenyl)- propanoic acid
(S,E)-2-amino-3-(4-((amino((2- (2-methoxyphenoxy)-6-
77 (piperidin- 1 -yl)benzyl) 545.63 546.3 amino)methylene)carbamoyl)- phenyl)propanoic acid
(S,E)-2-amino-3-(4-((amino((2-
HN (piperidin- 1 -yl)-6-(o-
78 to ly lo xy)benzy l)amino)- 529.63 530.3 methylene)carbamoyl)phenyl)- propanoic acid
(S,E)-2-amino-3-(4-((amino((2- (piperidin- 1 -yl)-6-(4- (trifluoromethyl)phenoxy)-
79 583.60 584.3 benzyl)amino)methylene)carba
moyl)-phenyl)propanoic acid
(S,E)-2-amino-3-(4-((amino((2- (3 -methoxyphenoxy)-6- (piperidin-1-
80 545.63 546.3 yl)benzyl)amino)methylene)- carbamoyl)phenyl)propanoic
acid
(S,E)-2-amino-3-(4-((amino((2-
HN (piperidin- 1 -yl)-6-(m-
81 to ly lo xy)benzy l)amino)- 529.63 530.3 methylene)carbamoyl)phenyl)- propanoic acid
(S,E)-2-amino-3-(4-((amino((2-
(piperidin- 1 -yl)-6-(2-
(trifluoromethyl)phenoxy)-
82 583.60 584.3 benzyl)amino)methylene)- carbamoyl)phenyl)propanoic
acid
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
propanoic acid
Figure imgf000102_0001
Figure imgf000103_0001
(S,E)-3-(4-((([ 1 , r-biphenyl]-2- ylamino)(amino)methylene)-
122 carbamoyl)phenyl)-2- 402.45 403.1 aminopropanoic acid
(S,E)-2-amino-3-(4-((amino((2-
HN methoxybenzyl)amino)-
123 methylene)carbamoyl)phenyl)- 370.40 371.1
O propanoic acid
(S,E)-2-amino-3-(4-((amino((2-
HN chlorobenzyl)amino)-
124 methylene)carbamoyl)phenyl)- 374.82 375.1 propanoic acid
(S,E)-2-amino-3-(4-((amino((2- (trifluoromethyl)benzyl)-
125 amino)methylene)carbamoyl)- 408.37 409.2 phenyl)propanoic acid y /TVCI (S,E)-2-amino-3-(4-
((amino((bis(4-chlorophenyl)- methyl)amino)methylene)-
126 carbamoyl)phenyl)propanoic 485.36 485.1 acid
CI
(S,E)-2-amino-3-(4-((amino((2- methylbenzyl)amino)-
127 354.40 355.2 methylene)carbamoyl)phenyl)- propanoic acid
(S,E)-2-amino-3-(4-((amino((2-
HN (difluoromethoxy)benzyl)-
128 amino)methylene)carbamoyl)- 406.38 407.1 phenyl)propanoic acid
(S,E)-2-amino-3-(4-((amino((2-
HN phenoxybenzyl)amino)-
129 methylene)carbamoyl)phenyl)- 432.47 433.3 propanoic acid
Figure imgf000105_0001
Figure imgf000106_0001
acid
Figure imgf000107_0001
Figure imgf000108_0001
^^^^^^^ yl)methyl)amino)methylene)-
Figure imgf000109_0001
acid
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
acid
Figure imgf000118_0001
enyl)propanoic acid NMR Data for Compounds of Table 11
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Example 117: (S,E)-2-amino-3-(4-(((((4 '-methyl- [1,1 '-biphenyl] -4-yl)methyl)amino) (methylamino)methylene)carbamoyl)phenyl)propanoic acid
Figure imgf000136_0002
Step 1: To a solution of (S)-4-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)benzoic acid [product of step 3, Intermediate A] (1 mmol) in 50 mL of CH2CI2 was added dropwise EDCI (1.5 mmol) and HOAt (1.5 mmol) at 0 °C. After 10 min, methyl
methylcarbamimidothioate (1 mmol) was added and the reaction was stirred at RT for 6 h. Then the reaction was concentrated in vacuo, and purified on normal phase silica gel to provide (S,E)- methyl 2-((tert-butoxycarbonyl)amino)-3 -(4-(((methylamino)(methylthio)
methylene)carbamoyl)phenyl)propanoate as a yellow solid.
Step 2: To a mixture of (S,E)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4- (((methylamino)(methylthio)methylene)carbamoyl)phenyl)propanoate (5 mmol) in 10 mL of toluene was added (4'-methyl-[l, -biphenyl]-4-yl)methanamine (7.6 mmol) followed by triethylamine (15.2 mmol). The mixture was heated to 110 °C for 6 h, then cooled to RT. The reaction mixture was then concentrated in vacuo and purified on I SCO combi- flash (Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: CH3CN Gradient: 5%-95% B in 1.5 min; Flow Rate: 2.0mL/min) to provide (S,E)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4- (((((4'-methyl-[ 1 , 1 '-biphenyl]-4 yl)methyl)amino)(methylamino) methylene)carbamoyl) phenyl) propanoate as a white solid.
Step 3: To a solution of (S,E)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(((((4'-methyl-[l, - biphenyl]-4-yl)methyl)amino)(methylamino)methylene)carbamoyl)phenyl)propanoate (3.4 mmol) in 50 mL of THF was added a solution of lithium hydroxide (402 mg, 16.8 mmol) in 3 mL water. The mixture was stirred at 50 °C for 6 h, then cooled to RT. The mixture was then filtered and concentrated in vacuo to (S,E)-2-((tert-butoxycarbonyl)amino)-3-(4-(((((4'-methyl- [1,1 '-biphenyl]-4-yl)methyl)amino)(methylam acid as a yellow solid which was used in Step 3 without further purification. Step 4: To a solution of (S,E)-2-((tert-butoxycarbonyl)amino)-3-(4-(((((4'-methyl-[l, - biphenyl]-4-yl)methyl)amino)(methylamino)methylene)carbamoyl)phenyl)propanoic acid (2.9 mmol) in 50 mL of CH2CI2 was added 10 mL of TFA, then the solution was stirred for 6 h at RT. The reaction mixture was concentrated in vacuo and the residue purified by prep-HPLC (Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: CH3CN Gradient: 5%-95% B in 1.5 min; Flow Rate: 2.0 mL/min) to provide the title compound as a white solid.
1H-NMR (400 MHz, DMSO-d6): δ ppm 10.11-10.53 (m, 1H), 7.99 (s, 2H), 7.61 (s, 2H), 7.54 (d, 2H, J = 7 Hz), 7.44 (d, 2H, J = 7.5 Hz), 7.26 (d, 4H, J = 7.5 Hz), 4.49-4.68 (m, 2H), 3.39 (s, 1H), 3.18 (d, 1H), 2.84-2.91 (q, 4H, J = 9.5 Hz), 2.34 (s, 3H).
LCMS (MH+): 445.
The compounds shown in Table 12 can be made as described above starting with the appropriate amine.
Table 12.
Figure imgf000137_0001
(S,E)-3-(4-(((([l,r-biphenyl]-3-
HN ylmethyl)amino)(methylamino)
methylene)carbamoyl)phenyl)- 430
121 2-aminopropanoic acid 431
Figure imgf000138_0002
Method 1 for the preparation of ester prodrugs: Example 238: (S,E)-ethyl 2-amino-3-(4-((amino((2-(azepan-l-yl)-6- methoxybenzyl)amino)methylene)carbamoyl)phenyl)propanoate
To a solution of (S,E)-2-amino-3-(4-((amino((2-(azepan-l-yl)-6- methoxybenzyl)amino)methylene)carbamoyl)phenyl)propanoic acid (0.11 mmol) in 5 mL of ethanol at 0 °C was added dropwise SOCb (0.44 mmol). The reaction mixture was stirred at RT for 12 h, then cooled to RT and concentrated in vacuo to provide the title compound as a yellow solid.
The compounds shown in Table 13 can be made using Method 1 described above starting with the appropriate propanoic acid.
Table 13.
Figure imgf000138_0001
Figure imgf000138_0003
Figure imgf000139_0001
pivalate (2S)-ethyl 2-amino-3-(4-((E)-
HN (amino((2-(2-methylpiperidin-
1 -yl)-6-(4-(trifluoromethyl)- 43 Et 625.68 626.7 phenoxy)benzyl)amino)- methylene)carbamoyl)phenyl)
F
propanoate
(2S)-ethyl 2-amino-3-(4-((E)-
H >N (amino((2-methoxy-6-(2- 44 Et methylpiperidin- 1 - 495.61 496.8 yl)benzyl)amino)methylene)c
arbamoyl)phenyl)propanoate
(S,E)-ethyl 2-amino-3-(4- ((amino((2-(piperidin- 1 -yl)-6- 45 Et (m-tolyloxy)benzyl)- 557.68 558.5 amino)methylene)carbamoyl)
phenyl)propanoate
(S,E)-ethyl 2-amino-3-(4-
P HN . ((amino((2-(azepan- 1 -yl)-6- 46 Et (trifluoromethyl)benzyl)- 533.59 534.5 amino)methylene)carbamoyl)
phenyl)propanoate
(S,E)-ethyl 2-amino-3-(4- ((amino((2-(2-
CI
chlorophenoxy)-6-(piperidin- 47 Et 578.10 578.6
1 -yl)benzyl)amino)- methylene)carbamoyl)phenyl)
propanoate
(S,E)-ethyl 2-amino-3-(4- ((amino((2-(azepan- 1 -yl)-6- 48 Et •4r (difluoromethyl)benzyl)- 515.60 516.5 amino)methylene)carbamoyl)
phenyl)propanoate
NMR Data for Compounds of Table 13
Figure imgf000140_0001
IH NMR (400 MHz, DMSO-d6 + D20-d2): δ ppm 7.98-7.92 (d, J = 8.2 Hz, 2H), 7.52-7.38 (m, 4H), 7.35-7.29 (d, J = 8.0 Hz, IH), 7.26-7.19 (t, J = 7.5 Hz, IH),
237 4.61 (s, 2H), 4.35-4.26 (dq, J = 10.0, 5.0, 3.9 Hz, IH), 4.19-4.05 (m, 2H), 3.31- 3.23 (m, IH), 3.22- 3.14 (m, IH), 2.93- 2.87 (t, J = 5.0 Hz, 4H), 1.77-1.69 (p, J = 5.3 Hz, 4H), 1.62-1.53 (dd, J = 11.5, 5.9 Hz, 2H), 1.16-1.06 (m, 3H)
IH NMR (400 MHz, DMSO-d6+D20): δ ppm 7.92- 8.09 (m, 2H), 7.15-7.29 (m, H), 6.77-6.87 (m, 2H), 4.66 (brs, IH), 4.32 (brs, IH), 4.00-4.02 (d, J = 6.5 Hz,
238
2H), 3.82 (s, 3H), 3.60-3.61 (m, IH), 3.02-3.04 (m, 4H), 2.85-2.86 (m, 2H), 1.59- 1.72 (m, 8H), 1.08-1.10 (m, 3H)
IH NMR (400 MHz, DMSO-d6 + D20): δ ppm 7.88-8.01 (m, 2H), 7.37-7.38 (m, 2H), 7.25-7.28 (m, IH), 7.13-7.15 (m, 3H), 7.02- 7.03 (d, J = 6.5 Hz, IH), 6.96-
239 6.98 (d, J = 7.0 Hz, IH), 6.53-6.55 (d, J = 7.5 Hz, IH), 4.68 (brs, IH), 4.34 (brs,
IH), 3.95-3.99 (m, 2H), 3.53 (m, IH), 2.84 (m, 6H), 1.45-1.70 (m, H), 1.04-1.07 (t, J = 7.0 Hz, 3H)
IH NMR (400 MHz, CDC13): δ ppm 8.13 (d, 2H, J = 6.9), 7.41-7.32 (m, 2H), 7.30-7.19 (m, 3H), 7.19-7.13 (m, IH), 7.11-7.03 (m, 2H), 6.91 (d, IH, J = 8.0),
240
6.63 (d, IH, J = 8.2), 5.14-4.74 (m, IH), 4.45 (s, 2H), 3.73-3.62 (m, IH), 3.20 - 2.74 (m, 6H), 1.94-1.68 (m, 6H), 1.20 (dd, 6H, J = 16.9, 6.3)
IH NMR (400 MHz, CDCI3): δ ppm 8.04 (d, 2H, J = 7.7 Hz), 7.40-7.31 (m, 2H), 7.24-7.18 (m, 3H), 7.18-7.11 (m, IH), 7.05 (d, 2H, J = 8.1), 6.90 (d, IH, J = 8.1),
241
6.62 (d, IH, J = 8.2), 5.25-5.04 (m, IH), 4.42 (s, 2H), 3.67-3.64 (m, IH), 3.14- 2.75 (m, 6H), 1.89-1.74 (m, 6H), 1.71-1.50 (m, 8H)
IH NMR (400 MHz, CDCI3): δ ppm 8.04 (d, J = 7.1 Hz, 2H), 7.35 (t, J = 7.9 Hz, 2H), 7.12 - 7.21 (m, 4H), 7.05 (d, J = 8.1 Hz, 2H), 6.93- 6.77 (m, IH), 6.61 (d, J =
242
8.2 Hz, 2H), 4.40 (s, 2H), 3.83-3.63 (m, IH), 3.14-2.70 (m, 6H), 1.86-1.70 (m, 6H), 1.44 (dd, J = 30.8, 5.4 Hz, 3H), 1.19 (d, J = 3.8 Hz, 9H)
1H-NMR (400 MHz, CDCI3): δ ppm 8.11 (d, 2H, J = 4.0), 7.61 (d, 2H, J = 8.0), 7.25-7.32 (m, 4H), 7.16 (d, 2H, J = 8.0), 7.01 (br, IH), 6.72 (d, IH), 4.49 (d, IH),
243 4.38 (d, lH), 4.15 (q, 2H, J = 8.0), 3.71 (dd, IH, J = 5.6, 8.0), 3.10 (dd, IH, J =
5.2, 13.2), 3.10 (br, IH), 2.89 (dd, IH, J = 7.6, 13.6), 2.71-2.74 (m, IH), 1.53-2.04 (m, 8H), 1.23 (t, 3H, J = 8.0), 0.98 (d, 3H, J = 8.0)
1H-NMR (400 MHz, DMSO-d6): δ ppm 9.84 (s, IH), 7.90-8.14 (m, 2H), 7.13- 7.31 (m, 4H), 6.84-6.88 (m, 2H), 4.24-4.42 (m, IH), 3.97-4.01 (q, 2H), 3.58-3.64
244
(m, IH), 3.82 (s, 3H), 2.81- 2.97 (m, 6H), 1.53-1.79 (m, 4H), 1.33-1.39 (m,2H), 1.05-1.08 (t, 3H), 0.71-0.78 (m, 3H)
IH NMR (400 MHz, CDCI3): δ ppm 8.22 (d, 2H, J = 8.2), 7.38 (d, 2H, J = 8.2), 7.19 -7.16 (m, 2 H), 6.92 (d, IH, J = 8.0), 6.86 - 6.81 (m, 3H), 6.60 (d, IH, J =
245 8.4), 4.45 (d, 2H, J = 6.2), 4.12 (q, 2H, J = 7.0), 3.87 (t, IH, J = 7.6), 3.21-3.16 (m,
IH), 3.08-3.04 (m, 2H), 2.95-2.88 (m, 4H), 2.27 (s, 3H), 1.80-1.75 (m, 6H), 1.18 (t, 3H, J = 246= 7.1)
IH NMR (400 MHz, CDCI3): δ ppm 8.07 (d, 2H, J = 8.0), 7.47 (m, 2H), 7.42(t, IH, J = 8.0), 7.19 (d, 2H, J = 8.2), 4.64 (s, 2H), 4.14 (q, 2H, J = 7.2), 3.71 (t, IH, J
246
= 7.8), 3.09-3.12 (m, 4H), 3.07-3.08 (d, IH), 2.85-2.90 (q, IH, J = 7.8), 1.86 (s, 4H), 1.78 (s, 4H), 1.19-1.23 (t, 3H, J = 7.2)
IH NMR (400 MHz, CDCI3): δ ppm 8.03 (d, 2H, J = 7.8), 7.42 (dd, IH, J = 1.5,
247
8.0), 7.21-7.15 (m, 3 H), 7.13-7.07 (m, 2H), 7.03 (d, IH, J = 7.8), 6.83 (d, IH, J =
Figure imgf000142_0001
Method 2 for the preparation of ester prodrugs:
Example 249: l-(((S)-2-amino-3-(4-((E)-(amino((2-phenoxy-6-(piperidin-l- yl)benzyl)amino)methylene)carbamoyl)phenyl)propanoyl)oxy)ethyl pivalate
Figure imgf000142_0002
Step 1: (S,E)-3-(4-((amino((2-phenoxy-6-(piperidin-l- yl)benzyl)amino)methylene)carbamoyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (1.07 g, 6.50 mmol), 1-chloroethyl pivalate (1.0 g, 1.62 mmol), and K2CO3 (336 mg, 2.44 mmol) were stirred in dimethylacetamide (5.0 mL) in a sealed tube at 40 °C for 18 h. Water was then added, and the reaction was extracted with EtOAc, washed with brine, then dried over Na2S04, concentrated in vacuo, then purified by chromatography on silica gel to provide l-(((S)-3-(4- ((E)-(amino((2-phenoxy-6-(piperidin-l-yl)benzyl)amino)methylene)carbamoyl)phenyl)-2-((tert- butoxycarbonyl)amino)propanoyl)oxy)ethyl pivalate.
Step 2: TFA (2.0 mL) was added dropwise to a solution of l-(((S)-3-(4-((E)-(amino((2-phenoxy-
6- (piperidin-l-yl)benzyl)amino)methylene)carbamoyl)phenyl)-2-((tert- butoxycarbonyl)amino)propanoyl)oxy)ethyl pivalate (990 mg, 1.33 mmol) in CH2CI2 (5.0 mL), at 0 °C. The mixture was stirred at RT completion of the reaction (about 2 h as measured by TLC). The reaction mixture was neutralized with saturated aqueous solution of NaHC03 to pH
7- 8. The aqueous layer was extracted with CH2CI2, washed with brine, dried over Na2S04, filtered, then concentrated in vacuo. The residue was purified by HPLC to afford the title compound as white solid.
1H NMR (400 MHz, CDC13) δ ppm: 8.04 (d, J = 7.1 Hz, 2H), 7.35 (t, J = 7.9 Hz, 2H), 7.12 - 7.21 (m,4H), 7.05 (d, J = 8.1 Hz, 2H), 6.93 - 6.77 (m, 1H), 6.61 (d, J = 8.2 Hz, 2H), 4.40 (s, 2H), 3.83 - 3.63 (m, 1H), 3.14 - 2.70 (m, 6H), 1.86 - 1.70 (m, 6H), 1.44 (dd, J = 30.8, 5.4 Hz, 3H), 1.19 (d, J = 3.8 Hz, 9H). LCMS (MH+): 644.
Example A: In vitro Inhibition Assays:
TPHl and TPH2 Assays
Recombinant human TPHl (rTPHl GenBank TM accession no. NP 004179) was expressed by cloning full length human TPHl cDNA in to a bacterial pMAL-c5E expression vector to produce maltose-binding protein (MBP) TPHl 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 TPHl (MBP- TPH1) was used directly to screen compounds as described below. Recombinant human TPH2 (rTPH2 GenBank TM accession no. 173353), PheOH (rPheOH GenBank TM accession no. K03020) and TH (rTH GenBank TM accession no. L20679) with an MBP tag were produced similarly.
TPHl 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 μΕ aliquots at lOOx final concentration. Fifty microliters of assay buffer containing 30 nM TPHl 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
Figure imgf000143_0001
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 TPHl 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 that inhibit TPHl with an less than 10,000 nM are considered active. Data for certain compounds of the invention are provided below in Table 14. Data for each of the compounds in Table 14 had measurable IC50's. Compounds that inhibited TPHl with an of 3,000 nM to 10,000 nM are indicated by +. Compounds that inhibited TPHl with an from 300 nM up to 3,000 nM are indicated by ++. Compounds that inhibited TPHl with an from 50 nM up to 300 nM are indicated by +++. Compounds that inhibited TPHl with an less than 50 nM are indicated by ++++.
Table 14. TPHl Inhibitory Activity
Figure imgf000144_0001
97 177
98 178
99 179
100 180
101 181
102 182
103 183
104 184
105 185
186
107 187
108 188
109 189
110 190
111 191
112 192
113 193
114 194
115 195
116 196
117 197a 118 198b 119 199
120 200
121 201
122 202
123 203
124 204
125 205
126 206
127 207
128 208
129 209
130 210
131 211
132 212
133 213
134 214
135 215
136 216
137 217
138 218
139 219
140 220
141 221 62 ++++ 142 ++ 222 ++
63 1 143 1 223 1 1
64 1 1 144 + 224
65 1 1 145 + 225 1
66 1 146 1 226
67 1 1 147 1 227 1 1
68 1 1 148 1 1 228 1
69 1 1 149 ++ 229 1
70 1 1 150 ++ 230 1 1
71 1 151 ++ 231
72 1 1 152 1 232 1
73 ++ 153 +++ 234 +++
74 ++++ 154 +++
75 ++++ 155 ++
76 ++++ 156 +++
77 ++++ 157 ++++
78 ++++ 158 +++
79 ++++ 159 +++
Example B: Intestinal 5-HT depletion assay
The efficacy of the TPH1 inhibitors of the invention was assessed for the ability to decrease intestinal serotonin concentration in mice. Mice (C57 BL6) were administered a single 150 mg/kg dose of test article by oral gavage. Each animal was euthanized by exsanguination under isoflurane anesthesia. Jejunal intestinal mucosa was isolated and homogenized in 300 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 were measured by HPLC. The remaining mucosal pellet was 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 were carried out with protocols approved by the Institutional Animal Care and Use Committee.
The Examples listed in Table 15 below were tested and found to elicit a reduction in mean mucosal 5-HT concentrations relative to vehicle-treated animals according to the above- described in vivo assay. P-values, indicating statistical significance of the data (ANOVA) are provided in the table: * indicates P<0.05, ** indicates P<0.01, *** indicates P<0.005, and **** indicates P<0.0005.
Table 15. In Vivo Efficacy of TPH1 Inhibitors In Mice (reduction of mucosal 5-HT concentrations one day after oral administration of a single 150 mg/kg dose)
Figure imgf000147_0001
Example C: 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 D: 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 E: In vivo assay for PAH
The utility of the compounds of the invention for the treatment 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 F: 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. in Am. J. Respir. Crit. Care Med. 187, 476-485 (2013).
Example G: 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 H: 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 I: 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 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. Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patent, patent applications, and publications, cited in the present application is incorporated herein by reference in its entirety.

Claims

What is claimed is:
1. A compound of Formula I:
Figure imgf000150_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;
R1 is H, Ci-io alkyl, C3-10 cycloalkyl, phenyl, -(CR10Rn)POC(O)R12, -(CR10Rn)PNR13R14 , or -(CR10Rn)pC(O)NR13R14, wherein said C1-10 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 C halo alkyl;
R2 is H, CM alkyl, C(0)Rb, C(0)NRcRd, or C(0)ORa;
R3 and R4 are each independently selected from H, C alkyl, C haloalkyl, OH, and C alkoxy;
R5 at each occurrence is independently selected from halo, C alkyl, and C alkoxy; R6 is H, CM alkyl, C(0)Rbl, C(0)NRclRdl, or C(0)ORal;
R7 is H or CM alkyl;
R8 at each occurrence is independently selected from H, halo, and CM alkyl;
R9 at each occurrence is independently selected from H, halo, CM alkyl, C2-6 alkenyl, C2-6 alkynyl, CM haloalkyl, C6-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO2, 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 CM 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, CM alkyl, C2-6 alkenyl, C2-6 alkynyl, CM 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;
R10 and R1 1 are each independently selected from H and
Figure imgf000151_0001
alkyl;
R12 is Ci-6 alkyl optionally substituted by 1 , 2 or 3 substituents independently selected from Ci-6 haloalkyl, C3-10 cycloalkyl, ORa3, and NRc3Rd3;
R13 and R14 are each independently selected from H and Ci-6 alkyl;
RA is H, Cy1, halo, Ci_6 alkyl, C2-e alkenyl, CN, N02, ORa4, SRa4, C(0)Rb4, C(0)NRc4Rd4, C(0)ORa4, OC(0)Rb4, OC(0)NRc4Rd4, NRc4Rd4, NRc4C(0)Rb4, NRc4C(0)ORa4,
NRc4C(0)NRc4Rd4, NRc4S(0)Rb4, NRc4S(0)2Rb4, NRc4S(0)2NRc4Rd4, S(0)Rb4, S(0)NRc4Rd4, S(0)2Rb4, or S(0)2NRc4Rd4, wherein said Ci-6 alkyl and C2-6 alkenyl are each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from 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)Rb4, OC(0)NRc4Rd4, NRc4Rd4, NRc4C(0)Rb4, NRc4C(0)ORa4, NRc4C(0)NRc4Rd4, NRc4S(0)Rb4, NRc4S(0)2Rb4, NRc4S(0)2NRc4Rd4, S(0)Rb4, S(0)NRc4Rd4, S(0)2Rb4, and S(0)2NRc4Rd4;
RB is H, 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, or S(0)2NRc5Rd5, wherein said Ci-6 alkyl and C2-6 alkenyl are each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from Cy2, halo, Ci-6 alkyl, C2- 6 alkenyl, Ci_6 haloalkyl, CN, N02, 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, 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 and C2-6 alkenyl are each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from C6-io aryl, C3-10 cycloalkyl, 5- 10 membered heteroaryl, 4-10 membered
heterocycloalkyl, halo, Ci_6 alkyl, C2-e 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;
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 RCy 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)-Ci_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,
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-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 Ra, Ral, Rb, Rbl, Rc , Rcl, Rd, and Rdl is independently selected from H, Ci_6 alkyl, Ci-4 haloalkyl, C6-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered hetero cyclo alkyl;
or Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6-, or 7- membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents
independently selected from halo, Ci-6 alkyl, and Ci-6 haloalkyl;
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, C haloalkyl, C2-e alkenyl, C6-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C6-io aryl-Ci-4 alkyl, C3-10 cyclo alkyl-C 1-4 alkyl, (5-10 membered heteroaryl)-Ci_ 4 alkyl, or (4-10 membered heterocycloalkyl)-Ci-4 alkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, C6- 10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-io aryl- C1-4 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 C 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;
or any of the following pairs of substituents: Rc2 and Rd2; Rc3 and Rd3; Rc4 and Rd4; Rc5 and Rd5; Rc6 and Rd6; and Rc7 and Rd7, together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered
heterocycloalkyl, C6-io aryl, 5-6 membered heteroaryl, halo, CN, ORa8, SRa8, 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, wherein said Ci_6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa8, SRa8, 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, CM alkyl, CM alkoxy, CM alkylthio, CM alkylamino, and di(Ci_4 alkyl) amino;
or any Rc8 and Rd8 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 OH, CN, amino, halo, CM alkyl, CM alkoxy, CM alkylthio, CM alkylamino, and di(Ci_4 alkyl)amino; p is 1, 2, or 3;
n is 0, 1, 2, 3, or 4; and
m is 0, 1, 2, or 3.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is H, Ci-io alkyl, C3-10 cycloalkyl, or -(CR10Rn)POC(O)R12.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is H or Ci-10 alkyl.
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is Ci-10 alkyl.
5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is H.
6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R2 is H.
7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 are both H.
8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R6 is H.
9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R7 is H.
10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R8 is H.
1 1. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R9 is H, Ci_6 alkyl, or phenyl, wherein said phenyl is optionally substituted with 1 , 2, or 3 halo.
12. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R9 is H.
13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein n is 0.
14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein m is 0.
15. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein m is 1.
16. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein m is 2.
17. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein m is 3.
18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein Ring A is C6-io aryl or 5 to 10-membered heteroaryl.
19. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, naphthalenyl, benzo[d][l ,3]dioxol-4-yl, 2,3- dihydrobenzo[b][l ,4]dioxin-5-yl, 2,3-dihydro-lH-inden-l-yl, or 9H-fluoren-4-yl.
20. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl.
21. The compound of any one of claims 1 to 5, 10 to 12, 14 to 17, and 18 to 20 having Formula II:
Figure imgf000156_0001
II
or a pharmaceutically acceptable salt thereof.
The compound of any one of claims 1 to 5, 14 to 17, and 18 to 20 having Formula III
Figure imgf000156_0002
III
or a pharmaceutically acceptable salt thereof.
The compound of any one of claims 1 to 5, 14 to 17, and 18 to 20 having Formula IV
Figure imgf000156_0003
IV or a pharmaceutically acceptable salt thereof.
The compound of any one of claims 1 to 5 having Formula V
Figure imgf000157_0001
V
or a pharmaceutically acceptable salt thereof.
25. The compound of claim 1 selected from:
(S,E)-3-(4-((((2-(lH-l,2,3-triazol-l-yl)benzyl)amino) (amino)methylene)carbamoyl)- phenyl)-2-aminopropanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(4-methyl- lH-imidazol- 1 -yl)benzyl)amino)
methylene)carbamoyl)phenyl)-propanoic acid;
(S)-3-(4-((E)-(((2-((3s,5s,7s)-adamantan- 1 -yloxy)benzyl) amino)(amino)methylene)- carbamoyl)phenyl)-2-aminopropanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(piperidin-4-yloxy)benzyl) amino)methylene)carbamoyl)- phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-chloro-6-(piperidin-l-yl)benzyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-((E)-(amino((2-(3-phenylpiperidin-l-yl)benzyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3 -(4-((amino((2-(4-(pyrrolidin- 1 -yl)piperidin- 1 - yl)benzyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(4-(2-hydroxyethyl)piperidin- 1 - yl)benzyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(azetidin-l-yl)benzyl)amino)methylene)- carbamoyl)phenyl)propanoic acid; (2S)-3-(4-((E)-(((2-(3-azabicyclo[3.1.0]hexan-3- yl)benzyl)amino)(amino)methylene)carbamoyl)phenyl)-2-aminopropanoic acid;
(S)-3-(4-((E)-(((2-((lR,5S)-8-azabicyclo[3.2.1]octan-8- yl)benzyl)amino)(amino)methylene)carbamoyl)phenyl)-2-aminopropanoic acid;
(S)-2-amino-3-(4-((E)-(amino((2-((R)-pyrrolidin-3- yloxy)benzyl)amino)methylene)carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(6-methoxy-2-methylpyridin-3-yl)benzyl) amino)methylene)carbamoyl)-phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(6-(dimethylamino)-4-methylpyridin-3- yl)benzyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(2-methylpyridin-3-yl)benzyl)amino)methylene) carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(6-(trifluoromethyl)pyridin-3- yl)benzyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino(((2,-chloro-4,-fluoro-[l,r-biphenyl]-2- yl)methyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino(((2*-ethyl-[ 1 , 1 *-biphenyl]-2-yl)methyl)
amino)methylene)carbamoyl)-phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino(((2'-isopropyl-[ 1 , 1 '-biphenyl]-2- yl)methyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((3-(oxazol-4-yl)benzyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino(((3'-(piperidin-l -ylmethyl)-[ 1 , 1 '-biphenyl]-4- yl)methyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S ,E)-2-amino -3 -(4-((amino((4-methoxy-2-(piperidin- 1 -yl)benzyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((5-bromo-2-(piperidin-l-yl)benzyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino(((3-(piperidin-l-yl)-[l, -biphenyl]-2-yl)methyl)amm^ methylene)carbamoyl)phenyl)-propanoic acid; (S,E)-2-amino-3-(4-((amino((2-chloro-6-(3-methyl-lH-pyrazol-l-yl)benzyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(cyclopentyloxy)-6-methoxybenzyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(cyclopentyloxy)-6- fluorobenzyl)amino)methylene)carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-fluoro-6-(2H-l,2,3-triazol-2- yl)benzyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2,6-di(2H-l,2,3-triazol-2-yl)benzyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(piperidin-l-yl)-6- (trifluoromethyl)benzyl)amino)methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(4-methoxypiperidin-l-yl)-6- (trifluoromethyl)benzyl)amino)methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(4-hydroxypiperidin-l-yl)-6- (trifluoromethyl)benzyl)amino)methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(pyrrolidin-l-yl)-6- (trifluoromethyl)benzyl)amino)methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-methyl-6-(piperidin- 1 -yl)benzyl)
amino)methylene)carbamoyl)-phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-ethyl-6-(piperidin-l-yl)benzyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-isopropyl-6-(piperidin-l-yl)benzyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(azepan-l-yl)-6- (trifluoromethyl)benzyl)amino)methylene)carbamoyl)phenyl)-propanoic acid;
(2S)-2-amino-3-(4-((E)-(amino((2-chloro-6-(3-hydroxypyrrolidin-l- yl)benzyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-fluoro-6-(lH-pyrazol-l-yl)benzyl)amino)methylene)- carbamoyl)phenyl)propanoic acid; (S,E)-2-amino-3-(4-((amino((2-fluoro-6- orpholinobenzyl)amino)methylene)carbamoyl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-((E)-(amino((2-(3-hydro
benzyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(4-hydroxypiperidin-l-yl)-6-methoxybenzyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-methoxy-6-(4-methoxypiperidin-l-yl)benzyl)- amino)methylene)carbamoyl)-phenyl)propanoic acid;
(2S)-2-amino-3-(4-((E)-(amino((2-(3-hydroxypyrrolidin-l-yl)-6-methoxybenzyl)- amino)methylene)carbamoyl)-phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-methoxy-6-(pyrrolidin-l-yl)benzyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(azepan-l-yl)-6-methoxybenzyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-ethoxy-6-(piperidin-l-yl)benzyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(2S)-2-amino-3 -(4-((E)-(amino((2-methoxy-6-(2-methylazepan- 1 - yl)benzyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((5-methyl-2-(piperidin-l-yl)benzyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S ,E)-2-amino -3 -(4-((amino((5 -methoxy-2-(piperidin- 1 -yl)benzyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S ,E)-2-amino-3 -(4-((amino((5 -ethyl-2-(piperidin- 1 -yl)benzyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((5-isopropyl-2-(piperidin-l-yl)benzyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((3-chloro-2-(piperidin-l-yl)benzyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((3-methyl-2-(piperidin-l-yl)benzyl)amino)methylene)- carbamoyl)phenyl)propanoic acid; (S ,E)-2-amino -3 -(4-((amino((3 -methoxy-2-(piperidin- 1 -yl)benzyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(azepan-l-yl)-3-methoxybenzyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino(((6-methoxy-[ 1 , 1 '-biphenyl]-2-yl)methyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino(((4-(piperidin-l -yl)-[ 1 , 1 '-biphenyl]-3- yl)methyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino(((4-(azepan- 1 -yl)-[ 1 , 1 '-biphenyl]-3- yl)methyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(piperidin-l-yl)-5-(thiazol-2- yl)benzyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino(((3-phenoxy-[ 1 , 1 '-biphenyl]-2-yl)methyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-((E)-(amino(((2'-chloro-6-methoxy-[ 1 , 1 '-biphenyl]-2- yl)methyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino(((2'-chloro-3-methoxy-[ 1 , 1 '-biphenyl]-2- yl)methyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-methoxy-6-(2-methylpyridin-3- yl)benzyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino(((3-methoxy-[ 1 , 1 '-biphenyl]-2-yl)methyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino(((2'-chloro-3-phenoxy-[ 1 , 1 '-biphenyl]-2- yl)methyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino(((3-ethoxy-[ 1 , 1 '-biphenyl]-2-yl)methyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino(((3-isopropoxy-[ 1 , 1 '-biphenyl]-2- yl)methyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(2S)-2-amino-3 -(4-((E)-(amino((2-methoxy-6-(2-methylpiperidin- 1 - yl)benzyl)amino)methylene)-carbamoyl)phenyl)propanoic acid; (S,E)-2-amino-3-(4-((amino((2-isopropoxy-6-(piperidin-l-yl)benzyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(cyclohexyloxy)-6-(piperidin-l- yl)benzyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-cyclobutoxy-6-(piperidin-l-yl)benzyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(azepan-l-yl)-6-((tetrahydro-2H-pyran-4-yl)oxy)benzyl)- amino)methylene)carbamoyl)-phenyl)propanoic acid;
(S,E)-2-amino-3 -(4-((amino((2-(azepan- 1 -yl)-6-(( 1 -methylpiperidin-4- yl)oxy)benzyl)amino)-methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-phenoxy-6-(piperidin-l-yl)benzyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(piperidin-l-yl)-6-(p-tolyloxy)benzyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(4-methoxyphenoxy)-6-(piperidin-l-yl)benzyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(2-methoxyphenoxy)-6-(piperidin-l-yl)benzyl) amino)methylene)carbamoyl)-phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(piperidin-l-yl)-6-(o-tolyloxy)benzyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(piperidin-l-yl)-6-(4-(trifluoromethyl)phenoxy)- benzyl)amino)methylene)carbamoyl)-phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(3-methoxyphenoxy)-6-(piperidin-l- yl)benzyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(piperidin-l-yl)-6-(m-tolyloxy)benzyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(piperidin-l-yl)-6-(2-(trifluoromethyl)phenoxy)- benzyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(piperidin-l-yl)-6-(3-(trifluoromethyl)phenoxy)- benzyl)amino)methylene)-carbamoyl)phenyl)propanoic acid; (S,E)-2-amino-3-(4-((amino((2-(azepan-l-yl)-6-phenoxybenzyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(4-chlorophenoxy)-6-(piperidin-l-yl)benzyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(2-chlorophenoxy)-6-(piperidin-l-yl)benzyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(3-chlorophenoxy)-6-(piperidin-l-yl)benzyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(azepan-l-yl)-6-(4-(trifluoromethoxy)phenoxy)- benzyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(azepan-l-yl)-6-(2-(trifluoromethoxy)phenoxy)- benzyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(azepan-l-yl)-6-(4-(2-methoxyethoxy)phenoxy)- benzyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(azepan-l-yl)-6-(2-(2-methoxyethoxy)phenoxy)- benzyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(azepan-l-yl)-6-(2-(tert-butyl)-phenoxy)benzyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(2S)-2-amino-3-(4-((E)-(amino(((l-methyl-2-oxo-4-phenylpiperidin-3- yl)methyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((( 1 -methyl-2-oxo-4-phenyl- 1 ,2-dihydropyridin-3- yl)methyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-chloro-3-methyl-6-(piperidin- 1 - yl)benzyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-chloro-3-methoxy-6-(piperidin-l-yl)benzyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino((2,3-dichloro-6-(piperidin-l-yl)benzyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-chloro-6-(piperidin-l-yl)-3- (trifluoromethyl)benzyl)amino)methylene)carbamoyl)phenyl)-propanoic acid; (S,E)-2-amino-3-(4-((amino(((5-(piperidin-l-yl)benzo[d][l,3]dioxol-4- yl)methyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino(((6-(azepan-l-yl)-2,3-dihydrobenzo[b][l,4]dioxin-5- yl)methyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(azepan-l-yl)-3-chloro-6-methoxybenzyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino(((2-methoxy-3 '-methyl-4-(piperidin- 1 -yl)-[ 1 , 1 '-biphenyl]-3- yl)methyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(azepan-l-yl)-3-chloro-6-phenoxybenzyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino(((5-phenylbenzo[d][l,3]dioxol-4- yl)methyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino(phenylamino)-methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino((cyclohexylmethyl)-amino)methylene)carbamoyl)- phenyl)propanoic acid ;
(S,E)-3-(4-(((([ 1 , 1 '-biphenyl]-2-ylmethyl)amino)(amino)-methylene)carbamoyl)phenyl)- 2-aminopropanoic acid;
(S,E)-2-amino-3-(4-((amino-(benzylamino)methylene)-carbamoyl)phenyl)propanoic acid
(S,E)-2-amino-3-(4-((amino(((4'-methyl-[ 1 , 1 '-biphenyl]-4-yl)methyl)amino)- methylene)carbamoyl)-phenyl)propanoic acid ;
(S,E)-3-(4-(((([ 1 , 1 '-biphenyl]-3-ylmethyl)amino)(amino)-methylene)carbamoyl)phenyl)- 2-aminopropanoic acid ;
(S,E)-2-amino-3-(4-((amino((4- (trifluoromethyl)benzyl)amino)methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino(methyl(naphthalen-2-ylmethyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S,E)-3-(4-(((([ 1 , 1 '-biphenyl]-2-ylmethyl)(methyl)amino)-(amino)methylene)carbamoyl)- phenyl)-2-aminopropanoic acid;
(S,E)-2-amino-3-(4-((amino(methyl((4'-methyl-[ 1 , 1 '-biphenyl]-4-yl)methyl)- amino)methylene)carbamoyl)-phenyl)propanoic acid; (S,E)-3-(4-(((([ 1 , 1 '-biphenyl]-3-ylmethyl)(methyl)amino)-(amino)methylene)carbamoyl)- phenyl)-2-aminopropanoic acid;
(2S)-2-amino-3 -(4-((E)-(amino(( 1 -(4'-methyl-[ 1 , l'-biphenyl]-4-yl)ethyl)amino)- methylene)carbamoyl)-phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino-(benzhydrylamino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-3-(4-((([ 1 , 1 '-biphenyl]-2-ylamino)(amino)methylene)-carbamoyl)phenyl)-2- aminopropanoic acid;
(S,E)-2-amino-3-(4-((amino((2-methoxybenzyl)amino)-methylene)carbamoyl)phenyl)- propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-chlorobenzyl)amino)-methylene)carbamoyl)phenyl)- propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(trifluoromethyl)benzyl)-amino)methylene)carbamoy phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((bis(4-chlorophenyl)-methyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-methylbenzyl)amino)-methylene)carbamoyl)phenyl)- propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(difluoromethoxy)benzyl)-amino)methylene)carbamoyl)- phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-phenoxybenzyl)amino)-methylene)carbamoyl)phenyl)- propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(piperidin-l-yl)benzyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-morpholinobenzyl)amino)- methylene)carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(pyrrolidin-l-yl)benzyl)amino)- methylene)carbamoyl)phenyl)propanoic acid;
(S ,E)-3-(4-((((2-( 1 H-pyrazo 1- 1 -y l)benzy l)amino)(amino)-methylene)carbamoyl)phenyl)- 2-aminopropanoic acid; (S,E)-3-(4-((((2-(lH-imidazol-l-yl)benzyl)amino)(amino)methylene)carbamoyl)phenyl)- 2-aminopropanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(3-methyl-lH-pyrazol-l-yl)benzyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S,E)-3-(4-((((2-(l H- 1 ,2,4-triazol- 1 -yl)benzyl)amino)-(amino)methylene)carbamoyl)- phenyl)-2-aminopropanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(cyclopentyloxy)benzyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-((l-methylpiperidin-4-yl)oxy)-benzyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(piperazin-l-yl)benzyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-3-(4-((((2-(2H-l,2,3-triazol-2-yl)benzyl)amino)-(amino)methylene)carbamoyl)- phenyl)-2-aminopropanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(trifluoromethoxy)benzyl)- amino)methylene)carbamoyl)phenyl)propanoic acid
(S,E)-2-amino-3-(4-((amino((2-((tetrahydro-2H-pyran-4-yl)oxy)benzyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(4-hydroxypiperidin-l-yl)benzyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(2-methyl-lH-imidazol-l-yl)benzyl)amino)methylene) carbamoyl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-((E)-(amino(((2-(3-hydroxypyrrolidin-l-yl)pyridin-3- yl)methyl)amino)-methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino(((2-(4-hydroxypiperidin-l-yl)pyridin-3-yl)methyl)amm^ methylene)carbamoyl)phenyl)-propanoic acid;
(2S)-2-amino-3-(4-((E)-(amino((2-(3-hydroxypyrrolidin-l-yl)benzyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(4-methoxypiperidin-l-yl)benzyl)amino)methylene)- carbamoyl)phenyl)propanoic acid; (S,E)-2-amino-3-(4-((amino(((2-(pyrrolidin-l-yl)pyridin-3-yl)methyl)amino carbamoyl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-((E)-(amino(((2-(3-hydroxypiperidin-l-yl)pyridin-3-yl)methyl)- amino)methylene)carbamoyl)-phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(2-ethoxy-2-oxoethoxy)benzyl)- amino)methylene)carbamoyl)-phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino(((2-(piperidin-l-yl)pyridin-3-yl)methyl)amino)methy carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(diethylamino)benzyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(2S)-2-amino-3-(4-((E)-(amino((2-(2,6-dimethylmorpholino)benzyl)- amino)methylene)carbamoyl)-phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino(((2-(4,4-difluoropiperidin-l-yl)pyridin-3- yl)methyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(4-phenylpiperidin-l-yl)benzyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(4-benzylpiperidin-l-yl)benzyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino(((3'-fluoro-[ 1 , 1 '-biphenyl]-2-yl)methyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino(((3'-methoxy-[ 1 , 1 '-biphenyl]-2- yl)methyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino(((2'-methyl-[ 1 , 1 '-biphenyl]-2-yl)methyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(4-(hydroxymethyl)piperidin- 1 - yl)benzyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(naphthalen-2-yl)ethyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S ,E)-2-amino -3 -(4-((amino((2-(4-carbamoylpiperidin- 1 -yl)benzyl)amino)methylene)- carbamoyl)phenyl)propanoic acid; (S)-2-amino-3 -(4-((E)-(amino(((R)- 1 -(naphthalen-2-yl)ethyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-((E)-(amino((2-(3-(hydroxymethyl)piperidin-l- yl)benzyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-((E)-(amino((2-(3-methylpiperidin-l-yl)benzyl)amino)methylene) carbamoyl)phenyl)propanoic acid;
(S,E)-3-(4-((((2-([ 1 , 1 '-biphenyl]-4-yl)ethyl)amino)(amino)- methylene)carbamoyl)phenyl)-2-aminopropanoic acid;
(S,E)-3-(4-((((3-([ 1 , 1 *-biphenyl]-4-yl)propyl)amino)(amino)- methylene)carbamoyl)phenyl)-2-aminopropanoic acid;
(2S)-2-amino-3 -(4-((E)-(amino((2-(2,6-dimethylpiperidin- 1 - yl)benzyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(2S)-3-(4-((E)-(((2-(2-azabicyclo[2.2.1]heptan-2-yl)benzyl)amino)(amino)- methylene)carbamoyl)phenyl)-2-aminopropanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(3,4-dihydroquinolin-l(2H)-yl)benzyl)amino)methyl carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(azepan-l-yl)benzyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(2S)-2-amino-3 -(4-((E)-(amino((2-(2-methylpiperidin- 1 -yl)benzyl)amino)methylene) carbamoyl)phenyl)propanoic acid;
(S,E)-3-(4-((((2-([ 1 , 1 '-biphenyl]-3-yl)ethyl)amino)-(amino)methylene)carbamoyl)- phenyl)-2-aminopropanoic acid;
(S,E)-3-(4-((((3-([ 1 , 1 '-biphenyl]-2-yl)propyl)amino)-(amino)methylene)carbamoyl)- phenyl)-2-aminopropanoic acid;
(2S)-2-amino-3 -(4-((E)-(amino((2-(octahydroquinolin- 1 (2H)-yl)benzyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-3-(4-((((2-([ 1 , 1 '-biphenyl]-2-yl)ethyl)amino)(amino)- methylene)carbamoyl)phenyl)-2-aminopropanoic acid;
(2S)-2-amino-3 -(4-((E)-(amino((2-(3 ,5-dimethylpiperidin- 1 -yl)benzyl)- amino)methylene)carbamoyl)-phenyl)propanoic acid; (S,E)-2-amino-3-(4-((amino((2-thiomorpholinobenzyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-3-(4-((((3-([ 1 , 1 '-biphenyl]-3-yl)propyl)amino)(amino)- methylene)carbamoyl)phenyl)-2-aminopropanoic acid;
(S,E)-2-amino-3-(4-((amino(((2'-methoxy-[l, -biphenyl]-2-yl)methyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino(((4'-methoxy-[l, -biphenyl]-2-yl)methyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino(((3'-chloro-[l, -biphenyl]-2-yl)methyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino(((3'-methyl-[ 1 , 1 '-biphenyl]-2-yl)methyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino(((4'-chloro-[l, -biphenyl]-2-yl)methyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino(((2'-chloro-[l, -biphenyl]-2-yl)methyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino(((4'-methyl-[ 1 , 1 '-biphenyl]-2-yl)methyl)- amino)methylene)carbamoyl)-phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino(((4'-methoxy-2'-methyl-[ 1 , 1 '-biphenyl]-2-yl)methyl)- amino)methylene)carbamoyl)-phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(naphthalen-l-yl)benzyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino(((2',3 '-dimethoxy-[ 1 , 1 '-biphenyl]-2-yl)methyl)- amino)methylene)carbamoyl)-phenyl)propanoic acid
(S,E)-2-amino-3-(4-((amino(((4'-(trifluoromethyl)-[ 1 , 1 '-biphenyl]-2-yl)methyl)- amino)methylene)carbamoyl)-phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino(((2'-(trifluoro
amino)methylene)carbamoyl)-phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((4-(3-chlorophenoxy)benzyl)-amino)methylene)carbamoyl)- phenyl)propanoic acid; (S,E)-3-(4-(((([ 1 , 1 '-biphenyl]-4-ylmethyl)amino)(amino)-methylene)carbamoyl)phenyl)- 2-aminopropanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(thiazol-2-yl)benzyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino((3-(thiazol-2-yl)benzyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino((3-(thiazol-4-yl)benzyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(l , 1 -dioxidoisothiazolidin-2- yl)benzyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((naphthalen-2-ylmethyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((3,4-dimethylbenzyl)-amino)methylene)carbamoyl)- phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2,5-dimethoxybenzyl)-amino)methylene)carbamoyl)- phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2,3-dichlorobenzyl)-amino)methylene)carbamoyl)- phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2,4-dichlorobenzyl)-amino)methylene)carbamoyl)- phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((3,5-dimethoxybenzyl)-amino)methylene)carbamoyl)- phenyl)propanoic acid;
(2S)-2-amino-3 -(4-((E)-(amino((2,3 -dihydro- 1 H-inden- 1 -yl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-chloro-4-fluorobenzyl)-amino)methylene)carbamoyl)- phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2,4-dimethoxybenzyl)-amino)methylene)carbamoyl)- phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2,5-dimethylbenzyl)- amino)methylene)carbamoyl)phenyl)propanoic acid; (S,E)-2-amino-3-(4-((amino((2-chloro-6-methylbenzyl)amino)- methylene)carbamoyl)phenyl)-propanoic acid;
(S,E)-2-amino-3-(4-((amino((2,6-dimethoxybenzyl)-amino)methylene)carbamoyl)- phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-chloro-5-(trifluoromethyl)-benzyl)amino)methyk carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2,6-difluorobenzyl)-amino)methylene)carbamoyl)- phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((3-chloro-2-methylbenzyl)-amino)methylene)carbamoyl)- phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((4-chloro-2-methylbenzyl)-amino)methylene)carbamoyl)- phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((3,5-dimethylbenzyl)-amino)methylene)carbamoyl)- phenyl)propanoic acid;
(S ,E)-2-amino-3 -(4-((amino((2 ,5 -difluorobenzy l)-amino)methylene)carbamoyl)- phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((naphthalen-l-ylmethyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2,3-dimethylbenzyl)- amino)methylene)carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-fluoro-6-(piperidin-l-yl)benzyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-fluoro-6-(pyrrolidin-l-yl)benzyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-fluoro-6-morpholinobenzyl)- amino)methylene)carbamoyl)-phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((4-chloro-2-(3-methyl-lH-pyrazol-l- yl)benzyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-chloro-6-(pyrrolidin-l-yl)benzyl)amino)methylene)- carbamoyl)phenyl)propanoic acid; (S,E)-2-amino-3-(4-((amino((2-chloro-6-(piperidin-l-yl)benzyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-chloro-6-(4-hydroxypiperidin- 1 - yl)benzyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-chloro-6-(4-methoxypiperidin- 1 - yl)benzyl)amino)methylene)-carbamoyl)phenyl)propanoic acid;
(S ,E)-2-amino -3 -(4-((amino((2-methoxy-6-(piperidin- 1 -yl)benzyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((4-chloro-2-(piperidin-l-yl)benzyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((4-methyl-2-(piperidin-l-yl)benzyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((5-chloro-2-(piperidin-l-yl)benzyl)amino)methylene)- carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-((amino((2-(piperidin-l-yl)-5- (trifluoromethyl)benzyl)amino)methylene)carbamoyl)-phenyl)propanoic acid;
(S,E)-3-(4-(((((9H-fluoren-4-yl)methyl)amino)(amino)methylene)carbamoyl)phenyl) aminopropanoic acid;
(S,E)-2-amino-3-(4-((amino((2,4,6-trimethylbenzyl)- amino)methylene)carbamoyl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-(((((4'-methyl-[ 1 , 1 '-biphenyl]-4-yl)methyl)amino)
(methylamino)methylene)carbamoyl)phenyl)propanoic acid;
(S,E)-3-(4-(((([ 1 , 1 '-biphenyl]-2-ylmethyl)amino)(amino)-methylene)carbamoyl)phen 2-aminopropanoic acid;
(S,E)-3-(4-(((([l,r-biphenyl]-3- ylmethyl)amino)(methylamino)methylene)carbamoyl)phenyl)-2-aminopropanoi^ acid;
(2S)-methyl 2-amino-3-(4-((E)-(amino((2,3-dihydro-lH-inden-l-yl)amino)- methy lene)carbamoy l)p heny l)propano ate ;
(S,E)-methyl 2-amino-3-(4-((amino((2,6-difluorobenzyl)- amino)methylene)carbamoyl)phenyl)propanoate; (S,E)-ethyl 2-amino-3-(4-((amino((2-(piperidin-l- yl)benzyl)amino)methylene)carbamoyl)phenyl)propanoate;
(S,E)-ethyl 2-amino-3-(4-((amino((2-(azepan-l-yl)-6- methoxybenzyl)amino)methylene)carbamoyl)phenyl)propanoate;
(S,E)-ethyl 2-amino-3-(4-((amino((2-phenoxy-6-(piperidin- 1 -yl)benzyl)- amino)methylene)carbamoyl)phenyl)propanoate;
(S,E)-isopropyl 2-amino-3-(4-((amino((2-phenoxy-6-(piperidin- 1 -yl)benzyl)- amino)methylene)carbamoyl)phenyl)propanoate;
(S,E)-cyclopentyl 2-amino-3-(4-((amino((2-phenoxy-6-(piperidin- 1 -yl)benzyl)- amino)methylene)carbamoyl)phenyl)propanoate;
1 -(((S)-2-amino-3 -(4-((E)-(amino((2-phenoxy-6-(piperidin- 1 -yl)benzyl)- amino)methylene)carbamoyl)phenyl)propanoyl)oxy)ethyl pivalate;
(2S)-ethyl 2-amino-3-(4-((E)-(amino((2-(2-methylpiperidin- 1 -yl)-6-(4-(trifluoromethyl)- phenoxy)benzyl)amino)-methylene)carbamoyl)phenyl)propanoate;
(2S)-ethyl 2-amino-3-(4-((E)-(amino((2-methoxy-6-(2-methylpiperidin- 1 - yl)benzyl)amino)methylene)carbamoyl)phenyl)propanoate;
(S,E)-ethyl 2-amino-3-(4-((amino((2-(piperidin-l-yl)-6-(m-tolyloxy)benzyl)- amino)methylene)carbamoyl)phenyl)propanoate;
(S,E)-ethyl 2-amino-3-(4-((amino((2-(azepan-l-yl)-6-(trifluoromethyl)benzyl)- amino)methylene)carbamoyl)phenyl)propanoate;
(S,E)-ethyl 2-amino-3-(4-((amino((2-(2-chlorophenoxy)-6-(piperidin-l- yl)benzyl)amino)-methylene)carbamoyl)phenyl)propanoate;
(S,E)-ethyl 2-amino-3-(4-((arnino((2-(azepan-l-yl)-6-(difluoromethyl)benzyl)- amino)methylene)carbamoyl)phenyl)propanoate;
1 -(((S)-2-amino-3 -(4-((E)-(amino((2-phenoxy-6-(piperidin- 1 - yl)benzyl)amino)methylene)carbamoyl)phenyl)propanoyl)oxy)ethyl pivalate,
or a pharmaceutically acceptable salt of any of the aforementioned.
26. A pharmaceutical composition comprising a compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
27. A method of inhibiting TPH1 comprising contacting said TPH1 with a compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof.
28. A method of lowering peripheral serotonin in a patient comprising administering to said patient a compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof.
29. 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, and inflammatory disease, comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1 to 25, or a
pharmaceutically acceptable salt thereof.
30. The method of claim 29 wherein said bone disease is osteoporosis, osteoporosis pseudoglioma syndrome (OPPG), osteopenia, osteomalacia, renal osteodystrophy, Paget's disease, bone fracture, and bone metastasis.
31. The method of claim 30 wherein said osteoporosis is primary type 1 osteoporosis.
32. The method of claim 29 wherein said cardiovascular disease is pulmonary arterial hypertension (PAH).
33. The method of claim 32 wherein said PAH is associated pulmonary arterial hypertension (APAH).
34. The method of claim 29 wherein said metabolic disease is diabetes or hyperlipidemia.
35. The method of claim 29 wherein said pulmonary disease is chronic obstructive pulmonary disease (COPD) or pulmonary embolism.
36. The method of claim 29 wherein said gastrointestinal disease is irritable bowel disease (IBD), colitis, chemotherapy-induced emesis, diarrhea, carcinoid syndrome, celiac disease, Crohn's disease, abdominal pain, dyspepsia, constipation, lactose intolerance, MEN types I and II, Ogilvie's syndrome, pancreatic cholera syndrome, pancreatic insufficiency,
pheochromacytoma, scleroderma, somatization disorder, Zollinger-Ellison Syndrome, or other gastrointestinal inflammatory conditions.
37. The method of claim 29 wherein said liver disease is chronic liver disease.
38. The method of claim 29 wherein said cancer is liver cancer, breast cancer,
cholangiocarcinoma, colon cancer, colorectal cancer, neuroendocrine tumors, pancreatic cancer, prostate cancer, bone cancer, or blood cancer.
39. The method of claim 29 wherein said inflammatory disease is allergic airway
inflammation.
PCT/US2014/069462 2013-12-11 2014-12-10 Acylguanidines as tryptophan hydroxylase inhibitors WO2015089137A1 (en)

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Cited By (6)

* Cited by examiner, † Cited by third party
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US9199994B2 (en) 2013-09-06 2015-12-01 Karos Pharmaceuticals, Inc. Spirocyclic compounds as tryptophan hydroxylase inhibitors
US9611201B2 (en) 2015-03-05 2017-04-04 Karos Pharmaceuticals, Inc. Processes for preparing (R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanol and 1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanone
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